KR870001569B1 - Preparing process for pyrolidine derivatives - Google Patents

Abstract

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Description

Method for preparing pyrrolidine derivative

The present invention relates to a new process for the preparation of the compound of formula (I) which is useful for the treatment of hypertension.

The preparation of the compounds of formula (I) has been studied by many inventors. For example, U. S. Patent No. 4,297, 282 describes that N- (D-α-methyl-β-acetylthio propionyl) -L-proline is prepared by removing an acetyl group with alcoholic ammonia to produce a target product.

In Japanese Patent Application Laid-Open No. 56-100760, 1- (3-bromo- (2S) -methylpropionyl) -pyrrolidine- (2S) -carboxylic acid is prepared with sodium thiosulfate, and then hydrochloric acid. It is described to produce the desired product by hydrolysis.

In addition, according to US Pat. No. 4,046,889, alkyl esters of 1- (3-alkylcarbonylthio-2-methylpropaneyl) -L-proline were treated with anisole and trifluoro acetic acid to obtain free acids followed by alcoholic ammonia. Alternatively, the target product is prepared by ammonolysis with a concentrated ammonium hydroxide solution or hydrolysis with an aqueous metal hydroxide solution.

The known method has a disadvantage in that a large amount of sulfide is present in the preparation of the target (I), and the reduction of the sulfide is not easy, so that the actual yield is not satisfactory.

The present inventors have studied the shortcomings of the prior art and have come to the following invention. That is, the present inventors react the compound of the following formula (III) with the compound of the following formula (IV) to prepare the compound of the following formula (II), and react the compound with a base to substitute the thiol to the compound of the formula (I). Invented a method for preparing the

Where

X is chlorine or bromine atom

Y is oxygen or nitrogen atom,

R is lower alkyl of 1 to 5 carbon atoms,

n is an integer of 1 or 2, provided that Y is 2 when nitrogen is 1 and 1 when Y is oxygen.

M is a sodium or potassium atom.

To prepare compound (I), the compound of formula (II) is hydrolyzed using a base, hydrazinylated with hydrazine anhydride or hydrazine hydrate, or ethylenediamine is reacted. The base used for the hydrolysis is potassium hydroxide, potassium carbonate or sodium hydroxide, sodium carbonate or ammonia aqueous solution and the like, and the base is used in 1 to 5 times molar ratio with respect to the compound of formula (II). At this time, the solvent used in the reaction is water or methanol, ethanol, isopropanol, acetone, 1,4-dioxane, tetriadrofuran, N, N-dimethylformamide, dimethyl sulfoxide or a mixed solvent of this organic solvent and water The reaction temperature is suitable to 40 ℃ to 130 ℃. In the case of the hydrazinosis reaction, the reaction solvent and the reaction conditions and the molar ratio of the compound of formula (II) to the compound of formula (II) are the same as those of the hydrolysis reaction in using hydrazine anhydride or hydrazine hydrate. .

In addition, the ethylene diamine is reacted with the compound of formula (II) to prepare the target (I), and the ethylene diamine is reacted with respect to compound (II) at 10 ° C. to 80 ° C. using 1 to 10 times molar. The solvent used at this time is carbon tetrachloride, chloroform, methylene chloride, ethyl acetate, tetrahydrofuran, 1,4-dioxane, or alcohols, and in some cases, reacted without solvent.

In order to prepare the compound of formula II, the compound of formula IV is reacted with the compound of formula III. At this time, the solvent used is the same solvent used for the hydrolysis in the preparation of the target (I) from the compound of formula (II), and the compound of formula (IV) is used 1 to 3 times molar relative to the compound of formula (III). do. The base used at this time is an inorganic base such as sodium bicarbonate, sodium carbonate, sodium hydroxide or potassium bicarbonate, potassium carbonate, potassium hydroxide or sodium acetate, and an organic base such as pyridine and triethylamine with respect to the compound of formula (III). Use 0.5 to 2.5 times and react for 30 minutes to 20 hours at 35 ℃ to 120 ℃.

The following examples are intended to illustrate the invention in more detail and do not limit the scope of the invention.

Example 1

5.64 grams of 1- [3-bromo-2S-methylpropionyl] -pyrrolidine-2S-carboxylic acid was added to 40 ml of distilled water and 4.96 grams of sodium diethyldithio carbamate was added. After stirring for 4 hours, the mixture was cooled to room temperature, maintained at pH 1.0 with concentrated hydrochloric acid, extracted twice with 40 ml of methylene chloride, dried over magnesium sulfate, distilled under reduced pressure, and dissolved 9.8 grams of potassium hydroxide in 35 ml of distilled water. And reflux for 8 hours. Wash twice with 20 ml of ethyl acetate, maintain pH1.0 with concentrated hydrochloric acid at room temperature, extract twice with 40 ml of methylene chloride, wash with saturated brine, dry with magnesium sulfate, filter, distillate under reduced pressure and 50 ml of 1N Add sulfuric acid and 0.1 gram of zinc powder, stir at room temperature for 2 hours, and wash twice with 10 ml of ethyl ether. After extracting twice with 45 ml of ethyl acetate, drying and distilling under reduced pressure, 4 ml of ethyl acetate and 5 ml of ethyl ether were added to the filtrate, and the obtained crystals were stirred at room temperature for 1 hour, and the resulting crystals were filtered to obtain 3.95 grams of 1- [3-mercapto. -2S-methylpropionyl] -pyrrolidine-2S-carboxylic acid is obtained.

Melting Point: 103 ℃ -104 ℃

[A] _D ²⁵ : -129.5 (C = 1.0, EtOH)

Example 2

2.82 grams of 1- [3-bromo-2S-methylpropionyl] -pyrrolidine-2S-carboxylic acid was added to 40 ml of ethanol, 2.4 grams of sodium dimethyl dithio carbamate was added and refluxed for 6 hours, followed by cooling to room temperature. After filtration, 10 ml of hydrazine hydrate was added to the filtrate, and the mixture was refluxed under reduced pressure until all dimethylamine was released.

35 ml of distilled water was added to the residue, pH 1.0 was maintained with concentrated hydrochloric acid, washed three times with 10 ml of ethyl ether, extracted twice with 40 ml of ethyl acetate, the organic layer was dried, filtered and evaporated under reduced pressure. To obtain grams.

To the filtrate was added 2 milliliters of ethyl acetate and 3 milliliters of n-hexane, and the precipitate was filtered, washed with n-hexane, and dried overnight, followed by 1.8 grams of 1- [3-mercapto-2S-methylpropionyl pyrrolidine. ] -2S-carboxylic acid is obtained.

Melting Point: 103 ℃ -104 ℃

[Α] _D ²⁵ : -129.8 (C = 1.0, EtOH)

Example 3

2.23 grams of 1- [3-chloro-2S-methylpropionyl-pyrrolidine] -2S-carboxylic acid is added to 30 ml of acetone and 1.76 grams of potassium santogenate are added and refluxed for 10 hours.

The precipitate obtained was filtered, the filtrate was distilled under reduced pressure, 50 ml of ethyl acetate and 15 ml of saturated brine were added thereto, the layers were separated, and the organic layer was dried over sodium sulfate and distilled under reduced pressure.

3.5 ml of ethylene diamine was added to the filtrate, which was then stirred at 30 ° C. for 3.5 hours while passing through nitrogen, the pH was adjusted to 1.0 at room temperature with 10% sulfuric acid, and 0.05 grams of zinc powder was added thereto, followed by stirring at room temperature for 2 hours. After washing, extracted twice with 35 ml of ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and distilled under reduced pressure to obtain 1.0 gram of 1- [3-mercapto-2S-methylpropionyl] -pyrrolidine-2S-. Obtain carboxylic acid.

Melting Point: 103 ℃ -105 ℃

[Α] _D ²⁵ : -128.8 (C = 1.0, EtOH)

Example 4

2.23 grams of 1- [3-bromo-2S-methylpropionyl] -pyrrolidine-2S-carboxylic acid and 0.4 grams of sodium hydroxide were added to 30 ml of a 50% acetone aqueous solution, and 1.8 grams of potassium acid togenate was added. Time to reflux. The solution was distilled under reduced pressure to remove acetone, the filtrate was kept at room temperature with concentrated hydrochloric acid at pH 1.0 and extracted with 35 ml of methylene chloride. The organic layer was dried over magnesium sulfate and distilled under reduced pressure, followed by 3.6 ml of ethylenediamine. Is added and stirred at 35 ° C. for 3 hours (at this time through dry nitrogen).

Then keep pH1.0 at room temperature with 15% sulfuric acid and stir for 1 hour. After washing with a small amount of ethyl ether and extracted twice with 40 ml of methylene chloride, the organic layer was dried, filtered and distilled under reduced pressure.

To the filtrate were added 3 milliliters of ether and 2 milliliters of ethyl acetate, stirred at room temperature for 2 hours, filtered and dried at 40 ° C. for 1 hr. Obtain -2S-carboxylic acid.

Melting Point: 103.5 ℃ -105 ℃

[A] _D ²⁵ : -130.0 (C = 1.0, EtOH)

Claims (11)

Preparation of the following compound of formula (I) characterized by reacting the compound of formula (III) with the compound of formula (IV) and then subjecting the compound of formula (II) to hydrolysis or hydrazinolysis or reaction with ethylenediamine Way.

In the above formula, X is chlorine or bromine, Y is oxygen or nitrogen atom, R is lower alkyl of 1 to 5 carbon atoms, n is an integer of 1 or 2 (wherein Y is 2, Y is 1 for oxygen). M is a sodium or potassium atom. The method according to claim 1, wherein in the reaction of the compounds of formulas (III) and (IV), water or methanol, ethanol, acetone, 1,4-dioxane, tetrahydrofuran, N, N-dimethylformamide as a solvent. , Dimethyl sulfoxide or an aqueous solution of these solvents. 3. Process according to claim 2, characterized in that compound (IV) is used in a 1 to 3-fold molar ratio relative to compound (III). The method of claim 2, wherein the reaction temperature and reaction time are performed at 35 ° C to 120 ° C and 30 minutes to 20 hours. The reaction according to claim 2, wherein sodium bicarbonate, sodium hydroxide, potassium bicarbonate, potassium carbonate, potassium hydroxide, sodium acetate, pyridine or triethylamine is used in a 0.5 to 2.5-fold molar ratio with respect to the compound of formula (III) as a base. Characterized by the above. The method of claim 1, wherein the hydrolysis of the compound of formula II is carried out using potassium hydroxide, potassium carbonate, sodium hydroxide or ammonia water. The method according to claim 1, wherein the hydrazinolysis reaction of the compound of formula II is carried out using hydrazine anhydride or hydrazine hydrate in a 1 to 5-fold molar ratio relative to the compound of formula II. The method according to claim 7, wherein the reaction temperature is performed at 40 ° C to 130 ° C. The method of claim 1, wherein the reaction of the compound of formula II with ethylene diamine is carried out at a molar ratio of 1 to 10 times the amount of ethylene diamine relative to the compound of formula III. 10. The process of claim 9, wherein the reaction is carried out at 10 ° C to 80 ° C. 10. The process according to claim 9, wherein the reaction is carried out in the presence or absence of a solvent such as carbon tetrachloride, chloroform, methylene chloride, ethyl acetate, tetrahydrofuran, 1,4-dioxane or alcohols.