JP3011784B2 - New pyridinesulfonic acid ester - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound of the general formula (1)

[0002]

Embedded image (Wherein, R ¹ is an optionally substituted phenyl group, R ² is an alkyl group having 1 to 5 carbon atoms, R ³ is an optionally substituted pyridyl group, and the star is R A pyridinesulfonic acid ester represented by an asymmetric carbon atom having a configuration or S configuration) and a method for producing the same.

[0003] R-2- (pyridinesulfonyloxy) -4-phenylbutyric acid ester or a derivative thereof contained in the above general formula is used for 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]

2. Description of the Prior Art The pyridinesulfonic acid ester represented by the above general formula and these compounds are represented by the general formula (4):

[0005]

Embedded image (Wherein, R ⁴ is a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms, and R ⁵ represents a hydrogen atom or an alkoxycarbonylalkyl group). General formula (5) in which the absolute configuration of the asymmetric carbon atom is reversed

[0006]

Embedded image (Wherein R ¹ , R ² , R ⁴ and R ⁵ are as defined above, and * ¹ represents the opposite absolute configuration to the above *). Not known at all.

[0007] The angiotensin converting enzyme inhibitor requires only one of the two conformations. Therefore, in their production, it is extremely important from an economic point of view to carry out the reaction while maintaining the stereoscopic state of the optically active raw material or to efficiently invert and maintain a high optical purity to obtain a target product from an economic viewpoint.

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

[0009]

According to the present invention, the above object is achieved by the general formula (2)

[0010]

Embedded image (Wherein R ¹ , R ² and the asterisk are as defined above) and a general formula (3)

[0011]

Embedded image (Wherein, R ³ is an optionally substituted pyridyl group, and X represents a halogen atom or an R ³ SO ₃ group).

[0012]

Embedded image (Wherein R ¹ , R ² , R ³ and the asterisk are as defined above) represented by the general formula (4)

[0013]

Embedded image (Wherein, R ⁴ is a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms, and R ⁵ represents a hydrogen atom or an alkoxycarbonylalkyl group). And the corresponding general formula (5)

[0014]

Embedded image (Wherein R ¹ , R ² , R ⁴ and R ⁵ are as defined above, and * ¹ represents the absolute configuration opposite to the above *). This led to the present invention.

In the general formula (1), R ¹ , R ² and R ³
Will be described in detail. R ¹ is a phenyl group which may be substituted, and examples thereof include a phenyl group, a p-tolyl group, and a p-chlorophenyl group. Particularly, a phenyl group is important as a raw material for synthesizing an angiotensin converting enzyme inhibitor. R ² 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, and a pentyl group. Of these, the ethyl group is particularly important. R ³ is a pyridyl group which may be substituted; 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 4-methyl-2
And a 3-pyridyl group can be preferably used.

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

Next, R ⁴ and R ^{5 in} the general formula (4) will be described. R ⁴ is a hydrogen atom or a carbon number of 1 to 8
A chain or cyclic hydrocarbon group such as a methyl group, an ethyl group, a propyl group, an i-propyl group, an allyl group, a butyl group, a t-butyl group and a cyclohexyl group; -Aromatic hydrocarbon groups such as a tolyl group and a benzyl group. R ^{5 includes} a hydrogen atom, a (1-benzyloxycarbonyl) ethyl group, a (1-t-butyloxycarbonyl) ethyl group, and the like.

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

The pyridine sulfonic acid ester of the general formula (1) is obtained by sulfonyloxylation of the -OH group of the optically active 2-hydroxybutyric acid ester of the general formula (2) with a pyridine sulfonyl compound of the general formula (3). It can be manufactured by doing. The pyridinesulfonyl compounds of the general formula (3) are R ³ -sulfonyl halide and R ³ -sulfonic anhydride. 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 hydrides such as benzene and toluene; ethers such as ether, i-propyl ether and butyl ether can be used. As the base, an inorganic or organic base can be used. As the inorganic base, for example, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide and the like can be used. As the organic base, tertiary amines such as pyridine, triethylamine and tripropylamine can be used.

The reaction is preferably carried out in an atmosphere of an inert gas such as nitrogen at a temperature in the range of -50 ° C to 100 ° C, preferably in the temperature range of -10 ° C to 60 ° C. In addition,
The 2-hydroxybutyric ester of the general formula (2) has an R configuration or an S configuration, but its steric shape is maintained throughout the reaction, and a pyridinesulfonic acid ester of the general formula (1) having a corresponding conformation can be obtained. .

The optically active 2-hydroxybutyrate of the general formula (2) is a known compound and can be produced by a method known per se (for example, EP 0 329 1).
56).

The pyridinesulfonic acid ester of the present invention reacts with the amines represented by the general formula (4) in the presence of a base while inverting to give an amino derivative of a butyric ester represented by the general formula (5). . Conventionally, a method for producing an α-aminocarboxylic acid ester derivative from an α-hydroxycarboxylic acid ester as a raw material without racemization is a method of converting an α-hydroxy group into an α-trifluoromethanesulfonyloxy group and then reacting ( Ang
w. Chem. , 95 , 50 (1983)), α-
A method in which a hydroxy group is converted to an α-nitrophenylsulfonyloxy group and then reacted (JP-A-61-2890).
No. 73) and so on, by reacting a so-called sulfonyloxy group having a strong electron withdrawing group with an amino compound. From this, it was unexpected and surprising that the pyridinesulfonic acid ester of the present invention did not undergo racemization with amines and caused a substitution reaction with inversion.

The reaction between the pyridinesulfonic acid ester of the general formula (1) and the amines 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, an inorganic base such as a carbonate or hydrogencarbonate of an alkali metal or an alkaline earth metal; and an organic tertiary amine such as triethylamine, tributylamine and pyridine are used. The amount of the base is practically equal to or more than the equivalent to the pyridinesulfonic acid ester, particularly 1.1 to 5 equivalents. The amines of the general formula (4) can be used in the form of a salt such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and the like, and the reaction can be carried out by generating amines in the reaction system. In this case, an additional amount of the base required for neutralizing the acid must be used. The amount of the amines is practically equal to or more than equimolar to the pyridinesulfonic acid ester, particularly 1.1 to 3 equivalents. The reaction is carried out in a temperature range from room temperature to 200 ° C, preferably from 30 ° C to about 100 ° C. 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 And lower alcohol esters of lower fatty acids such as tertiary amides such as N, N-dimethylformamide and N-methylpyrrolidone. The reaction involves inversion at the replacement position. That is, the absolute configuration at the 2-position of the general formula (1) is reversed through the reaction. Therefore, the pyridinesulfonic acid ester in which the absolute configuration at the 2-position is R gives an amino derivative of the general formula (5) in which the absolute configuration at the 2-position is S preferentially, and the absolute configuration of the pyridinesulfonic acid ester is opposite to this. In the case of (1), an amino derivative having the opposite absolute configuration is preferentially provided.

After completion of the reaction, the reaction solution is poured into water, extracted with a solvent such as isopropyl ether, washed with water,
By distilling off the solvent under reduced pressure, the desired amino derivative can be isolated. The isolated amino derivative can be used as such or as a synthetic intermediate such as an angiotensin converting enzyme inhibitor after purification by column chromatography or the like.

For example, in the general formula (5), R ¹ is a phenyl group, R ² is an ethyl group, R ³ is a hydrogen atom, R ⁵ is a benzyloxycarbonylethane-1-yl group, and * ¹ is S
The compound in the configuration is treated under the usual conditions for hydrogenolysis of a benzyl group, for example, as described in Chem. Pha
rm. Bull. , 37.280 (1989), N- (S-1-ethoxycarbonyl-3).
-Phenylpropyl) -L-alanine. This compound is described, for example, in Chem. Pharm. Bull
l. , 34.2852 (1986), which is known as an angiotensin converting enzyme inhibitor by reacting with L-proline-t-butyl ester, removing the t-butyl group and reacting with maleic acid. Can be guided to Enarabrill. From this,
It is apparent that the novel pyridinesulfonic acid ester provided by the present invention is useful as a raw material for synthesizing an angiotensin converting enzyme inhibitor.

[0026]

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

NMR spectrum (CDCl ₃ , 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) In a 1000 ml three-necked flask, 66.0 g of the above oil component, L
-81.7 g of alanine benzyl ester, 60.4 g of sodium carbonate and 300 g of tetrahydrofuran were taken, and reacted under a nitrogen gas atmosphere with vigorous stirring for 50 hours. The progress of the reaction was determined by gas chromatography (G
Tracked in C). After the reaction, 90 g of toluene was added to the reaction solution.
And 120 g of water, and the organic layer was separated. The organic layer was further washed twice with 150 g of water, and toluene was distilled off under reduced pressure using an evaporator to give 52.2 g of a light brown oil.
I got This oil was determined to be N- (S-1-
(Ethoxycarbonyl-3-phenylpropyl) -L-alanine benzyl ester.

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

HPLC conditions: column CHIRALCEL
OD, 4.6 × 250mm developing solution isopropanol /
Hexane = 1/10 Detector UV (254 nm) Reference Example Dissolve 29.9 g of oil [N- (S-1-ethoxycarbonyl-3-phenylpropyl) -L-alanine benzyl ester] obtained in Example in 717 g of ethanol. , 10
% Pd / C 2.4 g, hydrogen pressure 5 kg / c
The reaction was carried out at m ² and an internal temperature of 40 to 50 ° C. for 5 hours. After completion of the reaction, 10% Pd / C was filtered, and ethanol was distilled off under reduced pressure to obtain 21.5 g of a white powder. This white powder is N
The MR spectrum is described in the literature (Chem. Pharm.
l. , 37, 280 (1989).
It was confirmed to be N- (S-1-ethoxycarbonyl-3-phenylpropyl) -L-alanine.

[0030]

According to the present invention, there is provided a pyridinesulfonic acid ester which is useful as a raw material for synthesizing a drug such as an angiotensin converting enzyme inhibitor.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 213/71 CA (STN) REGISTRY (STN)

Claims (7)

(57) [Claims] 1. A compound of the general formula (1) (Wherein R ¹ is a phenyl group, a p-tolyl group,
R ² is a group selected from the group consisting of
R ³ is an unsubstituted or methyl group
Is a pyridyl group substituted with an asterisk (R) configuration or S
A pyridinesulfonic acid ester represented by the following formula: 2. The pyridinesulfonic acid ester according to claim 1, wherein R ¹ is a phenyl group, R ² is an ethyl group, R ³ is a pyridyl group, and the asterisk is an asymmetric carbon atom in the R configuration. . 3. The pyridinesulfonic acid ester according to claim 1, which is ethyl R-2- (3-pyridinesulfonyloxy) -4-phenylbutyrate. 4. A compound of the general formula (2) (Wherein R ¹ is a phenyl group, a p-tolyl group,
R ² is a group selected from the group consisting of
And an asterisk represents an asymmetric carbon atom having an R configuration or an S configuration.) An optically active 2-hydroxybutyrate represented by the general formula (3): Wherein R ³ is an unsubstituted or methyl-substituted pyridyl group, and X represents a halogen atom or an R ³ SO ₃ group, which is sulfonylated with a pyridinesulfonyl compound represented by the formula: General formula (1) characterized by the following: (Wherein R ¹ , R ² , R ³ and the asterisk are as defined above). 5. The method according to claim 4, wherein X is a chlorine atom. 6. A compound of the general formula (1) (Wherein R ¹ is a phenyl group, a p-tolyl group,
R ² is a group selected from the group consisting of
R ³ is an unsubstituted or methyl group
Is a pyridyl group substituted with an asterisk (R) configuration or S
A pyridinesulfonic acid ester represented by the general formula (4): Wherein R ⁴ is a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms, and R ⁵ represents a hydrogen atom or an alkoxycarbonylalkyl group. Characteristic general formula (5) (Wherein, R ¹ , R ² , R ⁴ and R ⁵ are as defined above, and * ¹ represents an absolute configuration opposite to the above *). 7. The process according to claim 6, wherein the butyric ester amine derivative is L-alanine ester.