JPS61183263A - Manufacture of pyrrolidine derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a new method for producing compounds of formula (I). This compound is effective in lowering blood pressure and preventing hypertension.

(Prior Art) Various methods for synthesizing compounds of formula (I) have been studied by many inventors. For example, U, S, I"at, N
A4297282 discloses a method for preparing a desired substance by deacylation of N-(D-α-methyl-β-acetylthiopropionyl)-L-proline using alcoholic aqueous ammonia.

JP-A-56-100760 discloses 1-(3-bromo-(2S)-methylpropionyl)pyrrolidine-(2
S) --By reacting carboxylic acid with sulfur thiosulfate to obtain Bunte salt (Bunte 5alt), and then hydrolyzing this Bunte salt with hydrochloric acid.

A method of producing a desired substance is disclosed.

Pyrrolidine derivatives are known and include U, S, Pat,
Obtained by the procedure described in Na4046889. That is, 1-(3-alkyl sulfonyl thio-
The alkyl ester of 2-methylpropionyl)-■,-proline is treated with anisole and trifluoroacetic acid to yield the free acid. The free acid thus obtained is either ammoniated (ammonolysis) by reaction with alcoholic aqueous ammonia or concentrated aqueous ammonia solution, or hydrated by reaction with an aqueous alkali metal hydroxide solution. decomposed, and as a result,
The desired 1-(3-mercapto-2-methylpropionyl)-I7-proline is obtained.

Known processes such as those described above have the disadvantage that the sulfides are not easily reduced and therefore the product yields are not very high. The present invention eliminates these drawbacks and
) We present a new and advantageous method for the preparation of compounds (IL).

As described above, the present invention provides a method for producing a compound of formula (I), and the method includes a method for producing a compound of formula (I) and a compound of formula (I).
TV) A step of reacting a compound with a compound of formula (I) to obtain a compound of formula (I) and a step of reacting a compound of formula (II) with a base to obtain a compound of formula (I)
The method includes a step of obtaining a compound.

■C] 13 Gate'S---C-Y-(R) ll...
...(IV) Here.

X is bromine or chlorine.

Y i; + oxygen atom or nitrogen atom.

R is a lower alkyl group of C, -C,.

n is an integer of 1 or 2 (if Y is nitrogen, n is 2; if Y is oxygen, n is 1).

The gate is the I. Liu broad atom or the potassium atom.

Furthermore, the present invention provides a novel and efficient method for obtaining the compound of formula (TI) by hydrolysis or hydrazinolysis, or by reacting it with ethylenediamine.

For hydrolysis, sodium carbonate, sodium hydroxide,
A base such as potassium carbonate, potassium hydroxide, or aqueous ammonia is used in an amount of 1 to 5 moles per mole of the compound of formula 5 (n). The solvents used in the reaction include water, methanol, and ethanol.

Isopropanol, acetate, 1,4-thioxane,
Tetrahydrofuran, N,N-dimethylbormamide,
There is also a mixed solvent of dimethyl sulfoxide or 11 water and the above organic solvent. The reaction temperature is between 40°C and 130°C.

In the case of hydrazinolysis, the compound of formula 2 (TI) is contacted with anhydrous hydrazine or hydrazine hydrate in a reaction solvent to form the compound 2 (I).

Anhydrous hydrazine or hydrazine hydrate may be used in an amount of 1 to 5 moles per mole of the compound of formula 2 (■). The reaction may be carried out at a temperature ranging from 40 to 130°C. The same solvent used for hydrolysis.

It can also be used for hydrazinolysis.

In addition, when the compound of formula 2 (TI) is reacted with ethylenecyamine to obtain the compound 2N), 1 to 10 mol of ethylenediamine is added to 1 mol of the metal compound of formula 1 (n).
Used at temperatures in the range of 0°C.

The solvent used for the reaction is carbon tetrachloride, chloroform,
methylene chloride, ethyl acetate, 1-rahydrofuran, 1
．． Including 4-dioxane or alcohols, in some cases the two reactions are carried out without solvent.

The compound of formula (n) of the present invention is prepared by reacting 1 mole of a compound of formula (II+) with 1 to 3 moles of a compound of formula (IV) in a solvent in the presence of two bases.

The solvent is the same solvent used in the hydrolysis, such as water, methanol, ethanol, isopropanol, acetone, 1,4-oxane, tetrahydrofuran, N, N-dimethylpolamide, dimethyl sulfoxide, or an aqueous solution thereof. That's fine. Bases include sodium hydrogen carbonate, sulfurium carbonate, sodium hydroxide, and potassium hydrogen carbonate.

Inorganic bases such as potassium carbonate, potassium hydroxide or sodium acetate or organic bases such as pyridine or triethylamine can be used. The base is per mole of the compound of formula 3 (rll).

It is used in an amount of 0.5 to 2.5 moles.

The reaction was carried out for 30 minutes to 2 hours at a crystallinity in the range of 35-120°C.
It can be carried out for 0 hours.

In carrying out the process of the invention to obtain the desired product.

Isolation, crystallization and final purification may be carried out according to the procedures described in the Examples below.

(Example) The present invention will be explained in detail in the following example. However, it is clear that there is no intention to limit the invention thereby.

1-(3-bromo-(2S)-methylpropionyl)
-Pyrrolidine-(2S)-carboxylic acid 5.64g in distilled water 40m7! After the mixture was dissolved, 4.96 g of diethylthiolhydramide acid salt was added.

The mixture was heated to 80-85°C and stirred at room temperature for 4 hours, then cooled to room temperature. The pH value was adjusted to 1.0 with concentrated hydrochloric acid. The mixture was then mixed with 40+nI! of methylene chloride!
The organic layer was dried over magnesium sulfate and then distilled under reduced pressure.

9.8g of potassium hydroxide and 35m7 of distilled water! The solution was added to this residue and refluxed for 8 hours.

The mixture was washed twice with 20 ml of ethyl ether.

The p11 value was adjusted to 1.0 with concentrated hydrochloric acid at room temperature. after that.

This mixture was extracted twice with 40 mff of methylene chloride.

Washed with saturated chloride solution. Further, it was dried over sodium sulfate, filtered, and distilled under reduced pressure.

2. For this residue. I N l12SO450m
I2 and 0.1 g of zinc powder were added, followed by IW stirring at room temperature for 2 hours. Pour the mixture into ethyl ether 10mj! and twice with 45 mN ethyl acetate,
The extracted organic layer was dried, filtered, and distilled under reduced pressure to obtain an oily residue. The oily residue thus obtained was mixed with 4 m7 of ethyl acetate! and 5m7 of ethyl ether! and stirred at room temperature for 1 hour. Filter the precipitate.

After washing and drying, ]-(]3-mercapto-2S
)-Methylpropionyl)-pylcolidine-(2S)-
3.95 g of carboxylic acid was obtained.

Gate, P: 103℃~104℃〔α) P-129,5° (c -1,0ELOII)
Dissolve 2.82 g of Daikyo-1-U-1-(3-B)-(23)-methylpropionyl)-pyrrolidine-(2S)-carboxylic acid in 40mE of ethanol, and then dissolve this liquid. To,
2.4 g of sodium dimethyl didiocarhamate was added. The mixture was passed iW for 6 hours, cooled to room temperature and filtered.

Add 10mj of hydrazine hydrate to this filtrate! was added and refluxed until all dimethylamine was expelled, followed by distillation under reduced pressure.

35 ml of distilled water was added to the resulting residue.

The pH value was adjusted to 1.0 with concentrated hydrochloric acid.

The mixture was then washed three times with ethyl ether]Om (4) and extracted twice with 40 ml of ethyl acetate. The extracted organic layer was dried, filtered and distilled under reduced pressure to obtain 2.1 g of an oily residue. Obtained.

The oily residue thus obtained was added to 2 ml of ethyl acetate and 3 ml of Barhexanes and stirred for 2 hours.

The precipitate was filtered, washed with n-hexane, and then dried overnight to obtain 1-(3-mercap 1-(2S)-methylpropionyl)pyrrolidine-(2S)-carboxylic acid.
8g was obtained.

Gate, 'P, = 103℃ ~ 104℃ [α] 65--129.8° ('c''-= 1,0
; EtOll) length is 1-(3-chloro-(2S)-methylpropionyl)-
2.23'g of pyrrolidine-(2S)-carboxylic acid and 30ml of acetone 1! To? Let me understand, please? At the same time, 1.76 g of potassium xanthate was added. The mixture was refluxed for 10 hours and then filtered to remove the precipitate. After distilling the filtrate under reduced pressure, 50 m of ethyl acetate was added thereto. and 15 m of saturated sodium chloride solution 7! was added and the phases were separated. The organic layer was dried over magnesium sulfate and distilled under reduced pressure.

The residue thus obtained was mixed with ethylenediamine 3.5+
nj2 and the mixture under a stream of dry nitrogen gas.

The mixture was stirred at 30°C for 3.5 hours. The mixture was cooled to room temperature and the p11 value was adjusted to 1.0 with 10% 11□S04. Thereafter, 0.05 g of zinc powder was added and stirred at room temperature for 2 hours. Wash the mixture with ethyl ether.

Extracted twice with 35 ml of ethyl acetate. It was further washed with saturated sodium chloride solution, dried over sulfur sulfate, filtered and distilled under reduced pressure.
(2S)-Methylpropionyl)-pyrrolidine-(2S
)-carboxylic acid 1.0 g was obtained.

Gate, P: 103°C to 105°C ((X) P = -128,86 (c = 1.0; P, t
oIl) Tip length 1-(3-bromo-(2S)-methylpropionyl)-
2.23 g of pyrrolidine-(2S)-carboxylic acid and 0.4 g of sodium hydroxide were dissolved in 50% acetic acid solution in water. night 3
To 0m1? Is this acceptable? 1.8 g of potassium xane-1-genate was added to the solution. After refluxing the mixture for 8 hours,
Acetone was removed by distillation under reduced pressure. The mixture was kept at room temperature and the r, lI values were adjusted to 1.0 with concentrated hydrochloric acid.

The pn-adjusted mixture was mixed with 35 m (4 m) of methylene chloride.
Extracted with. The extracted organic layer was dried over magnesium sulfate and then distilled under reduced pressure to obtain a residue.

To the residue thus obtained was added 3.6 m of ethylenediamine.
ff and the mixture under a stream of dry nitrogen gas.

The mixture was stirred at 35°C for 3 hours. The mixture was cooled to room temperature, the p11 value was adjusted to 1.0 with 15% sulfuric acid, and stirred for 1 hour. The mixture was then washed with ethyl ether and methylene chloride 40mj! Extracted twice. Thereafter, the two separated organic layers were dried, filtered, and distilled under reduced pressure.

The oily residue thus obtained was mixed with 3 m7 of ether. and 2 mρ of ethyl acetate, stirred at room temperature for 2 hours,
Filtered. Then, after drying at 240°C for a day and night, 1-
(3-Mercapl=-(2S)-methylbrocopionyl)-pyrrolidine-(2S)-carboxylic acid was obtained.

M, P,: IO2,5'C~105℃ [α) F
=”= 130.0° (c = 1,0, EtO
tl) (Effects of the Invention) According to the present invention, the pyrrolidine derivative represented by the formula (I) can be obtained in high yield. This compound is effective in lowering blood pressure and preventing hypertension.

Claims (1)

[Claims] 1. A method for producing a compound of formula (I), comprising a step of reacting a compound of formula (III) with a compound of formula (IV) to obtain a compound of formula (II); by hydrolysis or hydrazinolysis, or by reacting with ethylenediamine,
Method for producing pyrrolidine derivatives, including the process of obtaining the compound of formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼・
...(I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼... (IV) where, For oxygen, n is 1), and M is a sodium or potassium atom. 2. The reaction between the compound of formula (III) and the compound of formula (IV) can be carried out in water, methanol, ethanol, isopropanol, acetone, 1,4-dioxane, tetrahydrofuran, N,N
- The method for producing a pyrrolidine derivative according to claim 1, which is carried out in at least one solvent of dimethylformamide and dimethyl sulfoxide or an aqueous solution thereof. 3. Claim 2, wherein the compound of formula (IV) is subjected to the reaction in an amount of 1 to 3 moles per 1 mole of the compound of formula (III)
A method for producing a pyrrolidine derivative according to section 1. 4. The method for producing a pyrrolysine derivative according to claim 2, wherein the reaction temperature is between 35°C and 120°C and the reaction time is between 30 minutes and 20 hours. 5. At least one base selected from sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, potassium hydrogen carbonate, potassium carbonate, potassium hydroxide, sodium acetate, pyridine, and triethylamine is present in an amount of 0 per mole of the compound of formula (III). A process for producing pyrrolysine derivatives according to claim 2, wherein the pyrrolysine derivatives are used in an amount of .5 to 2.5 mol. 6. The compound according to claim 1, wherein the hydrolysis of the compound of formula (II) is carried out using at least one base selected from potassium hydroxide, potassium carbonate, sodium hydroxide, sodium carbonate, and aqueous ammonia. A method for producing a pyrrolidine derivative. 7. Hydrazine decomposition of the compound of formula (II) produces at least one of anhydrous hydrazine and hydrazine hydrate,
The method for producing a pyrrolysine derivative according to claim 1, which is carried out in an amount of 1 to 5 moles per mole of the compound of formula (II). 8. The method for producing a pyrrolidine derivative according to claim 7, wherein the hydrazine decomposition is carried out at a temperature between 40°C and 130°C. 9. Claim 1 in which ethylenediamine is subjected to the reaction in an amount of 1 to 10 moles per mole of the compound of formula (II)
A method for producing a pyrrolysine derivative according to section 1. 10. The method for producing pyrrolidine derivatives according to claim 9, wherein the reaction is carried out at a temperature between 10 and 80°C. Claim 9, wherein the reaction is carried out in the presence or absence of at least one solvent selected from the group consisting of 11. carbon tetrachloride, chloroform, methylene chloride, ethyl acetate, tetrahydrofuran, 1,4-dioxane, and alcohols. A method for producing a pyrrolidine derivative as described in .