DD282017A5 - METHOD OF PREPARATION OF SUBSTITUTED 3-PHOSPHONYL-2-AMINOCARBONE-SAE DERIVATIVES - Google Patents

Abstract

The invention relates to a preparation process for substituted 3-phosphonyl-2-aminocarbonsaeurederivate of the general formula (R1O) 2OCR2R3CR4O {3-phosphonyl-2-aminocarbonsaeurederivate; Phosphorigsaeuredialkylester; Phosphorigsaeurediarylester; Phosphorigsaeuredisilylester; Phosphorigsaeuredialkylsilylester; * *}

Description

For this 1 page formulas

Field of application of the invention

The invention relates to a process for the preparation of substituted S-phosphonyl-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 acids, a number of basic ancestors have been developed, for which summary reports are available (D.Redmore, Topics in Phosphorus Chemistry 3,1976,515, L. Maier, Phosphorus and Sulfur 14 [1983] 295, VPKukhar, V. Solodenko, Usp. Chim. 1987, 1504).

Synthetic access to phosphonyl aminocarboxylic acids is relatively difficult and involves PC / CN bond formation in several steps and often the use of amino-protecting groups (DE 3312165, E.E. Aboujaoude et al., Phosphorus and Sulfur 34 [1987] 93; N. Minowa u. a. Tetrahedr. Lett. 24,1983,2391). S-phosphonyl-S-aminocarboxylic acids are i.a. P-substituted β-lactams (M.M. Campbell et al., Tetrahedron 38 [1982] 2513) or via reactions of acetaminomethylenemalonic acid esters with dialkyl phosphites (J.Olyeksysyn et al., Monatsh. Chem., 113 (1982) 59) in multistage reactions. Especially for 3-phosphonyl-2-aminocarboxylic acid derivatives, the reaction of 2-acetaminoacrylic acid with trialkyl phosphites is described at higher temperatures (J.R. Chambers et al., J. Org. Chem., 29, 19664, 832). For the same type of compound arrive in elaborate synthesis Mitkilyuk u.a. (Zh., Obsc., Khim. 57 [119] 1987, 305). In all 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 z.i, which can be used as intermediates in further syntheses or as compounds themselves.

Explanation of the essence of the invention

It is an object of the invention to develop a favorable synthesis route to substituted 3-phosphonyl-2-aminocarboxylic acid derivatives of the general formula I on the basis of readily available starting compound,

·). _t \ Il

Il ·). _t \

in the for R ¹ n- or iso-alkyl or cycloalkyl radicals having 1 to 8 carbon atoms, aryl, substituted alkyl or

Aryl radicals, hydrogen or triorganosilyl radicals, for R ² , R ³ , R ^{4, the} same radicals as for R '

R ^{5 is} hydrogen, variously substituted benzoyl or acyl groups,

for R ⁸ hydroxy, alkoxy or Aroxygruppen, 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, wherein for R ~ and R ³ radicals of the general formula I and R ⁷ Phenyl or alkyl groups, which may also be substituted, are reacted with metal derivatives of dialkyl, diaryl or disilylphesphites with residues R ¹ in suitable solvents and the resulting products by interaction with organohalosilanes in the same reaction vessel in 4-phosphonylalkyl-5-siioxyoxazolderivate which are also accessible by the action of alkylsilyl phosphites on oaz oxazoline (A-2) -5-ones in suitable solvents at higher temperatures (Scheme 1). The 4-phosphonylalkyl-5-siloxyoxazolderivate be further with agents R ⁸ H directly or in the presence of ρ otic solvents ozw. with R * -Halogen and then R ⁸ H converted to compounds of general formula I (Scheme 2 and 3).

Suitable solvents for the preparation of the compounds of general formula I are aliphatic or cycloaliphatic ethers, tster, excess phosphite and mixtures of aliphatic or aromatic hydrocarbons with ethers or esters. The reaction is conveniently carried out at -3O ⁰ C to 100 ⁰ C, preferably at 20 ⁰ C to 60 ⁰ C, wherein the reaction time is 0.5 to 8 hours. The reaction of 4-phosphonylalkyl-5-siloxyoxazoiderivaten with R ⁸ H or R ⁴ halo can be carried out in the same solvent or after its removal, in water, alcohols, amines, carboxylic acids, aliphatic or aromatic solvents, which are to be chosen appropriately, that a simple isolation of the title compounds is possible

 The invention is explained below with reference to 5 examples.

example 1

14.0 g (0.05 mol) of 2-phenyl-4- (4-methoxybenzylidene) oxazoline (A-2) -5-one are added in THF with 11,0g (0.06 mol) of dimethyltrimethylsilyl phosphite and the mixture to the Discoloration heated to reflux. After the reaction mixture has cooled, 20 ml of methanol are added and the mixture is stirred at room temperature for 2 hours. Subsequently, the solvents are removed and the residue extracted with ether. After concentrating the organic phase and adding benzene, methyl 3-dimethylphofphonyl-3- (4-methoxyphenyl) -2-benzoylaminopropionate precipitates almost reagent-free. It can be recrystallized from ether / benzene. Yield 12.4 g (59% of theory); Mp 149-151 "C, ³¹ P: 26.2 ppm (benzene / MeOH); Analysis C 56.55% (calc. 56.89), H 5.721 (5.92), N 3.20 (3, 32)

Example 2

16.6 g (0.12 mol) of diethyl phosphite are converted into THF with excess sodium in the sodium salt. This THF ?. ³ S is added dropwise to a slurry of 25.0 g (0.1 mol) of 2-phenyl-4-benzylideno-oxazoline (A-2) -5-one in THF. After 1 to 2 hours, the reaction is complete, recognizable by the observed color changes. 0.12 mol of trimethylchlorosilane are added to the reaction mixture, followed by the addition of 30 ml of ethanol. After 3 hours at room temperature, the solvents are removed and the residue is taken up with ether and separated from the NaCl. After concentration of the solution crystallized in the cold S-diethylphosphonyl-S-phenyl ^ -benzoylaminopropionsäureethylester. Yield 32.4 g (75% of theory); . Mp 79-85 ⁰ C ³¹ P: 23,6ppm; Analysis C 60.53% (60.86), H 0.53 (6.5 '), N 3.52 (3.28)

Example 3

3.3 g (0.02 mol) of diisopropyl phosphite are converted into the sodium salt analogously to Example 2 and reacted with 4.8 g (0.02 mol) of 2-phenyl-4-cyclohexylidene-oxazoline (A-2) -5-one , After 2 hours at room temperature, 0.02 mol of trimethylchlorosilane and, after a further hour, 100 ml of water are added. This separates a tough oil. This is taken up with methanol / sodium methoxide, mixed with water and filtered from the small residue. After acidification of the aqueous solution, S-diisopropyl-phosphonyl-S-pentamethylene ^ -benzoylaminopropionic acid separates as an oil, which is brought to crystallization with ether. Auqut 6.6g (78% of Th.), Γρ. 158-161 ° C, ³¹ P: 29.15ppm (benzene); Analysis C 58.07% (59.28); H 7.55 (7.58), N 3.11 (3.29)

Example 4

4.2g (0.025 mol) of diisopropyl phosphite and 5.6g (0.02 mol) of 2-phenyl-4- (4-methoxybenzylidene) oxazoline (A-2) -5-one were reacted in THF and subsequently reacted with 0.025 mol of trimethylchlorosilane according to Example 2 to 4- (phosphonyl-4-methoxyphenylmethyl) -5-siloxyoxazole. After 30 minutes, this is mixed with excess dissolved in ethanol ammonia. After 2 hours, all volatiles are distilled off in vacuo and the residue taken up in ether. After standing overnight, 3-diisopropylphosphonyl-3- (4-methoxyphenyl) -2-benzoylaminopropionic acid amide precipitates. Yield 5.4 g (58% of theory); . Mp 140-142 ⁰ C ³¹ P: 24.1 ppm; Analysis C 58.87% (59.73), H 6.68 (6.76), N 5.87 (6.06)

Example 5

6.9 g (0.05 mol of diethyl phosphite, 13.9 g (0.05 mol) of 2-phenyl-4- (4-methoxybonzylidene) oxazoline (A-2) -5-one and 0.06 mol of trimethylchlorosilane are prepared according to Example 2 After distilling off the solvent in vacuo, the residue is taken up in Ethe ^r and separated from the NaCl formed by addition of pentane to the concentrated solution of 2-Phenvl-4- (diethylphosphonyl-4-methoxypheny! methyl) -5-siloxyoxazol as a tough The oil was eliminated and the residue was removed in vacuo, giving a yield of 21.1 g (92% of theory), ³¹ P: 22.9 ppm, ¹ H: 0.2 ppm (Me ₃ Si), 1.0 (t), 3.9 (m) (POEO, 3.4 (s) (CH ₃ O), ΛΑ (d, 25.7Hz) (PCH); Analysis C 62.18% (62.73), H 6.83 ( 7.02), N 2.93 (3.05)

-V-

(R ¹ O) ₂ P-CR ² R ³ -CR ^A -CR ⁶

NHR Formula I

RS

² Vf

-I *

(RiO) ₂ PCrM

R ⁷ \ (RiO) ₂ POSiR ^

0 (R ¹ O) ₉ P-

Ν <Ν / 0

OM

NyO R ⁷

Scheme 1

0 (R ¹ 0) oP-CR ² r3. / OSiRl

M'NyO

η R ⁶ H 0 K

(R ¹ O) ₂ P-CR ² r ³ -CH-CR ⁶

NHR ⁵

Scheme 2

iR ^

(R ¹ O) ₂ PCR ² R ³ . / OSiR

2.RÖH

T ₇ R ⁷

_(R 1 ₀₎ p_CR -CR ² R ^{3 Z} '-CR ⁶ ^ I

NHR ⁵

Scheme 3

Claims (4)

1. Production process for substituted 3-phosphonyl-2-aminocarboxylic acid derivatives of the general formula I ₁ "ΰ ;: ^Λ ί -ei '-ζ-'Λ • ''. 5 worn for R ¹ η- or iso-alkyl or cycloalkyl radicals having 1 to 8 carbon atoms, aryl .. substituted alkyl or aryl radicals, hydrogen or triorganosilyl radicals, for R ² , R ³ , R ^{4 are the} same radicals as for R ¹ R ^{5 is} hydrogen, variously substituted benzoyl or acyl groups for R ⁶ 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-alkylidenoxazoline (A-2) -5-ones having radicals R ² and R ^{3 of} the general formula I and R ^{7 is} phenyl - or alkyl groups which can also be substituted, is reacted with metal derivatives of dialkyl, diaryl or Disilylphosphiten in suitable solvents at temperatures from -30 ⁰ C to +100 ⁰ C and nachfolgendp "reaction with organohalosilanes in the same reaction vessel in 4. Phosphonylalkyl-5-siloxyoxazolderivate be converted, which are also accessible by direct conversion of oxazolin-5-ones with alkylsilyl, arylsilyl or Silylphosphiten, which hereinafter with R ⁶ H or with R ⁴ -halogen and R ⁶ H directly or in the presence reacting protic solvents to compounds of the formula I. 2. The method according to claim 1, characterized in that the 4-phosphonylalkyl-5-siloxyoxazoldeiivate be isolated and used in photoreactions. 3. The method according to claim 1, characterized in that after formation of 4-phosphonylalkyl-5-siloxyoxazolderivate the solvent used is removed and the subsequent reaction with R ⁶ H or R ⁴ -halogen and R ⁶ H is carried out in bulk or in protic solvents , 4. The method according to claim 1 to 3, characterized in that are used as solvents aliphatic or cycloaliphatic ethers, esters, excess phosphite or mixtures of aliphatic or aromatic hydrocarbons with ethers or esters.