JPH04312575A - New pyridinesulfonic acid ester - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as a synthetic raw material for medicines such as angiotensin converting enzyme inhibitors. CONSTITUTION:A compound, e.g. ethyl R-2-(3-pyridinesufonyloxy)-4- phenylbutyrate expressed by formula I (R<1> is phenyl; R<2> is 1-5C alkyl; R<3> is pyridine; the asterik mark indicates asymmetric carbon atom of R or S configuration). The aforementioned compound is obtained by sulfonyloxylating an optically active 2-hydroxybutyric acid ester expressed by formula II with a pyridinesulfonyl compound expressed by formula III (X is halogen or R<3>SO3).

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention relates to general formula (1)

000
2]

[Image Omitted] (In the formula, R1 is an optionally substituted phenyl group, R2 is an alkyl group having 1 to 5 carbon atoms, and R3
is an optionally substituted pyridyl group, and the asterisk represents an asymmetric carbon atom in the R or S configuration) and a method for producing the same.

[0003] R-2-(pyridinesulfonyloxy)-4-phenylbutyric acid ester or its derivatives included in the above general formula are used in the synthesis of pharmaceuticals such as angiotensin converting enzyme inhibitors such as delapril, quinapril, enalapril, ramipril, lisinopril, and spirapril. Useful as a raw material.

0004

[Prior Art and Problems] Pyridine sulfonic acid esters of the above general formula and these compounds have the general formula (
4)

[0005]

[Chemical formula 9] (wherein, R4 is a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms, and R5 is a hydrogen atom or an alkoxycarbonylalkyl group) and an amination reaction with inversion. General formula (5) in which the absolute configuration of the asymmetric carbon atom is reversed by causing

[0006]

This is what can be derived from the amine derivative of butyric acid ester represented by the following formula (wherein R1, R2, R4 and R5 are as defined above, and *1 represents the opposite absolute configuration to * above). completely unknown until now.

[0007] The above-mentioned angiotensin converting enzyme inhibitors are required to have only one conformation at the 2-position. Therefore, in the production of these materials, it is extremely important from an economic point of view to carry out the reaction while maintaining the steric structure of the optically active raw material or to invert it efficiently to maintain high optical purity and lead to the target product.

Therefore, the object of the present invention is to provide a novel pyridine sulfonic acid ester that can be easily derived from a known optically active 2-hydroxybutyric acid ester, and by using such a pyridine sulfonic acid ester, a high yield can be obtained. Another object of the present invention is to provide a method for producing synthetic intermediates such as angiotensin converting enzyme inhibitors with high optical purity.

[0009]

[Means for Solving the Problems] According to the present invention, the above object is achieved by formula (2)

0010

Optically active 2-hydroxybutyric acid ester represented by the formula (wherein R1, R2 and the asterisk are as defined above) and the general formula (3)

[0011]

[Formula 12] (wherein, R3 is an optionally substituted pyridyl group, and X represents a halogen atom or a R3 SO3 group)
General formula (1) that can be produced from the pyridine sulfonyl compound represented by

0012

A novel pyridine sulfonic acid ester represented by the general formula (4) (wherein R1, R2, R3 and the asterisk are as defined above)

[0013]

[Chemical formula 14] (wherein, R4 is a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms, and R5 is a hydrogen atom or an alkoxycarbonylalkyl group) and 2-
A substitution reaction accompanied by inversion occurs at the corresponding general formula (
5)

[0014]

The amine derivative of butyric acid ester represented by the formula (wherein R1, R2, R4 and R5 are as defined above, and *1 represents the opposite absolute configuration to * above) is obtained in good yield. This discovery led to the present invention.

R1, R2 and R3 in the above general formula (1) will be explained in detail. R1 is an optionally substituted phenyl group, such as phenyl group, p-tolyl group, p-
Examples include chlorphenyl group. In particular, the phenyl group is important as a raw material for the synthesis of angiotensin-converting enzyme inhibitors. R2 is an alkyl group having 1 to 5 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an i-propyl group, a butyl group, a t-butyl group, a pentyl group, and the like. Among these, the ethyl group is particularly important. Also,
R3 is an optionally substituted pyridyl group, and 2-
Examples include pyridyl group, 3-pyridyl group, 4-pyridyl group, 4-methyl-2-pyridyl group, and 3-pyridyl group is preferably used.

Next, X in general formula (3) will be explained. X represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or represents the sulfonyloxy group of R3 described above. Particularly preferred X is a chlorine atom and a 3-
It is a pyridine sulfonyloxy group.

Next, R4 and R5 of general formula (4)
I will explain about it. R4 is a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms, such as methyl group, ethyl group, propyl group, i-propyl group, allyl group, butyl group,
Chain or cyclic hydrocarbon groups such as t-butyl group and cyclohexyl group; aromatic hydrocarbon groups such as phenyl group, p-tolyl group and benzyl group. In addition, R5 is a hydrogen atom and (1-benzyloxycarbonyl)
Examples include ethyl group and (1-t-butyloxycarbonyl)ethyl group.

In the present invention, a pyridine sulfonic acid ester having an R configuration or an S configuration represented by the general formula (1) is provided, which is further subjected to a substitution reaction with amines. At this time, reversal occurs as will be described later. Therefore,
When producing an amino derivative of general formula (5) with S configuration used in the synthesis of angiotensin converting enzyme inhibitor, R
A pyridine sulfonic acid ester of the configuration is used.

The pyridine sulfonic acid ester of the general formula (1) is produced by sulfonyloxylating the -OH group of the optically active 2-hydroxybutyric acid ester represented by the general formula (2) with a pyridine sulfonyl compound represented by the general formula (3). It can be manufactured by The pyridine sulfonyl compounds of general formula (3) are, ie, R3-sulfonyl halides as well as R3-sulfonic anhydrides. The reaction is conveniently carried out in an inert solvent in the presence of a base. As the inert solvent, halogenated hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride; aromatic hydrogens such as benzene and toluene; and ethers such as ether, i-propyl ether, and butyl ether can be used. An inorganic or organic base can be used as the base. Examples of inorganic bases that can be used include sodium carbonate, potassium carbonate, sodium bicarbonate, and sodium hydroxide, and examples of organic bases that can be used include tertiary amines such as pyridine, triethylamine, and tripropylamine.

The reaction is preferably carried out under an inert gas atmosphere such as nitrogen at a temperature range of -50°C to 100°C, preferably -10°C to 60°C. In addition, although the 2-hydroxybutyric acid ester of general formula (2) has the R configuration or the S configuration, its stericity is maintained throughout the reaction, and it is possible to obtain the pyridine sulfonic acid ester of the general formula (1) with the corresponding configuration. Can be done.

The optically active 2-hydroxybutyric acid ester of general formula (2) is a known compound and can be produced by a method known per se (for example, EP 0 329
156).

The pyridine sulfonic acid ester of the present invention reacts with an amine represented by the general formula (4) in the presence of a base with inversion to give an amino derivative of the butyric acid ester represented by the general formula (5). . Conventionally, the method for producing α-aminocarboxylic acid ester derivatives without racemization using α-hydroxycarboxylic acid ester as a raw material is a method in which α-hydroxy group is converted to α-trifluoromethanesulfonyloxy group and then reacted ( Ange
w. Chem. , 95, 50 (1983)), α-
A method of converting a hydroxy group into an α-nitrophenylsulfonyloxy group and then reacting it (Japanese Patent Application Laid-Open No. 61-2890
73), etc., by reacting a sulfonyloxy group having a strong electron-withdrawing group with an amino compound. From this, it was unexpected and surprising that the pyridine sulfonic acid ester of the present invention would undergo a substitution reaction accompanied by inversion without causing racemization with amines.

The reaction between the pyridine sulfonic acid ester of the general formula (1) and the amine of the general formula (4) is preferably carried out in an atmosphere of an inert gas such as nitrogen or argon in the presence of a base. As the base, inorganic bases such as alkali metal or alkaline earth metal carbonates and hydrogen carbonates; organic tertiary amines such as triethylamine, tributylamine, and pyridine are used. Practically speaking, the amount of the base is at least equivalent to the pyridine sulfonic acid ester, particularly 1.1 to 5 equivalents. The amines of general formula (4) can also be used in the form of salts such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, etc., and the reaction can be carried out by generating the amines in the reaction system. In this case, the additional amount of base required to neutralize the acid must be used. Practically speaking, the amount of amines is at least equivalent molar to the pyridine sulfonic acid ester, particularly 1.1 to 3 equivalents. Further, the reaction is carried out under a temperature range of room temperature to 200°C, preferably 30°C to about 100°C. For the reaction, a solvent that does not adversely affect the reaction,
For example, halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform; linear or cyclic ethers such as 1,2-dimethoxyethane, tetrahydrofuran, and dioxane; lower alkanecarbonitrile such as acetonitrile; ethyl acetate, propyl acetate, and ethyl propionate. Lower alcohol esters of lower fatty acids such as: tertiary amides such as N,N-dimethylformamide and N-methylpyrrolidone are used. The reaction involves inversion at the position of substitution. That is, throughout the reaction, general formula (1)
The absolute configuration of the 2-position is reversed. Therefore, a pyridine sulfonic acid ester with an absolute configuration of R at the 2-position preferentially gives an amino derivative of general formula (5) with an absolute configuration of S at the 2-position, and the absolute configuration of a pyridine sulfonic acid ester is opposite to this. In the case of , amino derivatives with the opposite absolute configuration are preferentially given.

After the reaction is completed, the reaction solution is poured into water, extracted with a solvent such as isopropyl ether, and washed with water.
The desired amino derivative can be isolated by distilling off the solvent under reduced pressure. The isolated amino derivative can be used as a synthetic intermediate for angiotensin-converting enzyme inhibitors and the like, either as it is or after being purified by column chromatography or the like if necessary.

For example, in the general formula (5), R1 is a phenyl group, R2 is an ethyl group, R3 is a hydrogen atom, R5
Compounds in which is a benzyloxycarbonylethan-1-yl group and *1 is in the S configuration can be treated under normal hydrogenolysis conditions for a benzyl group, such as Che
m. Pharm. Bull. , 37.280 (1989
) can be derived from the known compound N-(S-1-ethoxycarbonyl-3-phenylpropyl)-L-alanine. This compound is described, for example, in Chem. Pharm.
Bull. , 34.2852 (1986), by reacting with L-proline-t-butyl ester, removing the t-butyl group, and reacting with maleic acid, it is known as an angiotensin-converting enzyme inhibitor. It can be guided to the enalabrils that are present. From this, it is clear that the novel pyridine sulfonic acid ester provided by the present invention is useful as a raw material for the synthesis of angiotensin-converting enzyme inhibitors.

[0026]

[Examples] The present invention will be explained below with reference to Examples, but the present invention is not limited thereto. Example Under a nitrogen atmosphere, 41.6 g of ethyl R-2-hydroxy-4-phenylbutyrate, 24.2 g of triethylamine, and 60 g of toluene were placed in a 500 ml three-necked flask, and 120 g of toluene was added to 37.6 g of 3-pyridinesulfonyl chloride.
The solution was added dropwise at an internal temperature of 20 to 35°C, and stirred at that temperature for 2 hours. The reaction was followed by TLC (developing solution: ethyl acetate/hexane = 4/6), and it was confirmed that ethyl R-2-hydroxy-4-phenylbutyrate had disappeared. Next, 90 g of 5% sulfuric acid water was added to this, and the mixture was stirred at room temperature for 1 minute. After separation, the organic layer was washed with water, and toluene was distilled off under reduced pressure to obtain 66 g of light brown oil. From the analysis results below, this oil is 3-pyridine sulfonyloxy-
It was confirmed that it was ethyl 4-phenylbutyrate.

NMR spectrum (CDCl3, ppm
) 1.20 (3H), 2.15-2.25 (2H), 2
．． 6-2.85 (2H), 4.1 (2H), 4.95-
5 (1H) 7.1-7.35 (5H), 7.52 (1H), 8.2
5 (1H), 8.9 (1H), 9.15 (1H) 66.0 g of the above oil in a 1000 ml three-necked flask,
81.7 g of L-alanine benzyl ester, 60.4 g of sodium carbonate, and 300 g of tetrahydrofuran were taken and reacted for 50 hours with vigorous stirring under a nitrogen gas atmosphere. The progress of the reaction was monitored by gas chromatography (GC).
) was tracked. After the reaction was completed, the reaction solution was poured into 90 g of toluene and 120 g of water to separate the organic layer. After washing the organic layer twice with 150 g of water, toluene was distilled off under reduced pressure using an evaporator to obtain 52.2 g of light brown oil. This oil was confirmed to be N-(S-1-ethoxycarbonyl-3-phenylpropyl)-L-alanine benzyl ester from the following analysis results.

GC conditions: Silicone OV-1
, Chromosorb W, 2%, 1m Column temperature 220°C Injection temperature 240°C Also, from liquid chromatography (HPLC) analysis,
N-(S-1-ethoxycarbonyl-3-phenylpropyl)-L-alanine benzyl ester (S) and N-(
R-1-ethoxycarbonyl-3-phenylpropyl)
-The ratio of L-alanine benzyl ester (R) is S/R
=98.4/1.6.

HPLC conditions: Column CHIRALCEL
OD, 4.6 x 250 mm Developing solution Isopropanol/hexane = 1/10 Detector UV (254 nm) Reference Example Oil obtained in Example [N-(S-1-ethoxycarbonyl-3-phenylpropyl)-L-alanine] Dissolve 29.9 g of benzyl ester in 717 g of ethanol,
After adding %Pd/C2.4g, the hydrogen pressure was 5kg/c.
m2, and the reaction was carried out for 5 hours at an internal temperature of 40 to 50°C. After the reaction was completed, 10% Pd/C was filtered and ethanol was distilled off under reduced pressure to obtain 21.5 g of white powder. This white powder is N
The MR spectra are from the literature (Chem.Pharm.Bul.
l. , 37, 280 (1989),
It was confirmed that it was N-(S-1-ethoxycarbonyl-3-phenylpropyl)-L-alanine.

[0030]

According to the present invention, a pyridine sulfonic acid ester useful as a raw material for synthesizing pharmaceuticals such as angiotensin converting enzyme inhibitors is provided.

Claims (7)

[Claims] Claim 1: General formula (1) [Formula 1] (wherein, R1 is an optionally substituted phenyl group, R2 is an alkyl group having 1 to 5 carbon atoms, and R3
is an optionally substituted pyridine group, and the asterisk represents an asymmetric carbon atom in the R or S configuration. [Claim 2] R1 is a phenyl group, R2 is an ethyl group, R3 is a pyridyl group, and the asterisk indicates R
The pyridine sulfonic acid ester according to claim 1, which has an asymmetric carbon atom configuration. 3. The pyridine sulfonic acid ester according to claim 1, which is ethyl R-2-(3-pyridinesulfonyloxy)-4-phenylbutyrate. [Claim 4] General formula (2) [Formula 2] (wherein, R1 is an optionally substituted phenyl group, R2 is an alkyl group having 1 to 5 carbon atoms, and the asterisk indicates the R configuration or An optically active 2-hydroxybutyric acid ester represented by the asymmetric carbon atom in the S configuration is expressed by the general formula (3) [
Chemical formula 3 (wherein, R3 is an optionally substituted pyridyl group, and X represents a halogen atom or a R3SO3 group)
A pyridine sulfone represented by the general formula (1) [Chemical formula 4] (wherein R1, R2, R3 and the asterisk are as defined above), which is sulfonyloxylated with a pyridine sulfonyl compound represented by Method for producing acid esters. 5. The production method according to claim 4, wherein X is a chlorine atom. [Claim 6] General formula (1) [Formula 5] (wherein, R1 is an optionally substituted phenyl group, R2 is an alkyl group having 1 to 5 carbon atoms, and R3
is an optionally substituted pyridyl group, and the asterisk represents an asymmetric carbon atom with R configuration or S configuration). is a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms, and R5 represents a hydrogen atom or an alkoxycarbonylalkyl group.
) A method for producing an amine derivative of butyric acid ester represented by the following formula: (wherein R1, R2, R4 and R5 are as defined above, and *1 represents the opposite absolute configuration to * above). 7. The method according to claim 6, wherein the amine derivative of butyric acid ester is L-alanine ester.