CS250250B2 - Method of n-acyl-l-proline's derivatives production - Google Patents

Description

R ₁ and R ₂ are as defined above, R ₃ is hydrogen, lower alkyl, phenyl (lower) alkyl, triphenylalkyl (C 1 -C 2) or R ₄ CO in which R ₄ is The compounds of formula VI may also form symmetrical disulfides The mercaptoacylprolines of formula VI have antihypertensive activity and inhibit the enzyme that converts angiotensin I to angiotensin II.

The term "lower alkyl" means straight or branched chain alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl.

This invention relates to the preparation of all possible isomers which exist due to the asymmetry of the carbon atoms carrying the substituents R and R _{t second} Proline has an L configuration.

Two possible methods are known for the preparation of compounds of formula I (NSR Laid-Open Patent No. 27 03 828).

According to a first method, the carboxylic acid of formula IV

Ra Ri O

I I y

X - CH - CH - CH 2 OH (IV) wherein

R _{1 (} R ₂ and X are as above) or a reactive derivative thereof is treated with L-proline of formula II

CO OH (II)

In this process, a very important fact is that proline is soluble in water only, but is not soluble or almost insoluble in organic solvents. Therefore, the reaction of proline with a reactive carboxylic acid derivative of the formula IV, generally with an acid chloride, must be carried out in an aqueous alkaline medium, usually by Schotten-Baumann reactions. The reactive carboxylic acid derivatives of formula IV readily decompose in such an environment. This, however, reduces the yield of the reaction.

In another known process, a carboxylic acid of formula IV or a reactive derivative thereof is reacted with a proline alkyl ester of formula VII

in which

R 4 represents a C 1 -C 4 alkyl group, and the resulting compound of formula VIII

Rz R / J x-ch-ch-c

O

COOR

Fairy in which

R 1, R 2, R 4 and X are as described above, hydrolyzed with trifluoroacetic acid and anisole or alkali to give a compound of formula I.

In this known process, however, the proline ester of formula VII must be synthesized from the L-proline separately by a complicated reaction route. The hydrolysis of the ester (VIII) must also be carried out in a separate reaction step. This results in lower yields and long reaction times.

Compounds of formula I wherein R 1 is methyl, R ₂ is hydrogen and X is halogen are prepared according to the German patent 30 49 273. Thus, proline of formula II is acylated with an acid chloride of formula IX

CH3

X - CH 2 - CH - COCI (iX) wherein

X represents a halogen atom, preferably a chlorine or bromine atom, according to Schotten-Baumann in an aqueous alkaline medium. Acidification of the aqueous solution gives the desired 1- [3-halo- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid as the monohydrate.

An important feature of this process is that the acylation is carried out with a water-sensitive aliphatic acid chloride in an aqueous alkaline medium, resulting in reduced yields.

It has been found that all the disadvantages of the known processes can be overcome by preparing the N-acyl-L-proline derivative of the general formula I from the proline trimethylsilyl ester of the formula III hA1. '

(H) this compound is acylated with a reactive carboxylic acid derivative of formula IV in an inert organic solvent in the presence of an acid binding agent to form a compound of formula V (V)

in which

Rj, _R2 а X are as defined above. This compound is finally hydrolyzed with water.

The L-proline trimethylsilyl ester is prepared by reacting the proline of formula II with trimethylsilyl halide. If desired, the trimethylsilyl ester of L-proline is acylated directly in the reaction mixture in which it was prepared without further separation.

The inert organic solvent may be any organic solvent that does not interfere with the acylation reaction. Preferred are halogenated aliphatic hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, or aromatic hydrocarbons such as benzene, toluene or xylene.

The acid-binding agent used in the acylation reactions is an organic base, preferably a tertiary amine, for example triethylamine or pyridine, or an inorganic base, preferably an alkali metal carbonate such as sodium carbonate or potassium carbonate.

The hydrolysis of the compound of formula (V) is preferably carried out in the same reaction mixture in which the compound is formed without isolating the above compound from the acylation reaction mixture.

According to a particularly preferred embodiment of the invention, the trimethylsilyl ester of L-proline prepared in situ from L-proline and trimethylsilyl chloride is acylated with racemic 3-bromo-2-methylpropionyl chloride or optically active 3-bromo-2-methylpropionyl chloride.

In this way, 1- [3-bromo- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid, i.e. a compound of formula I, in which R @ 1 is obtained, is obtained. R ₂ represents a hydrogen atom and X represents a bromine atom. This compound is a key intermediate in the synthesis of l- [3-mercapto- (2S) -methylpropionyl] -pyrrolidin (2S) -carboxylic acid, i.e. the compound of formula VI, wherein R _(is a methyl group and R ₂ and _R; > represents a hydrogen atom.

According to the process of the invention, the proline ester of formula III need not be prepared separately, but is formed in situ when trimethylsilyl chloride is added to a mixture of L-proline and an inert solvent. The reaction proceeds almost immediately at room temperature. The reaction can be easily controlled by adding trimethylsilyl chloride. During the reaction, the insoluble L-proline dissolves in the form of L-proline trimethylsilyl ester hydrochloride, which can be acylated in an anhydrous medium. Since the reactive carboxylic acid derivatives of formula (IV) are not hydrolyzed in the absence of water, almost theoretical yields are obtained. And since trimethylsilyl carboxylates are immediately hydrolyzed by the addition of water, the compound of formula V formed during acylation can be hydrolyzed by adding water to the reaction mixture. The product of formula I then selectively remains in the organic layer and all impurities including trimethylsilyl alcohol (formed in the hydrolysis) are transferred to the aqueous layer.

The process according to the invention is easy to carry out, in small volume and in a single technological step. No special apparatus is needed.

The invention is further illustrated by the following non-limiting examples.

Example 1

1- [3-Bromo (2S) -methyl-propionyl] -pyrrolidine- (2S) -carboxylic acid monohydrate

12.5 ml (10.8 g, 0.1 mol) of trimethylsilyl chloride are added dropwise to the stirred mixture of 11.5 g (0.1 mol) of proline powder and 80 ml of dichloromethane at room temperature over about five minutes. After addition of trimethylsilyl chloride, the temperature of the reaction mixture spontaneously increased to about 32 ^° C and the L-proline dissolved. The reaction mixture was cooled to 0 ° C, triethylamine (13.75 mL, 10.0 grams, 0.1 mol) was added dropwise at 0-5 ° C, and the temperature of the reaction mixture was lowered to -15 ° C. 11.6 ml (18.5 g, 0.1 mol) of racemic 3-bromo-2-methyl-propionyl chloride are added dropwise over a half hour at -15 to -10 ° C. The cooling was then removed, the temperature of the reaction mixture was allowed to rise to room temperature, and the mixture was stirred at this temperature for one hour. 50 ml of water are added, the phases are separated, the organic solution is extracted with 50 ml of water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. This gives 23.5 g (89.0%) of the honey product, which is a mixture of 1- [3-bromo- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid and 1- [3-bromo- ( 2R) -methylpropionyl] pyrrolidine- (2S) -carboxylic acid.

Some water was added to the product. The mixture is seeded with crystals of the desired 1- [3-bromo-25050]

- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid. On standing, 11.1 g (78.7%) of the title compound melting at 65-69 ° C was obtained.

Example 2

1- [3-Bromo- (2S) -methyl-propionyl] -pyrrolidine- (2S) -carboxylic acid monohydrate Follow the same procedure as in Example 1 except that 80 ml of 1,2-dichloroethane was used instead of dichloromethane. 22.1 g (83.7%) of a honey product which is a mixture of 1- (3-bromo- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid and 1- [3-bromo- (2R)) are obtained. (methylpropionyl) pyrrolidine- (2S) -carboxylic acid The mixture crystallizes by adding some water.

The crystals are filtered off and dried. 10.3 g (73%) of 1- [3-bromo-

(2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid, m.p. 64-69 ° C.

Example 3

1- [3-Bromo- (2S) -methyl-propionyl] -pyrrolidine- [2S] -carboxylic acid monohydrate Follow the same procedure as in Example 1 except that 80 ml of chloroform was used instead of dichloromethane. 23.0 g (87.1%) of a honey-like residue are obtained, which is a mixture of 1- [3-bromo- (2S) -methyl-propionyl] -pyrrolidine- (2S) -carboxylic acid and 1-

- [3-bromo (2R) -methyl-propionyl] -pyrrolidine- (2S) -carboxylic acid.

Add some water. The mixture is seeded with crystals of the desired isomer. On standing, 10.8 g (76.6%) of 1- [3-bromo-

- (2S) -methylpropionyl-pyrrolidine- (2S) -carboxylic acid.

Melting point: 64-68 ° C

Example 4

1- [3-Bromo (2S) -methyl-propionyl] -pyrrolidine- (2S) -carboxylic acid monohydrate

The procedure was as in Example 1 except that benzene was used instead of dichloromethane. The acylation is carried out at 0-5 ° C, the organic phase is extracted with water, then 100 ml of 1N sodium hydroxide, and the aqueous alkaline solution is acidified with concentrated hydrochloric acid to give 9.8 g (69.5%) of 1- [monohydrate]. 3-Bromo- (2S) -methyl-propionyl] -pyrrolidine- (2S) -carboxylic acid.

Melting point: 65-69 ° C.

Example 5

1- [3-Bromo- (2S) -methyl-propionyl] -pyrrolidine- (2S) -carboxylic acid monohydrate

The procedure was as in Example 1 except that 80 ml of toluene was used instead of dichloromethane. The acylation is carried out at a temperature of -5 to 0 ° C. 21.3 g (80.7%) of a honey-like residue are obtained, which is a mixture of 1- [3-bromo- (2S) -methyl-propionyl] -pyrrolidine- (2S (-carboxylic acid and 1- [3-bromo- (2R)]). 1-Methylpropionyl] -pyrrolidine- (2S) -carboxylic acid A little water is added The mixture is seeded with crystals of the desired isomer The product crystallizes on standing, filtered and dried to give 10.0 g (70.9%) of the title compound. : 64-69 ° C.

Example 6

1- [3-Bromo- (2S) -methyl-propionyl] -pyrrolidine- (2S) -carboxylic acid monohydrate

The procedure was as in Example 1 except that 7.91 g (0.1 mol) of pyridine was used instead of triethylamine to give 23.1 g (87.5%) of a honey-like residue which is a mixture of 1- [3-Bromo- (2S) -methyl-propionyl] -pyrrolidine- (2S) -carboxylic acid and 1- [3-bromo- (2R) -methyl-propionyl] -pyrrolidine- (2S) -carboxylic acid. The product crystallizes on standing to give 11.0 g (78.0%) of the title compound, m.p. 64-69 ° C.

Example 7

1- [3-Bromo- (2S) -methyl-propionyl] -pyrrolidine- (2S) -carboxylic acid monohydrate

To a mixture of 11.5 g (0.1 mol) of powdered L-proline and 80 ml of dichloromethane at room temperature was added dropwise 12.6 ml (10.8 g, 0.1 mol) of trimethylsilyl chloride at room temperature over 5 minutes. After addition of trimethylsilyl chloride, the temperature of the reaction mixture spontaneously increased to about 32 ° C and the L-proline dissolved. 10.6 g (0.1 mol) of powdered anhydrous sodium carbonate are then added in one portion to the reaction mixture. The mixture was stirred for an additional 30 minutes at 50 ° C, then cooled to -15 ° C and 11.6 ml (18.5 g, 0.1 mol) was added dropwise at -15 to -10 ° C over half an hour. of racemic 3-bromo-2-methylpropionyl chloride. The cooling is removed. The temperature of the reaction mixture was allowed to rise to room temperature and stirring was continued at this temperature for an additional hour. 100 ml of water are added, the pH is adjusted to 1 by the addition of ¹ concentrated hydrochloric acid, the organic phase is separated, extracted with 50 ml of water and the solvent is distilled off.

There was thus obtained 19.7 g (74.6%) of a honey product which was a mixture of 1- [3-bromo- (2SJ-methylproplonyl) -pyrrolidine- (2S) -carboxylic acid and 1- [3-bromo- (2R)]. 1-methylpropionyl] -pyrrolidine- (2S) -carboxylic acid A little water is added The mixture is seeded with 250250 crystals of the desired isomer and the product crystallizes on standing to give 10.0 g (70.9 why) of 1- [3] monohydrate -bromo- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid, m.p. 65-69 ° C.

Example 8

1- [3-Bromo (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid monohydrate

The procedure was as in Example 7 except that 13.8 g (0.1 mol) of powdered anhydrous potassium carbonate was used instead of sodium carbonate. 20.9 g (79.2%) of a honey-like residue is obtained, which is a mixture of 1- [3-bromo- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid and 1- [3-bromo- (2R)]. 1-methylpropionyl] -pyrrolidine- (2S (-carboxylic acid). A little water is added and the mixture is seeded with crystals of the desired isomer. The product crystallizes on standing to give 10.4 g (73.4%) of 1- [3-bromo-monohydrate]. - (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid, m.p. 64-69 ° C.

Example 9

1- [3-Bromo (2S) -methyl-propionyl] -pyrrolidine- (2S) -carboxylic acid monohydrate

To a mixture of 11.5 g (0.1 mol) of powdered L-proline and 80 ml of dichloromethane is added dropwise 12.6 ml (10.8 g, 0.1 mol) dropwise over about five minutes at room temperature, with stirring. trimethylsilyl chloride. After addition of trimethylsilyl chloride, the temperature of the reaction mixture is spontaneously raised to 32 ° C and the L-proline is dissolved. The reaction mixture was cooled to 0 ° C. It is added dropwise at 0-5 ° C

13.75 ml (10.0 g, 0.1 mol) of triethylamine. The mixture was cooled to -15 ° C. 11.6 ml (18.5 g, 0.1 mol) of optically active 3-bromo- (2S) -methylpropionyl chloride was added dropwise over 30 minutes at -15 to -10 ° C.

The cooling was removed, the temperature of the reaction mixture was allowed to rise to room temperature, and the reaction mixture was stirred at this temperature for an additional hour. 50 ml of water are added, the phases are separated, the organic phase is extracted again with water (50 ml) and then evaporated to dryness. 22.8 g (86.4%) of honey-like 1 [3-bromo- (2S) -methylpropionyl] -pyrrolidine- (2S (-carboxylic acid)) can be used directly for the preparation of 1- [3-mercapto- (2S). 1-Methylpropionyl] -pyrrolidine- (2S) -carboxylic acid.

A little water was added to the honey product and seeded with crystals of the title compound. On standing, 22.0 g of crystalline 1- [3-bromo- (2S) -methyl-propionyl] -pyrrolidine- (2S) -carboxylic acid, monohydrate, melting at 65-69 ° C, is obtained.

Example 10

1- [3-Bromo- (2S) -methyl-propionyl] -pyrrolidine- (2S) -carboxylic acid trimethylsilyl ester and 1- [3-bromo- (2R) -methyl-propionyl] -pyrrolidine- (2S) -carboxylic acid trimethylsilyl ester

The procedure was as in Example 5 except that after the acetylation the reaction mixture was not treated with 50 ml of water. Instead, the reaction mixture is filtered and evaporated to dryness under reduced pressure. 33.6 g (100%) of honey product, which is a mixture of 1- [3-bromo- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid trimethylsilyl ester and trimethylsilyl 1- [3-bromo- ( 2R-methylpropionyl-1-pyrrolidine- (2S) -carboxylic acid in a 1: 1 ratio.

IR: 1742 and 1614 cm ^{- 1} ^ (C = O), 2976 cm ^"J · [Si (CH3) 3].

Gas chromatography: column: 10% UCC W 982, column temperature: 230 ° C, detector temperature: 300 ° C, flame ionization detector, carrier gas: argon, carrier gas flow rate: 30 cm ³ / min, retention time (tk) : 8.1 min.

Claims (6)

A process for the preparation of N-acyl-L-proline derivatives of the general formula I Ro R i x i X - CH - CH - C II O (!) Wherein R 1 and R _{2 are each} independently hydrogen or C 1 -C 4 alkyl and X is halogen, characterized in that the proline trimethylsilyl ester of formula III COOSi ( ^C 3 ^J 3) is acylated with a reactive carboxylic acid derivative of the general formula IV R2 R O I I z in which X - CH - CH - C \ OH R _b, R 2 and X are as described above, in an inert organic solvent in the presence of an acid-binding agent to give (IV) a canine compound of formula R o Rg i * - COOSi (ch ₃ ) ₃ (v) in which R 1, R ₂ and X mean as above, preferably without isolation from the reaction mixture, hydrolyzes with water, 2. The process according to claim 1, wherein L-proline is reacted with trimethylsilyl chloride and the proline trimethylsilyl ester of formula III obtained is acylated without isolation from the reaction mixture in which it is formed. 3. The process of claim 1, wherein the inert organic solvent is a chlorinated aliphatic hydrocarbon or an aromatic hydrocarbon. 4. A process according to claim 3 wherein the chlorinated aliphatic hydrocarbon is dichloromethane, 1,2-dichloroethane or chloroform. 5. The process according to claim 3, wherein the aromatic hydrocarbon is an organic base, preferably triethylamine or pyridine. 7. A process according to claim 1, wherein the acid binding agent is an inorganic base, preferably an alkali metal carbonate.