DE3538747A1 - METHOD FOR PRODUCING PYRROLIDINE DERIVATIVES - Google Patents

Description

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Process for the preparation of pyrrolidine derivatives

The present invention relates to a new process for the preparation of compounds of the formula I which uses can be used to lower blood pressure and prevent high blood pressure.

CH ₃ -CH-CN ^L COOH (I)

CH ₂ SH

Various processes for the preparation of compounds of Formula I have been studied by a number of inventors been. For example, in USP 4,297,282 e * is described in process after the desired substance is through Deacylation from N- (D-oo-Pfethyl-ß-acetylthiopropionyl) -L-proline can be made with alcoholic ammonia.

In Japanese Patent Laid-Open No. 56-100760, a Process described, which consists in l- (3-bromo (2S) methylpropionyl) pyrrolidine (2S) carboxylic acid with sodium

U it

to implement thiosulphate and the resultant colored salt with Hydrolyze hydrochloric acid to produce the desired substance.

Pyrrolidine derivatives are known and can also be used according to the Procedure; as described in USP 4,04-6,889 will. Then the alkyl ester of 1- (3-alkyl ~ carbonylthio-2-methylpropionyl) If-proline with anisole and Trifluoroacetic acid treated to obtain the free acid, The free acid thus obtained is ammoniated

by reaction with alcoholic ammonia or concentrated aqueous ammonia, or hydrolyzed by reaction with the Solution of an alkali metal hydroxide to the desired l- (3-mercapto-2-methylpropionyl) -L-proline.

The above known methods have the disadvantage that the sulfide is not easy to reduce and the Production yield is not very high. The present invention eliminates these disadvantages and provides a new, advantageous process for the preparation of compounds of formula I available.

The inventive method for the preparation of compounds of formula I consists in using a compound of formula III

O ^ (III)

X - CH ₂ - CH - C - N ^{- 1} - COOH CH ₃

in which X represents bromine or chlorine, with a compound of the formula IV

• S

- Y - CR)

(IV) Μ® So- C - Y - (R)

wherein M represents a sodium or potassium ion, and

Y is oxygen or nitrogen atom, and η is either 1 (or when Y is nitrogen atom is) 2 means

converts to a compound of formula II

s 0

Il

I!

(R) _n - Y - C - S - CH ₂ - CH - C - N

I

(II)

where Y, R and η have the same meaning as in Formula in and IV

with a base to react to "compounds of Formula I to get.

CH ₃ -CH-CN L COOH

I.
CH ₂ SH

The invention also consists in the new and advantageous one Process for obtaining compounds of the formula I by hydrolyzing or hydrazinolysing compounds of the formula II or reacts with ethylenediamine.

A base, for example sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide or ammonia, is used for hydrolyzing in an amount of 1-5 mol per mol of the compound of the formula II. The solvent used for the reaction is water, methanol, ethanol, isopropanol, acetone, 1,4-dioxane, tetrahydrofuran, Ν, Ν-dimethylformamide, dimethyl sulfoxide or a mixture of water and organic solvent. The reaction temperature is between 4-0 and 13O ⁰ C.

For hydrazinolysis, the compound of formula II is reacted with anhydrous hydrazine or hydrazine hydrate in a solvent to form the compound of formula I. The anhydrous hydrazine or hydrazine hydrate can be used in an amount of 1-5 moles per mole of the compound of the formula II. The reaction may be carried out at a temperature between 40 and 13O ⁰ C. The same solvents as for the hydrolysis can also be used for this hydrazinolysis.

In the reaction of ethylenediamine with compounds of the formula II, by means of which compounds of the formula I are obtained, 1-10 moles of ethylenediamine are used per mole of the compounds of the formula II, at a temperature between 10 and 80 ^° C.

_BATH

• τ

The solvents used for this reaction can, for example, carbon tetrachloride, chloroform, methylene chloride, Ethyl acetate, tetrahydrofuran, 1,4-dioxane or alcohols and in some cases the reaction can also be carried out without such a solvent.

The compounds of formula II according to this invention are prepared by adding one mole of the compound of formula III with 1-3 mol of the compound of formula IV in a solvent in the presence of a base.

The solvent can be the same as that used for the hydrolysis, for example Water, methanol, ethanol, isopropanol, etc. The base used may be an inorganic base, for example Sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, potassium hydrogen carbonate, potassium carbonate, potassium hydroxide or sodium acetate, or an organic base such as pyridine or triethylamine. The base can be used in an amount of 0.5 up to 2.5 moles per mole of the compound of the formula III are used.

The reaction can be carried out at temperatures of 35-12O ⁰ C in a time of 30 minutes to 20 hours.

When carrying out the process according to the invention for producing the desired product, the separation, Crystallization and purification can be carried out according to the procedures described in the following examples.

These examples describe details of the invention, but are not intended to be construed as depicting the invention restrict in any way.

Example 1

5.64 g of 1- (3-bromo-2S-methylpropionyl) -pyrrolidine- ₍ ° 3-carboxylic acid are dissolved in 40 ml of distilled water and 4.96 g of sodium diethyldithlocarbamate are added.

The mixture is heated to 80-85 ° 0 and 4 hours at stirred at this temperature and then cooled to room temperature. The pH is adjusted with concentrated hydrochloric acid set to 1.0. The mixture is then extracted twice with 40 ml of methylene chloride each time and the organic Phase dried over magnesium sulfate and distilled under reduced pressure.

9.8 g of potassium hydroxide in 35 ml are added to the residue added distilled water and the mixture refluxed for 8 hours.

The mixture is extracted twice with 20 ml of ethyl ether each time and the pH value is adjusted to 1.0 at room temperature with concentrated hydrochloric acid. It is then extracted twice with 40 ml of methylene chloride each time, the extract is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and distilled under reduced pressure.

50 ml of 1N sulfuric acid and 0.1 g of zinc powder are added to the residue and the mixture is stirred at room temperature for 2 hours. The mixture is then extracted twice with 10 ml of ethyl ether each time and twice with 45 ml of ethyl acetate each time, the organic extracts are dried, filtered and distilled under reduced pressure, an oily residue being obtained. The oily residue obtained in this way is added to 4 ml of ethyl acetate and 5 ml of ethyl ether and stirred for 1 hour at room temperature, whereupon the precipitate is filtered off and washed. After drying, 3.95 g of l- (3-mercapto-2S-

BATH ORIGINAL

methylpropionyl) pyrrolidine-2S-carboxylic acid. -129.5 ° C (c = 1.0 ethanol)

Mp. 103-104 ⁰ G
² ^

Example 2

2.82 s of 1- (3-bromo-2S-methylpropionyl) -pyrrolidine-2S-carboxylic acid is dissolved in 40 ml of ethanol and 2.4 g of sodium dimethyldithiocarbamate added. The mixture is refluxed for 6 hours and, after cooling to room temperature, filtered.

10 ml of hydrazine hydrate are added to the filtrate and cooked until all of the diniethylamine is released. Afterward is distilled under reduced pressure. The resulting residue is 35 ^ l of distilled water added and the pH with concentrated hydrochloric acid set to 1.0.

The mixture is then extracted three times with 10 ml of ethyl ether and twice with 40 ml of ethyl acetate each time, and the combined organic extract layers dried, filtered and distilled under reduced pressure, with 2.1 g of a oily residue can be obtained.

The oily residue obtained in this way is added to 2 ml of ethyl acetate and 3 ml of η-hexane and stirred for 2 hours, whereupon the precipitate is filtered off and washed with η-hexane. The residue is then dried overnight to yield 1.8 g of l- (3-mercapto-2S-methylpropionyl) -pyi ⁱ rolidin-2S-carboxylic acid are obtained.
Mp. 103-104 ⁰ C

β *> 7 ²⁵ '= -129.8 ⁰ G (c = 1.0; ethanol) D.

^eAD

Example 3

2.23 g of 1- (3-chloro-2S-methylpropionyl) -pyrrolidine-2S-carboxylic acid are dissolved in 30 ml of acetone and 1.76 g of potassium xanthate added. The mixture is refluxed for 10 hours and filtered to remove a precipitate. Das .Filtrat is distilled under reduced pressure and then 50 ml of ethyl acetate and 15 ml of saturated sodium chloride solution added. The organic layer is separated, dried over magnesium sulfate and under reduced pressure Distilled pressure.

_ To the residue 3 »5 ml of ethylenediamine are added and the mixture stirred for 3» 5 hours at a temperature of 30 ⁰ C under a stream of dry nitrogen. The mixture is cooled to room temperature and the pH is adjusted to 1.0 with 10 # sulfuric acid. Then 0.05 g of zinc powder are added and the mixture is stirred at room temperature for 2 hours. The mixture is washed with ethyl ether and extracted twice with 35 ml of ethyl acetate each time. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and distilled under reduced pressure, 1.0 g of 1- (3-mercapto-2S-methylpropionyl) -pyrrolidine-2S-carboxylic acid being obtained.

^V > m.p. 103-1O5 ° C

²⁵ = -128.8 ⁰ O (c = 1.0; ethanol) D.

Example 4-

2.23 g of 1- (3-bromo-2S-methylpropionyl) -pyrrolidine-2S-carboxylic acid and 0.4 g of sodium hydroxide are dissolved in 30 ml of a 50% aqueous acetone solution, 1.8 g of potassium xanthate added. The mixture is refluxed for 8 hours,

BATH ORIGINAL

then distilled under reduced pressure to obtain the Remove acetone. While the solution is kept at room temperature, the pH is adjusted with koi: centered hydrochloric acid set to 1.0. Then the solution with 35 ml Extracted methylene chloride. The extracted organic layer is dried over magnesium sulfate and under reduced pressure Distilled off under pressure to obtain a residue.

This is mixed with 3 »6 nil ethylenediamine and the mixture thus obtained is ^{stirred for 3 hours at .35 0} O under a stream of dry nitrogen. The mixture is then cooled to room temperature, the pH is adjusted to 1.0 with 15% sulfuric acid and the mixture is stirred for a further hour. The mixture is then washed with ethyl ether and extracted twice with 4-0 ml of methylene chloride each time. Thereafter, the separated organic layers are dried, filtered and distilled off under reduced pressure.

The oily residue thus obtained is added to 3 ml of ether and 2 ml of ethyl acetate and stirred for 2 hours at room temperature. The precipitate is filtered off and dried overnight at a temperature of 4-0 ⁰ C to yield 1.6 g of l- (3 ~ mercapto-2S-methyl-propionyl) -pyrrolidine-2S-carboxylic acid are obtained.

Mp. 103.5 to 105 ⁰ O. .

ßol ²⁵ = -130.0 ⁰ O (c = 1.0; ethanol) D.

Claims (11)

ι -J patent r. η SDr u ehe 1. Process for the preparation of compounds of the formula I. CH ₃ - CH - C - N ^L COOH (i) I.
CH ₂ SH characterized in that compounds of the formula III X-CH ₂ - CH -S- NL _COOH CUD CH ₃ in which X is bromine or chlorine with a compound of the formula IV S (IV) M® S β - C - Y - (R) in which Y is an oxygen or nitrogen atom, R is a lower alkyl group with 1-5 C atoms, η denotes the number 1 when Y is an oxygen atom and the number 2 denotes when Y is a nitrogen atom converts and the compound of formula II obtained S ο (R) _n - YCS-CH ₂ -CH-C- N LcoOH ^(II) I CH ₃ in which Y, R and η have the same meaning as in formula in and IV hydrolyzed, hydrazinolyzed or react with ethylenediamine!;, whereby compounds of formula I are obtained. BAD ORfOINAL I * I adjusted 2. The method according to claim 1, characterized in that the Reaction of the compounds of the formula III with compounds of the formula IV in a solvent such as water, methanol, Ethanol, isopropanol, acetone, 1,4-bioxane, tetrahydrofuran, Ν, Ν-dimethylformamide, dimethyl sulfoxide or an aqueous one Solution to be carried out. 3. The method according to any one of claims 1 or 2, characterized in that that a compound of the formula IV is used in an amount of 1-3 moles per mole of the compound of the formula III will. ν 4 ·. Process according to one of Claims 1-3, characterized in that the reaction ^{temperature is between 35 and 120 0} C and the reaction time between 30 minutes and 20 hours. 5. The method according to any one of claims 1-4, characterized in, that a base, in particular sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, potassium hydrogen carbonate, Potassium carbonate, potassium hydroxide, sodium acetate, pyridine or Triethylamine in an amount of 0.5-2.5 moles per mole of the Compound of formula III is used. 6. The method according to any one of claims 1-5, characterized in that that the hydrolysis of the compound of formula II is carried out in the presence of a base, which in particular Potassium hydroxide, potassium carbonate, sodium hydroxide, sodium carbonate or ammonia. 7. The method according to any one of claims 1-5, characterized in that that the hydrazinolysis of the compound of formula II with anhydrous hydrazine or hydrazine hydrate in an amount of 1-5 moles per mole of the compound of formula II. 8. The method according to claim 7, characterized in that the hydrazinolysis at a temperature between 40 ⁰ C and 130 ⁰ C is carried out. BATH ORIGINAL 9. The method "according to claims 1-5» characterized in that the reaction is carried out with ethylenediamine in an amount of 1-10 moles per mole of the compound of formula II. 10. The method according to claim 9 »characterized in that the reaction at e; is carried out. the reaction at a temperature between 10 and 80 ⁰ G 11. The method according to claim 9 or 10, characterized in that the reaction in the absence of a solvent or in a solvent such as carbon tetrachloride, chloroform, methylene chloride, ethyl acetate, tetrahydrofuran, 1,4-dioxane or alcohol. BAD ORfGlNAL