FI91961B - Process for producing (S) -ethyl-2-oxo-1-pyrrolidine acetamide - Google Patents

Description

91961

Process for the preparation of (S) -α-ethyl-2-oxo-1-pyrrolidineacetamide - Preparation of (S) -α-ethyl-2-oxo-1-pyrrolidineacetamide

The invention relates to a new process for the preparation of (S) -α-ethyl-2-oxo-1-pyrrolidineacetamide of the formula O- ·

OF

^ c CH, -CH7 '^ / \ / conh2

B

U.S. Patent Nos. 4,696,943 and 4,837,223 to the same applicant describe this compound having the absolute configuration (S) and show that it has specific therapeutic properties that are completely unexpectedly different from those of the racemic form. Due to its properties, the S-enan thiomer is more suitable than the racemic form for the treatment and prevention of aggressions due to hypoxia and anemia of the central nervous system.

The preparation of (S) -α-ethyl-2-oxo-1-pyrrolidineacetamide is: described in the aforementioned U.S. Patent Nos. 4,696,943 and 4,837,223. According to these patents, a compound cannot be obtained directly from a racemic mixture by separation of two enantiomers. It must be prepared in another way, and these U.S. patent publications describe 2 methods for preparing a compound. In the first method, (S) -α-ethyl-2-oxo-1-pyrrolidineacetic acid is reacted stepwise with an alkyl haloformate, preferably ethyl chloroformate, and ammonia. In another method, alkyl (S) -4 - [[2- (aminocarbonyl) propyl] amino] butyrate or (S) -N- [1- (aminocarbonyl) propyl] -4-halobutanamide is cyclized to prepare 91961 2 2 of the compound itself. in the case of (S) -aminobutanamide.

The two methods have the same disadvantage in common. Both require the preparation of a starting material reactant that already has the correct stereochemical configuration. This starting material is obtained by resolution of the corresponding racemic compound, racemic (±) -α-ethyl-2-oxo-1-pyrrolidineacetic acid for the first method, and (±) -2-aminobutanamide for the second method. The necessary pre-separation of the enantiomer of the desired configuration results in a 50% loss of the starting material used from the beginning. Furthermore, given that the recovery of the optical isomer is rarely performed in quantitative yield, the total loss of raw material is well over 50% of the racemic starting material.

A method that would not have this disadvantage while being relatively easy to perform would be highly desirable.

The present invention thus provides a new method which does not have the disadvantage of the previous methods and which, as a result, is more economical. Furthermore, this new method also has the advantage of using a naturally occurring amino acid, L-mentionin or an readily available amide thereof as a starting material.

The process of the invention for the preparation of (S) -Of-ethyl-2-oxo-1-pyrrolidineacetamide comprises the hydrogenation of (S) -α- (methylthio) -ethyl] -2-oxo-1-pyrrolidineacetamide with a desulfurization reagent according to the following reaction equation in accordance with

N N

I -> I

^ c ^ - c CH3SCH2CH £ "\ ch3-ch2" ^ i \ / conh2 / conh2

H H

91961 Desulfurization of 3 (S) -α- [2- (methylthio) ethyl] -2-oxo-1-pyrrolidineacetamide is stereoselective. The reaction is generally carried out in water at a temperature of 50 to 100 ° C with a desulfurization reagent such as NaBH 4 / NiCl 2 • 6H 2 O (RB Boar et al., J. Chem. Soc., Perkin Trans. I (1973), p. 654), Raney nickel W-2, or preferably Raney nickel T1 at normal or elevated pressure (X. Dominiguez et al., J. Org. Chem. 26 (1961), p. 1625).

(S) -α- [2- (methylthio) ethyl] -2-oxo-1-pyrrolidineacetamide, which is the starting material of this process, is a novel compound. It can be prepared by one of the following 2 methods: 1) by reacting (S) -2-amino-4- (methylthio) butanamide hydrochloride with a halobutyl halide of the formula HalCH 2 CH 2 CH 2 COHal, wherein Hal is a halogen atom, preferably a chlorine atom, according to the following reaction equation:

NH2 · HCl I \ = O

I Hal-CH2CH2CH2COHal

I -> I

^ ^ C KOH ^ C

ch3sch2ch2 "/ \ ch3sch2ch ^ / \ / conh2 / conh2

H H

This reaction is usually carried out in an inert solvent, for example dichloromethane, at a temperature of about 0 ° C in the presence of a catalyst such as tetrahydrobutylammonium bromide in the presence of powdered potassium hydroxide.

2) a) by first reacting (S) -2-amino-4- (methylthio) butanamide with a 4-halobutyrate of formula XCH 2 CH 2 CH 2 COOR wherein X is a halogen atom and R is an alkyl radical having 1 to 4 carbon atoms, the following according to the reaction equation: 4 91961 r \ nh2 nh) = 0 I XCH2CH2CH2COOR I /

I -> I OR

CV -C

CH3SCH3CH2 "/ \ CH3SCH2CH2" "/ \ / conh2 / conh2

H H

This reaction is usually carried out by heating for several hours at 80 to 100 ° C in an inert solvent such as toluene in the presence of an acid acceptor such as a tertiary organic base such as triethylamine.

b) then cyclizing the (S) -4 - [[1- (aminocarbonyl) -3- (methylthio) propyl] amino] butyrate obtained in step a) according to the following formula: n.

NH 1 = 0 ^ fc = 0

Y / N

I OR -> I

^ C ^ - c ch3sch2ch2 "'/ \ ch3sch2ch ^' J \: / conh2 / conh2

H H

This cyclization is usually carried out in an inert solvent such as toluene or xylene by heating at a temperature between 100 and 130 ° C for several hours in the presence of a catalyst such as 2-hydroxypyridine.

(S) -2-Amino-4- (methylthio) butanamide, as the free base, can be prepared from L-methionine according to the method described by: E. Sandrin and R.A. Boissonnas; Helv. Acta, 46 (1963), pp. 1637-1669.

Sp. : 50 - 51 ° C. [α] D 20 = -27.7 ° (c = 2, dimethylformamide).

Il 91961 5 (S) -2-Amino-4- (methylthio) butanamide hydrochloride, a known compound, can be prepared from a base by the method described by A. Eberle et. ai .: Helv. Chim. Acta, 61, (1978), pp. 2360-2374.

Sp. : 212 - 215 ° C. [α] = + 26.4 ° (c = 2, dimethylformamide).

The following example is presented to illustrate the invention.

In this example, the optical purity of the final product was confirmed by calorimetric determination of differential enthalpies (C. Fouquey and J. Jacques, Tetrahedron, 23, (1967)).

Example I. Preparation of starting material (S) -α- [2- (methylthio) ethyl] -2-oxo-1-pyrrolidineacetamide 1) 84 g of anhydrous sodium sulfate from 4-halobutyryl halide are added to a suspension of 92.22 g (0, 5 mol) of S-2-amino-4- (methylthio) butanamide in 600 ml of dichloromethane at room temperature. The mixture is then cooled to 0 [deg.] C. and 115 g of ground potassium hydroxide and 8.1 g (0.025 mol) of tetrabutylammonium bromide dissolved in 100 ml of dichloromethane are added to the suspension. A solution of 77.5 g (0.55 mol) of 4-chlorobutyryl chloride in 100 ml of dichloromethane is added dropwise at the same temperature with vigorous stirring. During the addition, the reaction medium is diluted simultaneously with 550 ml of dichloromethane. After stirring for 2 h at 0 ° C, 29 g of powdered potassium hydroxide are added to the mixture. After 4.5 h of the reaction, a further 29 g of powdered potassium hydroxide are added and stirring is continued for 1 h at 0 ° C. The reaction mixture is then filtered through Hyflocel, and the filtrate is evaporated under reduced pressure. The residue is purified by chromatography on silica gel (eluent: dichloromethane / methanol / ammonia 95.5: 4.5: 0.2, by volume). 66 g of (S) -or- [2- (methylthio) ethyl] -2-oxo-1-91 * 61 6 pyrrolidineacetamide are obtained in the form of a white powder, [α] D = -39.1 ° (c = 1, methanol)

Yield: 61%

Elemental analysis: C 9 H 18 Cl 2 S%: Calculated: C 50.00; H 7.41; N 12.96 Found: 50.15; 7.80 12.94 2) Alkyl 4-halobutyrate a) Ethyl (S) -4 - [[1- (aminocarbonyl) -3- (methylthio) propyl] amino] butyrate 10.57 ml (76 mmol) triamine is added to a suspension of 10 g (68 mmol) of (S) -2-amino-4- (methylthio) butamide in 100 ml of toluene. The mixture is heated to 80-85 ° C with vigorous stirring, and 13.26 g (68 mmol) of ethyl 4-bromobutyrate are added dropwise. This temperature is maintained for 8 h. The solvent is then evaporated off under reduced pressure and the residue is taken up in 100 ml of dichloromethane. The mixture is refluxed for 30 min and filtered hot. The filtrate is evaporated to dryness and the residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia 10: 0.1: 0.1, by volume). 6.2 g of ethyl (S) -4 - [[1- (aminocarbonyl) -4- (methylthio) propyl] amino] butyrate are thus obtained.

[α] H 6 = -14.1 ° (c = 1, methanol) * Yield: 35% This intermediate is used as such without further purification to carry out the final cyclization.

b) 0.6 g (2.29 mmol) of the crude product obtained in a) and »21.3 mg (0.225 mmol) of 2-hydroxypyridine are mixed in 1.15 ml of p-xylene. The mixture is heated at 130 ° C under nitrogen for 4.5 h. It is then cooled and stirred for 30 min at room temperature. The precipitate formed is filtered off and recrystallized from ethyl acetate. 0.18 g of (S) -α- [2- (methylthio) ethyl] -2-oxo-1-pyrrolidineacetamide is obtained.

n 91961 7 [α] π5 = -36.5 ° (c = 1, methanol)

Yield: 36%

Elemental analysis: C 9 H 16 N 2 O 2 S%: Calculated: C 50.00; H 7.41; N 12.96 Found: 49.88; 7.49 12.68 II. Preparation of (S) -α-ethyl-2-oxo-1-pyrrolidineacetamide 50 g of Raney nickel T-1 (X.A. Bominiguez et al., J. Org. Chem.

26, (1961), p. 1625), 386 ml of water and 7 g (0.0324 mol) of (S) -α- [2- (methylthio) ethyl] -2-oxo-1-pyrrolidineacetamide are added successively in 1-1 in a three-necked round-bottomed flask. The mixture is heated to 75 ° C and stirred at this temperature for 1 h.

It is filtered and the water is evaporated off under reduced pressure. The residue (5.3 g) is recrystallized from 60 ml of ethyl acetate. 3.86 g of (S) -α-ethyl-2-oxo-1-pyrrolidineacetamide are obtained.

M.p .: 112-115 ° C. [α] D = -90 ° (c = 1, acetone)

Yield: 69%

Elemental analysis: C 8 H 14 N 2 O 2%: Calculated: C 56.45; H 8.29; N 16.46 Found: 56.30; 8.42 16.18 «

Claims (4)

1. A process for the preparation of (S) -Q1-ethyl-2-oxo-1-pyrrolidinacetamide, characterized in that (S) hydrogenated by desulphurizing reagent. Process according to claim 1, characterized in that the desulphurizing reagent is Raney nickel T-1. 3. A process according to claim 1 or 2, characterized in that the hydrogenolysis is carried out in water at a temperature between 50 and 100 ° C. 4. (S) -a- [2- (methylthio) ethyl] -2-oxo-1-pyrrolidine acetamide.