DD282016A5 - PROCESS FOR PRODUCING NEW UNSATURATED AMINO ACID COMPOUNDS - Google Patents

Abstract

The invention relates to processes for the preparation of unsaturated amino acid compounds of the formula ## STR1 ## in which the protected groups Z6 and optionally Z.sup.1, Z.sup.2 and / or Z.sup.5 are liberated in a compound of the formula (II) by treatment with a tri-lower alkylhalosilane and, if desired, the compound obtained is converted into another compound of the formula I, a resulting mixture of optical isomers is separated into the components and the desired isomer is separated off and / or a resulting free compound is converted into a salt or a salt obtained in the free compound or in another salt. Formulas (I) and (II) {Process; manufacture; Aminosaeureverbindungen; spasticity; Epilepsy}

Description

Berlin, the 28th of April 1985. 70 §73 / 11

Process for the preparation of novel unsaturated amino acid compounds ^ -._

Field of application of the invention

The invention is used in the pharmaceutical industry. The compounds prepared by the process of the invention are useful in the treatment of spasticity, epilepsy, anxiety or manic conditions.

Characteristic of the known state of the art

The inhibitory effect of the compounds according to the invention on NMDA-sensitive excitatory amino acid receptors can be determined in vitro by using G. Fagg and A. Matus, Proc. Nat. Acad. Sci., USA, 81, 6876-80 (1984), to what extent the binding of L-H-glutamic acid to NMDA-sensitive receptors is inhibited. In vivo , the inhibitory effect on NMDA-sensitive excitatory amino acid receptors can be demonstrated in that NMDA-induced convulsions are inhibited in the mouse.

The anticonvulsant properties of the compounds of this invention are further demonstrated by their effectiveness in preventing audiogenic seizures in DBA / 2 mice (Chapman et al., Arzneimittel-Forsch. 34, 1261, 1984).

The anticonvulsant properties can also be demonstrated by the activity of the compounds according to the invention as antagonist antagonists on the mouse or on the rat.

An indication of the anxiolytic activity of the compounds of the present invention indicates their good effectiveness in the conflict model of Cook / Davidson (Psychopharmacologia 15>, 159-168 (1968)).

The good activity of the compounds of the formula I depends to a surprisingly high degree on the configuration of the double bond. This is how the raceniat turns out to be from Agric. Biol. Chem. 41, 573-579 (1979), B.K. Park et al., Known D-2-amino-5-phosphono-3-cis-pentenoic acid z. In its ability to bind to the NMDA-sensitive receptor, the racemate of the 2-amino-5-phosphono-3-trans-pentenoic acid provided by the invention (in the examples, these compounds are referred to as "E-series" compounds) far inferior.

Object of the invention

The compounds provided by the process according to the invention have valuable pharmacological properties. For example, they are active and selective antagonists of N-methyl-D-aspartic acid (NMDA) -sensitive excitatory amino acid receptors in mammals. They are therefore suitable for the treatment of diseases that respond to blocking NMDA sensitive receptors, such as. Cerebral ischemia, muscle spasms (spasticity), convulsions (epilepsy), anxiety

or manic states.

Explanation of the essence of the invention

^/ The invention has for its object to provide a process for the preparation of unsaturated amino acid compounds.

The invention relates to a process for the preparation of unsaturated amino acid compounds of the formula

ι ³ i ⁴

I - BCR ₅ (I).

HO P - A '

R ₁

wherein R ^ is hydrogen, alkyl or hydroxy, R "is hydrogen, alkyl, halo-lower alkyl, hydroxy lower alkyl, lower alkoxy, aryl-lower alkyl, lower alkenyl, halogen or aryl, R, is hydrogen, alkyl or aryl, R _{4 is} hydrogen or alkyl, R ₅ R _{6 is} an unsubstituted or substituted by lower alkyl or aryl-lower alkyl amino group, A is unsubstituted or substituted by alkyl (X, (J) alkylene having 1 to 3 carbon atoms (C atoms) or a direct bond, and B represents methylene or a bond, provided that A represents unsubstituted or alkyl-substituted O, 6J-alkylene of 1 to 3 carbon atoms when B is a direct bond and their salts.

- 2a -

The compounds of formol I contain at least one chiral center and can be present as enantiomers) or as mixtures of enantiomers, such as racemates, provided they have more than one chiral center, also as diastereomers or as mixtures of diastereomers. The carbon-carbon double bond of the compounds of the invention is insonfigured with respect to Rp and R_ and with respect to A and B vr, respectively. H. the compounds of the formula I are the compounds of the E series.

Compounds of the formula I in which R 1 is hydrogen are phosphonous acids, those in which R 1 is alkyl are phosphinic acids, and those in which R 1 is hydroxyl are phosphonic acids ( English: phosphonic acids). As prefixes in the naming of the compounds of formula I which are to be referred to as substituted carboxylic acids, "phosphino" (Ri means hydrogen), "phosphonyl" (Ri means alkyl) and "phosphono" (Ri means hydroxy) are used.

Esterified carboxy is, for example, with an aliphatic or araliphatic alcohol, such as an optionally substituted lower alkanol or phenyl-lower alkanol, esterified carboxy, such as corresponding lower alkoxy or phenyl-lower alkoxycarbonyl. Preferably, this is pharmaceutically acceptable esterified carboxy, such as e.g. esterified carboxy, which can be converted into carboxy under physiological conditions. These esters of formula I may also be referred to as prodrug esters.

Pharmaceutically acceptable esterified carboxy means, for example, lower alkoxycarbonyl; lower alkoxycarbonyl substituted by amino, mono- or di-lower alkylamino or hydroxy at a position higher than the α position; carboxy-substituted lower alkoxycarbonyl, e.g. a-carboxy-substituted lower alkoxycarbonyl; lower alkoxycarbonyl-substituted lower alkoxycarbonyl, e.g. a-lower alkoxycarbonyl-substituted lower alkoxycarbonyl, aryl-lower alkoxycarbonyl, e.g. unsubstituted or substituted benzyloxycarbonyl, or pydridylmethoxycarbonyl; Lower alkanoyloxy-substituted methoxycarbonyl, e.g. pivaloyloxymethoxycarbonyl; lower alkoxymethoxycarbonyl substituted by lower alkanoyloxy or lower alkoxy; Bicyclo [2.2.1] -heptyloxycarbonyl-substituted methoxycarbonyl such as bornyloxycarbonylmethoxycarbonyl; 3-phthalidoxycarbonyl; lower alkyl, lower alkoxy or halogen substituted 3-phthalidoxycarbonyl; or lower alkoxycarbonyloxy-lower alkoxycarbonyl, e.g. 1- (methoxy- or ethoxycarbonyloxy) -ethoxycarbonyl.

-A-

Particularly preferred prodrug esters are e.g. the lower alkyl esters having up to four carbon atoms, e.g. Butyl or ethyl esters, the lower alkanoyloxymethyl esters, e.g. Pivaloyloxymethyl esters containing lower alkyl substituted lower alkyl esters having di-lower alkylamino and having from two to four carbon atoms in each lower alkyl group, e.g. 2-Diethylaminoethylester, and pyridylmethyl esters such as 3-pyridylmethyl ester.

In amidated carboxy, the amino group is, for example, optionally monosubstituted by hydroxy or mono- or disubstituted by aliphatic radicals amino, such as amino, hydroxyamino, mono- or di-lower alkylamino or lower alkylene amino having 5 to 7 ring members. Preferably, this is pharmaceutically acceptable amidated carboxy, e.g. amidated carboxy, which can be converted into carboxy under physiological conditions.

Preferred pharmaceutically acceptable amides are compounds of formula I in which R 5 is carbamoyl, lower alkylcarbamoyl, e.g. Ethylcarbamoyl, di-lower alkylcarbamoyl, e.g. Diethylcarbamoyl, or N- (diloweralkylamino) lower alkylcarbamoyl, e.g. as N- (2-diethylaminoethyl) carbamoyl or as N- (3-diethylaminopropyl) carbamoyl.

Alky] in the context of this invention means a saturated aliphatic hydrocarbon radical with e.g. up to 12 carbon atoms, in particular having up to 8 carbon atoms, the latter region being also represented by the term lower alkyl.

α, ω-alkylene having 1 to 3 carbon atoms is methylene, 1,2-ethylene or 1,3-propylene. Alkyl substituted α, ω-alkylene is substituted at any position. Thus, alkyl-substituted methylene, e.g. 1,1-ethylene, 1,1-butylene or 1,1-octylene, alkyl-substituted 1,2-ethylene, e.g. 1,2-propylene, 1,2-butylene, 2,3-butylene, 1,2-pentylene or 1,2-nonylene, and alkyl substituted 1,3-propylene e.g. 1,3-butylene, 1,3-pentylene or 1,3-decylene.

By lower alkyl or Arylniedera.lkyl substituted amino is mono- or di-lower alkylamino or Arylniederalkylamino.

Aryl, also in definitions such as aroyl or aryl-lower alkoxycarbonyl, is unsubstituted or substituted by lower alkyl, hydroxy, protected hydroxy, lower alkoxy, halogen, amino, lower haloalkyl, hydroxy lower alkyl, amino lower alkyl or nitro, and is for example unsubstituted or substituted correspondingly substituted 1- or 2-naphthyl, but preferably unsubstituted or correspondingly substituted phenyl, such as phenyl, lower alkylphenyl, for example methylphenyl, hydroxyphenyl, halophenyl, for example h- halophenyl, such as 4-chlorophenyl, benzyloxyphenyl, nioderalkoxyphenyl, for example methoxyphenyl, hydroxymethylphenyi, aminomethylphenyl or nitrophenyl.

Unless otherwise defined, the general terms used above and below have the following meanings:

The term "lower" means that correspondingly defined groups or compounds contain up to and including 8, preferably up to and including 4 carbon atoms.

Lower alkyl is, for example, C 1 -C ₄ -alkyl, such as methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl or tert-butyl, but may also be C 5 -C 20 -alkyl, such as n-pentyl, n-hexyl, n-heptyl or n-octyl, but is preferably methyl.

Aryl-lower alkyl, also in definitions such as aryl-lower alkylamino, e.g. Aryl-Ci-Ci, -alkyl, wherein aryl has the meanings given above, and stands primarily for example. for unsubstituted phenyl-C 1 -C 4 -alkyl, such as benzyl or 1- or 2-phenylethyl.

Lower alkenyl preferably contains up to 6 carbon atoms and is attached through an sp ³ -hybridized carbon atom, and is, for example, 2-propenyl, 2- or 3-butenyl or 3-pentenyl, but may also be vinyl.

Lower alkoxy stoht primarily to C1-C, -alkoxy, such as Mevboxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy oc ¹ r tert-butoxy.

Halogen preferably has an atomic number up to 35 and is especially chlorine, furthermore fluorine or bromine, but may also be iodine.

Halo-lower alkyl is z.U. Halo-Ci-C ^ -alkyl, such as fiuormethyl, trifluoromethyl or 1- or 2-chloroethyl.

Hydroxyniederalkyl is z.S. Mono- or dihydroxy-Cx-Cv-alkyl, carries the hydroxy group (s) in particular in higher than the α-position and means e.g. Hydroxymethyl or in particular mono- or dihydroxy-C2-C7-alkyl, such as 2-hydroxyethyl, 3-hydroxy or 2,3-dihydroxy-propyl, 4-hydroxy or 2, A-dihydroxybutyl, 5-hydroxy, 2,5-dihydroxy- or 3,5-dihydroxy-pentyl.

Lower alkoxy lower alkyl is e.g. For example, mono- or di-Ci-Cii-alkoxy-Ci-Cy-alkyl, carries the lower alkoxy group (s) in particular in higher than the α-position and is in particular Ci-Cii-Aikoxy-Ca-C ^ -alkyl, e.g. 2-methoxy, 2-ethoxy, 2-propoxy or 2-isopropoxy-ethyl, 3-methoxy or 3-ethoxy-propyl or 3,3-dimethoxy, 3,3-diethoxy, 2,3- Dimethoxy- or 2,3-diethoxypropyl or A, 4-dimethoxy-butyl, but can also be methoxy, ethoxy, dimethoxy or i'ropoxy-i.der isopropoxymethyl.

Mono- or di-lower Ikylamino is, for example, N-Ci-Ci ₁ -AlkVl- or N, N-di-Ci-Ci, -Alkylamino, such as methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino or butylamino.

Salts of compounds according to the invention are primarily pharmaceutically acceptable, non-toxic salts of compounds of the formula I. Such salts are formed, for example, by the carboxy group present in compounds of the formula I and are primarily metal or ammonium salts, such as alkali metal and alkaline earth metal, for example, sodium, potassium, magnesium or calcium salts, and ammonium salts with ammonia or suitable organic amines, such as lower alkylamines, for example methylamine, diethylamine or triethylamine, Hydroxyniederalkylaminen, eg 2-hydroxyethylamine, bis (2-hydroxyethyl) amine, tris (hydroxymethyl) methylamine or tris (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, eg 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkylene amines, eg 1-ethylpiperidine, lower alkylenediamines, eg ethylenediamine, cycloalkylamines , eg dicyclohexylamine, or J5enzylamines,

ylendiarnine, cycloalkylamines, ζ. Dicyclohexylamine, or benzylamines, e.g. B. N ₁ N 'dibenzylethylenediamine, In, 2yltrimethylammoniumhydroxid, dibenzylamine or N-Ben2yl-ßphenylethylamin. Compounds of the formula I having primary or secondary amino group can also acid addition Sal2e, ζ. b. with preferably pharmaceutically acceptable inorganic acids, such as hydrogen halides, hydrochloric or hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, eg. acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, fumaric acid, maleic acid , Tartaric, oxalic, citric, pyruvic, benzoic, mandelic, malic, ascorbic, pamoic, nicotinic, mathansulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, 4-toluenesulfonic or naphthalenesulfonic acids.

For isolation or purification it is also possible to use pharmaceutically unsuitable salts. For therapeutic use, only the pharmaceutically acceptable, non-toxic salts, which are therefore preferred.

The beneficial effects of the compounds can be demonstrated in vitro or in in vivo test assays. In this case, preferably mammals are used, for. As mice, rats or monkeys, or tissue or enzyme preparations of such mammals. The compounds may be administered enterally or parenterally, preferably orally; or subcutaneously, intravenously or intraperitoneally, e.g. B. in Ge.latinekapseln or in the form of aqueous suspensions or solutions. The in vivo dose to be used may range between 0.1 and 600 mg / kg, preferably between 1 and 300 mg / kg.

- 7a -

In vitro, the compounds may be used in the form of aqueous solutions, with concentrations ranging between 10 molar and 10 molar solutions.

Compounds of the formula I have proven to be particularly effective in which the C atom bearing the R _β group has R configuration.

Preference is given to the preparation of compounds of the formula I in which R 2 is hydrogen, alkyl or aryl.

The invention relates in the first place to a process for the preparation of compounds of formula I wherein R 1 is hydrogen, alkyl of up to and including 12 carbon atoms or hydroxy, R 2 is hydrogen, lower alkyl, lower haloalkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, unsubstituted or phenyl-substituted phenyl lower alkyl, lower alkenyl , halogen or unsubstituted or substituted phenyl, R3 is hydrogen, lower alkyl or uni> uhstituiertes or substituted phenyl, R ₄ is hydrogen or lower alkyl, R5 is free or pharmaceutically acceptable esterified or amidated carboxy, R6 is amino, mono- or di-lower alkylamino A is unsubstituted or lower alkyl substituted α, ω-alkylene having from 1 to 3 carbon atoms or a bond, and B is methylene or a bond, provided that A is other than B when B is a bond wherein the Substituents of Ph enyl are selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, halogen, amino, haloloweralkyl, hydroxyloweralkyl, amino-lower alkyl and nitro, and lower radicals having, for example, bis and having 8 carbon atoms, and pharmaceutically acceptable salts thereof.

The use of the process for the preparation of compounds of formula I is preferred wherein Ri to Ri ₁ , A and B are as defined above and on the one hand R5 Niederalkoxyca-bonyi or by amino, mono- or di-lower alkylamino, hydroxy or Niederalkanoyioxy substituted lower alkoxycarbonyl means and R 6 is amino or lower alkylamino, or R 5 is carboxy and R 6 is Anu-n-O, in particular their relative to the atom carrying the amino group, R-enantiomers, as well as pharmaceutically acceptable salts thereof.

Also preferred is the use of the process for the preparation of compounds of formula I wherein Ri, Ri ₁ to R6 and A and B are as defined immediately above and R2 and R3 are independently hydrogen, lower alkyl, phenyl or lower alkyl, Hydrjxy, lower alkoxy , Halogen, amino, halo-lower alkyl, hydroxy

lower alkyl, amino-lower alkyl or nitro substituted phenyl, in particular of their relative to the atom bearing the Anrnogruppe, R enantiomers, and of pharmaceutically acceptable salts thereof.

More particularly, the invention relates to a process for the preparation of compounds of formula I wherein Ri is hydrogen, alkyl of up to and including 12 carbon atoms or hydroxy, R2 is hydrogen, lower alkyl, phenyl, halophenyl or phenyl-lower alkyl, R3 and Ri _{1 are} hydrogen or Lower alkyl mean, and on the one hand R5 is alkoxycarbonyl or Hydroxyniederalkoxycarbonyl and R6 is amino or Mononiederalkylamino or otherwise R5 is carboxy and Rg amino, wherein each A is unsubstituted or substituted by lower alkyl α, ω-alkylene having 1 to 3 carbon atoms or a bond and B represents methylene or a bond, with the proviso that A is different from a bond when B is a bond, in particular from its relative to the atom carrying the amino group, R enantiomers, and pharmaceutically acceptable salts thereof.

The invention particularly relates to a process for the preparation of compounds of formula I ₁ wherein Rj is hydrogen, alkyl of up to and with 12 C atoms or hydroxy, R _{2 is} hydrogen, lower alkyl or halophenyl, R _{3 is} hydrogen or halophenyl, Ri ₁ Is hydrogen and on the one hand R5 is lower alkoxycarbonyl or hydroxy-lower alkoxycarbonyl and R6 is amino or mono-lower alkylamino or R5 is carboxy and Re is amino, where each A is α, ω-alkylene having 1 to 3 carbon atoms or a bond and B is methylene or a BinJung with the proviso that A is different from a bond when B is a bond, in particular of its with respect to the atom carrying the amino group, R enantiomers, and pharmaceutically acceptable salts thereof.

More particularly, the invention relates to a process for the preparation of compounds of formula I, wherein Ri is hydrogen, lower alkyl or hydroxy, Rz is hydrogen or lower alkyl, R3 and Ri, are hydrogen and on the one hand R5 is lower alkoxycarbonyl or on the other hand carboxy and R6 is amino means, each A for

- 10 -

a, (/) - is alkylene having 1 to 3 carbon atoms, D is a bond, in particular of its relative to the atom carrying the amino group, R-enantiomers and pharmaceutically acceptable salts thereof.

The invention relates, first and foremost, to a process for the preparation of compounds of formula I in which Ri is hydroxy, R2 is hydrogen or lower alkyl, R3 and Ri, are hydrogen and R5 is lower alkoxycarbonyl or carboxy, R6 is amino, A is methylene and B represents a bond, in particular of its with respect to the atom carrying the amino group, R enantiomers, as well as pharmaceutically acceptable salts thereof.

The invention relates in particular to the preparation of the compounds mentioned in the examples and their pharmaceutically acceptable salts.

The inventive method is characterized in that in a compound of formula

(ID,

wherein Zi is optionally protected hydroxy, Z2 is a group Ri or protected hydroxy, Z5 is a group R5 or protected carboxy, Zc is a protected group Rc and Ri, R2, R3, Ri ₁ , R5, R6, A and B are the above have defined meanings which releases protected groups Zg and optionally Zi, Z2 and / or Z5 by treatment with a tri-lower alkylhalosilane and, if desired, converts the compound obtained into another compound of formula I, separates a mixture of optical isomers obtained into the components and the desired isomer separated and / or a resulting free compound is converted into a salt or a salt obtained in the free compound or in another salt.

Protected hydroxy Zi and / or Z2 in intermediates of the formula II is, for example, hydroxyl etherified with an aliphatic alcohol, such as with an optionally halogen or in higher than the α-position by hydroxy, oxo, lower alkoxy, lower alkanoyloxy and / or mono- or

- 11 -

Diniederalkylamino substituted lower alkanol, lower alkenol or lower alkynol etherified hydroxy and means, for example, lower alkoxy, halo-lower alkoxy. or corresponding hydroxy, oxo, lower alkoxy, lower alkanoyloxy or mono- or di-lower alkylamino lower alkoxy. Compounds of the formula II in which Zi and / or Z 2 are etherified hydroxy are esters of the phosphorus-containing acid group and, depending on the meaning of R 1 phosphonous acid ester, phosphinic acid ester or phosphonic acid ester. Preferred esters are the respective lower alkyl esters and hydroxy lower alkyl esters.

Groups Zg in intermediates of formula II are, for example, acyl-substituted groups R6, ie, optionally substituted by lower alkyl or aryl-lower alkyl-substituted acylamino, wherein acyl is the acyl radical of an organic acid with, for example, up to 18 carbon atoms, especially an optionally, for example by halogen, amino or Phenyl, substituted alkanecarboxylic acid or optionally, for example by halogen, lower alkoxy or nitro, substituted benzoic acid, or a carbonic monoester. Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl or propionyl, halo-lower alkanoyl, such as 2-haloacetyl, in particular 2-fluoro, 2-bromo, 2-iodo, 2,2,2-trifluoro or 2,2,2 Trichloroacetyl, aroyl such as optionally substituted benzoyl, eg benzoyl, halobenzoyl such as 4-chlorobenzoyl, lower alkoxybenzoyl such as 4-methoxybenzoyl, or nitrobenzoyl such as 4-nitrobenzoyl. In particular, lower alkenyloxycarbonyl, eg allyloxycarbonyl, or especially optionally substituted in the 1- or 2-position lower alkoxycarbonyl, in particular lower alkoxycarbonyl, eg tert-butoxy, further methoxy or ethoxycarbonyl, further optionally substituted benzyloxycarbonyl, for example benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, or Aroylmethoxycarbonyl, wherein the aroyl group is optionally substituted, for example by halogen, such as bromine substituted benzoy ¹ , for example phenacyloxycarbonyl or bromophenacyloxycarbonyl.

Further, in a corresponding acylamino group, Zs may be acylamino substituted by amino and / or phenyl, carbamoyl, carboxy, imidazolyl, lower alkylthio, tetrahydropyrrolyl, hydroxy, indolyl or hydroxyphenyl, so as to include, for example, the acyl radicals of amino acids, eg, of course occurring amino acids, ie

- 12 -

Al.anyl, Asparagj.nyl, aspartyl, glycyl, histidyl, isoleucyl, leucyl, lysyl, methionyl, phenylalanyl, prolyl, seryl, threonyl, tryptophyl, tyrosyl or valyl; also included are the acyl residues of oligopeptides, e.g. Di- or tripeptides, such as oligopeptides of alanine, asparagine or aspartic acid.

Furthermore, protected amino Zg may represent a diacylamino group. In this diacyl means e.g. two acyl radicals as defined above or diacyl is, for example, the acyl radical of an organic dicarboxylic acid with e.g. up to 12 carbon atoms, especially a corresponding aromatic dicarboxylic acid, such as phthalic acid. Such a group is primarily phthalimido.

In addition, protected amino Z & may also be amino substituted by substituted lower alkoxycarbonyl, such as by 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (tris-substituted silyl) -ethoxycarbonyl, such as 2-tri-lower alkylsilylethoxycarbonyl, e.g. 2-trimethylsilylethoxycarbonyl or 2- (di-n-butyl-methylsilyl) -ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbonyl-substituted amino or etherified mercapi.oamino or silylamino, or as an enamino, nitro or azido group. An etherified mercaptoamino group is primarily a phenylthioamino group or a pyridylthioamino group optionally substituted by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine or bromine, and / or nitro. Corresponding groups are, for example, 2- or 4-nitrophenylthioamino or 2-pyridylthioamino. A silylamino group is primarily an organic silylamino group. In these, the silicon atom preferably contains lower alkyl, e.g. Methyl, ethyl, η-butyl or tert-butyl, further aryl, e.g. Phenyl as a substituent. Suitable silyl groups are primarily tri-lower alkylsilyl, in particular trimethylsilyl or dimethyl-tert-butylsilyl. Enamino groups contain on the double bond in 2-Ste.llung an electron-withdrawing substituent, such as a Csrbonylgruppe. Protecting groups of this type are, for example, 1-acyl-lower-alk-1-en-2-yl radicals, in which acyl is e.g. the corresponding residue of a lower alkanecarboxylic acid, e.g. Acetic acid, an optional, e.g. by

- 13 -

Lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as nethoxy, halogen, such as chlorine, and / or nitro substituted benzoic acid, or in particular a carbonic monoester, such as a carbonic acid lower alkyl, for. methyl-half-ester or -ethylhalbesters, and Niederalk-1-en, in particular 1-propene means. Corresponding protecting groups are primarily 1-lower alkanoyl-prop-1-en-2-yl, e.g. 1-acetyl-prop-1-en-2-yl, or 1-lower alkoxycarbonyl-prop-1-en-2-yl, e.g. l-ethoxycarbonyl-prop-l-en-2-yl.

Protected carboxy Z5 is usually protected in esterified form, which ester group may be cleavable under reductive, such as hydrogenolytic, or solvolytic, such as acidolytic or hydrolytic, such as acidic, basic or neutral hydrolytic conditions. A protected carboxy group may further be a cleavable under physiological conditions or one slightly in another functionally modified carboxy group, such as in another esterified carboxy, convertible, esterified carboxy group. Such esterified carboxy groups contain, as esterifying groups, primarily silyl groups, in particular tri-lower alkylsilyl groups, and also lower-alkyl groups suitably substituted in the 1- or 2-position. Preferred esterified carboxy groups include tri-lower alkylsilyloxycarbonyl, e.g. Trimethylsilyloxycarbonyl, (hetero) arylmethoxycarbonyl having 1 to 3 aryl radicals or a monocyclic heteroaryl radical, these optionally being e.g. by lower alkyl, such as tert-lower alkyl, e.g. tert-butyl, halogen, e.g. Chloro, and / or nitro mono- or polysubstituiert. Examples of such groups are optionally, e.g. as mentioned above, substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl, optionally, e.g. as mentioned above, substituted diphenylniethoxycarbonyl, e.g. Diphenylmethoxycarbonyl, or triphenylmethoxycarbonyl, or optionally, e.g. as mentioned above, substituted picyloxycarbonyl, e.g. 4-picolyloxycarbonyl, or furfuryloxycarbonyl, such as 2-furfuryloxycarbonyl.

In particular, protected hydroxy Zi and / or Z 2 is lower alkoxy such as methoxy, ethoxy or isopropyloxy, protected carboxy tri-lower alkyl silyloxycarbonyl such as trimethylsilyloxycarbonyl and protected amino optionally substituted by lower alkyl or aryl-lower alkyl !

- 14 -

Lower alkanoylamino, especially formylamino, N-lower alkanoyl-N-lower alkylamino, especially N-formyl-N-lower alkyl-amino, e.g. N-formyl-N-methyl-amino, or lower alkoxycarbonylamino, preferably tertiary-butyloxycarbonyl-amino.

Triniederalkylhalogensilane are, for example Triniederalkyljodsilane or Triniederalkylbromsilane in particular, preferably those in which the lower alkyl groups are identical Ci-C ^ -alkyl radicals. Preference is given to trimethylbromosilane, in the second trimethyliodosilane.

The release of the protected groups, ie hydroxyl-protected hydroxy groups Zi and / or Zz, carboxy-protected carboxy groups Z5 and / or optionally substituted by lower alkyl or phenyl-substituted amino from protected amino groups Zf, by treatment with a Triniederalkylhalogensilan for example in an inert Solvent such as a halogenated, preferably aliphatic hydrocarbon, for example in dichloromethane or secondarily tri- or tetrachloromethane, trichloroethane or tetrachloroethane, in the temperature range from about -25 ° C to »50 ⁰ C, preferably from about 0 ⁰ C to about 3O ⁰ C, for example at temperatures in the range of room temperature, ie at about 15 ° C to about 25 ⁰ C, preferably under substantially anhydrous conditions and under inert gas, for example under argon or nitrogen.

The workup is carried out in a conventional manner, in particular, two cleaning operations prove to be advantageous. Either the crude product can be converted to a volatile derivative, e.g. by silylation, and as such recovered by distillation, then desilylated. Or the crude product may be treated with an agent that reacts with and removes excess acid, such as hydrohalic acid. For example, Compounds to which a corresponding acid can add, e.g. Lower alkylene oxides (Fpoxides), such as propylene oxide.

If, as end products, compounds of the formula I are to be obtained in which R 5 is esterified or amidated carboxy, such as lower alkoxycarbonyl or carbarnoyl, the starting materials of the formula II and

- 15 -

Process conditions are chosen so that in the last step, although Z ₁ , Z2 and Zf, are released, whereas Z ^, which stands for the desired group R5, remains unchanged in this process step.

A particularly preferred embodiment is accordingly directed to the preparation of compounds of the formula I in which R 5 is C 1 -C 4 -alkoxycarbonyl and Re is amino. This embodiment is preferably based on compounds of the formula II in which Z) and Z _{2 are} lower alkoxy or lower alkoxy in a position higher than the α-position by halogen, such as chlorine, Z 5 is C ₁ -C ₁ -alkoxycarbonyl and Ze is lower alkanoylamino, such as formylamino, or lower alkoxycarbonylamino such as tertiarybutyloxycarbonylamino. Starting from such compounds of formula II, release of the protected groups in an inert solvent, such as a halogenated hydrocarbon, eg, dichloromethane, at room temperature, with a reagent such as trimethylbrotosilane, can be followed by treatment with a lower alkanol, such as ethanol, and a hydrogen halide scavenger, such as an aliphatic epoxide, especially an epoxy-lower alkane, eg, propylene oxide, so as to directly give compounds of formula I, wherein R) is hydroxy, R5 is C) -Ci, alkoxycarbonyl, Re amino and the variables Ra, R3 and Ri have the meanings given for formula I.

This process is particularly preferred for the preparation of compounds of the formula I in which A is methylene or 1,3-propylene and B is a bond, R3 and Ru are hydrogen and R2 is alkyl having up to 4 carbon atoms n, such as methyl.

Another, equally preferred embodiment relates to the preparation of compounds of formula I wherein R5 is carboxy. In this case, preference is given to compounds of the formula II where Zi and Z 2 are lower alkoxy or higher than the α-position by halogen, such as chlorine substituted Nieueralkoxy Zs for optionally protected, for example by treatment with N, 0 bis Silylated, carboxy and Z is ( lower alkoxycarbonylamino, in particular α-branched lower alkoxycarbonylamino, such as tert-butyloxycarbonylamino, in which case the carboxy group is preferred, but not

- 16 -

necessarily intermediately protected, for example by treatment with

a silylating agent such as an N, O-silyl-lower alkanoic acid amide, ". " with N, O-tris-thylsilyl-cetamide.

Intermediates of formula II are preferably prepared by reacting a compound of formula

(III)

wherein R ₂ , R ₃ , R ₁ , A and B are as defined for formula I, Z 5 is R 5 or is protected carboxy, Z is a protected group R 6 and X is reactive esterified hydroxy, with a compound of formula

OR

Z ₁ -

(IV) ₁

wherein Zi is optionally protected hydroxy, Zz d: e has the meaning of Ri or is protected hydroxy and R is an etherifying group, and can we''den used without isolation or special purification.

Compounds of formula III can be e.g. prepared by an N-protected Aminomalonsaureester the formula

ZS-CH-Z ₅ (V),

wherein Z5 and Zs are the same or different esterified carboxy groups, e.g. Lower alkoxycarbonyl groups, mean with Verbindui.gen the formula

/ BX ¹ (VI)

X-A-j ⁷

R2

- 17 -

in a manner known per se, in which X and X 'independently of one another are reactive esterified hydroxy, such as halogen. The compounds of the formula thus obtained

(VII)

can be converted into compounds of formula III, wherein Ri, is hydrogen, by, e.g. under hydrolytic conditions such as acid hydrolysis, e.g. with hydrohalic acids, such as with hydrochloric acid, preferably saponified and decarboxylated with heat or dealkoxycarbonyliert without previous saponification by heating in ein ω aqueous aprotic solvent, such as dimethyl sulfoxide, in the presence of an alkali metal halides, such as sodium chloride.

Accordingly, this variant is particularly suitable for the preparation of compounds III in which Ri _{4 is} hydrogen, Zs free or esterified carboxy and Ze protected amino, such as lower alkanoylamino means.

Intermediates III, wherein A is optionally substituted by alkyl methylene, B is a bond, X is halogen and Ze formylamino, can be further prepared by adding a compound of formula

/ R ₂ D = C 1 (VIII),

wherein D is optionally alkyl-substituted methylidene, such as a corresponding α, β-unsaturated aldehyde, e.g. Acrolein or methacrolein is reacted with a ct-Isocyanessigsäurederivat, such as a a-Isocyanessigsäureniederalkylester. Under suitable catalysis, such as lower order, i. with metal salts derived from metals of Groups I and II of the periodic table of elements, e.g. corresponding metal oxides or metal halides such as zinc chloride, cadmium chloride, silver oxide or, preferably, copper oxide or complexes of gold I-tetrafluoroborate with aliphatic or cycloaliphatic isocyanides, e.g. Bis (cyclohexyl isocyanide) gold (I) tetrafluoroborate ,, thus, if known, 5-vinyl-2-oxazoline-4-carboxylic acid derivatives, e.g. ester of the formula

- 18 -

R ₂

D-C

obtained in the open-chain compounds of the formula

(X)

where D is optionally substituted by Alkyi. substituted methylidene. These compounds in turn can be converted into compounds of the formula III by selective halogenation, such as bromination or chlorination, preferably with cooling, and with displacement of the double bond in the sense of an allylic rearrangement.

Another method for the preparation of compounds II, wherein Ri, is hydrogen, A is methylene or 1,3-propylene and R5 is carboxy, based on the principle that a compound of formula

V Λ- «

o (X (χι),

R. R _n η B

wherein R and R ^ are hydrogen or preferably lower alkyl, such as methyl, and R is an amino protecting group, with a 2-R ₂ -acetic acid ester or condensed first with a 1-R ₂ -Ethenmetallverbindung, for example with Isiöpropenylmagnesiumbromid, and then with an acetic acid ester in the obtained compound of the formula

R3

/ \ ² (XIIa) or (/ \ ^ΛΖ (XIIb) \ / V \ / V

^R A ^R B ^R A ^R B

- 19 -

wherein Zs is esterified carboxy, e.g. Lower alkoxycarbonyl is, this group e.g. by means of diisobutylaluminum hydride, reduced to hydroxymethyl, the hydroxymethyl group halogenated, e.g. brominated by means of tetrabromomethane / triphenylphosphine, the resulting compound of the formula

where A is methylene or 1,3-propylene, X is halogen, for example ¹ × bromine, means a compound of Fornel IV further, the oxazolidine ring, for example by means of an ion exchanger, such as Amberlyst 15 ¹ ^, split and in the resulting Compound of the formula

(XIV)

wherein Zg is a protected Aminogr.ippe the formula R-NH- (II ¹ ), the hydroxymethyl group oxidized in the usual way to carboxy.

In carrying out the processes described above, the preparation of intermediates III and their further conversion to intermediates II, it is not necessary to isolate all intermediates. Thus, in particular the conversion of compounds X into compounds III and their Weitervnsetzung with compounds IV in intermediates II can be advantageously carried out in situ .

Accordingly, a preferred embodiment of the process according to the invention consists in that a compound of the formula

(I) I),

- 20 -

wherein R ₁ , R ₃ , R ₁ , A and B are as defined for formula I, Z 5 is R 5 or is protected carboxy, Zo is a protected group R c, for example protected amino, and X is reactive esterified hydroxy , with a compound of the formula

Zi-1 '(IV),

Z ₂

wherein Zi is optionally protected hydroxy, Z2 has the meaning of Ri or is protected hydroxy and R is an etherifying group, the protected groups Zf, and optionally Zi, Z2 and / or Z5 by treatment with a Triniederalkylhalogensilan, for example with Trimethylbromosilane, and, if desired, converting a compound of the formula I obtained into another compound of the formula I and / or, if desired, converting a compound of the formula I obtained into a salt or a salt obtained into another salt or into a free compound of the formula I. and / or, if desired, an optical isomer of a mixture of stereoisomeric forms of a resulting compound of formula I or a salt thereof.

A reactive esterified hydroxy group, such as X, is a hydroxy group esterified with a strong organic acid. e.g. one with an aliphatic or aromatic sulfonic acid (such as a Vederalkansulfonsäure, in particular methanesulfonic acid, trifluorinethanesulfonic acid, especially benzenesulfonic acid, p-toluenesulfonic acid, p-bromoenzolesulfonic acid and p-nitrobenzenesulfonic acid) or with a strong inorganic acid, in particular sulfuric acid, or a Halogenwasserstnffsäure, such as hydrochloric acid or most preferably, hydrogen iodide or hydrobromic acid, esterified hydroxy group.

Attention should be drawn in this connection to the surprising finding that the preparation of the intermediates II and their further conversion according to the invention to the end products I can be carried out stereoselectively. That neither in the reaction sequence III + IV -> II or Ha -> I, nor in the reaction sequences X -> III and XI - »XII -> XIII -> XIV -> II configuration reversal or appreciable Racemiaierung occurs. The invention

- 21 -

This method is therefore excellently suitable for the direct preparation of compounds of the formula I with the preferred R configuration on the C-atom carrying the amino group Ro. The preparation of sterically uniform compounds of the formula I and sterically uniform intermediates of the formulas II, III, X, XI, XII, XIII and / or XIV is a further subject of the present invention.

According to another preferred embodiment, a compound of the formula is subjected

(X)

the selective halogenation, for example by means of thionyl chloride, to the corresponding intermediate III and sets this in situ , ie without Isolie.ung with the component IV.

As mentioned, compounds obtainable according to the invention can be converted into other compounds of the formula I. In particular, a free amino group may be substituted with R &min;, e.g. converted into an optionally phenylated alkylamino group, free carboxy R5 esterified or esterified or amidated carboxy R5 converted into free carboxy and / or free or esterified carboxy R5 are converted into amidated carboxy.

For converting an amino group into an optionally phenylated alkylamino group, the amino group may be substituted, e.g. with a reactive esterified optionally phenylated alkanol, such as an alkyl halide, or reductive, such as with an aldehyde or ketone, and catalytically activated hydrogen, or in the case of formaldehyde, advantageously with formic acid as a reducing agent, alkylated.

Free carboxylic acids of the formula I or their salts can be converted into the corresponding esters with the appropriate alcohols or corresponding derivatives thereof by known methods, i. in compounds of formula I, e.g. are present as lower alkyl, aryl lower alkyl, lower alkanoyloxymethyl or lower alkoxycarbonyl lower alkyl ester.

- 22 -

For esterification, a carboxylic acid directly with a diazoalkane, especially diazomethane, or with an appropriate alcohol in the presence of a strongly acidic catalyst (eg, a hydrogen halide, sulfuric acid or an organic sulfonic acid) and / or a dehydrating agent (eg Dicyclohexylcarbodi-imirl) are implemented , Alternatively, the carboxylic acid may be converted to a reactive derivative, such as a reactive ester, or a mixed anhydride, e.g. with an acid halide (e.g., especially an acid chloride), and this activated precursor is reacted with the desired alcohol.

Compounds of the formula I in which R 5 is esterified carboxy, in particular lower alkoxycarbonyl, for example ethoxycarbonyl, can be converted into compounds of the formula I in which R 5 is carboxy, for example by hydrolysis, in particular in the presence of inorganic acids, such as hydrohalic acids or sulfuric acid, or secondarily, aqueous alkalis such as alkali metal hydroxides, eg, lithium hydroxide or sodium hydroxide. In this connection, it should be noted that the release from carboxy esterified carboxy can be conducted so that no appreciable racemization takes place. This can be achieved in particular by treating with about 0.2 to about 4 normal, for example about 1 normal, ie about 0.5 to about 2 normal aqueous mineral acid, if necessary with heating, for example to about 6O ⁰ C to about boiling point, ie about 100 ⁰ C. Surprisingly, the saponification proceeds, for example, of phosphonic acid <rbonsäure-. lower alkyl esters of the formula I even without the addition of acidic or basic reagents in high yield. A preferred process for the preparation of carboxylic acids of formula I from the corresponding lower alkyl esters, such as the respective ethyl esters, is therefore acid hydrolysis by treatment with about 0.2 to about 4 normal aqueous mineral acid, eg hydrochloric acid, sulfuric acid, phosphoric acid or the like , as well as in the - possibly autocatalytic - saponification in water, preferably at elevated temperatures, such as by heating under reflux.

- 23 -

The above reactions are carried out by standard methods in the presence or absence of diluents, preferably those which are inert to the reagents and which are solvents of catalysts, condensing agents or other agents and / or in an inert atmosphere, at low temperatures, room temperature or elevated temperatures, preferably at the boiling point of the solvents used, at atmospheric or superatmospheric pressure.

The art further includes any variant of the present processes in which an intermediate obtainable at any stage thereof is used as the starting material and the remaining stages are carried out, or the process is interrupted at any stage thereof or the starting materials are formed under reaction conditions or in which the reaction components are used in the form of their salts or optically pure antipodes. Mainly those starting materials should be used in these reactions leading to the formation of the compounds specified above as being particularly valuable.

The invention also relates to novel starting materials and processes for their preparation.

Depending on the choice of starting materials and methods, the novel compounds may be in the form of one of the possible optical isomers or mixtures thereof, for example, depending on the number of asymmetric carbon atoms, as pure optical isomers, such as antipodes, or as mixtures of optical ones Isomers, such as racemates, or mixtures of diastereoisomers from which an antipode can be isolated if desired.

Obtained mixtures of diastereoisomers and mixtures of the racemates can be separated in a known manner into the pure isomers, diastereoisomers or racemates, for example because of the physico-chemical differences of the constituents. by chromatography e and / or fractional crystallization.

The racemates (racemic diastereoisomers) obtained can furthermore be converted into the optical antipodes by methods known per se, for example by recrystallization from an optically active solvent, with the aid of microorganisms or enzyme catalysts in free or immobilized form or by reaction of an acidic end product with an optically active Base which forms salts with the racemic acid, and separation of the salts thus obtained, for example on the basis of their different solubilities, into which diastereoisomers from which the antipodes can be released by the action of suitable means are separated. Basic racemic products may also be incorporated into the antipodes, e.g. by separating their diastereoisomeric salts, e.g. fractionated crystallisates · from their d or Jl tartrates. Any racernischon intermediates or starting materials can be separated in a similar manner.

Finally, the compounds according to the invention are obtained either in free form or in the form of their salts. Any base obtained may be converted to a corresponding acid addition salt, preferably using a pharmaceutically acceptable acid or an anion exchange preparation, or salts obtained may be converted to the corresponding free bases, for example using a stronger base such as a metal or ammonium hydroxide or a basic salt, eg of an alkali metal hydroxide or carbonate, or a cation exchange preparation. A compound of the formula I can also be converted into the corresponding metal or ammonium salts. These or other salts, for example the picrates, can also be used for the purification of the bases obtained. The bases are converted into the salts, the salts are separated, and the bases are released from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever mention is made in this application of a compound also includes a corresponding salt of this compound, provided that this is possible or useful under the circumstances ,

- 25 -

The compounds, including their salts, can also be obtained in the form of their hydrates or contain other solvents used for the crystallization.

The pharmaceutical compositions of this invention are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals, including humans, for the treatment or prevention of diseases responsive to the blockade of NMDA receptors, such as e.g. Cerebral ischemia, muscle spasms (spasticity), convulsions (epilepsy), anxiety or manic states. They comprise an effective amount of a pharmacologically active compound of the formula I or a pharmaceutically acceptable salt thereof, alone or in combination with one or more pharmaceutically acceptable carriers.

The pharmacologically active compounds of the invention are useful in the preparation of pharmaceutical compositions comprising an effective amount thereof alone or in combination or admixture with excipients or carriers suitable for enteral or parenteral use. Preferred are tablets and gelatin capsules containing the active ingredient together with a) diluents, e.g. Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine,

b) lubricants, e.g. Silica, talc, stearic acid, its magnesium or calcium salt and / or polyethylene glycol, for tablets as well

c) binders, e.g. Magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, if desired d) disintegrating agents, e.g. Starches, agar, alginic acid or its sodium salt, or foaming mixtures and / or e) absorbents, colorants, flavorings and sweetening agents. Injectable preparations are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fat emulsions or suspensions. These compositions may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, dissolution promoters, salts for the regulation of osmotic pressure and / or buffers. In addition, they may also contain other therapeutically valuable substances. These preparations are after

26 -

prepared by conventional mixing, granulation or coating methods and contain about 0.1 to 100 %, preferably about 1 to 50 %, of the active ingredient. A unit dose for a mammal of about 50 to 70 kg may contain between about 1 and 500 mg, preferably between about 10 and 500 mg of active ingredient.

The following examples are intended to illustrate the invention and not limit it. The temperatures are given in degrees Centigrade, and all parts are in terms of parts by weight. Unless otherwise stated, all evaporations are carried out under reduced pressure, preferably between about 2 and 13 kilopascals (l <Pa).

embodiments

Example 1; E-2-amino-4-methyl-5-phospho.no-3-pentenoate

a) Ethyl 5- (2-propenyl) -oxazoline-4-carboxylate (in each case 1.6 g of red copper (I) oxide are initially charged in 200 ml of benzene, with vigorous stirring, a solution of 140 is added to this suspension within 10 minutes g of isocyanatoethyl acetate and 105 g of freshly distilled methacrolein in 200 ml of benzene, the reaction temperature being kept between 30 and 32 by ice-cooling and after completion of the addition the mixture is kept at 30-32 ° until the exotherm subsides and then at room temperature for 1 hour After filtering off excess copper (I) oxide, the filtrate is evaporated in vacuo at 30 ° C. The residue

- 26a -

is added 600 ml of ether, filtered through Celite and evaporated in vacuo to dryness. This gives the 5- (2-propenyl-2-oxazoline-4-carboxylic acid ethyl ester as a colorless oil of bp. 110-130 ° (5.3 Pa).

b) ethyl E-2-formylamino-3-hydroxy-4-methyl-4-pentenoate (^).

139 Cj of 5- (2-propenyl) -2-oxazoline-4-carboxylic acid ethyl ester are dissolved in 70 ml of tetrahydrofuran and treated with 27.4 g of water and 3.5 g of triethylamine. The reaction mixture is stirred for 62 hours at 65-70 ° and taken up after cooling in 200 ml of dichloromethane. The solution is dried over 200 g of magnesium sulfate, filtered and evaporated in vacuo. Purification of the remaining viscous oil by column

- 27 -

Chromatography (silica gel, hexane / ethyl acetate 3: 2) gives the 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester as a mixture of diastereomers, mp. 67 °.

c) E-Z-Formylamino-α-methyl-S-diisopropylphosphono-S-pentenoic acid ethyl ester (3).

To a solution of 40.20 g of crude 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid in 600 ml of 1,2-dichloroethane at 20 ° under argon 18.6 ml of thionyl bromide are added dropwise within 5 minutes (weak cool). After two hours of stirring at room temperature, 400 ml of water are added, with the first 50 ml are slowly added dropwise. The mixture is stirred well for 15 minutes. The organic phase is separated and washed three times with ice-water and once with ice / saturated potassium bicarbonate solution (pH ca. 7.5). After drying over sodium sulfate and Abdesti.llieren the 1,2-dichloroethane at 35 ° in vacuo, the crude bromide is obtained as an intermediate, which at room temperature with 160 ml of triisopropyl phosphite and then at 75 ° (bath temperature) under a partial vacuum (about 13 kPa ) Is stirred for 17 hours. Then the excess triisopropyl phosphite and other volatile by-products are distilled off in a high vacuum (bath temperature 90 °). Chromatography of the residue on ten times the amount by weight of Kie. Elgel (particle size 0.04-0.06 mm) with ethyl acetate as Eluierungsmittal gives the E-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentenoic acid ethyl ester as a light yellow honey , IR (CH ₂ Cl ₂ ): 3410 (NH); 1740 (CO ester); 1690 (CO amide); 1235 (P = O); 980-1015 (POC).

d) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester (4)

To a solution of 25.42 g of E-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentenoic acid ethyl ester in 102 ml of dry dichloromethane are added dropwise at 20 ° under argon 56.7 ml of trimethylbromosilane within 15 minutes. After stirring for 20 hours at room temperature, 102 ml of ethanol are added dropwise within 15 minutes, and the whole is stirred for a further 20 hours. Then the clear reaction solution is completely evaporated in vacuo. The residue is evaporated three times after the addition of 100 ml of toluene. The oily residue is dissolved in 102 ml of ethanol and added dropwise with a

- 28 -

Solution of 102 ml of propylene oxide in 102 ml of ethanol. The crystalline product is filtered off after 2 hours (room temperature) and washed with ethanol and ether. After drying (80 °, ^y ! Hours) in a high vacuum, the E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester is obtained analytically pure, mp 212 ° (dec.).

Example 2: E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester

a) E - ^ -formylamino-A-methyl-S-dimethylphosphono-S-pentenoic acid ethyl ester O)

100.5 g of 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester are dissolved in 1.5 l of dichloroethane, at 20-25 ° 47 ml of thionyl bromide are added dropwise, and the mixture is stirred for 1 hour at room temperature. The reaction mixture is mixed with 750 ml of water and stirred vigorously for 10 minutes. The organic phase is separated, extracted with 1 liter of ice water, 1 liter of 1 N potassium bicarbonate solution and again 1 liter of ice water, dried over magnesium sulfate and evaporated. The resulting E-5-bromo-2-formylamino-4-methyl-3-pentenoic acid ethyl ester, a yellow oil, is treated immediately with 50 ml of trimethyl phosphite and stirred for 15 hours at 70 ° C. bath temperature and about 15 kPa The product obtained is taken up in 600 ml of water and extracted three times with 500 ml of ethyl acetate each time The combined organic phases are washed twice with 300 ml of water each time are combined, saturated with sodium chloride and extracted three times with 500 ml of dichloromethane.The combined organic phases are dried over magnesium sulfate and evaporated, the product is chromatographed on silica gel (ethyl acetate / isopropanol 7: 2) to obtain the E ^ -Formy. lamino ^ -methyl-S-S-dimethylphosphono-pentenoic acid ethyl ester as a yellow oil, ¹ H-NMR (DMSO): 1.82 (d, 3H, 4-CH _3), 2.69 (d, 2H), 5.03 (m, IfO, 5.32 (m, IH).

b) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester (ii)

16.9 g of ethyl ^ -formylamino-methyl-S-dimethylphosphono-p-pentenoate are dissolved in 80 ml of dichloromethane under a nitrogen atmosphere, and at about 25 °, 30 ml of trimethylbromosilane within

- 29 -

Dropped for 30 minutes. It is stirred for 20 hours at room temperature, and then werden.bei about 25 ° 80 ml of ethanol are added dropwise within 30 minutes, then stirred for a further 22 hours at room temperature and then evaporated. The residue is dissolved in 80 ml of ethanol and, with gentle cooling, 80 ml of propylene oxide in 80 ml of ethanol are added dropwise. It is stirred for 1 hour at room temperature, filtered and washed with ethanol and ether. This gives the ethyl E-2-aminoethyl 4-methyl-5-phosphono-3-pentanoate, m.p. 215-217 ° (dec.).

Example 3: E-2-amino-4-methyl-1-phosphono-3-pentenoic acid ester

a) E-2-Formylamino-4-methyl-5-di (2-chloroethyl) phosphono-3-pentenoic acid ethyl ester (O.

8.2 g of ethyl E-5-bromo-2-formylamino-4-methyl-3-pentenoate and 19 ml of tris (2-chloroethyl) phosphite are stirred for 20 hours at 70.degree. The resulting mixture is chromatographed on silica gel, eluting with ethyl acetate and ethyl acetate / isopropanol (7: 1), the product is crystallized from ethyl acetate / diethyl ether. This gives E-2-formylamino-4-methyl-5-di (2-chloroethyl) phosphono-3-pentenoic acid ethyl ester, mp. 47-49 °.

b) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester (2) Using 3 g of E-2-formylamino-4-methyl-5-di (chloroethyl) phosphono Ethyl 3-pentenoate is likewise obtained in an analogous manner as in Example 2, the ethyl E-amino-S-phosphono-S-pentenoate, mp 215 ° (dec.).

Example 4: E-2-amino-4-phosphonomethyl-3,6-heptadienoic acid

a) 2-methylene-4-pentenaldehyde (1_)

A mixture of 14.7 g of piperazine, 20.5 g of glacial acetic acid and 21.28 g of water is mixed with 24.5 g of a 37% aqueous formaldehyde solution and stirred for 10 minutes at room temperature. With continued stirring, 25.35 g of 4-pentenaldehyde are added and the reaction mixture is heated at 75 ° for 3 hours. After cooling to room temperature, the organic phase is separated, and the aqueous phase is extracted three times with 50 ml of diethyl ether. The combined organic

- 30 -

Phases are washed three times with 50 ml of a saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. Fractional distillation of the residue gives the 2-methylene-4-pentenaldehyde as a colorless oil, bp 65 ° / 6.6 kPa.

b) Methyl 5- [2- (1,4-pentadienyl)] - 2-oxazoline-4-carboxylate (By reaction of isocyanacetic acid methyl ester with 2-methylene-4-pentenaldehyde in toluene, in a manner analogous to that described in Example 1 and according to After purification by column chromatography (silica gel, ethyl acetate / hexane 1: 4), the 5- (2- (1,4-pentadienyl)) - 2-oxazoline-4-carbonyl methacrylate is obtained as a colorless OeI, ¹ H-NMR (CDCl ₃ ): 2.80 (d, 2H, CH ₂ ); 4.45 (dd, IH, C (4) -H); 5.82 (m, IH, C = CH-); 7.00 (d, IH, C (2) -H).

8.1 g of 5- (2- (1,4-pentadienyl)) - 2-oxazoline-4-carboxylic acid methyl ester are dissolved in 20 ml of tetrahydrofuran and mixed with 10 ml of water. The reaction mixture is stirred at 75 ° C. for 1.5 hours and, after cooling, evaporated in vacuo. Crystallization of the resulting residue from isopropanol / hexane gives the 2-methyl-3-hydroxy-4-methylene-6-heptenoic acid methyl ester as a mixture of diastereomers. Mp 75-77 °.

c) E-2-formylamino-4-bromomethyl-3,6-heptadienoic acid O)

5.0 g of 2-For ^ nylamino-3-hydroxy-4-methylene-6-hepten8äuremethyle8teΓ in 200 ml of dry tetrahydrofuran are cooled to -78 ° and treated with 20 ml of 1,5-hexadiene. 9 ml of thionyl bromide are slowly added dropwise so that the reaction temperature does not exceed -50 °. After completion of the addition, the reaction solution is heated to 0 ° within about 3 hours and stirred at this temperature for 3 hours. The solution is then poured onto 300 ml of a cold (5-10 °) saturated sodium bicarbonate solution and extracted with diethyl ether. The organic extracts are washed with saturated brine, dried over magnesium sulfate and evaporated in vacuo. After purification by column chromatography (silica gel, ethyl acetate / hexane 1: 1) of the E-2-formylamino-4-bromomethyl-3,6-heptadienoic acid methyl ester is a colorless oil. obtained ¹ H-NMR _(CDCl3): 3.20 (d, 2H, C (5) -H); 4.00 (p, 2H, CH ₂ Br).

- 31 -

d) E-2-Formylamino-4-diethyl] .phosphonomethyl-3,6-heptadienoic acid ethyl ester (4)

3.7 g of E ^ -formylamino ^ -broir.niethyl-S, 6-hep tadiensäur erne thy le ster are dissolved in 37 ml of triethyl phosphite and heated at 75 ° for 8 hours. Excess triethyl phosphite is then distilled off in a high vacuum. By column chromatography (silica gel, methanol / ethyl acetate 1:10) of E ^ -formylamino-A-diethylphosphonomethyl-3,6-heptadienoic acid methyl ester is obtained as a colorless OeI, ¹ H-NMR (CUCl ₃ ): 2.54 (d, 2H , P-CH ₂ ); 3.10 (m, 2H, C (S) -H); 5.10 (m, 2H, C (7) -H); 5.37 (d, IH, C (2) -H); 5.74 (m, IH, C (6) -H).

e; E-2-amino-4-phosphonomethyl-3,6-heptadienoic acid (5) 0.74 g of E-2-formylamino-4-diethylphosphonomethyl-3,6-heptadienoic acid methyl ester are dissolved in 12 ml of dichloromethane and added dropwise with 0.7 ml Trimethyljodsilan added. After four hours of stirring at room temperature, an amount of IN sodium thiosulfate solution is added until the reaction solution lightens. Thereafter, the reaction mixture is mixed with 10 ml of a 4.5 N hydrochloric acid solution and stirred for 30 minutes at room temperature. The aqueous phase is separated, washed twice with 20 ml of dichloromethane and evaporated in vacuo. The residue is dissolved in 10 ml of 4.5 N hydrochloric acid, stirred for 16 hours at room temperature and then evaporated in vacuo. The residue thus obtained is taken up in 40 ml of ethanol, clarified by filtration and treated dropwise with 10 ml of propylene oxide / ethanol (1: 1). The resulting white precipitate is filtered off and purified by column chromatography (Dowex 50 χ 8 / H2O). After concentration, the E-2-amino-4-phosphonotnethyl-3,6-heptadienoic acid is obtained as a white crystals, mp. 154-157 °, ¹ H-NMR (D ₂ O): 2.64 (d, 2H, P -CH ₂ ); 3.15 (m, 2H, C (5) -H); 5.20 (m, 2H, C (7) -H); 5.50 (dd, IH, C (3) -H); 5.90 (m, IH, C (6) -H).

- 32 Bei Piel 5: (2R) -2-amino-4 ntensäiire-inethy.l-5-phosphono-3-pi?

a) (L) -N-tert. Butoxycarbonyl-serine-N-methoxy-N-methvlarnide (1).

To a solution of 1 kg of (L) -N-tert-butoxycarbonyl-serine in 1 liter of tetrahydrofuran is added at -20 "to -25 ° within 5 minutes to 541.6 ml of N-methylmorpholine Temperature 699.6 ml of isobutyl chloroformate within 42 min and 445.8 ml of N-methoxy-N-methylamine are added within 40 min, allowed to warm to room temperature and the solvent is evaporated on a rotary evaporator The solution is extracted with 3.5 l of 2N hydrochloric acid and 3 l of saturated NaHCO.sub.2 solution, the aqueous phases are extracted three times with 1 l of ethyl acetate, the organic phases are washed with 2 l of saturated NaCl solution, dried with MgSO.sub.2 and concentrated The residue is stirred for 2 hours under ice-cooling with 3.5 l of hexane, the white suspension is filtered, the filter material is washed with 1 l of hexane, and drying at 40 ° C. under reduced pressure 781 g of J 2, m.p. 116-117 ° C ₁₀ IIzON ₂ O ₅ , calculated: C 48.38% , H 8.12%, N 11.28 % , C 48.28%, H 8.02%, N 11.32%.

b) (L) -3-tert-Butoxycarbonyl-2,2-dimethyl-oxazolidine-4-carboxylic acid N-methoxy-N-methylamide (2_) ·

A mixture of 781 g 1_, 3.3 1 acetone dimethyl acetal and 42 g of pyridinium (to.luol-4-sulfonate) is heated to 72 ° and then boiled under reflux for 17 hrs. After addition of 20 g of pyridinium tosylate is boiled for a further 9 hours, with about 750 ml of solvent distilled off and replaced by 700 ml of acetone dimethyl acetal. The solvent is evaporated and the residue is dissolved in 2 liters of diethyl ether. The organic phase is extracted twice with in-acid (1 1, 0.5 1) and once each with saturated NaHC0.i- or NaCl solution (each 0.3 1). The water phases are extracted twice with 0.5 l diethyl ether. The residue of the with MgSOi, dried organic phase is hot dissolved in 850 ml of hexane / diethyl ether = 9: 1. After addition> -on 600 ml of hexane and 50 ml of diethyl ether is cooled and diluted during the crystallization with 1.1 1 of hexane.

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The uspension is filtered. The filter material is washed with hexane.

Drying at 40 ° C on a vacuum gives 640 g, mp 67-68 °. Ci ill? Ι, Ν ^ Ο ^;

Calculated: C 54.15%, H 8.39 Z, N 9.72 Z, found: C, 3.96%, II, 8.37%, N, 9.91%.

c) (4S ) -2,2 -dimethyl-4-formyl-3-oxazolidine-carboxylic acid-tert. butyl ester (3).

c, a) reduction with LiAlHu

2.53 g of LiAlHij are added to a solution of 28.8 g of 2 in 350 ml of dry diethyl ether with ice-cooling; Internal temperature 5-15 ° C. After 1.5 hours of stirring at 5 °, a solution of 5.77 g KHSOi, in 60 ml of water is added dropwise so quickly that the temperature does not rise above 15 ° (40 min.). The suspension is filtered and the filtrate is washed with ether. With addition of ice, the filtrate is washed twice with 200 ml of 1 η hydrochloric acid, twice with 150 ml of 5% NaHCO j solution and with saturated NaCl solution. The water phases are extracted once with diethyl ether, the organic extracts are dried with NaOSOii and concentrated. Distillation of the residue at 0.4 mbar gives 17.78 g of 3 (bp 85-90 ⁰ C.), [A] _D = -93 ° (c = l, CHClj);

; Calculated: C 57.63%, H 8.35%, N 6.11%, 0 27.91%; Found: C 57.59%, H 8.54%, N 6.17 Z, 0.27.74%.

c, b) reduction with diisobutylaluminum hydride

66 ml of a 1M solution of diisobutylaluminum hydride in hexane are added dropwise with ice-cooling to a solution of 10 g of 2 in 120 ml of dry diethyl ether. It is stirred for 10 min. At room temperature, cool again to 0 ° and add a solution of 38 g KHSOi, in 160 ml of water (Temp. 0-15 °). It will take 30 min. stirred at room temperature and filtered. The filtered material is washed with diethyl ether and water, the organic phase of the filtrate is under ice cooling twice with 100 ml of 1N hydrochloric acid, twice with 100 ml of 10% NaHCO 3 solution and twice with 100 ml of sat. Washed NaCl solution. The organic extracts are dried with NajSOi, and evaporated. Distillation of the residue at 0.2 mbar gives 5.83 g of 3 (bp 78 ° C).

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d) 3 - ((4'R) -N-tert-butyloxycarbonyl-2 ', 2'-dime-th'-4'-oxazolidinyl) -2-methyl-propenoic acid ethyl ester (^)

A solution of 39.5 g (4S) -2,2-dimethyl-4-formyl-oxazolidine-3-carboxylic acid tert-butyl ester 3 in 200 ml dichloromethane is added over 2 hours to a solution of 68.7 g. Ethoxycarbonylethyliden-triphenylphosphorane in 900 ml of dichloromethane added dropwise. After stirring for 6 hours at room temperature, the mixture is cooled to 10 ° and 530 ml of a 10% aqueous Natriumhyrirogenpliosphatlösung added dropwise within 15 minutes T-ha'b. After stirring for 30 minutes at 15 °, the organic phase is separated and the water phase extracted with 250 ml of dichloromethane. The organic phases are dried over magnesium sulfate and evaporated. The residue is stirred with 70 ml of ether. The suspension is filtered, the filter material is washed with ether. The filtrate is evaporated, the residue is separated by chromatography on silica gel. Elution with hexane / ethyl acetate = 9: 1 gives, in addition to 2.32 g of cis isomer and 2.21 g of mixed fraction (cis / trans = 38:62) 45.4 g of 4. ¹ H-NMR (60 MHz, CDCl ₃ , trans isomer): inter alia 4.7 ppm (m, HC (4 ')); 6.7 ppm (d, J = 9, HC (3)). ¹ H-NMR (60 MHz, CDCl ₃ , cis isomer): inter alia 5.2 ppm (m, H ~ C (4 ')); 6.08 ppm (d, J = 7, HC (3)).

e) (4R) -2,2-Dimethyl-4- (3 ¹ -hydroxy-2'-methyl-prop-1'-enyl) -oxazolidine-3-carboxylic acid tert-butyl ester (5)

To a cooled to 3 ° solution of 48.7 g of 4 in 1 1 dry diethyl ether 389 ml of a 1 molar solution of diisobutylaluminum hydride in hexane are added within 15 minutes. It is allowed to warm to 11 ° and are added under ice-cooling 100 ml of ethyl acetate, followed by 50 ml of 2N sodium hydroxide solution. It is allowed to warm without cooling to about 28 ° and further 7 ml of 2N sodium hydroxide solution. The mixture is stirred for 15 hours at room temperature, sodium sulfate is added and filtered. Evaporation of the filtrate gives 42.1 g of crude 5. A sample (0.97 g) is purified by chromatography on 40 g of silica gel. Elution with hexane / ethyl acetate = 3: 1 gives 0.74 g of 2. ¹ H-NMR (300 MHz, DMSO-d ₆ ): et al

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3.52 (dxd, J = 9 and 3) and 4.02 (dxd J = ¹ J and <>) (2H-C (5)); 3.78 (m, 2H-C (3 ')); 4.54 (tn, HC (A)); A, 81 (t, J = 6, OH); 5.33 (d, J = 9, HC (I ¹ )).

f) (4R) -2,2-Dimethyl-4- (3'-bromo-2'-methyl-prop-1'-enyl) -oxazolidine-3-carboxylic acid tert. butyl ester (ι).

47.6 g of triphenylphosphine are added at 0 ° to a solution of 41.0 g of 5 and 60.2 g of tetrabromomethane in 1 liter of dry diethyl ether. After 30 minutes, the cooling bath is removed and stirred for 17 hours at room temperature. 20 g of tetrabromomethane and 15.9 g of triphenylphosphine are added and the mixture is stirred at room temperature for 2 hours. The white suspension is filtered and the filter cake is washed with ether. The evaporation residue of the filtrate is chromatographed on 0.9 kg of silica gel. Elution with hexane / ethyl acetate = 9: 1 gives 30.59 g of 6, mp. 62-65 ° C. ¹ H-NMR (300 MHz, DMSO-d, ·,): inter alia 3.55 (dxd, J = 9 and 2) and 4.04 (dxd, J = 9 and 6) (2H-C (5)) ; 4.15 (m, 2H-C (3 ')); 4.49 (m, HC (A)); 5.65 (d, J = 9, HC (I ¹ )).

g) tert-butyl (4R) -2,2-dimethyl-A- (3'-dimethylphosphono-2'-methyl-prop-1'-enyl-oxazolidine-3-carboxylate (_7)

A solution of 13.4 g of 6 in 70 ml of trimethyl phosphite is stirred for 15 hours at 80 °. The excess phosphite is evaporated off at 24 mbar. Drying of the residue in a high vacuum gives 14.3 g crude ] _. ¹ H-NMR (300 MHz, DMSO-d ₆ ): inter alia 2.63 (d, J = 23, 2H-C (3 ')); 3.59 (d, J = II, (CH ₃ O) ₂ PO).

h) N - ((2R) -5-Dimethylphosphono-1-hydroxy-A-methyl-3-penten-2-yl) -carbamic acid tert-butyl ester (%)

To a solution of IA, 0 g] in 250 ml of methanol is added 7 g of Amberlyst ¹ -15 (H-form, 20-50 mesh). The mixture is stirred at room temperature for 17 hours, filtered and the filtrate is evaporated. Chromatography of the residue on 0.33 kg of silica gel with ethyl acetate / methanol = 10: 1 as eluent gives 10.6 g of 8. ¹ H-NMR (300 MHz, DMSO-d ₆ ): inter alia A, 60 (t, J = 6 , OH); 6.67 (d, J = 7, NH).

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i) (2R) -2-tert.butoxycarbonylamino-5-dimethylphosphono-4-methyl-3-pentenoic acid (9).

, a) oxidation with chromosulfuric acid

To a solution of 0.323 g of 8 in 10 ml of acetone is added 0.77 ml of a solution which is 3.25 molar of chromium trioxide and 5.29 molar of sulfuric acid. Stir at room temperature for 40 minutes, add 2 ml of isopropanol followed by 50 ml of ethyl acetate, and add 0.1 g of charcoal to the mixture. After 10 minutes, it is filtered and washed with 50 ml of ethyl acetate. The filtrate is extracted three times with 50 ml of 10% sodium bicarbonate solution. The water phase is extracted twice with 40 ml of ethyl acetate, acidified to pH 1 with 2N hydrochloric acid and extracted three times with 70 ml of ethyl acetate. The organic extracts are washed with saturated brine, dried over magnesium sulfate and evaporated. Chromatography on 8 g of silica gel with chloroform / methanol / acetic acid = 18: 1: 1 as eluant gives 65 mg of 9. ¹ F-NMR (300 MHz, DMSO-dc): 1.37 (s, (CHj) ₃ CO ); 1.82 (d, J = 2, CH ₃ -CU)); 2.63 (d, J = 22, 2H-C (5)); 3.61 (d, J = II, (CH ₃ O) ₂ PO); 4.62 (t, J = 8, HC (2)); 5.25 (m, HC (3)); 7.18 (d, J = 8, NH); 11.7-12.5 (CO _n H).

i, b) oxidation with oxygen / platinum

To a solution of 0.66 g of {3 and 0.2 g of sodium bicarbonate in 20 ml of water and 2 ml of dioxane is added a suspension of platinum prepared by hydrogenating 313 mg of platinum oxide in 50 ml of water. In a zylinderischen apparatus is passed under vigorous stirring at 53 ° oxygen by means of a glass frit from bottom to top. It is filtered, washed with water and the filtrate extracted five times with 100-150 ml of ethyl acetate. Evaporation of the extracts gives 220 mg of educt 5. The water phase is mixed with 1 g of Amberlist * 15 (strongly acidic), filtered and evaporated at 40 ° in vacuo. Purification as f, a) gives 156 mg ^.

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¹ H-NMK (300 MHz, CDCl _3): 1.43 (s, (CHj) ₃ C); 1.96 (d, J = 3, CH ₃ -C (A)); 2.55 and 2.71 (2 dxd, J-22 and 15, 2H-C (5)); 3.75 and 3.76 (2 d, J = II, 2 OCH ₃ ); 4.97 (m, HC (2)); 5.25-5.45 (m, NH and HC (3)).

j) (2R) -2-amino-4-methyl-5-phono-3-pentenoic acid (10).

To a solution of 123 mg 9 in 3 ml of dichloromethane are added at 0 °

Added 0.71 ml of trimethylsilyl bromide. After stirring for 4 hours at 0 ^c , 20 ml of water are added. After 30 minutes, the dichloromethane phase is separated, and washed three times with 15 ml of water. The water phases are extracted three times with 20 ml dichloromethane and evaporated in vacuo. The residue is dissolved in 10 ml of 5N hydrochloric acid and stirred for 48 hours, diluted with 20 ml of water and extracted three times with 20 ml of dichloromethane. The aqueous phase is evaporated in vacuo, the residue dried under high vacuum, dissolved in 3 ml of ethanol and treated dropwise with about 1 ml of propylene oxide. The suspension is filtered. Washing the filter material with ethanol and drying under high vacuum at room temperature gives 62 mg K), mp 165 ° C (decomposition).

A sample is derivatized to the amide for analysis of the enantiomeric moiety with (R) - (+) - methoxy-trifluoromethyl-phenyl-acetic acid chloride. ¹ H NMR (300 MHz) analysis by integration of the OCH ₃ signals yields> 5% (2R) isomer (3.44 ppm) and <5% (2S) isomer (3.37 ppm).

Example 6; (2R) -2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester

a) (4R) -2,2-Dimethyl-4- (3'-diisopyropylphosphono-2'-methyl-prop-1-enyl) -oxazolidine-3-carboxylic acid tert-butyl ester O).

A solution of 6.68 g of bromide according to Example 5f) in 14.8 ml of dry Triiuopropylphosphit is heated to 70 ⁰ C for 17 hours at a pressure of 100 mbar. The mixture is evaporated at 0.4 mbar / 70 ^o . Chromatography on 350 g of silica gel (eluent, hexane / ethyl acetate = 1: 1) gives 8.28 g of 1, R _f = 0.077.

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b) N - ((2R) -5-Diisopropylphosphono-1-hydroxy-4-methyl-3-penten-2-yl) -carbamic acid tert-butyl ester (2).

2.25 g of Amberlyst® 15 (H-form, 20-50 mesh) are added to a solution of 4.49 g of phosphonic acid ester 1_ according to a) in 100 ml of methanol. The mixture is stirred for 2 days at room temperature, filtered and the filtrate is evaporated. Chromatography of the residue on 125 g of silica gel (eluent ethyl acetate / methanol = 20: 1) gives 2.44 g of 2.

c) (2R) -2-tert.butoxycarbonylamino-S-diisopropylphosphono-methyl-S-pentenoic acid (3).

To a solution of 1.6 g of alcohol 2 according to b) in 60 ml of acetone at 0-5 ° 3.3 ml of a solution containing 3.25 molar of chromium (VI) oxide and 5.29 molar sulfuric acid is given. The mixture is stirred at 0 ° for 6 hours and at room temperature for 12 hours. After addition of 5 ml of isopropanol and 40 ml of 20% saline solution is stirred for 10 minutes, then extracted for 15 hours in a coachman Steudel apparatus continuously with methyl acetate. The organic phase is dried over sodium sulfate, evaporated and the residue chromatographed on 75 g of hexane / ethyl acetate / acetic acid = 16: 10: 1. This gives 0.92 g 3, [a) _D = -94.5 ° (c = 1, 2, CHCl ₃ ). ¹ H-NMR (300 MHz, CDCl _3): 1.2-1.3 (4d, (2-PropO) _2); 1.4 (s, (CH ₃ ) ₃ CO). 1.95 (d, J = 3, CH ₃ -C (4)); 3.5 and 3.62 (2 dxd, J = 23 and 15, 2H-C (5)); 4.66 (m, (2-PropO) ₂ ); 4.92 (m, HC (2)); 5.30 (m, HC (3); 5.42 (d, J = 7, NH), 9.0-10.0 (broad, CO ₂ H).

d) (2R) -2-tert-Butoxycarbonylamino-S-diisopropylphosphono-methyl-S-pentenoic acid ethyl ester (4).

0.09 g of 1-amino-1-chloro-Ν, Ν, 2-trimethylpropene are added to a solution of 0.2 g of acid 3 in accordance with c) in 15 ml of dry dichloromethane at 0 ° -5 °. After stirring for 30 minutes at 0 °, 0.4 g of pyridine in 5 ml of ethanol was added. The mixture is stirred for 90 minutes at 0 ° and 15 hours at room temperature, diluted with 20 ml of dichloromethane and washed twice with 20 ml of water. The organic phase is dried with sodium sulfate, evaporated and chromatographed on 25 g of silica gel. Elution with ethyl acetate / methanol = 10: 1 gives 0.12 g of 4.

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¹ H-NMR (300 MHz, CDCl ₃ ): 1.2-1, A (m, 2 (CH ₁ ) SCHO, CJi ₁ CH ₂ O); 1.45 ( _s , (CHj) ₃ CO); 1.98 (d, J = 3, CH ₃ -C (A)); 2.55 (d, J = 23, 2H-C (5)); A, 2 (m, CH ₃ CH ₁ O); 4.69 (m, 2 (CH ₃ ) ZCHO); 5.0 (m, HC (2)); 5.16 (m, HC (3), NH).

e) (2R) -2-Amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester (5).

0.11 ml of trimethylsilyl bromide are added at 0 ° to a solution of 0.1 g of ester 4_ in accordance with d) in 10 ml of dichloromethane. The mixture is stirred at 0 ° for 4 hours and at room temperature for 15 hours. 20 ml of water are added, the mixture is stirred for 15 minutes, the water phase is separated off and the water is evaporated off in a high vacuum. The residue is dissolved twice in 5 ml of ethanol, evaporated and redissolved in 5 ml of ethanol. There are added 0.5 ml of propylene oxide. The precipitate is filtered off, washed with ethanol and dried for 15 hours under high vacuum (15 hours); 48 mg 5, [n] _D = -75 ° (c = 0.5, H ₂ O),

A sample is derivatized to the enantiomeric purity with (R) - (+) - methoxy-trifluoromethylphenylacetic acid chloride followed by diazomethane to amide dimethyl ester. 'H NMR (300 MHz) analysis by integration of the OCH3 signals gives> 97% (2R) isomer (3.5 ppm) and <3 % (2S) isomer (3.37 ppm).

Example 7: (2R) -2-Amino-4-methyl-7-phosphono-3-heptenoic acid

a) tert-butyl (4R) -2,2-dimethyl-4- (1'-hydroxy-2'-methylprop-2'-enyl) -oxazolidine-3-carboxylate O).

To a solution of 6.9 g (4S) -2,2-dimethyl-4-formyl-oxazolidine-3-carboxylic acid tert-butyl ester (according to Example 5c)) in 60 ml of dry tetrahydrofuran is added within 25 minutes at 0 Add 45 ml of a 1.1 molar solution of isopropenylmagnesium bromide drop by drop. The mixture is stirred for 45 minutes at 0 °, allowed to warm to room temperature, cooled again to 10 ° and 90 nil buffer solution (1-m, phosphate, PH-7) to. It is filtered and the filtrate extracted twice with 100 ml of ethyl acetate. The organic phase is washed twice with 50 ml of water each time and with saturated brine, dried with sodium sulfate.

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net. Evaporation of the solvent gives 8 g, oin Diasteromerengemisch. The separation can be carried out by chromatography on silica gel with hexane / ethyl acetate = 4: 1 and yields crystalline (1'S) -threo-epimer (R value: 0.2) and (1'R) -eiythro-epimer (R value: 0.16) in the ratio of about 1: 2.

b) tert-butyl ester (AR) -4- (1'-acetoxy-2'-methyl-prop-2'-enyl) -2,2-dimethyl-oxazolidine-3-carboxylate (2)

To a solution of 15.6 g Epimerengemisch according to a) in 60 ml of pyridine 60 ml of acetic anhydride are added dropwise at 0-5 ° within 10 minutes. The mixture is stirred for 15 hours at room temperature, diluted with 0.5 liter of diethyl ether and are added under ice-cooling 200 ml of 2N hydrochloric acid. The organic phase is washed with 250 ml of 2N hydrochloric acid and twice with 200 ml of 10% sodium carbonate solution. Drying over sodium sulfate and evaporation of the solvent gives 15.4 g of 2.

c) tert-butyl (4R) -4- (4'-carboxy-2 '-: -ethyl-butenyl) -2,2-dimethyl-oxazolidine-3-carboxylate (3).

A solution of 5.25 g of diisopropylamine in 200 ml of dry tetrahydrofuran is mixed at 0 ° with 34.5 ml of a 1.6 molar solution of butyllithium in hexane. It is cooled to -75 ° C and added dropwise within 10 minutes, a solution of 15 g of acetate 2 according to b) in 100 ml of tetrahydrofuran and after 5 minutes, a solution of 8 g of tert-butyldimethylsilyl chloride in 30 ml of 1,3-dimethyl -3,4,5,6-tetrahydro-2- (1H) -pyrimidinone. Allow to warm to room temperature, heat to reflux for 2 hours, cool to room temperature, add 230 ml of 45% ammonium fluoride solution, stir for 20 hours at room temperature and evaporate. The oily evaporation residue of the organic phase is added under ice-cooling with 150 ml of n-sodium hydroxide solution and the mixture is extracted twice with 200 ml of dichloromethane. The water phase is acidified with 300 ml of 20% citric acid solution and extracted three times with 300 ml of dichloromethane. The organic phases are washed with 20% saline, over

- 41 -

Sodium sulfate dried and evaporated. Chromatography of the residue on 50 g of silica gel with hexane / ethyl acetate = 1: 1 as eluant gives g solid 3.

d) (4R) -4- (4 ^l -Carbaethoxy-2'-methyl-butenyl) -2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (4).

d, a) Based on the acid 3

To an ice-cooled solution of 7.8 g of carboxylic acid 3 gemäs3 c) in 100 ml of dry dichloromethane is added dropwise within iü minutes 3.9 ml of 1-amino-l-chloro-Ν, Ν, 2-trimethylpropen added. After 30 minutes at 0 °, a solution of 2.2 g of pyridine in 80 ml of ethanol is added within 20 minutes. After stirring for 12 hours at room temperature, it is diluted with 100 ml of dichloromethane and washed twice with 100 ml of water each time. The organic phase is dried over sodium sulfate and evaporated. Chromatography of the residue on silica gel with hexane / ethyl acetate = 10: 1 gives 6.5 g of ester 4, [α] - + 6.17 ° (c = 1, CHCl ₃ ).

Ci ₈ H ₃ INO ₅ , calculated: C 63.32%, H 9.15%, N 4.10%; Found: C 63.4%, H 9.2%, N 4.5%.

d, b) From the epimer mixture I ^

A solution of 8 g of alcohol I ^ according to a) and 0.05 ml of propionic acid in 10.5 ml of triethyl orthoacetate is heated with slow distillative distillation of ethanol for 14 hours at 135-140 °. It is evaporated at a high vacuum at 40 °. Chromatography of the residue on silica gel with hexane / ethyl acetate = 10: 1 gives 8 g of 4.

e) (4R) -2,2-Dimethyl-4- (5'-hydroxy-2'-methyl-pent-1'-enyl) -oxazolidine-3-carboxylic acid tert-butyl ester (_5).

To a solution of 14.5 g of 4 ^ according to d) in 250 ml of absolute diethyl ether are added in portions 1.61 g of lithium aluminum hydride at 0 °. The mixture is stirred for 18 hours at 0-2 ° and under cooling with acetone / dry ice, a solution of 5 g of potassium bisulfate in 60 ml

- 42 -

Add water. It is filtered and washed four times with 200 ml of diethyl ether. The organic phase is washed three times with 80 ml of n-hydrochloric acid, three times with 80 ml of saturated sodium bicarbonate solution, washed twice with 200 ml of saturated common salt solution, dried over sodium sulfate and evaporated. Chromatography on silica gel with hexane / ethyl acetate = 1.1 gives 11.3 g of 5, CicHr.gNOi ,, calculated, C 64.19%, H 9.77%, N 4.68%; found: C 63.6%, H 9.8%, N 4.7%.

f) (4R) -4- (5'-Bromo-2'-methyl-pent-r-enyl) -2,2-dimethyl-oxazolidine-3-carboxylic acid tert -butyl ester (6).

At 0-2 ° are added to a solution of 4.4 g of alcohol 5 according to e) in 200 ml of dichloromethane 4.87 g of tetrabromomethane, 3.85 g of triphenylphosphine and 0.6 ml of pyridine. After 12 hours at 0-2 ° further 1 g each of tetrabromomethane and triphenylphosphine are added and stirred at 0 ° for 6 hours. It is evaporated, taken up in ethyl acetate, filtered and concentrated. Chromatography on silica gel with hexane / ethyl acetate = 10: 1 gives 4.5 g of 6, Ci ₆ H ₂₀ NO ₃ Dr; Calculated: C 53.04%, H 7.79%, N 3.87%, Br 22.06%; found C 53.1%, H 7.7%, N 3.9 %, Br 21.6%.

(g) (4R) -2,2-Dimethyl-4- (2'-methyl-5 ¹ -diisopropylphosphono-pent-1'-enyl) -oxazolidine-3-carboxylic acid tert-butyl ester (2)

A solution of 10.9 g of bromide 6 in 22 ml of triisopropyl phosphite is heated at 100 mbar for 24 hours at 135-140 °. The excess reagent is evaporated at 0.1 mbar / 60 ^o . Chromatography of the residue on silica gel with hexane / ethyl acetate = 1: 1 gives 10.7 _o .

h) N - ((2R) -1-Hydroxy-4-methyl-7-diisopropylphosphono-hept-3-en-2-yl) -carbamic acid tert-butyl ester (S) .

To a solution of 3 g of 1_ according to g) in 100 ml of ethanol are added 3 g of Amberlyst® 15 (H form). The mixture is stirred for 20 hours at room temperature, filtered, evaporated and chromatographed on 50 g of silica gel. Elution with ethyl acetate / methanol = 10: 1 gives 2.3 g of 8, [α] = -5.9 ° (c = 1, CHCl ₃ ).

- 43 -

Ci ₉ H ₃₈ NO ₆ P; Calculated: C 56.0%, H 9.4%, N 3.44%, P 7.6%; found C 55.4%, H 9.3%, N 3.4%, P 7.3 %.

i) (2R) -2-tert.-Butoxycarbonylamino-4-methyl-7-diisopropylphosphono-3-heptenoic acid (9).

i, a) oxidation with chromic acid

0.84 ml of a solution which is 3.25 molar of chromium trioxide and 5.29 molar of sulfuric acid are added dropwise at 0-5 ° to a solution of 0.5 g of alcohol 8 according to h) in 15 ml of acetone. The mixture is stirred at 0 ° for 30 minutes and at room temperature for 35 minutes. 4 ml of isopropanol, 80 ml of ethyl acetate and 30 ml of 20% saline are added and the mixture is filtered. The water phase is extracted three times with 20 ml of ethyl acetate each time. The organic phase is dried over sodium sulfate and evaporated. Chromatography on 20 g of silica gel with hexane / ethyl acetate / acetic acid = 16.10: 1 gives 0.34 g of 9, ["] = -35.25 ° (c = 1, 39, CHCl ₃ ), ¹³ C-NMR (75 MHz, CDCl ₃ ): 173.8 (CO ₂ H); 155.0 (OCON); 140.4 (C (4)); 121.1 (C (3)); 79.5 (OC (CH ₃ ),); 70.3 (OCH); 52.1 (C (2)); 39.7 (d, J = 18, C (5)); 28.3 ((CH ₃ ) ₃ C); 25.7 (d, J = 142, C (7)); 24.0 ((CHj) ₂ CH); 20.2 (d, J = 5, C (6)).

i, b) oxidation with platinum oxygen

To a solution of 3 g of alcohol 8 according to h) in 105 ml of dioxane is added at 55 °, a suspension of platinum in 45 ml of water, prepared by hydrogenation and degassing of 1 g of platinum oxide in 45 ml of water. At 55 - 60 °, oxygen is passed through with vigorous stirring (about 1900 rpm). It is filtered through Celite®, washed twice with 80 ml of water and the filtrate is evaporated at 40 ° in a high vacuum. Dissolve in 200 ml of water, add 1 g of sodium bicarbonate and 50 ml of 20% saline and extract three times with 100 ml of ethyl acetate each time. The organic phases are dried over sodium sulfate. Filtration and evaporation gives 1.8 g of starting material 8 ^. The water phase is acidified with about 20 ml of η-sulfuric acid and

- 44 -

extracted five times with 120 ml of ethyl acetate each time. Drying over sodium sulfate, evaporation and chromatography of the residue according to i, a) gives 0.8 g of acid 9.

j) (2R) -2-amino-4-methyl-7-phosphono-3-heptenoic acid (10).

A solution of 3.3 g of acid 9 according to i) and 2.6 g of N, O-bis-trimethylsilylacetamide is stirred for 1 hour under argon at room temperature. After addition of 4.4 g of trimethylbromosilane is stirred for 24 hours. The reaction mixture is added dropwise at 0 ° to 400 ml of water and stirred for 30 minutes. The organic phase is separated and washed three times with 50 ml of water. The water phases are extracted three times with 30 ml of dichloromethane and concentrated at 40 ° in a high vacuum to 10 ml. Chromatography on 20 ml of Dowex® 50 Wx8 with water as the eluent and lyophilization of the eluate gives 0.4 g of J ₁ O as an amorphous white powder of mp 252 ° (decomposition); [a] _ß = -86.5 ° (c ^ l, H ₂ O); C ₀ H ₁₆ NO ₅ PI H ₂ O; calculated C 37.05%, H 6.9 %, N 5.5%, found: C 36.3%, H 6.5%, N 5.6%.

A sample is derivatized to the amide with (R) - (+) - methoxy-trifluoromethyl-phenyl-acetic acid chloride to analyze the enantiomeric purity. ^ H NMR (300 MHz) analysis by integration of the OCH ₃ signals gives> 94% (2R) isomer (3.24 ppm) and <6 % (2S) isomer (3.17 ppm).

Example 8: (2R) -2-amino-7-phosphene-3-heptenoic acid

a) tert-butyl (4R) -2,2-dimethyl-4- (1'-hydroxy-prop-2'-enyl) -oxazolidine-3-carboxylate O).

To a solution of 25 g of (4S) -2,2-dimethyl-4-f ormyl-oxazol.idin-3-carboxylic acid tert-butyl ester (according to Example 5c) in 300 ml of dry tetrahydrofuran is added within 30 minutes 0-5 ° 60 ml of a 2.4 M solution of vinylmagnesium bromide in tetrahydrofuran. The mixture is stirred for 1 hour at 0 °, allowed to warm to room temperature and stirred for 1 hour at room temperature. While cooling to 10 ° C., 300 ml of buffer solution (1 molar, phosphate, pH 7) are added. After 10 minutes, it is filtered, extracted twice with 150 ml of ethyl acetate and twice

- 45 -

washed with 100 ml of water. The water phase is extracted twice with 100 ml of ethyl acetate. The organic extracts are dried over sodium sulfate and evaporated. Chromatography of the residue on silica gel with hexane / ethyl acetate = 4: 1 gives 24.2 g Epimerengemisch 1; Ci ₃ H ₂₃ NO,.; Calculated: C 60.68%, H 9.01%, N 5.44%; Found: C 60, ~>%, H 9. t%, N 5.6%.

b) tert-butyl (4R) -4- (4'-ethoxy-carboryl-butylbul-enyl) -2,2-dimethyl-oxazolidine-3-carboxylate (2).

A solution before 22.5 g of alcohol 1_ according to a) and 0.3 ml of propionic acid in 38.5 ril of triäthylester Orthoameisensäure is heated under slow AbdestilL .vion of ethanol for 4 hours at 135- 140 ⁰ C. It is evaporated at 50 ° in a high vacuum and chromatographed on 300 g of silica gel. Elution with hexane / ethyl acetate = 4: 1 gives 23.9 g of 2, [α] _D = -10.0 ° (c = 1.5, CHCl ₃ ); Ci ₇ H ₂₉ NO ₅ ; Calculated: C 62.36%, H 8.93%, N 4.28%; found: C 62.2%, H 8.9%, N 4.4%.

c) (4R) -2, 2 -Dimethy1-4- ^{(5-hydroxy-1-pentenyl)} oxazolidin-3-carboxylate O).

At 0-2 ° is added to a solution of 23.5 g of 2 according to b) in 550 ml of absolute diethyl ether per pcrtionenweise 2.7 g of lithium aluminum hydride. After stirring for 3 hours at 0-2 °, a solution of 25 g of potassium bisulfate in 250 ml of water is added dropwise with cooling. Filter through Celite® and wash well with diethyl ether. The organic phase is washed twice with 200 ml of hydrochloric acid η and twice with 250 ml of 10% sodium bicarbonate solution. The water phases are extracted twice with 100 ml of ether. The washed with 20% saline organic phases are dried over sodium sulfate and evaporated. Chromatography on silica gel with hexane / ethyl acetate as eluent gives 18.6 g of 3, [cv] "= -10.1 ° (c = 1.4,

~ D

CHCl ₃ ); Ci ₅ H ₂₇ NOu; Calculated: C 63.13%, H 9.54%, N 4.91%; Found: C 63.0%, H 9.5%, N 5.0%.

- 46 -

d) (4R) -4- (5'-Broin-pentenyl) -2,2-dimethyl-oxazolidine-3-carboxylic acid tert -butyl ester (^).

To a solution of 18.5 g of alcohol 3 according to c), 28.2 g of tetrabrominethane and 22.3 g of triphenylphosphine in 600 ml of dichloromethane are added dropwise at 0 ° 7 ml of pyridine. The mixture is stirred for 12 hours at 0-2 °, evaporated, taken up in 150 ml of ethyl acetate, filtered, concentrated to 50 ml and chromatographed on 200 g of silica gel. Elution with hexane / ethyl acetate 10: 1 gives 19.9 g of bromide 4, [α] _β = -18.9 ° (c = 1, CHCl ₃ ); Ci ₅ H ₂₆ NO ₃ Br; Calculated: C 51.73%, H 7.53%, N 4.02%, Br 22.94%; found: C 51.7%, H 7.7%, N 4.2%, Br. 23.0%.

e) tert-butyl (4R) -2,2-dimethyl-4- (5'-di-2-propylphosphono-pentenyl) -oxazolidine-3-carboxylate (5).

A solution of 19.9 g of bromide 4 according to d) in 60 ml of triisopropyl phosphite is heated under 100 mbar for 20 hours at 130-135 °. The excess reagent is distilled off at 60 ° / 0.1 mbar, the residue is chromatographed on 250 g of silica gel. Elution with hexane / ethyl acetate = 1: 1 gives 20.6 g of phosphonic acid ester 5, [α] = -8.6 ° (c = 0.8, CHCl ₃ ); C ₂ H _{10 10} NO ₆ P; Calculated: C 58.18%, H 9.30%, N 3.23%, P 7.15%; found: C 57.4%, H 9.3%, N 3.2%,? 7.5%.

f) N - ((2R) -1-Hydroxy-7- (diisopropylphosphono-hept-3-en-2-yl) -carbamic acid tert-butyl ester (6).

A solution of 20.6 g of 5 according to e) in 800 ml of methanol stirred wild for 20 hours with 30 g of Amberlyst® 15 (H form) at room temperature. It is filtered, washed with methanol, evaporated and chromatographed on 100 g of silica gel. Elution with ethyl acetate gives 14.8 g of 6, [α] = -3.6 ° (c = 1.5, CHCl ₃ ); Ci ₈ H ₃₆ NO ₆ P; Calculated: C 54.95%, H 9.22%, N 3.56%, P 7.87%; found: C 53.6%, H 9.0%, N 3.4%, P 9.0%.

- 47 -

g) (2R) -2-tert. Uutoxycarbonylamino-7-diisoprojylphosphono-3-heptenoic acid (2)

To a solution of 7.4 g of alcohol 6 according to f) in 300 ml of acetone at 0 - 2 ⁰ C within 20 minutes 15 ml of a solution which 3.25 molar of chromium trioxide and 5.29 molar at Sulfuric acid is added dropwise. The mixture is stirred for 2 hours at 0-2 °, 4 hours at room temperature and then 30 ml of isopropanol, 300 ml of ethyl acetate and 200 ml of 20% saline solution. The water phase is extracted three times with 250 ml of ethyl acetate, the organic phases are dried over sodium sulfate and evaporated. Chromatography on 200 g gravel. ¹ gel with hexane / ethyl acetate / acetic acid = 16: 10: 1 gives 4.55 g of acid 2 × [α] _D = -24.9 ° (c = 0.8, CHCl ₃ ).

h) (2R) -2-amino-7-phosphono-3-heptenoic acid (8).

A solution of 3.1 g of acid ] and 3 ml of Ν, Ο-bis-trimethylsilylacetamide in 200 ml of dry dichloromethane is stirred for 1 hour at room temperature. 3.5 ml of triethylbromosilane are added and the mixture is stirred at room temperature for 30 hours. The volatiles are evaporated, the residue is taken up in 50 ml of dichloromethane and mixed at 0-2 ° with 250 ml of water. The water phase is separated and concentrated in a high vacuum to 10 ml. Chromatography on 20 ml Dowex® 50 Wx8 with water as eluent and lyophilization of the eluate gives 1.04 g ^ as an amorphous powder, [α] = -65.2 ° (c = 1, H ₂ O); ¹³ C-NMR (75 MHz, D ₂ O): 172.8 (CO ₂ H); 140.3 (C (4)); 122.2 (C (3)); 56.4 (C (2)); 33.3 (d, J = 17, C (5)), 27.3 (i.e., J = 134, C (7)); 22.6 (d, J = 4, C (6)). A sample is derivatized to the enantiomeric purity with (R) - (+) - methoxytrifluoromethylphenylacetic acid chloride followed by diazomethane to amide trimethyl ester. 'H NMR (300 MHz) analysis by integration of the OCH ₃ signals gives> 95% (2R) isomer (3.54 ppm) and <5 % (2S) isomer (3.37 ppm).

Example 9: (2R) -2-amino-4-fiorior-S-phosphono-'i-pentenoic acid (JM ·

a) (4R) -4- (2'-Carbomethoxy-2'-luor-vinyl) -2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1).

To a suspension of 13 g of zinc powder and 2 g of copper (I) chloride in a solution of 8.2 g of (4S) -2,2-dimethyl-4-formyl-oxazolidine ~ 3-carboxylic acid tert-butyl ester (according to Example 5c ) in 200 ml of dry tetrahydrofuran and 4.1 g of acetic anhydride are added with stirring and heating 8.1 g of methyl dichloroacetate (argon atmosphere). Reflux for 2 hours, allow to cool, dilute with diethyl ether, filter through Gelite® and evaporate the filtrate. Chromatography of the residue on silica gel with hexane / ethyl acetate = I ¹ J ₁ I as eluent gives 5.07 g ^ .i Masrenspektrum (field desorption): 303 (! And 8.5, HC (I ')).

desorption): 303 (M ⁺ ); ¹ H-NMR (60 MHz, CDCl ₁ ): inter alia 5.93 (dxd, .1 = 31

b) tert-butyl (4R) -2,2-dimethyl-4- (2'-fluoro-3'-hydroxy-propenyl) -oxazolidine-3-carboxylate (2).

To a solution of 4.9 g of ester 1_ according to a) in 160 ml of absolute diethyl ether are added dropwise at 0-5 ° 39 ml of lM-LHsting of diisobutylaluminum hydride in hexane. The mixture is stirred for 1 h. At 0-5 °, 80 ml Ethy.lacetat followed by 25 ml of 2N sodium hydroxide solution, while the temperature is kept below 25 °. It leaves 30 min. stir at room temperature, 50 g of sodium sulfate, filtered and washed with ethyl acetate. Dry the filtrate with sodium sulfate, evaporate and chromatograph on 100 g of silica gel with hexane / ethyl acetate = 3: 1 to give 3.7 g of 2, (] _D = + 2.5 lc = 2.5, CHCl ₃ ); C ₁₃ C ₂₂ NOi ₁ F; Calculated: C 56.72%, H 8.06%, N 5.09%; found: C 56.2%, H 8.2%, N 5.1 Z.

c) (4R) -4- (3'-Bromo-2'-fluoro-propenyl) -2,2-dimethyl-oxazolidin-3-carboxylic acid tert-butyl ester (J) -

To a solution of 3.7 g of alcohol 2 ^ according to b) in 200 ml of dry dichloromethane at 0-2 ° within 10 min. Added 6.63 g of tetrabromomethane and 5.24 g of triphenylphosphine. After 15 hours stirring at 0-2 °

- 49 -

is evaporated, taken up in 80 ml of ethyl acetate, filtered, the filtrate is evaporated. Chromatography of the residue on 50 g of silica gel with hexane / ethyl acetate = 4: 1 gives 3.7 g of bromide 3 ( "°] = + 12.7 ° (c = l, CHCl _3); C ₃ H _{3 n} iNBrFO calculated C 46.17%, H 6.26%, N 4.14%, found: C 46.4%, H 6.3%, N 4.2%.

d) (4R) -2,2-Dimethy1-4- (2'-fluoro-3 ¹ -di-2-propylphosphono-propenyl) -oxazolidine-3-carboxylic acid tert-butyl ester (4).

A solution of 3.7 g of bromide _3 according to c) in 30 ml of tri-2-propyl phosphite is heated to 130-135 ° C. over a period of 7 hours at 100 mbar. The excess reagent is heated at 90 ° / 0.1 ml-ir evaporated. Chromatography of the residue on 100 g of silica gel with hexane / ethyl acetate = 3: 1 gives 2.8 g of phosphonate 4; [«) _ = -8.6 ° (c = 3, CHCl ₃ ); Ci ₉ H ₃₅ NFO ₆ P; Calculated: C 53.89%, H 8.33%, N 3.31%; Found: C 53.7%, H 8.4%, N 3.4%.

e) N - ((2R) -4-Fluoro-1-hydroxy-5-di-2-propyl-phosphono-pent-3-en-2-yl) -carbamic acid tert-butyl ester (5).

A solution of 2.3 g of phosphonate ^ according to d) in 250 ml of methanol is stirred with 5 g of Amberlyst-15 (H-form) for 20 hrs. At room temperature. It is filtered, evaporated and chromatographed on 80 g of silica gel. Elution with ethyl acetate gives 1.31 g of alcohol 5, [u] _ = -21.1 ° (c = 1, CHCl ₃ ); Ci ₃ H ₃ INFO ₅ P; Calculated: C 52.31%, H 8.51%, N 3.81 %; found: C 50.2%, H 8.2 %, N 3.7%.

f) (2R) -2-tert.butoxycarbonylamino-4-fluoro-5-di-2-propylphosphono-3-pentenoic acid (6).

To a solution of 1.3 g of alcohol 5 according to e) in 80 ml of acetone are added at 0-2 ° 2.5 ml of a solution which is 3.25 M of chromium trioxide and 5.29 M of sulfuric acid. It is stirred for 2 hours at 0-2 ° and allowed to warm to room temperature within 4 hrs. After addition of 10 ml of 2-propanol, 100 ml of ethyl acetate and 50 ml of 20% NaCl solution, the aqueous phase is separated and extracted four times with 100 ml of ethyl acetate. Dry the organic phases with sodium sulfate, evaporation,

- 50 -

and chromatography on 70 g of silica gel with hexane / ethyl acetate / enigmaic acid = 10: 16: 1 as eluent gives 0.87 g of acid 6, M ₀ = -72.9 ° (c = 0.8, CHCl ₃ ).

g) (2R) -2-amino-4-fluoro-5-phosphono-3-pentenoic acid (_7)

A solution of 0.8 ρ 6 gemβß f) and 0.84 ml of Ν, Ο-bis-trimethylsilylacetamide in 80 ml of dry dichloromethane is stirred for 1 hr. At room temperature. After addition of 0.98 ml Trimethy'bromsilan is stirred for 30 hrs. At room temperature. The volatiles are evaporated, the residue is dissolved in 50 ml of dichloromethane and treated at 0-5 ° with 200 ml of water. The organic phase is separated and washed twice with 50 ml of water. The water phases are concentrated in a high vacuum to 10 ml. Chromatography on 30 ml Dowex 50 Wx8 with water as eluant and lyophilization of the eluate gives 0.22 g _7> [α] = -44.8 ° (c = 0.5, H ₂ O); Fast-atom bombardment: 214, (M + H) ⁺ . ¹³ C-NMR (75 MHz, U ₂ O): 172.7 (CO ₂ H); 161.5 (dxd, J = 263 and 12, C (4)); 100.9 (t, J ca. 11, C (3)); 49.5 (C (2)); 33.5 (dxd, J = 128 and 26, C (5)).

A sample is derivatized to the amide with (R) - (+) - methoxy-trifluoromethylphenylacetic acid chloride to analyze the enantiomeric purity. 'H NMR analysis (300 MHz) by integration of the OCH ₃ series gives> 90% (2R) isomer (3.49 ppm) and <10% (2S) isomer (3.38 ppm).

Example 10: (2R) -2-Ami.iO-4-methyl-5-phosphono-3-pentenoic acid ethyl ester a) (2R ₁ 3S) -2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester ( 1).

aa) starting from 1,1,3,3-tetramethyl-l, 3-disila-2-azolidine-N-acetic acid ethyl ester.

To a solution of 2.26 ml of N-cyclohexyl-N-isopropylamine in 60 ml of absolute tetrahydrofuran was added at -20 ° 7.6 mJ of a 1.6 molar solution of butyllithium in hexane. After 20 minutes, it is cooled to -78 ° and a solution of 3 g of 1,1,3,3-tetramethyl-1,3-disila-2-azolidine-N-acetic acid ethyleste. added dropwise in 60 ml of tetrahydrofuran. The mixture is stirred for 1 hour at -78 ° and then gives 142 ml

- 51 -

an approximately 0.035 molar solution of cyclopentadienyl bis-O-1,2: 5,6-diisopropylidene-D-glucofuranosyl titanium (IV) chloride in ether and stirred for 17 hours at -78 °. The reaction solution is transferred by means of a steel cannula by argon pressure into a vessel with a cooled to -78 ° solution of 1.1 ml of methacrolein in 15 ml of tetrahydrofuran. Allow to warm slowly to room temperature, stir for 2 hours, add 1.5 ml of water. ι and filtered. The filtrate is diluted with 250 ml of diethyl ether, washed three times with 250 ml of approximately 10% saline solution and with 250 ml of saturated sodium chloride solution. The water phases are extracted twice with 250 ml of diethyl ether. The organic phases are dried over sodium sulfate, evaporated and dissolved hot in 150 ml of cyclohexane. Upon cooling, 1,2: S-di-O-isopropylidene-D-glucofuranose crystallizes. The mother liquor is evaporated, the residue taken up in 120 ml of tetrahydrofuran, 24 ml of water and 4.5 ml of acetic acid and stirred for 2 hours at room temperature. Evaporation under high vacuum at room temperature gives 10.6 g of residue containing (2R, 3S) -2-amino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester. A sample (5 mg) is derivatized for 2 hours with 0.2 ml trifluoroacetic anhydride in 0.3 ml dichloro-ethane. Capillary gas chromatography (Chirasil®-L-Val, 90-18O ° / 2 ° per minute) gives 99.25% (2R, 3S) enantiomer (retention time T 10.28 minutes) and 0.75% (2S, 3R ) Enantiomer (retention time T

11.48 minutes). It is then heated for 5 1/2 hours in 80 ml of ethyl formate to reflux. Evaporation and chromatography on silica gel with hexane / ethyl acetate = 1.1 gives 1.64 g of formamide K. Analysis of a sample (5 mg) as acetate by gas chromatography (Chirasil®-L-Val, 160-180 °, 1 ° / min): 99.2 % (2R, 3S) -Enan-

Tiomer (T = 13.64 minutes). 0.8% (2S, 3R) enantiomer (T = ret. Ret

13.94 minutes)

 a, b) starting from Isocyanessigsäureethylester

To a solution of 24.88 g of isocyanacetic acid ethyl ester and 18.51 g of methacrolein in 220 ml of 1,2-dichloroethane are added at 50 ° 1.65 g of (S) -N-methyl-N [2- (dimethylamine)) - ethyl] ^1- l - [(R) -I-1,2-bis (diphenylphosphino) -ferrocenyl] -ethylamine and 1.105 g of bis (cyclohexyl isocyanide) gold (I) tetrafluoroborate are added and the mixture is stirred for 5 hours

- 52 -

under argon, evaporated, taken up in 400 ml of diethyl ether, filtered and the filtrate is evaporated. Distillation of the evaporation residue on high vacuum (0.04 mbar) yields 33.62 g of a stereoisomer of 5- (2-propenyl) oxazoline-4-carboxylic acid ethyl ester of boiling point 42 - 52 °. MS .: m / e = 183 (2%, M ⁺ ), 110 (80%), 85 (100%). A solution of 33 g of this mixture in 74 ml of water and 33 ml of tetrahydrofuran is heated to reflux for 3 hours. Evaporation on vacuum gives 36.1 g of a mixture of stereoisomeric 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester 2. A sample (35 mg) is dissolved in 2 ml of dichloromethane with 0.05 ml of N, O. Derivatized bis-trimethylsilylacetamide and analyzed by capillary gas chromatography (Chirasil® L-VaI, 150 °): 89.1% (2R, 3S) isomer (T = 22.1 minutes), 5.8 % (2S, 3R ) Isomer (T = 23.1 minutes), 2.8% (2R, 3R) -isomer

ret

(T = 24.3 minutes), 2.3 % (2S, 3S) isomer (T = 25.4 minutes), ret ret

To a solution of 20.2 g of 2, 16.83 ml of triethylamine and 0.62 g of 4- (dimethylamino) pyridine in 300 ml of dichloromethane is added within 25 minutes at 0-3 °, a solution of 11.42 ml of acetic anhydride in the 50th ml of dichloromethane was added dropwise. After 30 minutes, it is washed twice with ice-cold 2N hydrochloric acid and twice with 10% saline. The water phases are extracted with 100 ml of dichloromethane. The evaporation residue of the dried over sodium sulfate organic phases is hot in hexane / ethyl acetate = 4: 1 dissolved. Upon slow cooling to about 30 crystallize 1.82 g of racemic (2R, 2S) -2-formylamino-3-acetoxy-4-ethyl-4-pentenoic acid ethyl ester, mp. 98-106 °. The mother liquor is slowly cooled to -12 ° C and held at this temperature for 1 hour. Filtration gives 15.04 g of acetate 3, mp 73-75 °, [a] _n = -75.6 ° (c = 1, CHCl ₃ ), gas chromatographic analysis (Chirasil ^ -L-Val, 160-180 °, 1 ° per minute): (2R, 3S) isomer 93.5% (T = 14.5 minutes), (2S, 3R) isomer 2.2%

ret

(T = 14.8 minutes), (2R, 3R) isomer 2.2% (T = 16.8 minutes), ret ret

(2S, 3S) -lomeromer 2.1% (T = 17.1 minutes).

ret

To a solution of (2R, 3S) -2-formylamino-3-acetoxy-4-methyl-4-pentenoic acid ethyl ester (3) in 400 ml of absolute ethanol at -16 ° is added 20.64 g of anhydrous potassium carbonate. After stirring for 4 hours at -18 ° to -11 ° C., 500 ml of buffer solution (1 molar,

- 53 -

Phosphate, pH = 7). The mixture is stirred for 30 minutes at room temperature and extracted three times with 350 ml dichloromethane. Chromatography of the evaporation residue of the organic phases dried over sodium sulfate on 1 kg of silica gel with hexane / ethyl acetate = 1: 2 as eluent gives 9.8 g of alcohol J.

b) (2R) -2-Formylamino-4-methyl-5-diisopropylphosphono-3-pentenoic acid ethyl ester (4).

To a solution of IA, 19 g _1 according to a) in 210 ml of 1,2-dichloroethane are added at 18 - 20 ° 6.57 ml of thionyl bromide and after stirring for 2 hours 135 ml of water. After 15 minutes, the organic phase is separated and washed three times with 150 ml of ice water and once with 100 ml of ice-cold saturated sodium hydrogencarbonate solution. The evaporation residue of the dried with sodium sulfate organic; ^J ise is dissolved in 60 ml Triisopropylphosphit stirred for 17 hours at 75 ° / 100 mbar. The excess reagent is distilled off under high vacuum at 90 °. Chromatography of the residue on 650 g of silica gel with ethyl acetate / methanol = 20: 1 gives 10.88 g of phosphonic acid ester 4, (α) = -123.5 ° (c = 1, CHCl ₃ ). ^ 1 NMR analysis (300 MHz) with the addition of (1R) -1- (9'-anthracenyl) -2,2,2-trifluoroethanol shows an enantiomeric purity of> 90%.

L) (2R) -2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester (5).

23 ml of trimethylbromosilane are added dropwise at room temperature within 15 minutes to a solution of 10.3 g of 4 in accordance with b) in 42 ml of dichloromethane. After 21 1/2 hours 42 ml of ethanol are added with ice cooling and stirred for 20 hours. It is evaporated, the residue is dissolved three times in 70 ml of toluene and evaporated in each case again. The residue is dissolved in 42 ml of ethanol and mixed with 42 ml of propylene oxide. After 1 1/2 hours, filtered. Drying of the filter material in Vakuultspxsiccator over P ₂ O ₅ / KOH (3 hours / 80 ^o ) gives 6.17 g of 5; [α] = -78 ° (c = 0.6, H ₂ O); M.p. 194-197 ° (dec.), C ₈ Hi ₆ NO ₅ P; Calculated: C 40.51%, H 6.80%, N 5.91%, P 13.06%; found: C 39.4%, H 7.09%, N 5.73%, P 12.98%.

- 54 -

A sample is derivatized with (R) - (+) - methoxytrifluoromethylphenylacetic acid chloride and diazomethane to amide dimethylphosphonate for analysis of the enantiomeric purity and analyzed by ¹ H-NMR (300 MHz) based on the integration of the OCHβ signals: ( 2R) isomer> 93% (3.51 ppm), (2S) isomer <7% (3.37 ppm).

Example 11 : (2R) -2-amino-4-methyl-5-phosphono-3-pentenoic acid.

A solution of 100 mg (2R) -2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester according to Example 10 in 3 ml of η-hydrochloric acid is 4 1/2 hours

warmed in a bath of 100 ⁰ C. It is evaporated and the residue is dried for 30 minutes in a high vacuum at 60 °. The residue is dissolved in 15 ml of ethanol and admixed with 4 ml of propylene oxide. Filtration and drying of the filter material in a vacuum desiccator over P ^ Os / KOH gives 62 mg of acid.

A sample is derivatized with (R) - (+) - methoxy-trifluoromethyl-phenyl-acetic acid chloride to give the amide and analyzed by ¹ H-NMR (300 MHz), integration of the OCH ₃ signals to determine the enantiomeric purity:> 95% (2R) Enantiomer (3.25 ppm) and <5% (2S) enantiomer (3.18 ppm).

Example 12: E-2-amino-4-methyl-5-phosphono-3-pentenoic acid (1)

12 g of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester are stirred in 70 ml of water under reflux for 19 hours. The reaction mixture is cooled slowly to room temperature, stirred for 1 hour in an ice bath, filtered and washed with cold water. This gives E-2-amino-4-methyl-5-phosphono-3-pentenoic acid as a monohydrate, mp 163 ° (dec.). Example 13 E-2-dimethyl-4-methyl-5-phosphono-3-pentenoic acid

A mixture of 3.56 g of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester, 45 ml of 98% formic acid and 30 ml of 37% aqueous formaldehyde solution is 30 minutes at a bath temperature of 105 ° touched. Then it is evaporated to dryness in vacuo. The residue is taken up in a little water and the whole again evaporated in vacuo. This procedure is repeated twice more. The solid

- 55 -

The residue is stirred with 80 ml of water. After one hour, the insoluble matter is separated over a hard filter and washed with water. The filtrate and washings are evaporated to dryness in vacuo. The residue is suspended in 100 ml of water and after addition of 30 ml of 1 N sodium hydroxide solution? TfigR is left at room temperature. The reaction mixture is evaporated to a residual volume of about 25 ml in vacuo and purified by ion exchange chromatography (Dowex 50 W χ 8 HnO). The fractions containing the desired product are combined, evaporated in vacuo and recrystallized from water / ethanol. This gives the E ^ -dimethylamino-A-methyl-S-phosphono-S-pen-

tartaric acid, mp 239 ° (decomp.)

 ">

Example 14: E, 4-Dimethylamino-A-methyl-S-phosphono-S-pentenoic acid ethyl ester

1.19 g of E-2-dimethylamino-4-methyl-5-phosphono-3-pentenoic acid are mixed with 30 ml of 8-n ethanolic hydrogen chloride solution and stirred at 40 ° for 24 hours. The reaction mixture is evaporated to dryness in vacuo. Further evaporation after addition of 30 ml of pure ethanol gives 1.90 g of reddish OeI, which is dissolved in hot isopropanol. After cooling, the crystalline E ^ -Dimethylamino ^ -methyl-S-phosphono-S-pentenoic acid ethyl ester hydrochloride is obtained, mp 203 ° (dec.).

Example 15: E ^ -Benzylamino ^ -methyl-S-phosphono-S-pentenoic acid ethyl ester

A solution of 5.69 g of E ^ -Amino ^ -methyl-S-phosphono-S-pentenoic acid ethyl ester in 48 ml of water and 48 ml of ethanol with 16 ml of glacial acetic acid, 5.90 g of sodium acetate (anhydrous) and 12.2 ml of benzaldehyde. Under intensive cooling with ice / common salt, 15.70 g of sodium borohydride are added within about one hour in about 70 portions, after which, after half of the addition, after about 30 minutes, 4 ml of benzaldehyde are added. The temperature of the reaction mixture is kept between 0 and 10 °. After completion of the addition, the mixture is stirred for 1 hour at 0 ° and then added dropwise 1 N hydrochloric acid until the congoous reaction. The undissolved salts are filtered off and washed with water. The filtrate is evaporated to dryness in vacuo, the residue is added twice more

Addition of ethanol evaporated. Now, the residue is stirred with 150 ml of ethanol, the undissolved filtered off and washed with ethanol. The filtrate is mixed with 25 ml of propylene oxide and stirred for 2 hours. The crystallized material (mainly starting material) is filtered off. The mother liquor is evaporated to dryness and stirred with 350 ml of ethyl acetate. The crystalline crude product obtained after suction filtration is recrystallized from ethanol. This gives E-2-benzylamino-4-methyl-5-phos- ·

Phono-3-pentenoic acid ethyl ester, mp 192 ° (dec.). )

Example 16: Ethyl E ^ -Benzylamino - ^ - methyl-S-phosphono-S-pentenoate

A solution of 1.00 g of ethyl E - ^ -benzylamino-A-methyl-S-phosphono-S-pentenoate in 6 ml of water is stirred under reflux for 20 hours. The reaction mixture is evaporated to dryness in vacuo. The residue is mixed with ethanol and evaporated again. This process is repeated twice more. The residue is dissolved in boiling methanol. After cooling, the crystalline E-2-benzylamino-4-methyl-5-phosphono-3-pentenoic acid is obtained, mp. 150 ° (dec.).

Example 17: Ethyl E - ^ -isopropylamino-A-methyl-S-phosphono-pentenoate

A solution of 6.40 g of E - ^ - amino ^ -methyl-S-phosphono-S-pentenoic acid ethyl ester in 54 ml of water and 18 ml of glacial acetic acid is added 6.64 g of sodium acetate (anhydrous) and 18 ml of acetone. Under intensive cooling with ice / common salt, 17.67 g of sodium borohydride are added over the course of 90 minutes in about 70 portions, with 18 ml of acetone being added after 20 minutes and 50 minutes. After completion of the addition, the thick, white suspension is stirred for 30 minutes at 0 ° and then added dropwise 1 N hydrochloric acid until the congoous reaction. The resulting clear solution is evaporated in vacuo, the residue is evaporated twice more after addition of ethanol. The residue is stirred with 200 ml of ethanol at room temperature, the insoluble matter is filtered off and washed with ethanol. The filtrate is evaporated in vacuo and the residue becomes

- 57 -

recrystallized from isopropanol. This gives the E-2-isopropylamino-A-methyl-S-phosphono-S-penterisa'ureethylester hydrochloride, mp 203-205 ° (dec.).

Example 18: E-2-isopropylamino-4-methyl-5-phosphono-3-pentenoic acid

A solution of 1.20 g of ethyl E ^ -isopropylamino-A-methyl-S-phosphono-S-pentenoate hydrochloride in 7 ml of water is stirred at reflux for 20 hours. The reaction mixture is evaporated to dryness in vacuo. The residue is mixed with ethanol and evaporated again. This process is repeated twice more. The residue is dissolved in 25 ml of ethanol, treated dropwise with stirring with a total of 5 ml of propylene oxide and the whole is evaporated to dryness. The residue is dissolved in a little water and ethanol is added to turbidity. The four-hour stirring at room temperature is slow crystallization. The product is filtered off, washed with ethanol and diethyl ether and dried at 100 ° under high vacuum. This gives E-2-isopropylamino-4-methyl-5-phosphono-3-pentenoic acid, mp 225-227 ° (dec.).

Example 19: E ^ -Methylamino-A-methyl ^ -phosphono-S-pentenoic acid

a) 2- (N-methyl-N-bromylamino) -3-hydroxy-4-methyl-4-pentenoic acid ethyl ester O)

20.60 g of ethyl 5- (2-propenyl) -2-oxazoline-4-carboxylate, prepared according to Example 1, are dissolved in 200 ml of dry dichloromethane under argon. At 15 °, a suspension of 16.60 g of trimethyloxonium tetrafluoroborate in 200 ml of dry dichloromethane is then added dropwise. The reaction mixture is stirred for 17 hours at room temperature and then slowly added with 150 ml of water and 45 ml of saturated Kaliumbicarbonatlosung, so that a pH of 7 results. The separated organic phase is washed twice with water and once with saturated brine and dried over sodium sulfate. After distilling off the dichloromethane, the oily residue is distilled in a bulb tube, bp. 120-130 ° / 13 Pa. You get that

- 58 -

2- (N-MOt ¹ I νl -formylamino) -3-hydroxy-4-methyl-4-pentenoic acid ethyl ester as a light yellow honey, IR (CHnCl ₂ ): 3550 (H ₂ O); 1740 (CÜ ester); 1675 (CO amide).

b) E-2- (N-methyl-N-formylamino) -4-methyl-5-diisopropylphosphono-3-pentenoic acid thy lester (2_)

To a solution of 17.80 g of 2- (N-methylformylamino) -3-hydroxy-4-methyl-4-pentensa'ureethylester in 248 ml of 1, 2-dichloroethane are at 2! "'° under argon 7.70 ml The mixture is stirred for 2 hours at room temperature, then 150 ml of water are added dropwise with gentle cooling (20 ° C.) The two-phase mixture is stirred well for a further 20 minutes The organic phase is separated and washed three times with water / ice, once with The intermediate product obtained after drying over sodium sulfate and distilling off the 1,2-dichloroethane at 35 ° in vacuo is treated at room temperature with 66 ml of triisopropyl phosphite and then at 75 ° under reduced pressure 13 kPa) is stirred for 17 hours, then the excess triisopropyl phosphite and other volatile by-products are distilled off under high vacuum, purified by column chromatography (silica gel, ethyl acetate r) gives the E-2- (N-methyl-formylamino) -4-methyl-5-diisopropylphosphono-3-pentenoic acid ethyl ester as a yellowish honey; IR (CH ₂ Cl ₂ ): 1740 (CO ester); 1670 (CO amide); 1235 (P = O), 980-1010 (POC). The compound is present according to ¹ H-NMR spectrum as a mixture of two rotamers.

c) E-2-methylamino-4-methyl-5-phosphono-3-pentenoic acid (3)

To a solution of 9.50 g of E-2- (N-methyl-formylamino) -4-methyl-5-diisopropylphosphono-3-pentenoic acid in 40 ml of dry dichloromethane 20 ml of trimethylbromosilane are added dropwise at 20 ° under argon within 10 minutes , After stirring for 20 hours at room temperature, 37 ml of ethanol are added dropwise within 15 minutes, and the whole is again stirred for 20 hours. Then the clear reaction solution is evaporated to dryness in vacuo. The residue is evaporated twice more after addition of 30 ml of toluene. The resulting OeI is mixed with 128 ml of 2N hydrochloric acid and 16 hours.

stirred at a bath temperature of 85 °. The reaction mixture is evaporated in vacuo. Double evaporation after addition of ethanol / toluene 1: 1 gives an oily residue, which is dissolved in 51 ml of ethanol and treated dropwise with a solution of 51 ml of propylene oxide in 51 ml of ethanol. The crystalline product is filtered off after 2 hours and recrystallized from water / ethanol. This gives E-2-methylamino-4-methyl-5-phosphono-3-pentenoic acid, mp 239 ° (dec.).

Example 20:

In a manner analogous to that described in Examples 1-3 or 6 and 9, it is also possible to prepare:

E-2-amino-5-phosphino-3-pentenoic acid ethyl ester, mp 172-173 °. E-2-amino-5-phosphino-3-pentenoic acid butyloter, mp 160-161 °. E-2-amino-5-phosphono-3-pentenoic acid ethyl ester, mp 167-168 °. E-2-Amino-5-phosphono-3-pentenoic acid butyl ester "... 160-161 ° E" "-" "-" "-o-S-phosphono-S-pentenoic acid octyl ester, mp 161-162 ° E-2-amino-5- Phosphono-3-pentenoic acid propyl ester, mp 161-162 ° E-2-Amino-5-phosphono-3-pentenoic acid pentyl ester, mp 160-161 ° E-2-amino-5-phosphono-3-pentensa ' ureisobutyl ester, mp 163-164 °, E-2-amino-5-phosphono-3-pentenoic acid secondary butyl ester, mp 169-170 °, methyl E-amino-S-phosphono-S-pentenoate, m.p. Mp 193-194 °, [water / acetone (9: 1)];

E-2-amino-4-methyl-5-phosphono-3-pentenoic acid propyl ester, m.p. 184-185 °, (water);

N-butyl E-2-amino-4-methyl-5-phosphono-3-pentenoate, m.p. 186-187 °, [water / acetone (2: 1)];

E-2-amino-4-methyl-5-phosphono-3-pentenoic acid isobutyl ester, m.p. 181-182 °, [water / acetone (9: 1)];

Pentavalent E-2-amino-4-methyl-5-phosphono-3-pentenoate, m.p.2Ο7- · 2Ο8 °;

Hexyl E-2-amino-4-methyl-5-phosphono-3-pentenoate, m.p. 207-208 °. E-2-Ajnino-7-phosphono-4-heptenoic acid butyl ester, mp 186 °. E-2-amino-5-phosphono-4-pentenoic acid methyl ester, mp 219-220 °. Ethyl E-2-amino-5-phosphono-4-pentenoate, mp 234 °.

- 60 -

E-2-amino-5-phosphono-4-pentenoic acid butyl ester, mp 239 °. E-2-Am: ino-5-phosphono-4-pentenoic acid octyl ester, mp 236 °. E ^ -Amino-S-phosphono ^ -pentensäure ^ -hydroxyethyl ester, mp. 197 °

Example 21: In a manner analogous to Examples 4, 12, 13 and 19 or 5, 7, 8, 9 and 11, it is also possible to prepare:

E ^ -amino-S-phosphono-A-pentenoic acid, m.p. 219-220 °; E-2-amino-5-methylphosphonyl-4-pentenoic acid, m.p. 222 °; E - ^ - amino-S-butylphosphonyl-p-pentenoic acid, m.p. 232-233 °; E ^ -Amino-S-octylphosphonyl-pentenoic acid, m.p. 221-223 °; E ^ -Amino-S-dodecylphosphonylpentanoic acid, m.p. 211 °; E ^ -amino-G-phosphono-A-hexenoic acid, m.p. 244-246 °; E ^ -Amino-o-methylphosphonyl ^ -hexenoic acid, m.p. 145-150 °; E-2-amino-6-butylphosphonyl-4-hexenoic acid, m.p. 216 °; E ^ -Amino-o-octylphosphony.l ^ -hexenoic acid, mp 209-210 °; E - ^ - amino-δ-dodecylphosphonyl-hexenoic acid, mp 197-200 °; E ^ -Amino ^ -phosphonoheptenoic acid, mp 125 ° (decomposition); E-2-amino-5-phosphono-3-pentenoic acid, white amorphous powder, ¹ H-NMR (D ₂ O): 2.39 (dd, 2H, C (5) -H); 4.27 (d, IH, C (2) -H); 5.53 (m, IH, C (3) -H); 5.87 (m, IH, C (4) -H), mp after recrystallization from ethanol / water 191-192 °;

E-2-amino-4-methyl-5-phosphono-3-pentenoic acid, ¹ H-NMR (D;> 0): 1.73 (s, 3H, CH ₃ ); 4.55 (a, IH, C (2) -H);

E-2-amino-5-methylphosphonyl-3-pentenoic acid, amorphous white powder, ¹ H-NMR (D ₂ O): 2.55 (dd, 2H, C (5) -H); 4.38 (d, IH, C (2) -H); 5.64 (m, IH, CO) -H); 5.91 (m, IH, C (4) -H);

E, -Amino-S-phosphino-S-pentenoic acid, m.p. 139-140 °; E-2-amino-4-methyl-5-phosphino-3-pcrenoic acid, m.p. 176-177 °; (2S) -E-2-A'.nino-4-methyl-5-phosphono-3-pentenoic acid, m.p. 196 °, [al * = + 97.1 + 1.9 ° (c = 0.5 ; Water); E-2-amino-4-methyl-5-methylphosphonyl-3-pentenoic acid, ¹ H-NMR (D ₂ O): 1, (d, 3H, CH ₃ -P); 1.75 (d, 3H, CH _3); 2.45 (d, 2H, C (5) -H); 4.50 (d, IH, C (2) -H); 5.15 (m, IH, C (3) -H); E-2-amino-2-methyl-5-phosphono-3-pentenoic acid, m.p. 225-226 ° (from water);

- 61 -

E - ^ -amino-S-methyl-S-phosphono-S-pentenoic acid, white powder, mp 168 °, ¹ H-NMR (D ₂ O): 1.50 (d, 3H, CH ₃ ); 2,4 (m, 2H, CH ₂ ); 4.30 (s, IH, C (2) -H); 5.60 <m, IH, C (4) -H);

E ^ -Amino-S-methyl-S-phosphono-S-pentenoic acid, which is an amorphous solid. ¹ H-NMR (D ₂ O): 1.05 (dd, 3H, CH ₃ ); 2.45 (m, IH, C (5) -H); 4.33 (d, 2H, C (2) -H); 5.5 and 5.9 (2m, 2H, C (3) -H and C (4) -H); E-2-amino-4-ethyl-5-phosphono-3-pentenoic acid, m.p. 176 °; E, -Amino -propyl-S-phosphono-S-pentenoic acid, m.p. 193 °; E-2 Amino-4-butyl-5-phosphono-3-pentanoic acid, m.p. 186-187 °, E-2-A: nino-4-isopropyl-5-phosphono-3-pentene acid, m.p. 201 °; E-2 Α-mono-4-tert-butyl-5-phosphono-3-pentenoic acid, mp 252-253 °, ¹ H-NMR (D ₂ O): 0.95 (s, 9H, (CH ₃ ) ₃ C);

Z-2-Amino-4-tert - butyl-S-phosphono-S-pentenoic acid; ¹ H-NMR (D ₂ O): 1.08 (s, 9H, (CH ₃ ) ₃ C); 2.45 (m, 2H, CH ₂ ); 4.95 (d, IH, C (2) -H); 5.20 (m, IH, C (3) -H).

E ^ -Amino ^ -benzyl-S-phosphono-S-pentenoic acid, colorless needles, mp 196-198 °;

E-2-Amino-4-phenyl-5-phosphono-3-pentenoic acid, colorless needles, mp 230-233 °;

E-2-amino-4-methyl-5-methylphosphono-3-pentenoic acid by-product, mp 149-150 °.

Example 22: E-2-mythiol-4-mythi-3-pentenoic acid ester

1.20 g of E-2-methylamino-4-methyl-5-phosphono-3-pentenoic acid are mixed with 50 ml of 8 N ethanolic hydrogen chloride solution and stirred for 25 hours at 40 °. The reaction mixture is evaporated to dryness in vacuo. Double evaporation after addition of ethanol / toluene 1: 1 gives an oily residue, which is dissolved in 5 ml of ethanol and treated dropwise with a solution of 5 ml of propylene oxide in 5 ml of ethanol. The crystalline product is filtered off after 2 hours and washed with ethanol and ether. After drying (80 °, 4 hours) under high vacuum, the E ^ -Methylamino ^ -methyl-S-phosphono-S-pentenoic acid ethyl ester, mp. 235 ° - 240 ° (with decomposition).

Example 23: Production of 1000 capsules containing in each case 1.0 mg of the active spar die of Example 6 with the following composition:

E-2-amino-o-phosphono-4-hexenoic acid 10.0 g

Lactose 207.0 g

Modified starch 80.0 g

Magnesium stearate 3.0 g

Procedure: All powdered ingredients are sieved with a sieve of 0.6 mm mesh size. Danr is the active ingredient in a suitable

and mixed to homogeneity first with magnesium stearate, then with lactose and starch. No. 2 gelatin capsules are filled with each 300 mg of this mixture using a capsule filling machine.

Capsules are prepared in an analogous manner containing 10-200 mg of another disclosed compounds mentioned in Examples 1-21.

Example 24: Preparation of 10 ¹ OOO tablets with a content of 10 .ng the active Subtanz of Example 6 with the following composition:

E-2-amino-6-phosphono-4-hexenoic acid 100.00 g

Milk sugar 2,535.00 g

Cornstarch 125,00 g

Polyethylene glycol 6000 150.00 g

Magnesium stearate 40.00 g

purified water q.s.

'' Out: All powdered ingredients are screened with a sieve of 0.6 mm mesh size. Then the active ingredient is mixed with lactose, magnesium stearate and half of the starch in a suitable mixer. The other half of the starch is suspended in 65 ml of water, and the suspension is added to the boiling solution of polyethylene glycol in 260 ml of water, the resulting paste is added to the powders and, if appropriate with the addition of another water solution.

- 63 -

quantity, granulated. The granules are dried overnight at 35 °, forced through a sieve of 1.2 mm mesh size and pressed into tablets having a score line.

Tablets containing 10-200 mg of one of the other compounds mentioned in Examples 1-21 are prepared in an analogous manner.

Claims (62)

L - 64 - 9820 \ 6 Patent a nsprüch e ]. Process for the preparation of unsaturated Ami riosäureverbinaungen the formula wherein Ri is hydrogen, alkyl or flydroxy, R? Is hydrogen, alkyl, halo, Hydroxyniederslkyl, lower alkoxy, aryl-lower alkyl, lower alkenyl, halogen or aryl, R 3 is hydrogen, alkyl or aryl, Ri _(hydrogen or alkyl, R 5 is optionally esterified or amidated carboxy, Rf, an unsubstituted amino group substituted by lower alkyl or aryl-lower alkyl, A is unsubstituted or alkyl substituted, w is alkylene having from 1 to 3 carbon atoms (C atoms) or a direct bond, and B is methylene or a bond, with the proviso that A is unsubstituted or substituted alkyl substituted α, ω-alkylene having 1 to 3 carbon atoms, when B is a direkce bond, and their salts, characterized in that in a compound of formula (ID, where Zi is optionally protected hydroxy, Z2 is a group Ri or protected hydroxy, Z5 is a group R5 or protected carboxy, Ζ $ is a protected group R ^ and Ri, Rz, Rj, Ri), R5, Rg, A and B have the meanings given above _, e protected groups "L ^ and optionally Zj, Z2 and / or Z5 by treatment with a Triniederalkylhalogensilan liberated and, if desired, the compound obtained is converted into another compound of formula I, a mixture of optical isomers obtained in the components and the desired isomer is separated off and / or a resulting free compound is converted into a salt or a salt obtained in the free compound or in another salt. 2. Method according to claim 1, characterized in that a compound of the formula (III) wherein R2, R3, Ri ₍ , A and B are as defined for formula I, Z * has the meaning of R ^ or is protected carboxy, Zs is a protected group Rr, and X is reactive esterified hydroxy, with a Compound of the formula Zi-! ' (IV), wherein Zj is optionally protected hydroxy, Z2 is Ri or is protected hydroxy and R is an etherifying group, in the resulting intermediate of formula (II) the protected groups Ze and optionally Zi, Zo and / or Z ^ are liberated by treatment with a tri-lower alkyl halide and, if desired, in a compound obtainable by the process wherein R5 is esterified carboxy, the esterified carboxy group in carboxy or in a compound obtainable by the process R5 carboxy, the carboxy group is converted into an esterified carboxy group and / or, if desired, a resulting compound of the formula I is converted into a salt or a salt obtained into another salt or into a free compound of the formula I and / or if desired an optical isomer a mixture of stereoisomeric forms of an obtained compound of formula I or a salt thereof. / ίί 3. The method according to claim I for the preparation of compounds of formula I, wherein Rj, R;>, Rj, Ri ,, Rf ₁ , Λ and B have the meanings given in claim 1 and R ^ is esterified or amidated carboxy, and their Salts, characterized in that a compound of the formula (III) wherein R 1, R 1, R 1, A, and B are as defined for formula I, Z 1 is the meaning of R 1, Z, is protected amino and X is reactive esterified hydroxy, with a compound of formula III, OR Z ₁ -! (IV) wherein Z _{1 is} optionally protected hydroxy, Z? the meaning of R] or is protected hydroxy and R is an etherifying group reacting, in the obtained intermediate the protected groups Zf ₁ and optionally Zj, Zz and / or Z ^ to obtain the group Rs by treatment with trimethylbromosilane fi3isetzt and if desired, converting a compound of formula I obtained into a salt or a salt obtained into another salt or into a free compound of formula I and / or, if desired, an optical isomer comprising a stereoisomeric forms of a compound of formula I or a salt obtained isolated from it. 4. The method according to claim 1 for the preparation of compounds of formula I, wherein R), Rj, Rj, Ri ,, R ^, A and B have the meanings given in claim 1 and R, denotes carboxy, and their salts, characterized characterized in that in a compound of formula II wherein Zj is optionally protected hydroxy, Z2 is a group Ri or protected hydroxy, Z5 is carboxy or esterified, amidated or protected carboxy and Z & is a protected group Rc, and R ₁ , R ₂ , Ri, Ri ,, R ₆ , A and B have the above meanings, the al protected groups Zf, and optionally Zj, /, -> and / or Zs by treatment with a Triniederalkylhalogensilan releases and / or, if desired, in a compound obtainable according to the invention in which Ro is esterified or amidated carboxy, the esterified or amidated carboxy group converting an obtained compound of the formula I into a salt or a salt obtained into another salt or a free compound of the formula I and / or, if desired, isolating an optical isomer from a mixture of stereoisomeric forms of an obtained compound of the formula I or a salt thereof , 5. The method according to any one of claims 1-4, characterized in that starting from a compound of formulas II or IV, wherein protected hydroxy Zi and / or Z < with an aliphatic alcohol etherified hydroxy, such as with an optionally halogen or in higher than the α-Stcllung by hydroxy, oxo, lower alkoxy, lower alkanoyloxy and / or mono- or di-lower alkylamino-substituted lower alkanol, Niederalkenoi or lower alkynol etherified hydroxy represents. 6. The method according to claim 3, characterized in that starting from a compound of formulas II or IV, wherein protected hydroxy Zi and / or Zj with an aliphatic alcohol etherified hydroxy, such as with an optionally by I 'lies or higher than the α-position represented by hydroxy, oxo, lower alkoxy, lower alkanoyloxy and / or mono- or di-lower alkylamino-substituted lower alkanol, lower alkenoi or lower alkynol etherified hydroxy. 7. The method according to any one of claims 1-4, d ^ adurch characterized in that one starts from a compound of formulas II or IV, wherein protected hydroxy Zi and / or Z ^ means lower alkoxy. 8. The method according to claim 3, characterized in that starting from a compound of formulas II or IV, wherein protected hydroxy Zi and / or Zj is lower alkoxy. / IA - 68 / - 9. The method according to any one of claims 1-8, characterized in that one starts from a compound of formulas II or III and IV, wherein the protected group Zf, an optionally represented by lower alkyl or Arvlniederalkyl N-substituted acylamino group. 10. The method according to any one of claims 3, 6 and 8, characterized durch marked that starting from a compound of formulas II or III, wherein the protected group Zf, represents an acylamino group. 11. The method according to any one of claims 1-9, characterized in that starting from a compound of formulas II or III and IV, wherein the protected group Zf, an optionally dvirch lower alkyl or aryl-lower alkyl N-substituted acylamino group, wherein acyl is the acyl group of a Koii Lensäurehalbesters means represents. 12. Verfaliren according to any one of claims 1-9, characterized in that one starts from a compound of formulas II or III and IV, wherein the protected group Zf, a substituent optionally in the 1- or 2-substituted lower alcohol.xycarbonylaininogruppe, for example Tertiarybutyloxycarbonylamino. 13. The method according to any one of claims 1-9, characterized in that one starts from a compound of formulas II or III and IV, wherein the protected group Zf, an optionally substituted by lower alkyl or aryl-lower alkyl N-substituted lower alkanoylamino group, for example formylamino. 14. The method according to any one of claims 3, 6 and 8, d adurc h characterized in that one starts from a compound of formulas II or III, wherein protected amino Zf, a lower alkanoylamino group, for example formylamino represents. 15. The method according to any one of claims 1-14, characterized in that one uses as Triniederalkylhalogensilan a Triniederalkylchlorsiian, Triniederalkyljodsilan or Triniederalkylbromsilan. 16. The method according to any one of claims 1-14, characterized in that lbromsilan used as Triniederalky'.hri logens Π to a Triniederalky. 17. The method according to any one of claims 3, 6, 8 and 10, characterized in that in. used as Tr iii.i ederalkvlhalogensilan trimethylbromosilane. 18. A method according to eiuoir: the claims 1-14, characterized in that ΐΐκ'η used as Triniederalkylhalogensilan trimethylbromosilane. 19. The method according to any one of claims 1-18, characterized in that one never makes release of the protected groups Z \, Z ^, Z ^ and / or Zf, in a lu.logenierten hydrocarbon. 20. A process according to any one of claims 3, 6, 8, 10, 14 and 17, as by in that, performs the release of the protected groups Z j, Z ?, Z5 and / ODOF Zf in a halogenated hydrocarbon. 21. The method according to any one of claims 1-20, characterized in that one carries out the release of the protected groups Z \, Z.., Z ^ and / or Zr, in a halogenated aliphatic hydrocarbon. 22. The method according to any one of claims 1-19, characterized in that one works in dichloromethane as a solvent or diluent. 23. A method according to one of m of claims 3, 6, 8, 10, 14, 17 and 20, characterized in that one works in dichloromethane as a solvent or diluent. 24. The method according to any one of claims 1-22, characterized in that one adds a hydrogen halide scavenger. 25. Process according to one of claims 3, 6, 8, 10, 14, 17, 20 and 23, characterized in that a hydrogen bromide interceptor is added, 2ίι. A process according to any one of Claims 1-25, characterized in that an epoxy-lower alkane is added in admixture with a lower alkanol as a halogenated water toffabf. 27. A method according to any one of claims 1-26, characterized in that I'ropylenoxid in admixture with ethanol as H.-. leucure hydrogen scavenger adds. 28. The method according to any one of claims 3, 6, 8, 10, 14, 17, 20, 23 and 25, characterized in that propylene oxide in Gemiscli with Ethanol as Bromwasserstoffabfän "he adds. 29. The method according to any one of claims 1-27 for the preparation of unsaturated amino acid compounds of the formula Π) wherein Ri is hydrogen, alkyl or hydroxy, R? R 1 is hydrogen, alkyl or aryl, R 1 is hydrogen or alkyl, IU is optionally substituted or amidated carboxy, R 9 is an unsubstituted one or less Is lower alkyl or aryl-lower alkyl substituted amino group, Λ unsubstituted or substituted by alkyl η, ω-alkylene having 1 to 3 carbon atoms (C atoms) or a direct bond and B is methylene or a bond, with the proviso that A is unsubstituted or by Alkyl substituted ", ω-alkylene having 1 to 3 carbon atoms, when B is a direct bond, in the form of those enantiomers in which the C atom, which carries the amino group Rf, has R configuration, and their Salts, d characterized in that one starts from a compound of formula II or of compounds of formulas III and IV, wor into the C atom bearing the group Z 1 has R configuration. 30. The method according to any one of claims 1 to 29, characterized in that a method according to the available compound of formula I. (Ib) wherein Ri, R2, R3. Ru, and R6 have the meanings given in claim 1 and Rs is an esterified carboxy group hydrolyzed without the addition of acid or base in water to the acid. 31. A method according to any one of claims 3, 6, 8, 10, 14, 17, 20, 23, and 28, characterized ichnet gekennze in that a method according obtainable compound of formula I in which Ri, R2, R3, Ri ₄ and R6 have the meanings given in claim 1 and R5 is a lower alkoxycarbonyl group, hydrolyzed to the acid. 32. The method according to any one of claims 1-31, characterized in that one compounds of formula I, wherein Ri is hydrogen, alkyl having up to 12 carbon atoms or hydroxy, R2 is hydrogen, lower alkyl, halo-lower alkyl, Hydroxiliederalkyl, Niederalkoxyniederalkyl, unsubstituted or im R3 is hydrogen, lower alkyl or unsubstituted or substituted phenyl, Ri is hydrogen or lower alkyl, R5 is free or pharmaceutically acceptable esterified or amidated carboxy, R 6 is amino, mono- or di-lower alkylamino, A is unsubstituted or substituted by lower alkyl α, ω-alkylene having 1 to 3 carbon atoms or a bond, and B is methylene or a bond, with the proviso that A is is different from a bond when B is a bond wherein the substituents of phenyl are selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, halogen, amino, halo-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl and nitro, or a pharmaceutically acceptable salt thereof. / ι Κ -γί- 33. The method according to any one of claims 3, 6, 8, 10, IA, 17, 20, 23, 25 and 28, characterized in that compounds of formula I, wherein Ri is hydrogen, alkyl having up to 12 carbon atoms or hydroxy R 2 is hydrogen, lower alkyl, lower haloalkyl, hydroxyloweralkyl, lower alkoxy-lower alkyl], phenyl-lower alkyl unsubstituted or substituted in the phenyl moiety, lower alkenyl, halogen or unsubstituted or substituted phenyl, R 3 is hydrogen, lower alkyl or unsubstituted or substituted phenyl, Ri _{4 is} hydrogen or lower alkyl, R5 is pharmaceutically acceptable esterified or amidated carboxy, R6 is amino, mono- or di-lower alkylamino, A is unsubstituted or lower alkyl substituted α, ω-alkylene of 1 to 3 carbon atoms or a bond, and B is methylene or a bond means, with the proviso that A is different from a bond, if B means a bond wherein the substituents of phenyl are selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, halo, amino, halo-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl and nitro, or a pharmaceutically acceptable salt thereof. 34. A process according to claim 33, wherein compounds of the formula I are prepared in which Ri to Ri ₁ , A and B have the meanings given in claim 31, R 5 is lower alkoxycarbonyl or substituted by amino, mono- or di-lower alkylamino, hydroxy or lower alkanoyloxy Lower alkoxycarbonyl and R6 is amino or Mononiederalkylamino, or produces a pharmaceutically acceptable salt thereof. 35. The method according to any one of claims 1-31, characterized in that compounds of formula I, wherein Ri is hydrogen, alkyl having up to and having 12 carbon atoms or hydroxy, R2 is hydrogen, lower alkyl, phenyl, Halogenpheny.l or phenyl R3 and Ri are hydrogen or lower alkyl, R5 is carboxy and R6 is amino, wherein A is unsubstituted or substituted by lower alkyl α, ω-alkylene having 1 to 3 carbon atoms or a bond and B is methylene or a bond, with with the proviso that A is different from a bond when B is a bond or a pharmaceutically acceptable salt thereof. -μ- 36. The method according to any one of claims 3, 6, 8, 10, 14, 17, 20, 23, and 28, characterized in that compounds of formula I, wherein Ri is hydrogen, alkyl having up to and with 12 carbon atoms or hydroxy R2 is hydrogen, lower alkyl, phenyl, halophenyl or phenyl-lower alkyl, R3 and Ri, hydrogen or lower alkyl, R5 is alkoxycarbonyl or Hydroxyniederalkoxycarbonyl and R is amino or Mononiederalkylamino, wherein A is unsubstituted or substituted by lower alkyl α, ω-alkylene with 1 to 3 carbon atoms or a bond and B means methylene or a bond, with the proviso that A is different from a bond when B is a bond, or produces a pharmaceutically acceptable salt thereof. 37. The method according to any one of claims 1-31, characterized in that compounds of the formula I in which Ri is hydrogen, alkyl having up to and with 12 C atoms or hydroxyl, R ₂ is hydrogen, lower alkyl or halophenyl, R ₃ is hydrogen or halophenyl, R 1 is hydrogen, R _{5 is} carboxy and R 6 is amino, where A is α, ω-alkylene having 1 to 3 carbon atoms or a bond and B is methylene or a bond, with the proviso that A is different from a bond, if B is a bond, or a pharmaceutically usable salt thereof. 38. The method according to any one of claims 3, 6, 8, 10, 14, 17, 20, 23, and 28, characterized gekennzeich.net that compounds of formula I, wherein Ri is hydrogen, alkyl with bis and with 12 C R2 is hydrogen, lower alkyl or halophenyl, R3 is hydrogen or halophenyl, Ri, is hydrogen, R5 is lower alkoxycarbonyl or Hydroxyniederalkoxycarbonyl and R6 is amino or Mono-lower alkylamino, A is α, ω-alkylene having 1 to 3 carbon atoms or B is a bond and B is methylene or a bond, with the proviso that A is different from a bond when B is a bond or a pharmaceutically acceptable salt thereof. 39. The method according to any one of claims 1-29, characterized in that compounds of formula I, wherein Ri is hydrogen, lower alkyl or hydroxy, R _{2 is} hydrogen or lower alkyl, R3 and Rt, are hydrogen, R5 is carboxy or Niedeialk ^ xycarbonyl and R6 is amino, wherein A is α, ω-alkylene having 1 to 3 carbon atoms, B is a bond, or a pharmaceutically acceptable salt thereof sι. 40. The method according to any one of claims 3, 6, 8, 10, IA, 17, 20, 23, 25 and 28, characterized in aass compounds of formula I, wherein Ri is hydrogen, lower alkyl or hydroxy, R _{2 is} hydrogen or lower alkyl, R3 and Ri, are hydrogen, R5 is lower alkoxycarbonyl and R6 is amino, wherein A is α, ω-alkylene having 1 to 3 carbon atoms, B is a bond, or produces a pharmaceutically acceptable salt thereof. 41. The method according to any one of claims 1-31, characterized in that one of compounds of formula I, wherein Ri is hydroxy, R _{2 is} hydrogen or lower alkyl, R ₃ and Ri _{1 is} hydrogen, R 5 is lower alkoxycarbonyl or carboxy, R7 is amino, A is methylene and B is a bond, or produces a pharmaceutically acceptable salt thereof. .42. Process according to one of Claims 3, 6, 8, 10, 14, 17, 20, 23, 25, 28 and 31, characterized in that compounds of the formula I in which R 1 is hydroxy, R _{2 is} hydrogen or lower alkyl, R3 and Ri are hydrogen, R5 is lower alkoxycarbonyl or carboxy, R7 is amino, A is methylene and B is a bond, or a pharmaceutically acceptable salt thereof is prepared. 43. The method according to any one of claims 1, 2, 4, 5, 7, 9, 11-13, 15, 16, 18, 19, 21, 22, 24, 26 and 27 characterized in that one E-2-amino 4-methyl-5-phosphono-3-pentenoic acid ethyl ester or a pharmaceutically acceptable salt thereof. -A- 44. The method according to any one of claims 3, 6, 8, 10, 14, 17, 20, 23, 25 and 28, characterized in that E - ^ - amino - ^ - methyl-S-phosphono-3-pentenoic acid ethyl ester or a pharmaceutically acceptable salt thereof. 45. Verfahrun genäse one of claims 1, 2, 4, 5, 7, 9, 11-13, 15, 16, 18, 19, 21, 22, 24, 2 ', 2Ί and 30, characterized ge of marking et that E-2-amino-4-methyl-5-phosphono-3-pentenoic acid or a pharmaceutically acceptable salt thereof is prepared. 46. The method according to claim 31, characterized in that one prepares E-2-amino-4-methyl-5-phosphono-3-pentenoic acid or a pharmaceutically acceptable salt thereof. 47. The method according to any one of claims 1, 2, 4, 5, 7, 9, 11-13, 15, 16, 18, 19, 21, 22, 24, 26 and 27, characterized in that one E-2 Amino-4-methyl-5-phosphono-3-pentenoic acid methyl ester or a pharmaceutically acceptable salt thereof. 48. The method according to any one of claims 1, 2, 4, 5, 7, 9, 11-13, 15, 16, 18, 19, 21, 22, 24, 26 and 27, characterized in that one E-2 Amino-4-methyl-5-phosphono-3-pentenoic acid n-propyl ester or a pharmaceutically acceptable salt thereof. 49. The method according to any one of claims 1, 2, 4, 5, 7, 9, 11-13, 15, 16, 18, 19, 21, 22, 24, 26 and 27, characterized in that one E-2 • amino-4-methyl-5-phosphono-3-pentenoic acid n-butyl ester or a pharmaceutically acceptable salt thereof. 50. The method according to any one of claims 1, 2, 4, 5, 7, 9, 11-13, 15, 16, 18, 19, 21, 22, 24, 26 and 27, characterized in that one E-2 Amino-4-methyl-5-phosphono-3-pentenoic acid iso-butyl ester or a pharmaceutically acceptable salt thereof. 51. The method according to any one of claims 1, 2, 4, 5, 7, 9, 11-13, 15, 16, 18, 19, 21, 22, 24, 26 and 27, characterized in that one E-2 Amino-4-methyl-5-phosphono-3-pentenoic acid n-pentyl ester or a pharmaceutically acceptable salt thereof. 52. The method according to one of claims 1, 2, 4, 5, 7, 9, 11-'3, 15, 16, 18, 19, 21, 22, 24, 26 and 27, characterized in that E-2 Amino-4-methyl-5-phosphono-3-pentenoic acid n-hexyl ester or a pharmaceutically acceptable salt thereof. 53. The method according to any one of claims 3, 6, 8, 10, 14, 17, 20, 23, 25 and 28, characterized in that one E-2-amino-4-methyl-5-phosphono-3-pentensä ' uremethyl ester or a pharmaceutically acceptable salt thereof. 54. Method according to one of claims 3, 6, 8, 10, 14, 17, 20, 23, 25 and 28, characterized in that E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-propyl ester or a pharmaceutically acceptable salt
of it manufactures. 55. The method according to any one of claims 3, 6, 8, 10, 14, 17, 20, 23, 25 and 28, characterized in that E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-butyl ester or a pharmaceutically acceptable salt
of it manufactures. 56. Process according to one of claims 3, 6, 8, 10, 14, 17, 20, 23, 25 and 28, characterized in that E-2-amino-4-methyl-5-phosphono-3-pentenoic acid iso-butyl ester or a pharmaceutically acceptable salt
of it manufactures. 57. A process according to any one of claims 3, 6, 8, 10, 14, 17, 20, 23, 25 and 28, characterized geke nnzeichne t that one E-2-amino-4-methyl-5-phosphono-3- pentenoic acid n-pentyl ester or a pharmaceutically acceptable salt
of it manufactures. - γί - 58. The method according to any one of claims 3, 6, 8, 10, 14, 17, 20, 23, 25 and 28, characterized in that E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-hexyl ester or a pharmaceutically acceptable salt thereof. 59. Varfahren according to claim 1 for the preparation of E-2-amino-4-phosphonomethyl-3,6-heptadienoic acid and its pharmaceutically acceptable salts, characterized in that E - ^ - formylamino-A-diethylphosphonomethyl-3,6-heptadiensäuremethylester in Dichlormethi.n reacted with trimethyliodosilane and treated the primary product with hydrochloric acid. ^. A process according to any one of claims 1-59, characterized in that one prepares that enantiomer in which the carbon atom carrying the amino group R6 possesses R-configuration. 61. The method according to any one of claims 1, 2, 4, 5, 7, 9, 11-13, 15, 16, 18, 19, 21, 22, 24, 26, 27 and 29-31, characterized in that (2R) -E-2-amino-4-methyl-5-phosphono-3-pentenoic acid or a pharmaceutically acceptable salt thereof. 62. The method according to claim 31, characterized in that one produces (2R) -E-2-amino-4-methyl-5-phosphono-3-pentenoic acid or a pharmaceutically acceptable salt thereof. 63. The method according to any one of claims 1, 2, 4, 5, 7, 9, 11-13, 15, 16, 18, 19, 21, 22, 24, 26, 27 and 29, characterized in that (2R ) -E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester or a pharmaceutically acceptable salt thereof. 64. ^ experience according to one of claims 3, 6, 8, 10, 14, 17, 20, 23, 25, and 28, characterized in that (2R) -E-2-amino-4-methyl-5- phosphono-3-pentenoic acid ethyl ester or a pharmaceutically acceptable salt thereof. / I _n -JS- 65. The method according to any one of claims 1, 2, 4, 5, 7, 9, 11-13, 15, 16, 18, 19, 21, 22, 24, 26, 27 and 29-31, characterized in that (2R) -E-2-amino-4-methyl-7-phosphono-3-heptenoic acid or a pharmaceutically acceptable salt thereof.