JPH0484896A - Production of optically active isoindoline-1-one derivative - Google Patents

Abstract

PURPOSE:To obtain the title derivative as a useful antiarrhythmic agent by reaction between an isoindoline-1-one derivative and a carboxylic acid, etc., in a solvent containing a specific enzyme. CONSTITUTION:Firstly, by selection from lipase, etc., derived from Pseudomonas microorganisms, an enzyme capable of asymmetrically acylating an isoindoline-1- one derivative of formula I (A) [ triacylglycerol lipase (B)] is obtained. Second, a reaction liquid (C) is prepared by adding to a solvent such as toluene (1) 0.5-25wt.% of the component A, (2) a carboxylic acid of formula II (R is lower alkyl) (ester) or its reactive derivative (e.g. propionic acid) and (3) 0.1-50wt.%, based on the component A, of the component B. Third, the component C is reacted at -20 to 50 deg.C for 1-46hr to stereoselectively acylate the component A into an acylated compound (D). Finally, the component D is separated from the component C and put to hydrolysis treatment, thus producing the objective optically active isoindoline-1-one derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a method for producing optically active isoindolin-1-one derivatives. Optically active isoindolin-1-one derivatives are useful as raw materials for producing optically active forms of 2-diethylaminoethylisoindolin-1-one derivatives useful as antiarrhythmic drugs.

Prior Art Methods for preparing isoindolin-1-one derivatives are reported in US Pat. No. 3,091,568 and US Pat. No. 3,849,570. Regarding the 2-diethylaminoethylisoindolin-1-one derivative, its strong antiarrhythmic action is disclosed in JP-A-63264457 along with its synthesis method. All of these are racemates, and no method for producing optically active isoindolin-1-one derivatives is known.

Problems to be Solved by the Invention In general, for racemic compounds known to have certain pharmacological effects, their optically active forms are expected and sought after for research and development.

An object of the present invention is to provide a method for producing an optically active isoindolin-1-one derivative "JBk" which is useful as a raw material for producing an optically active diethylaminoethyl isoindolin-1-one derivative having a strong antiarrhythmic effect. There is a particular thing.

Means for Solving the Problems The present invention provides an isoindolin-1-one derivative represented by the following formula (I) [hereinafter referred to as compound (1)] and the formula (wherein R represents a lower alkyl group). Compound (1) is stereoselectively produced by reacting the carboxylic acid represented by the formula (1), its ester, or its reactive derivative in a solvent in the presence of an enzyme capable of asymmetrically acylating compound (1). Acylated, and the acylated compound (
The present invention relates to a method for producing an optically active form of compound (1), which comprises separating compound (1) and then subjecting it to hydrolysis treatment.

Furthermore, the present invention provides stereoselective hydration of a compound represented by the following formula (II) (wherein R represents a lower alkyl group) in the presence of an enzyme capable of converting the compound (hereinafter referred to as compound (II)). The present invention relates to a method for producing an optically active compound (I), which comprises decomposing the compound (I) and separating the hydrolyzed compound (II) from a reaction solution.

In the definition of formula (II), lower alkyl groups include straight or branched alkyl groups having 1 to 4 carbon atoms, such as methyl,
Included are ethyl, propyl, isopropyl, butyl, isobutyl, 5ec-butyl, tert-butyl, and the like.

Next, a method for producing optically active compound (1) will be explained.

By stereoselectively acylating the racemic compound (1) obtained in Reference Example 1 with a carboxylic acid or its ester or its reactive derivative in the presence of an enzyme capable of asymmetric acylation in a solvent. An optically active form of compound (ff) which is an acylated form can be obtained. Any enzyme capable of stereoselectively acylating compound (r) can be used as the enzyme capable of asymmetric acylation. For example, if compound (II) is asymmetrically hydrolyzed in an aqueous medium, triadylglycerol lipase (EC3,1,1,3), carboxyesterase (ε [: 3.1.1. I), purified products of allyl esterase (EC3,1,1゜2), acetyl esterase (EC3,1,1,6), cholesterol esterase (EC3,1,1,13), etc. , crudely purified products, and products containing these enzymes, such as bacterial cells or treated bacterial cells containing these enzymes. Examples of triadylglycerol lipase include Lipase P Amano (
Lipoprotein lipase (LPL; derived from a microorganism of the genus Pseudomonas, manufactured by Ohno Pharmaceutical Co., Ltd.), Lipoprotein lipase (LPL; derived from a microorganism of the genus Monas, manufactured by Kyowa Medex), Cancidal lipase (derived from a microorganism of the genus Cancida, manufactured by Sigma), Porcine pancreas III I
In addition to enzymes such as J-pase (PPL; manufactured by Sigma) or immobilized enzymes such as lipozyme (derived from microorganisms of the genus Mucor, manufactured by Novo), Pseudomonas
s), Rhizopus spp., Aspergillus spp., Mucor spp.
Examples include triadylglycerol lipase produced by microorganisms from the genus Or), Candida, and Arthrobacter.

Examples of bacterial cell-treated products include dried bacterial cells, surfactant-treated products, enzyme-treated products, sonicated products, mechanically triturated products,
Solvent-treated products, protein fractions of bacterial cells, immobilized products of bacterial cells and treated bacterial cells, etc. are used.

As the solvent, toluene, benzene, ethyl acetate, dimethylformamide, tetrahydrofuran, isopropyl ether, chloroform, etc. are used alone or in combination. Examples of carboxylic acids include lower aliphatic carboxylic acids such as acetic acid, propionic acid, and butyric acid, and examples of their esters include lower alkyl esters or enol esters such as methyl ester, ethyl ester, vinyl ester, isopropenyl ester, and butyl ester. etc., and acid anhydrides and the like are used as the reactive derivatives thereof.

Compound (1) is used in an amount of 0.5 to 25% by weight based on the reaction solution, and enzyme is used in an amount of 0.1 to 50% by weight based on compound (I). The reaction is carried out at -20 to 50°C and is usually completed in 1 to 46 hours.

Next, the optically active form of compound (II) and unreacted compound (1) are separated.

Since compound (1) is stereoselectively acylated, unreacted compound (1) is also obtained as an optically active form.

Furthermore, optically active compound N) can be obtained by hydrolyzing the optically active form of compound (II) using a known method.

Optically active compound (I) can also be synthesized in the presence of an enzyme capable of asymmetrically hydrolyzing compound (II>) in an aqueous medium.
It can be obtained by stereoselective hydrolysis. As compound (It), in addition to the racemate, an optically active form of compound (II) obtained by the asymmetric acylation reaction may be used.

Enzymes that have the ability to asymmetrically hydrolyze compounds (
Any enzyme capable of stereoselectively hydrolyzing U) can be used. For example, triazylglycerol lipase (EC3,1,1,3) produced by microorganisms or isolated from animal tissues.
, purified products and crude products of carboxyesterase (EC3,1,1,1), allyl esterase (EC3,1,1,2), acetyl esterase (EC311,6), cholesterol esterase (EC3,11,13), etc. ,
Materials containing these enzymes include, for example, bacterial cells or treated bacterial cells containing these enzymes. Examples of triadylglycerol lipase include Lipase P Amano (derived from Pseudomonas microorganisms, Amano Pharmaceutical Co., Ltd. +/M)
Enzymes such as lipoprotein lipase (LPL: derived from a microorganism of the genus Pseudomonas, manufactured by Kyowa Medex), cansida lipase (derived from a microorganism of the genus Cansida, manufactured by Sigma), porcine pancreatic lipase (PPL; manufactured by Sigma), or lipozyme ( In addition to immobilized enzymes such as Mucor microorganisms (manufactured by Novo), Pseudomonas
Genus, Rhizopus II, Genus Aspergillus, Mucor
Examples include triadylglycerol lipase produced by microorganisms derived from the genus Or), the genus Candida, and the genus Arthrobacter Ii.

Examples of the bacterial cell-treated product include those similar to those mentioned above.

As the aqueous medium, water or a mixed solvent of water and ethanol, acetone, dimethylformamide, tetrahydrofuran, etc. is used. In addition, in order to improve the dispersibility of the substrate compound (II), nonion (manufactured by NOF Corporation),
Surfactants such as Span (manufactured by Kanto Kagaku Co., Ltd.) and Triton (manufactured by Gyudon Kagaku Co., Ltd.) can also be added.

Furthermore, a buffer solution can also be used to keep the pH constant during the reaction. As a buffer solution, sodium phosphate,
Examples include buffers of inorganic acid salts such as potassium phosphate, and buffers of organic acid salts such as sodium acetate and sodium citrate. It is also possible to add a base such as sodium hydroxide, if necessary.

Compound (II) is used in an amount of 0.1 to 50% by weight based on the reaction solution, and enzyme is used in an amount of 0.1 to 50% by weight based on compound (II). The reaction is carried out at 10-70°C, preferably at 2
It is carried out at 0 to 50°C and is completed in 1 to 24 hours.

Since compound (II) is stereoselectively hydrolyzed,
The unreacted compound (ff) is also obtained as an optically active compound. By hydrolyzing this unreacted optically active compound (I[) by a known method, optically active compound (I) is obtained.
can be obtained.

The optically active compound (r) is useful as an antiarrhythmic drug.
It is useful as a raw material for producing an optically active form of -diethylaminoethylisoindolin-1-one derivative [hereinafter referred to as compound (Illr)], and the method for producing compound (III) will be described below.

The optically active compound (I) is reacted with methyl chloride, tosyl chloride, etc. in a solvent in the presence of a base to activate the hydroxyl group, and then reacted with diethylamine to form an optically active compound (II) represented by the following formula. [) can be obtained.

As the solvent, dimethylformamide, acetone, tetrahydrofuran, chloroform, etc. are used alone or in combination. As the base, an organic base such as triethylamine or methylmorpholine is used in an amount of 1 to 10 equivalents based on compound (II). Diethylamine is used in an amount of 2 to 10 equivalents based on compound (II). The reaction is completed in 1 to 24 hours at a temperature between room temperature and 100°C.

The target compound in the above production method can be isolated and purified by filtration, extraction, washing, drying, concentration, recrystallization, and various types of chromatography. Furthermore, the intermediate can be used in the next reaction without being particularly purified.

Examples and reference examples are shown below.

Example 1 3-(2-amino-5cyanophenyl)-2-(2-hydroxyethyl)isoindoline obtained in Reference Example 1
Dissolve 400 mg of 1-one in 10-ethyl acetate and add 0.28 mcy of acetic anhydride (!: lipoprotein lipase (
67 mg of LPL (manufactured by Kyowa Medex Co., Ltd.) was added, and the mixture was reacted at room temperature for 4 hours. (+)-3-(2
-amino-5-cyanophenyl)-2-(2-a7toxyethylnisoindolin-1-one [hereinafter referred to as (+)~
abbreviated as acetate] 213■ (yield 46%) and unreacted (-)-3-(2-amino-5-cyanophenyl)
-2-(2-hydroxyethyl)isoindoline-1-
2in [hereinafter abbreviated as (-)-alcohol 1183
mg (yield 45.8%). Their optical purity was determined by high performance liquid chromatography [HPLC, column Chiralcel OD (manufactured by Daicel Corporation), using hexane:ethanol:diethylamine-900/100:1, flow rate 0.8
The optical purity of (+)-acetate and (-)-alcohol were 80% ee and 95% ee, respectively, as measured by absorption at 254 nm. (−)−
The optical rotation of alcohol was −46.5° (c=1.ethanol).

Examples 2 to 4 The following enzymes were used instead of LPL used in Example 1,
The reaction was carried out in the same manner as in Example 1. The generated (+
)-acetate, (-) indicates the optical purity of alcohol.

Table 1 Lipase P Amano 18 46 22 Ribozyme 4 12 10 Cancidal Lipase 24 32 28*: Reaction time is approximately 50% acylated time.

Example 5 159 g (+)-acetate obtained in Example 1 (optical purity 88% ee) was dissolved in 1.6 d dimethylformamide, and 80- phosphate buffer containing 60 mg LPL and 0.5% Triton X was added. A mixed solvent of solution (p) 17) and 8-ethanol was added to suspend the mixture, and the mixture was reacted at room temperature for 5 hours. The reaction solution was extracted with 100-ethyl acetate, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 960a+g (yield 6).
9%) of (+)-alcohol was obtained.

[Optical purity:>95%ee, optical rotation: -4-57,3
゜(C=1, ethanol)] Reference example 1 2-cyano-11-hydroxy-5,11-dihydro-
6H-DibenzoCb,e] 2.5 g of azepine 6-one
was dissolved in 40 ml of tetrahydrofuran and 2,8-dimethylacetamide, and 2.1 g of triethylamine and 15 g of mesyl chloride were added under water cooling. The reaction solution was reacted at room temperature for 1 hour, 2.2 g of monoaminoethanol was added, and the reaction was further allowed to react for 3 hours. 50ml of water and 100ml of ethyl acetate were added to the reaction solution for extraction and the organic layer was separated. This organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Ethanol 50 proof saturated with hydrogen chloride was added to the residue, and the mixture was heated under reflux for 3 hours. After cooling, the reaction solution was concentrated. Ethyl acetate was added to the resulting residue, which was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (200d; eluted with ethyl acetate) to obtain 2.1 g (yield 71.7%) of 3-
(2-Amino-5-cyanophenyl)-2-(2-hydroxyethyl)isoindolin-1-one was obtained as a pale yellow powder.

Reference Example 2 748 mg of (-)-alcohol obtained in Example 1 was added to 1
The solution was dissolved in 5 liters of methylene chloride, and 0.569 liters of triethylamine and 0.303 liters of mesyl chloride were added dropwise under water cooling. After reacting at room temperature for 1 hour, 50-chloroform was added to perform extraction. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 820 mg (yield: 86.6%) of mesylate powder [optical rotation: 13
5.4° (c=1. ethanol)].

This powder was dissolved in 15-chloroform, and 0°91-diethylamine was added thereto, followed by gentle heating under reflux for 4 hours. After cooling, extraction was performed by adding chloroform, and the organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluted with ethyl acetate:triethylamine-40.1), and the eluate was concentrated under reduced pressure. The obtained residue was dissolved in a small amount of ethanol, ethanol saturated with hydrogen chloride was added to form a hydrochloride salt, solidified with water, and dried to give (-)3-(2-amino-5-cyanophenyl). )−
2(2-diethylaminoethyl)isoindoline-1-
690 mg (yield 70.4%) of On.hydrochloride was obtained. [
Optical purity: 93%ee, melting point = 131-134°C, optical rotation: -87,8° (C-1, ethanol)] Reference example 3 (-) - Obtained in Example 3 instead of alcohol (+
)-Producted in the same manner as in Reference Example 2 except for using alcohol,
712 mg (yield 71.2%) of (+)-3-(2-amino-5-cyanophenyl)-2-(2-diethylaminoethyl)isoindolin-1-one hydrochloride was obtained [
Optical purity: 95%ee, melting point °129-132 °C, optical rotation: 91.4 ° (c = 1. ethanol)].

Effects of the Invention The present invention provides a method for producing optically active isoindolin-1-one derivatives.

Claims (4)

[Claims] (1) Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼The isoisodrin-1-one derivative represented by (I) [hereinafter referred to as compound (I)] and the formula represents an alkyl group) or its ester or its reactive derivative in a solvent in the presence of an enzyme capable of asymmetrically acylating compound (I). ) is stereoselectively acylated, the acylated compound (I) is separated from the reaction solution, and then subjected to hydrolysis treatment. (2) From the reaction solution according to claim 1, unreacted compounds (
A method for producing an optically active form of compound (I) according to claim 1, which comprises collecting I). (3) Formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R represents a lower alkyl group.) A compound [hereinafter referred to as compound (II)] is aqueous. A claim characterized in that Compound (II) is stereoselectively hydrolyzed in a medium in the presence of an enzyme capable of asymmetrically hydrolyzing the compound, and the hydrolyzed Compound (II) is separated from the reaction solution. Item 1. A method for producing an optically active form of compound (I) according to item 1. (4) From the reaction solution according to claim 3, unreacted compound (I
2. A method for producing an optically active form of compound (I) according to claim 1, which comprises separating I) and subjecting it to a hydrolysis treatment.