DD282015A5 - METHOD OF PREPARATION OF SUBSTITUTED 3-PHOSPHINYL-2-AMINOCARBONE-SAE DERIVATIVES - Google Patents

Abstract

The invention relates to a preparation process for substituted 3-phosphinyl-2-aminocarbonsaeurederivate of the general formula R1 (R2O) O {3-phosphinyl-2-aminocarbonsaeurederivate; Phosphonous alkylsilyl ester; Phosphonous arylsilylester; Phosphonous disilylester; Phosphonigsaeurealkylester; * *}

Description

For this 1 page formulas

Field of application of the invention

The invention relates to a process for the preparation of substituted S-phosphinyl ^ -aminocarboxylic acids and their derivatives, which can be used as intermediates in syntheses or used directly as substances.

Characteristic of the known state of the art

For the synthesis of aminophosphonic and aminophosphinic acids, a variety of methods have been developed, for which summary reports are available (D.Redmore, Topics in Phosphorus Chemistry 8, 1976, 515, L. Maier, Phosphorus and Sulfur 14,1983, 295, VPKukhar , Usp.Chim. 1987, 1504).

Synthetic access to phosphinyl-aminocarboxylic acids is comparatively difficult and involves the introduction of the amino function, which often occurs only after removal of protective groups (E.Gruszecka et al., Pol.J.Chem.53, 1979, 3227; H.Gross et al. J.prokt.Chem.318, 1976, 157; EEAboujaoudeu et al

Phosphorus and Sulfur 34, 987.93; DE 3,312,165).

3-phosphinyl-3-aminocarboxylic acids are u.a. by ring opening P-substituted β-lactams (N ".M. Campbell et al., Tetrahedron 38, 1982, 2513) or by reaction of acetaminomethylenemalonic acid ester with o-alkyl alkyl phosphonites (J. Oleksyszyn et al.

Monatsh.Chem.113,1982,59) in multistep syntheses.

3-phosphinyl-2-aminocarboxylic acids are accessible by reaction of 2-aceto-aminoacrylic acid with o-alkyl-alkylphosphonites at high temperatures (M.Soroka et al., Rocz. Chem. 50, 1976, 661). In these cases, substitution on the carbon chain is not possible.

Object of the invention

The aim of the invention is to provide a simple, low-fume access to variously substituted phosphorus-containing aminocarboxylic acids and their derivatives, which can be used as intermediates in further syntheses or as compounds themselves.

Explanation of the essence of the invention

The object of the invention is to develop a favorable synthesis route to substituted S-phosphinyl-S-aminocarboxylic acid derivatives of the general formula I on the basis of easily accessible starting compounds,

, 1 li, L; "l" In Il-i.I. -Will I.

IjIII ₁

in the for

R 'n- or iso-alkyl or cycloalkyl radicals having 1 to 8 carbon atoms, aryl, substituted alkyl or aryl radicals or hydrogen,

R ² radicals such as R 'or triorganosilyl radicals, R ³ , R ⁴ , R ⁵ radicals such as R ¹

R ^{e are} hydrogen, variously substituted benzoyl or acyl groups, R ^{7 are} hydroxy, alkoxy or aroxy groups which may also be substituted, amino or substituted

Amino groups, N-linked amino acids or peptides can stand.

According to the invention the object is achieved in that 4-arylidenoxazoline (A-2) -5-one or 4-Alkylidenoxazolin (A-2) -5-one, where R ³ and R ⁴ radicals of the general formula I and R ⁸ Phenyl or alkyl groups which may also be substituted, are reacted with alkyl or arylphosphonous alkylsilyl esters, -arylsilylestern or -disilylestern in suitable solvents in 4-phosphinylalkyl-5-siloxyoxazolderivate, which are also by the action of metal derivatives of alkyl or Arylphosphonigsäurealkylestern or -aiylestern on oa oxazoline (A-2) -5-one and subsequent reaction with organohalosilanes in the same reaction vessel are accessible (Scheme 1). The formed 4-phosphinylalkyl-5-siloxyoxazolderivato be with agents R ⁷ H directly or in the presence of protic solvents or with R ⁵ -halogen and then R ⁷ H to compounds of general formula I urngesetzt (Scheme 2 and 3).

Suitable solvents for the preparation of the compounds of general formula I are aliphatic or cycloaliphatic esters, esters, excess phosphonous esters and mixtures of aliphatic or aromatic hydrocarbons with ethers or esters. The reaction is conveniently carried out at temperatures of -30 ° C to 100 ⁰ C, preferably at 2O ⁰ C to 6O ⁰ C, wherein the reaction time is 0.6 to 8 hours. The reactions of the 4-phosphinyl-5-siloxyoxazolderivate with R ⁷ H or R ⁵ -halogen and subsequently R ⁷ H can be carried out in the same solvent or after its removal in water, alcohols, amines, carboxylic acids, aliphatic or aromatic solvents which suitably be chosen so that a simple isolation of the title compounds is possible.

embodiments

The invention is explained below with 4 examples.

example 1

5.6 g (0.02 mol) of 2-phenyl-4-methoxybenzylidenoxazoline (Δ-2) -5-o in we THF with 4.9 g (0.02 mol) phenylphosphonous ethyl trimethylsilylester within 3 hours at 50 ° C. reacted. Thereafter, 10 ml of water are added and stirred for 3 hours at room temperature. After distilling off the solvent in vacuo, the residue is extracted with ether, after from the ethereal solution, after concentration and addition of pentene 3-phenyl-O-ethyl-phosphinyl-3- (4-methoxphenyl) -2-benzylaminopropionic acid as an oil under the solvent slowly crystallized. Yield 7.6 g (81% of theory), mp 161-164 ⁰ C, ³¹ P: 39.2;. 40.2ppm (1: 1); Analysis C63.38% C (calc.64.22), H5.45 (5.61), N2.85 (3.00).

Example 2

6.9 g (0.05 mol) of butylphosphonous acid ethyl ester are added to the sodium derivative with excess sodium in THF, and 11.1 g (0.05 mol) of 2-phenyl-4-benzylidenoxazoline (Ai ^> ) -5 -one in THF at room temperature. After 6 hours, 0.05 mol of trimethylchlorosilane are added and the mixture is stirred for a further hour. After addition of 10 ml of methanol, the mixture is warmed to 5O ⁰ C, then the solvents are removed in vacuo and the residue extracted with fcther. After adding pentane, 3-butyl-0-ethylphosphinyl-3-phenyl-2-benzoylaminopropionic acid methyl ester precipitates out as a crystalline solid. Yield 6.8 g (35% D.Th.), mp 125-13O ⁰ C, analysis C 63.04% (64.02), H 6.86 (7.01), N 3.27 (3.25) ,

Example 3

2.4 g (0.01 mol) of 2-Pheryl-4-cyclohexylidene-oxazoline (A-2) -5-on and 3.0 g (0,012MMoI) Phosphonigsäureethyl trimethylsilyl be kept 5 hours at 4O ⁰ C in THF. After distilling off the solvent, the residue is taken up in ether, filtered from insolubles, the solution concentrated and pentane 2-phenyl-4- (phenyl-0-ethylphosphinyl-phenylmethyl) -5-trimethylsiloxyox, zol deposited as a viscous oil. Yield 4.2 g (37% of theory), ³¹ P: 44.8 ppm; Analysis C6ϊ, 57% (64.13), H7.28 (7.04); N 2.63 (2, J /).

Example 4

0.025 mol of 2-phenyl-4-benzylidene-oxazoline (A-2) -5-one and 0.028 mol Methylphosphonigsa'uroethyl-silyl ester are reacted analogously to Example 1. The reaction mixture is concentrated and 20 ml of abs are added. Acetic acid and 0.25 moles of glycine. The mixture is garührt 4 hours at 100 ⁰ C. The volatiles are removed in vacuo, the residue washed several times with ether and water and water / acetone. There remains 3-methyl-0-ethylphosphinyl-3-phenyl-2-benzoylaminopropionyiglycine. Yield 6.0 g (61% d.Th.), M.p. 198-205 ⁰ C, ³¹ P: bO, 95;. 51.8ppm (6: 3); Analysis C was 56.82% (58.33), H5.71 (5.83), N6.35 (6.48).

NHR6 ü i $

Formula I

R ^

R ¹ (R2o) PO "M

P-CR ³ R ^A

NYO

OM

Scheme 1

OSiR

n R? H

/ P-CR ³ R 1 -CH-COR ⁷ I _c NHR ⁶

R ¹

Scheme 2

OSiR R ² O

2.R7H

j NHR ⁶

Scheme 3

Claims (4)

1. Production process for substituted S-phosphinyl ^ -amino-carboxylic acid derivatives of the general formula I. R ¹ (R ² O) P-CR ³ R ⁴ -CR ^:> -COR ⁷ I ONLY ⁶ in which R ^{1 is} n- or iso-AlKyl- or cycloalkyl radicals having 1 to 8 carbon atoms, aryl, substituted alkyl or aryl radicals or hydrogen, R ² radicals, such as R ¹ or triorganosilyl radicals,
R ³ , R ⁴ , R ⁵ radicals such as R ¹ R ^{6 is} hydrogen, variously substituted benzoyl or acyl groups, R ^{7 is} hydroxyl, alkoxy or aroxy groups, which may also be substituted, amino or substituted amino groups, N-linked amino acids or peptides, characterized in that 4-arylidene or 4-Alkylidenoxazolin (A-2) -5-one with residues R ³ and R ^{4 of} the general formula I and R ^{8 is} phenyl - or alkyl groups which can also be substituted with alkyl or aryl phosphonous alkylsilylestern, or -arylsilylestern-disilylestern in suitable solvents at temperatures from -30 ⁰ C to 100 ⁰ C within 0.5 to 8 hours in the 4- Phosphinylalkyl-5-siloxyoxazolderivate be transferred, which are also accessible by the action of metal derivatives of alkyl or Arylphosphonigsäurealkylestern or aryl esters on the oxazoline (A-2) -5-one and subsequent reaction with Organohalogensilanen hereinafter with R ⁷ H or with R ⁵ -halogen and R ⁷ H react directly or in the presence of protic solvents to give compounds of formula I. 2. A method according to claim 1, characterized in that the 4-phosphinylalkyl-5-siloxyoxazolderivate be isolated and used in subsequent reactions. 3. The method according to claim!, Characterized in that after formation of the 3-phosphinylalkyl-5-siloxyoxazolderivate the solvent used and the subsequent reaction with R ⁷ H or R ⁵ halogen and R ⁷ H in substance or carried out in protic solvents becomes. 4. The method according to claim 1 to 3, characterized in that are used as solvents aliphatic or cycloaliphatic ethers, esters, excess phosphonite or mixtures of aliphatic or aromatic hydrocarbons with ethers or esters.