JP3135769B2 - Method for producing intermediate of angiotensin converting enzyme inhibitor - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an optically active 1- (D-3).
1- (D-3) which is a synthetic intermediate of -mercapto-2-methylpropanoyl) -L-proline or 1- (D-3-acetylthio-2-methylpropanoyl) -L-prolyl-L-phenylalanine -Acetylthio-2-
Methylpropanoyl) -L-proline.

[0002]

2. Description of the Related Art 1- (D-3-mercapto-2-D-methylpropanoyl) -L-proline (general name: captopril) represented by the formula (III) and 1- (D) represented by the formula (IV)
(D-3-acetylthio-2-methylpropanoyl)-
L-Prolyl-L-phenylalanine (generic name: alacepril) both have potent angiotensin converting enzyme inhibitory activity and are known as excellent blood pressure lowering agents.

[0003]

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[0004]

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[0005] The formula (I), which is an important intermediate between captopril of the above formula (III) and alacepril of the formula (IV),
Representative methods for the synthesis of 1) 1- (D-3-acetylthio-2-methylpropanoyl) -L-proline include JP-A-56-18958 and JP-A-5-221966. . In both of these methods, the Schotten-Baumann reaction is used, and in any case, the D-3- of formula (I) is introduced into an aqueous solvent of L-proline under basic conditions.
A method of dropping acetylthio-2-methylpropanoic acid chloride is employed.

[0006]

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[0007]

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[0008]

However, first, Japanese Patent Application Laid-Open No. 56-18958 and Japanese Patent Application Laid-Open No. 5-221966 are disclosed.
In the method for synthesizing 1- (D-3-acetylthio-2-methylpropanoyl) -L-proline disclosed in Japanese Unexamined Patent Publication (Kokai) No. H11-209, it is necessary to strictly adjust the pH of the reaction system. Because it changes the reaction temperature,
pH adjustment is complicated. Further, in both cases, D-3-
Acetylthio-2-methylpropanoic acid chloride and L-
Since one of the main raw materials of proline is used in excess, it is hardly an industrially advantageous method.

Further, USSRSU 1,165,233 discloses that an L-prolinesilyl compound and D-3-amine are present in the presence of a third organic base.
Although a method of reacting acetylthio-2-methylpropanoic acid chloride at room temperature is described, the silyl form of L-proline is unstable to heat such as heat generated during condensation,
It may decompose to generate ammonia gas.

[0010]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems. As a result, 1- (D-
For the production of 3-acetylthio-2-methylpropanoyl) -L-proline (II), in the reaction of D-3-acetylthio-2-methylpropanoic acid chloride with L-proline, a conventional method such as the aforementioned USSRSU 1,165,233
As described in the publication, instead of first silylating L-proline and then reacting it with the acid chloride of formula (I), the acid chloride of formula (I), L
-When proline, trimethylsilyl chloride and the like coexist and an organic tertiary amine such as triethylamine is dropped into this mixed solution, surprisingly, 1- of the formula (II)
(D-3-acetylthio-2-methylpropanoyl)-
L-proline was found to be produced quantitatively. The present invention has been completed by further research based on this discovery.

That is, the gist of the present invention is to provide an optically active D-3-acetylthio-2-methylpropanoic acid chloride represented by the formula (I), L-proline and a silyl chloride derivative in an aprotic solvent. Wherein an organic tertiary amine is added dropwise to the compound represented by the formula (II).
(D-3-acetylthio-2-methylpropanoyl)-
The present invention relates to a method for producing L-proline.

[0012]

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[0013]

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Hereinafter, the present invention will be described in detail. First, a method for producing 1- (D-3-acetylthio-2-methylpropanoyl) -L-proline of the formula (II) will be described.

The optically active D-3-acetylthio-2-methylpropanoic acid chloride used in the production method of the present invention can be produced by a conventional method. For example, D-
It can be produced by dissolving 3-acetylthio-2-methylpropanoic acid and N-methylmorpholine in methylene chloride, heating the mixture to reflux temperature, and then dropwise adding thionyl chloride to this solution. Commercially available L-proline can be used.

The silyl chloride derivative used in the production method of the present invention includes trimethylsilyl chloride,
n-butyldimethylsilyl chloride and tert-
One or more selected from the group consisting of butyldimethylsilyl chloride is exemplified. Particularly preferred is trimethylsilyl chloride. This is because they are inexpensive, high in general-purpose use, and have sufficient reactivity in the present invention.

The organic tertiary amine used in the production method of the present invention may be at least one selected from the group consisting of triethylamine, trimethylamine and N-methylmorpholine. Particularly, triethylamine is preferable. The aprotic solvent used in the production method of the present invention is at least one selected from the group consisting of halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform and carbon tetrachloride and aromatic hydrocarbons such as benzene and toluene. Among them, methylene chloride, ethylene chloride, chloroform and carbon tetrachloride are particularly preferred.

In the production method of the present invention, as in the case of a reaction using a conventional silylating agent, D-3-acetylthio-2-hydroxy is added to a solution containing a silyl derivative of L-proline.
Instead of adopting the method of reacting by dropping methylpropanoic acid chloride, on the contrary, D-3-
Acetylthio-2-methylpropanoic acid chloride, L-
The greatest feature is that a method is employed in which proline and trimethylsilyl chloride, which is a silylating agent, coexist, and an organic tertiary amine is dropped into this mixed solution.

By the method of the present invention, surprisingly, by using the theoretical amount of each starting compound, 1- (D-3-acetylthio-2-methylpropanoyl) -L-proline (II ) Can be manufactured. According to a method via a normal silylated derivative, that is, a method in which D-3-acetylthio-2-methylpropanoic acid chloride is dropped into a solution containing a silyl derivative of L-proline to cause a reaction, The results of the process of the present invention are indeed surprising in view of the low yields that would have to be said to be inappropriate for the application of the process via silylated derivatives.

There may be various reasons for this unexpected result. First, the silylation of L-proline is extremely easy, and second, the silyl derivative of L-proline is extremely unstable. That is. For this reason, when acid chloride is added dropwise to a solution containing a silyl derivative of L-proline as in a normal method, as can be seen from the formation of ammonia, a decomposition reaction occurs, and the yield is significantly reduced. It seems to be.

In the case of the production method of the present invention, D-3-acetylthio-2-methylpropanoic acid chloride, L-proline and a silylating agent are stably coexisted in an aprotic solvent. When the organic tertiary amine is added dropwise, the silylation reaction of L-proline partially occurs first, and the disilyl derivative of L-proline thus formed immediately reacts with the nearby D-3-acetylthio-2-methylpropanoic acid chloride. And stable 1- (D-3-acetylthio-2-methylpropanoyl) -L-proline-monosilyl derivative is formed, and the unstable disilyl derivative of L-proline is present in the reaction solution for a long time to cause a decomposition reaction. It is thought that receiving will be avoided.

The usual silylation reaction requires trimethylsilyl chloride and acetamide and a tertiary amine as a reaction initiator, but the reaction of the present invention does not necessarily require the presence of acetamide. This means that L-
Since the silylation reaction of proline proceeds extremely easily, the silylating agent does not need to be trimethylsilylacetamide, suggesting that trimethylsilyl chloride acts directly as a silylating agent for L-proline.
However, addition of acetamide, dimethylacetamide, dimethylformamide, or the like to the reaction system does not hinder the reaction, but rather may contribute to an improvement in the reaction yield.

In the production method of the present invention, D-3-acetylthio-2-methylpropanoic acid chloride, L-proline, trimethylsilyl chloride,
Acetamide and triethylamine are all stoichiometric,
That is, it is sufficient to use 2 times the molar amount of the silylating agent, and to use equimolar amounts of the other components. This fact also proves that few side reactions have occurred.

The method for dropping an organic tertiary amine in the production method of the present invention is usually carried out at -20 to 45 ° C. for 1 to 24 hours. More preferably, at 15 to 45 ° C, 1
Perform over 10 hours. The reaction temperature after the addition is usually -2.
The reaction is performed at 0 to 85 ° C, preferably 5 to 65 ° C, more preferably 15 to 45 ° C. The reaction time after dropping depends on the reaction temperature, but is 1 to 48 hours, preferably 2 to 10 hours.

1- (D) obtained by the production method of the present invention
-3-acetylthio-2-methylpropanoyl) -L-
To isolate proline (II), water is added to the reaction-terminated liquid to hydrolyze the silyl group of the product, the organic solvent layer is washed with water, dried over anhydrous magnesium sulfate, and the like. It can be carried out by distilling off the solvent. Since the reaction yield is quantitative, the product yield and its purity are very high.

[0026]

The present invention will be described in more detail with reference to the following Examples and Comparative Examples, but the present invention is not limited to these Examples and the like.

Example 1 Preparation of 1- (D-3-acetylthio-2-methylpropanoyl) -L-proline D-3-acetylthio-2-methylpropanoic acid 30.0
g (0.185 mol) and 0.1 g of N-methylmorpholine.
05 g was dissolved in 60 ml of methylene chloride, and the temperature was raised to the reflux temperature. 24.2 g of thionyl chloride (0.203
Mol) was added dropwise over 1 hour, and the mixture was further stirred under reflux for 4 hours. Under reduced pressure, methylene chloride and residual thionyl chloride were distilled off, then 240 ml of methylene chloride was added, and the temperature of the solution was adjusted to room temperature. Next, L
-21.3 g (0.185 mol) of proline and 40.2 g (0.370 mol) of trimethylsilyl chloride were added.

Finally, 37.4 g (0.370 mol) of triethylamine was slowly added dropwise at room temperature over 30 minutes, and the mixture was further stirred for 4 hours.

The silyl derivative is hydrolyzed by adding 60 ml of water, the methylene chloride layer is further washed with 60 ml of water, dried with anhydrous magnesium sulfate, and methylene chloride is distilled off under reduced pressure to give 1- ( D-3-acetylthio-2-methylpropanoyl) -L-proline was converted to 46.6.
g (97.2% yield). This product has high purity (96.0% by HPLC method) and can be purified by recrystallization from ethyl acetate or a mixed solvent of ethyl acetate-n-heptane.

Example 2 Preparation of 1- (D-3-acetylthio-2-methylpropanoyl) -L-proline D-3-acetylthio-2-methylpropanoic acid 50.0
g (0.308 mol) and N-methylmorpholine 0.0
5 g was dissolved in 100 ml of methylene chloride and heated to the reflux temperature. 40.4 g of thionyl chloride (0.340
Mol) was added dropwise over one and a half hour, and the mixture was further stirred under reflux for 4 hours. Under reduced pressure, methylene chloride and residual thionyl chloride were distilled off, and 100 ml of methylene chloride was added.
A solution of 3-acetylthio-2-methylpropanoic acid chloride in methylene chloride was obtained. To this solution, add methylene chloride 3
35.5 g (0.308 mol) of L-proline in 00 ml
And 36.5 g (0.616 mol) of acetamide were added in suspension, and 67.0 g of trimethylsilyl chloride was further added.
(0.616 mol) and the aforementioned D-3-acetylthio-
A solution of 2-methylpropanoic acid chloride in methylene chloride was added.

Finally, at room temperature, triethylamine 6
2.4 g (0.616 mol) was slowly added dropwise over 30 minutes, and the mixture was further stirred for 7 hours. After hydrolyzing with 100 ml of water,
The methylene chloride layer was washed with 200 ml of water, dried over anhydrous magnesium sulfate, and methylene chloride was distilled off under reduced pressure to obtain 1- (D-3-acetylthio-2-methylpropanoyl) -L-proline 79. .2 g were obtained. 99.1% yield. When the product was analyzed by the HPLC method, the purity was 98.8%.

Comparative Example 1 Preparation of 1- (D-3-acetylthio-2-methylpropanoyl) -L-proline D-3-acetylthio-2-methylpropanoic acid 50.0
g (0.308 mol) and N-methylmorpholine 0.0
5 g is dissolved in 100 ml of methylene chloride and the temperature is raised to the reflux temperature. 40.4 g of thionyl chloride (0.340
Mol) was added dropwise over one and a half hour, and the mixture was further stirred under reflux for 4 hours. Under reduced pressure, methylene chloride and residual thionyl chloride were distilled off, and 100 ml of methylene chloride was added to add D-
A solution of 3-acetylthio-2-methylpropanoic acid chloride in methylene chloride was obtained. Next, 35.5 g (0.308 mol) of L-proline and 36.5 acetamide were added to this solution.
g (0.616 mol) were suspended in methylene chloride (300 ml), and trimethylsilyl chloride (67.0) was further added.
g (0.616 mol) was added. To this, 62.4 g (0.616 mol) of triethylamine was added dropwise at room temperature over 30 minutes, and the mixture was further stirred at 25 to 35 ° C for 2 hours.

Finally, the aforementioned D-3-acetylthio-2
A methylene chloride solution of -methylpropanoic acid chloride was added dropwise at room temperature over 1 hour. After stirring at room temperature for 4 hours,
Hydrolysis with 100 ml of water, and methylene chloride layer
And washed. The methylene chloride layer was dried with anhydrous magnesium sulfate and concentrated to obtain an oily target substance having a purity of about 70%. This was further purified with ethyl acetate-n-heptane 1: 2 to obtain 54.7 g of 1- (D-3-acetylthio-2-methylpropanoyl) -L-proline. Yield 68.4%, purity 97.0% (HPLC method).

Comparative Example 2 Preparation of 1- (D-3-acetylthio-2-methylpropanoyl) -L-proline 1- (D-3-acetylthio-2-methylpropanoyl) -L-proline 1- (D-3-acetylthio-2-methylpropanoyl) -L-proline (D-3-acetylthio-2-methylpropanoyl) -L-proline was produced. The color of the reaction mixture was poor, and the content of the target compound in the obtained oily substance was 46.6% (HPLC), and the yield was 4%.
It was 4.7%.

[0035]

According to the production method of the present invention, by a simple operation, a stoichiometric amount of the starting compound is used and almost quantitatively,
High-purity 1- (D-3-acetylthio-2-methylpropanoyl) -L-proline can be produced.

Claims (5)

(57) [Claims] 1. An organic tertiary amine in the presence of an optically active D-3-acetylthio-2-methylpropanoic acid chloride, L-proline and a silyl chloride derivative represented by the formula (I) in an aprotic solvent. 1- (D-3-acetylthio- represented by the formula (II) characterized by being added dropwise.
Production method of 2-methylpropanoyl) -L-proline. Embedded image Embedded image 2. The method according to claim 1, wherein the silyl chloride derivative is at least one selected from the group consisting of trimethylsilyl chloride, n-butyldimethylsilyl chloride and tert-butyldimethylsilyl chloride. 3. The method according to claim 1, wherein the aprotic solvent is at least one selected from the group consisting of methylene chloride, ethylene chloride, chloroform and carbon tetrachloride. 4. The method according to claim 1, wherein the organic tertiary amine is triethylamine, trimethylamine or N-methylmorpholine. 5. The method according to claim 1, wherein acetamide, dimethylacetamide or N, N-dimethylformamide is further present.
The manufacturing method described in the item.