WO2000076995A1 - Process for the preparation of (-)-1,4-benzothiazine-2-acetic acid derivatives - Google Patents

Abstract

A process for the preparation of (-)-1,4-benzothiazine-2-acetic acid derivatives, characterized by conducting the optical resolution of a racemic modification of a 1,4-benzothiazine-2-acetic acid derivative represented by general formula (I) by forming a salt of the (-)-enantiomer of the derivative with an optically active substance: (wherein R?1 and R2¿ are each hydrogen or the like; R3 is carboxyl or the like; R?4, R5, R6 and R7¿ are each hydrogen, halogeno, or the like; and X is oxygen or the like). This process makes it possible to separate (-)-1,4-benzothiazine-2-acetic acid derivatives respectively from the corresponding (±)-1,4-benzothiazine-2-acetic acid derivatives in high yield and at high optical purity.

Description

 Item =

 (-) Method for producing 1,1,4-benzothiazin-2-acetic acid derivative

 The present invention relates to a method for producing (1) -1,4-benzothiazine-2-acetic acid derivative. More specifically, it is described that the (Sat) 1,1,4-benzothiazine-2-acetic acid derivative is subjected to optical resolution by forming a salt between the (I) monoenantiomer of the derivative and an optically active substance. (1) The present invention relates to a method for producing a monoacetic acid derivative.

 Landscape technology

 General formula (I)

(In the formula, R ¹ and R ² may be the same or different, show it it hydrogen atom, C androgenic atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, triflate Ruoromechiru group or Torifuruorome butoxy group, R ³ Represents a carboxyl group which may be esterified; R ⁴ , R ⁵ , R ⁶ and R ⁷ may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or A 1,4-benzothiazine_2-acetic acid derivative represented by a trifluoromethyl group, and X represents an oxygen atom or a sulfur atom, is capable of reducing aldoses such as glucose and galactose. It has the effect of inhibiting aldose reductase, an enzyme that converts to sorbitol and galactitol, so It is a compound being developed as an agent for treating diabetic complications such as nephropathy and retinopathy (JP-A-5-92961, EP 0 492 667 A1). In addition, a method has been reported in which the above compound is optically resolved using (1) brucine to obtain an (-)-enantiomer of the above compound having an optical purity of 98.5% (Chem. Pharm. Bull., 42 (6), 1264-1271 (1994)). However, this method

 (1) The salt formation process and recrystallization are performed in a stationary state.

 (2) Recrystallization is required three times, which increases costs.

 (3) Low yield.

And other disadvantages during industrialization.

 An object of the present invention is to provide a method for producing a (_)-11,4-benzothiazine-12-acetic acid derivative represented by the above general formula (I).

 Disclosure of the invention

 In view of the above problems, the present inventors have conducted various studies, and found that the 1,4-benzothiazine_2-acetic acid derivative represented by the above general formula (I) can be dissolved in an optically active substance and acetate nitrile. The reaction is performed to racemize the (+)-enantiomer of the derivative and to form a salt between the (-) enantiomer of the derivative and the optically active substance, thereby performing optical resolution. In this case, it has been found that (1) a single enantiomer of the derivative can be obtained with high yield and high optical purity. In addition, (h) _1,4-benzothiazine-12-acetic acid derivative is reacted with an optically active substance in a solvent under heating conditions, and the (1) -enantiomer of the derivative and the optically active substance are reacted. It has been found that, when optical resolution is performed by forming a salt with, a (−) mono-enantiomer of the derivative having high optical purity can be obtained. Furthermore, it has been found that in these methods, when a specific optically active amine is used as the optically active substance, a novel salt of (1) one enantiomer of this derivative and the optically active amine can be obtained. The present invention has been made based on such findings.

 That is, the present invention is as follows.

[1] General formula (I):

(In the formula, R ¹ and R ² may be the same or different, show it it hydrogen atom, C androgenic atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, triflate Ruoromechiru group or Torifuruorome butoxy group, R ³ Represents a carboxyl group which may be esterified; R ⁴ , R ⁵ , R ⁶ and R ⁷ may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or Represents a trifluoromethyl group, and X represents an oxygen atom or a sulfur atom.) (1) — 1,4-benzothiazine-12-acetic acid derivative is reacted with an optically active substance in acetonitrile to obtain the derivative. The racemization of the (+)-enantiomer of the derivative and the formation of a salt between the (1) enantiomer of the derivative and the optically active substance Ri and performing optical resolution (one) one 1, 4-Benzochia Jin manufacturing method of an 2-acetic acid derivatives.

 [2] The method further comprises heat-treating the salt of the (1) -enantiomer of the derivative and the optically active substance in a solvent. A method for producing an nzothiazin-1-acetic acid derivative.

[3] General formula (I):

(式中、 R¹および R²は同一または異なっていてよく、 それぞれ水素原子、 ハ ロゲン原子、 低級アルキル基、 低級アルコキシ基、 低級アルキルチオ基、 トリフ ルォロメチル基またはトリフルォロメ トキシ基を示し、 R ³はエステル化されて いてもよいカルボキシル基を示し、 R⁴、 R⁵、 R⁶および R⁷は同一または異な つていてよく、 それそれ水素原子、 ハロゲン原子、 低級アルキル基、 低級アルコ キシ基またはト リフルォロメチル基を示し、 Xは酸素原子または硫黄原子を示 す。 ） で表される （士） — 1， 4—ベンゾチアジン— 2—酢酸誘導体を光学活性 物質と溶媒中、 加熱条件下で反応させて、 該誘導体の （一） 一鏡像異性体と該光 学活性物質との塩を生成させることにより光学分割を行うことを特徴とする

(Wherein R ¹ and R ² may be the same or different and each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a trifluoromethyl group or a trifluoromethoxy group, and R ³ represents Represents a carboxyl group which may be esterified; R ⁴ , R ⁵ , R ⁶ and R ⁷ may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or Represents a trifluoromethyl group, and X represents an oxygen atom or a sulfur atom.) The 1,4-benzothiazine-2-acetic acid derivative is reacted with an optically active substance in a solvent under heating conditions. Optical resolution is performed by forming a salt between the (1) one enantiomer of the derivative and the optically active substance.

(-) — Method for producing 1,4-benzothiazine-2-acetic acid derivative.

[4] The method further comprises heat-treating the salt of the (1) -enantiomer of the derivative and the optically active substance in a solvent. Nzothiazine-A method for producing 2-acetic acid derivatives.

 [5] (Sat) represented by the general formula (I) —1,4-benzothiazine—2-acetic acid derivative is (S) -1,3,4-Dihydro-1-3-oxo-14-1 ([4 , 5,7-Trifluoro-2-benzothiazolyl) methyl] — 2H—1,4-benzothiazine-12-acetic acid, (1) — according to any one of [1] to [4], A method for producing 1,4-benzothiazine-2-acetic acid derivatives.

 [6] The (-) 1-1,4 according to any one of [1] to [5], wherein an (−)-enantiomer of the derivative having an optical purity of more than 98.5% is obtained. —Benzothiazine—A method for producing 2-acetic acid derivatives.

[7] General formula (I):

(Wherein R ¹ and R ² may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a trifluoromethyl group or a trifluoromethoxy group, ³ represents a carboxyl group which may be esterified; R ⁴ , R ⁵ , R ⁶ and R ⁷ may be the same or different, and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group; Or X represents an oxygen atom or a sulfur atom.), And its optical purity is higher than 98.5%. (1) 1,1,4-Benzothiazin-2-acetic acid derivative or its drug Physically acceptable salt.

 [8] — The (1) — 1,4-benzothiazine — 2-acetic acid derivative represented by the general formula (I) is (1) 1, 3, 4-dihydro-13-oxo-1 4-— ((4, 5,7-Trifluoro-2-benzothiazolyl) methyl] —2H—1,4-benzothiazine-monoacetic acid (1) described in [7] —1,4-benzothiazine-2-acetic acid derivative or Its pharmacologically acceptable salts.

[9] General formula (I):

(Wherein R ¹ and R ² may be the same or different and each represents a hydrogen atom, A hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a trifluoromethyl group or a trifluoromethoxy group; R ³ represents a carboxyl group which may be esterified; R ⁴ , R ⁵ , R ⁶ and R ⁷ may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a trifluoromethyl group, and X represents an oxygen atom or a sulfur atom. (1) — 1,4-benzothiazine-12-acetic acid derivative, cinchonine, dehydroabiabiethylamine and D — (—) 12-amino-1- (p-ditrophenyl) (I) A salt with an optically active amine selected from the group consisting of 1,3-propanediol.

 [10] The (1) -11,4-benzothiazine-12-acetic acid derivative represented by the general formula (I) is converted to (1) -3,4-dihydro-3-oxo-4 — [(4,5 , 7-trifluoro-2-benzothiazolyl) methyl] —2H—1,4-benzothiazine-12-acetic acid.

 Detailed description of the invention

 In the present specification, unless otherwise specified, the general formula (I) is a racemic form of a 1,4-benzothiazine-2-acetic acid derivative ((P) -11,4-benzothiazine-12-acetic acid derivative), Includes (—) — enantiomer ((—) — 1,4-benzthiazine-12-acetic acid derivative) and (+) — enantiomer ((+) — 1,4-benzothiazine-2-acetic acid derivative) It shall be. In the formula, carbon atoms marked with * indicate asymmetric carbon atoms. The definition of each substituent in the general formula (I) is as follows. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

 As the lower alkyl group, a linear or branched alkyl group having 1 to 6 carbon atoms is preferable. For example, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl, pentyl, Examples include isopentyl, hexyl, and isohexyl.

As the lower alkoxy group, a linear or branched alkoxy group having 1 to 6 carbon atoms Preferred are, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, isohexyloxy and the like. As the lower alkylthio group, a straight-chain or branched alkylthio group having 1 to 6 carbon atoms is preferable. Examples include isopentylthio, hexylthio, and isohexylthio.

 The carboxyl group which may be esterified means a carboxyl group or an esterified carboxyl group.

 Examples of the esterified carboxyl group include lower alkoxy groups having 1 to 6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, and tert-butoxycarbonyl. Alkoxycarbonyl; cycloalkyloxycarbonyl having 5 to 10 carbon atoms in a cycloalkyl moiety such as cyclohexyloxycarbonyl and cyclopentyloxycarbonyl; or a halogen atom, a lower alkyl group, a lower alkoxy group on a benzene ring, Even if it has a substituent such as a nitro group, aryloxycarbonyl or benzyloxycarbonyl may, for example, be mentioned.

 The pharmacologically acceptable salt of the compound represented by the general formula (I) is not particularly limited as long as it is a pharmacologically acceptable non-toxic salt. For example, lithium salt, sodium salt, potassium Alkali metal salts such as salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; salts with organic bases such as triethylamine salts, pyridine salts; and basic amino acids such as lysine salts and arginine salts. Salt etc.

In the general formula (I), R ⁴ , RR ⁶ and R ⁷ may be the same or different, and a compound each of which is a hydrogen atom, a fluorine atom or a chlorine atom is a compound of the present invention. Preferred as a compound.

 In the present invention, preferred specific examples of the compound represented by the general formula (I) include, for example, the compounds described in JP-A-5-92961 (EP 0 492 667 A1). Typical examples thereof include, for example, 3,4-dihydro-3-oxo-4-[(4,5,7-trifluoro-2-benzothiazolyl) methyl] —2H—1,4-benzothiazine 2-Acetic acid can be mentioned.

 The process for producing the (-)-1,4-benzothiazine-12-acetic acid derivative of the present invention comprises preparing the (±)-1,4, -benzothiazine-12-acetic acid derivative represented by the above general formula (I). Reacting the optically active substance with acetonitrile to racemize the (+)-enantiomer of the derivative and to form a salt between the (-) enantiomer of the derivative and the optically active substance It is characterized by performing optical division.

 In the production method of the present invention, the (Sat) —1,4-benzothiazine_2-acetic acid derivative represented by the above general formula (I) used as a starting material is disclosed in, for example, Japanese Patent Application Laid-Open No. 5-92961 (EP 0 492 667 A1).

 The optically active substance used in the production method of the present invention is not particularly limited as long as it forms a salt with the compound represented by the above general formula (I). ) —Brucine (anhydrous or dihydrate), cinchonine, dehydroabiethylamine, D — (—) _ 2—amino-1- (p-ditrophenyl) -1,3-propanediol, S — (-) — 1-phenylethylamine, R-(+) — 1-phenylethylamine, (+) —norephedrine, (1) 1-norphedrine, etc.) Preferred are optically active amines, and particularly preferred is (1) -brucine (anhydride or dihydrate). The addition amount is 0.5 to 1.0 equivalent, preferably 1.0 equivalent, per the above-mentioned (P) -1,4-benzothiazine-2-acetic acid derivative.

The optical resolution in the production method of the present invention is preferably performed in acetonitrile. (1) -mirror of compound represented by the above general formula (I) with respect to acetonitrile The salt of the enantiomer and the optically active substance has much lower solubility than the salt of the (+)-enantiomer of the compound and the optically active substance. Acetonitrile also has the effect of racemizing the enantiomer of the compound due to its solvent effect. Therefore, when a racemate of the compound represented by the above general formula (I) is reacted in acetonitrile under conditions such that the optically active substance and the enantiomer of the compound are racemized, (1) One enantiomer is hardly racemized because it forms a salt with an optically active substance and precipitates in the reaction solution, whereas the (+)-enantiomer of the compound is present in the reaction solution. Racemized because it is dissolved. (+) —Arising from the racemization of enantiomers (1) One enantiomer also forms a salt with the optically active substance and precipitates out, resulting in (+) —most of the enantiomer is (−) It will be converted to one enantiomer. Accordingly, it is necessary to obtain (-) one enantiomer of the compound represented by the above general formula (I) in the form of a salt with the optically active substance in a higher yield and higher optical purity than ordinary optical resolution. Can be.

 The above-mentioned optical resolution is carried out under conditions where the enantiomer of the compound represented by the above general formula (I) is racemized. The conditions are not particularly limited as long as the enantiomer of the compound is racemized, and include, for example, room temperature to heating conditions, and preferably heating conditions. As the reaction temperature under heating conditions,

40-: L00. C, preferably 80 to: L 00 ° C, particularly preferably the temperature at which acetonitrile is refluxed (in this case, the reaction is carried out under reflux). The reaction time is not particularly limited, but may be, for example, 1 to 100 hours, preferably 40 to 50 hours.

The optical resolution is preferably carried out in the presence of a reaction accelerator. The reaction time can be shortened by coexisting the reaction accelerator. Examples of the reaction accelerator include organic bases (eg, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] —7-indene, N-methylmorpholine, etc.), inorganic bases (eg, sodium hydroxide) , Hydroxide hydroxide, sodium hydrogen carbonate, potassium carbonate, etc.). Preferred are organic bases, particularly preferred. Preferable is triethylamine. The amount of addition is 0.1 to 1.0 equivalent, preferably 0.2 to 0.5 equivalent, per the above-mentioned (soil) 1,4-benzothiazine_2-acetic acid derivative.

 The salt of the (1) —1,4-benzothiazine-12-acetic acid derivative represented by the above general formula (I) and the optically active substance obtained by the above optical resolution can be obtained by a conventional separation method, for example, filtration, centrifugation It can be separated from the reaction solution by distillation (eg, distillation under reduced pressure, distillation under normal pressure, etc.), decantation and the like.

 The optical resolution can be performed while evaporating acetonitrile (for example, distillation under reduced pressure, atmospheric pressure, etc.) while concentrating. This concentration is preferably carried out intermittently, whereby the optical resolution efficiency is increased, and the (1) 1, 4-benzothiazine 1-2-represented by the above general formula (I) obtained after the completion of the reaction is obtained. Separation of the salt between the acetic acid derivative and the optically active substance can be facilitated.

 The yield of the salt of the (−) — 1,4-benzothiazine-2-acetic acid derivative represented by the above general formula (I) and the optically active substance obtained by the above optical resolution is 50% or more (preferably Is 80% or more). The yield referred to here was obtained based on the total amount of the starting materials used ((P) _1,4-benzothiazine-12-acetic acid derivative represented by the general formula (I)) and the optically active material used. It is the ratio (%) of the amount of salt formed between the (1) enantiomer of the compound and the optically active substance (the amount of formation is the difference between the (+)-enantiomer of the compound and the optically active substance). Includes salt production). The optical purity of (1) -enantiomer in this salt is 70% or more (preferably 80% or more). The optical purity here is a value measured by the method described later (the optical purity in the following description of the present specification is also a value measured by the method described later). Such high yield and high optical purity cannot be obtained by ordinary optical resolution.

Another method for producing (-)-1,4-benzothiazine-12-acetic acid derivative according to the present invention is a method for producing a (Sat) -1,4-benzothiazine-12-acetic acid derivative represented by the general formula (I) by photoirradiation. Reaction with a biologically active substance in a solvent under heating conditions to obtain the (1) -enantiomer of the derivative And optically resolving the optically active substance by forming a salt thereof.

 As the (±) -1,4-benzothiazine-12-acetic acid derivative represented by the general formula (I) used in the above production method, those defined above can be mentioned. Examples of the optically active substance include those defined above, but are preferably

(1) — Brusin (anhydride or dihydrate) and cinchonine. The solvent used in the optical resolution in the above-mentioned production method is appropriately selected depending on the optically active substance used. Examples thereof include ethyl acetate, water, methanol, ethanol, isopropyl alcohol, acetone, dimethylformamide and these. Mixed solvents, etc., preferably ethyl acetate, methanol, ethyl acetate containing 0.1 to 5% (v / v) (preferably 0.2 to 2% (v / v)) water

(Hydrous ethyl acetate), mixed solvent of ethyl acetate and methanol [10: 1 to 1: 1

(Preferably 5: 1 to 2: 1) (volume ratio)].

 The optical resolution is performed under heating conditions. The reaction temperature is from room temperature to 100 ° C, preferably 70 to 100 ° C, particularly preferably the temperature at which the solvent used is refluxed.

(In this case, the reaction is carried out under reflux). The reaction time is not particularly limited, but may be, for example, 0.1 to 5 hours, and preferably 0.5 to 2 hours.

 The salt of the (-) — 1,4-benzothiazine-2-acetic acid derivative represented by the above general formula (I) and the optically active substance obtained by the above optical resolution can be obtained by the usual separation method as described above. It can be separated from the reaction solution. In addition, the optical resolution can be performed while concentrating as described above.

The salt of (1) an 1,1,4-benzothiazine-2-acetic acid derivative represented by the general formula (I) obtained by the optical resolution in the production method of the present invention and a specific optically active amine is a novel salt. is there. For example, (—) — 1,4-benzothiazine-2-acetic acid derivative and cinchonine, dehydroabiabiethylamine or D — (—)-12-minamino-11 (p-nitrophenyl) 1-1,3 —The salt with propanediol is It is a salt not known until.

 The above general formula obtained in the optical resolution in the production method of the present invention as described above

The salt of the (1) —1,4-benzothiazine-12-acetic acid derivative represented by (I) and the optically active substance can be further purified by a conventional purification method such as recrystallization, chromatography, decantation and the like. It can be purified.

 The production method of the present invention preferably comprises the above-mentioned general formula generated by the optical resolution.

The method includes heat-treating a salt of an (-)-1,4-benzothiazine-12-acetic acid derivative represented by (I) with an optically active substance in a solvent. As a result, the optical purity of the (-)-1,4, -benzothiazine-12-acetic acid derivative in the salt of the (-)-1,4-benzothiazine-2-acetic acid derivative and the optically active substance can be improved. The solvent used here can be appropriately selected depending on the (1) 1,4-benzothiazine-12-acetic acid derivative used and the optically active substance. Examples of the solvent include ethyl acetate, water, methanol, ethanol, and the like. Examples include isopropyl alcohol, acetone, dimethylformamide and a mixture thereof, preferably ethyl acetate, 0.1 to 5% (v / v) (preferably 0.2 to 2% (v / v) ) Aqueous ethyl acetate or a mixed solvent of ethyl acetate and methanol [10: 1 to 1: 1 (preferably 5: 1 to 2: 1) (volume ratio)]. Further, the treatment temperature in the heat treatment is from room temperature to 100 ° C., preferably 70 to 100 ° C., and particularly preferably the temperature at which the solvent is refluxed (in this case, the treatment is performed in a reflux state). The processing time is not particularly limited, but is, for example, 0.5 to 10 hours, and preferably 1 to 5 hours. In addition, this treatment can be applied to the residue obtained after concentrating to dryness by distilling off the used solvent after completion of the optical resolution.

From the salt of the (1,1) -1,4-benzothiazine-12-acetic acid derivative represented by the general formula (I) obtained as described above and an optically active substance, an acid is used according to a usual method. (-) It can be obtained by liberating a 1,4-benzothiazine-12-acetic acid derivative. Preferably, the free form of the (—) — 1,4-benzothiazine-2-acetic acid derivative represented by the general formula (I) is a derivative of the (—) — 1,4-benzothiazine-12-acetic acid derivative and an optical derivative. It is obtained by treating a salt with an active substance in a mixed solvent of an organic solvent and water under acidic conditions. Examples of the acid used here include mineral acids such as hydrochloric acid, sulfuric acid and nitric acid, and organic acids such as citric acid and maleic acid, and preferably hydrochloric acid. The concentration of the acid in the mixed solvent is not particularly limited as long as the mixed solvent becomes acidic. Examples of the organic solvent in the mixed solvent of the organic solvent and water include toluene, acetone, and methanol, and preferably toluene. The mixing ratio of the organic solvent to water is 1: 1 to 1: 2 (preferably 1: 1) (volume ratio). The processing conditions are not particularly limited. For example, the processing temperature may be room temperature to 50 ° C. (preferably room temperature), and the processing time may be 0.1 to 2 hours (preferably 0.5. ~ 1 hour). After the treatment, the organic solvent layer in which the free form of (-) 1-1,4-benzothiazine_2-acetic acid derivative is present is separated, the solvent is dried and evaporated, and the residue is evaporated with a solvent (eg, ethyl acetate, Hexane) or by filtering, washing, and drying the crystals precipitated from the mixed solvent to obtain the free (-)-1,4-benzothiazine-12-acetic acid derivative Can be.

 The thus obtained free form of the free form represented by the above general formula (I) (-) 1-1: 4-benzothiazine-12-acetic acid derivative can be purified by ordinary purification such as recrystallization, chromatography, decantation and the like. The method can be used for further purification. For example, the recrystallization is preferably carried out by using a solvent such as ethyl acetate, hexane, heptane, ethanol, water, acetic acid, isopropyl alcohol or a mixed solvent thereof, particularly preferably a mixed solvent of ethyl acetate and hexane (for example, : 1 to 1:20, preferably 1: 2 to 1:10 (volume ratio)).

 In the manufacturing method of the present invention, the above-described steps may be repeatedly performed as necessary.

(-)-1 and 4 represented by the above general formula (I) obtained by the production method of the present invention. The optical purity of —benzothiazine—2-acetic acid derivatives (including those in the salts of (1-)-1,4-benzothiazine-12-acetic acid derivatives and optically active substances) is preferably higher than 98.5%, especially It is preferably higher than 99.0%, and more preferably 99.8% or more. The upper limit is not particularly limited, but is substantially (+) — optical purity substantially free of enantiomer (for example, 99.99%, which is the measurement limit of the method for measuring optical purity in the present specification). be able to. Such high optical purity (-)-1,4-benzothiazine-12-acetic acid derivatives have not been known so far. Therefore, it is preferable that the (+) — 1,4, -benzothiazine-2-acetic acid derivative is present in the (—) — 1,4-benzothiazine-2-acetic acid derivative represented by the general formula (I) even in a trace amount. The optical purity obtained by the production method of the present invention is higher than 98.5% in the use of (1,1) -1,4-benzothiazine-12-acetic acid derivative. The acetic acid derivative is much more useful than the one with an optical purity of 98.5% obtained so far.

 The (—) — 1,4-benzothiazine-12-acetic acid derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof obtained by the production method of the present invention includes, for example, cataract, neurosis, It can be used as an active ingredient of preventive and therapeutic agents for diabetic complications such as nephropathy and retinopathy.

 Example

Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples. In the following examples, 3,4-dihydro-3-oxo-1-[(4,5,7_trifluoro-2-benzothiazolyl) methyl] —2H_1,4-benzothiazine-2-acetic acid (A compound of the following general formula (II): Compound A) is represented by (A), one compound A, (-) one enantiomer, (-) one compound A, and (+) —enantiomer as ( +) —Represented as compound A.

 The optical purity was determined by separating the two enantiomers by high performance liquid chromatography (HPLC) using an optically active column under the following conditions and determining the area percentage.

 HP L C condition)

 Column: CH I RAL CE L 0 D R (4.6 mm ^ x 250 mm)

 Mobile phase: acetonitrile / water / 85% phosphoric acid = 660/340/2

 Flow rate: 0.6 mL / m1n

 Column temperature: 25 ° C

 Detection: 230 nm (UV)

 Sample injection volume: 5〃L [Each sample (5mg) / acetonitrile (1 OmL)]

(Earth) — Compound A (25.0 g; 58.9 mmol) dissolved in acetone (60 OmL) by heating. (1) — Brusin 2H ₂ 〇 (25.4 g) 58.9 mMol) and refluxed for 24 hours. Acetonitrile (30 OmL) was distilled off, and the mixture was further refluxed for 19 hours. Then, acetonitrile (15 OmL) was distilled off, and after refluxing for 22 hours, the solvent was concentrated to dryness. 2% aqueous ethyl acetate (383 mL) was added to the residue, and the mixture was heated under reflux for 1 hour, stirred under water cooling for 2 hours, and the crystals were collected by filtration. (1) Compound A · (-) — brucine salt ( 43.9 g; optical purity 98.9% de, yield 91%).

Example 2:

(A) — Compound A (25.0 g; 58.9 mmol) was added to acetonitrile (60 OmL), (1) -brucine (23.2 g; 58.9 mmol) was added thereto, and the mixture was refluxed for 24 hours. Acetonitrile (30 OmL) was distilled off, and the mixture was further refluxed for 19 hours. Subsequently, acetone nitrile (15 OmL) was distilled off, and the mixture was refluxed for further 22 hours, and the solvent was concentrated to dryness. 2% aqueous ethyl acetate (383 mL) was added to the residue, and the mixture was heated under reflux for 1 hour, stirred under water cooling for 2 hours, and the crystals were collected by filtration to give (-)-Compound A · (-)-Bursin A salt (43.2 g; optical purity: 98.6% de, yield: 90%) was obtained.

Example 3:

 (H) — Compound A (4.24 g; 10.0 mmol) was dissolved by heating in acetonitrile (50 mL), and (1) — Brusin (3.94 g; 10.0 mmol) was added. In addition, the mixture was refluxed for 46 hours, stirred at room temperature for 2 hours, and ice-cooled for 1 hour. The crystals were collected by filtration, and (-)-compound A · (-)-brucine salt (7.78 g; optical purity) 83.0% de, yield 95%). The obtained crystals (7.0 g) were refluxed in 2% aqueous ethyl acetate (105 mL) for 1 hour, then stirred under water cooling for 1 hour, and the crystals were collected by filtration to give (-) — Compound A. (-) — Bursin salt (6.63 g; optical purity 99.4% de, total yield 81%) was obtained.

Example 4:

After dissolved by heating; (5. 0 mm ol 2. 1 2 g) in Asetonitoriru (50 m L), (I) - brucine _{· 2 H 2 ◦ (2. 1} 5 g; - ( Sat) Compound A 5. 0 mmo 1) and triethylamine (0.36 mL; 2.5 mmo 1) were added, and the mixture was refluxed for 9 hours, stirred at room temperature for 1 hour and ice-cooled for 1 hour, and the crystals were collected by filtration. A · (—) — brucine salt (3.61 g; optical purity 87.4% de, yield 88%) was obtained. The obtained crystals (3.61 g) were refluxed in 2% aqueous ethyl acetate (32.6 mL) for 1 hour, then stirred under water cooling for 1 hour, and the crystals were collected by filtration. A · (-) — brucine salt (3.37 g; optical purity 99.2% de, total yield 82%) was obtained.

Example 5: (Earth) —Compound A (2.12 g; 5.0 mmol) dissolved in acetonitrile (50 mL) by heating, and then (-) 1 brucine 2H ₂ ◦ (2.15 g; 5.0 mmol) 1) Add triethylamine (0.14 mL; 1. Ommo 1), reflux for 18 hours, stir at room temperature for 1 hour and under ice-cooling for 1 hour, filter the crystals, and (1) one compound A (-) — Brucin salt (3.70 g; optical purity 86.9% de, yield 90%) was obtained. The obtained crystals (3.70 g) were refluxed in 2% aqueous ethyl acetate (32.6 mL) for 1 hour, then stirred under water cooling for 1 hour, and the crystals were collected by filtration to give (-)-Compound A · (—) — Bursin salt (3.30 g; optical purity 99.1% de, total yield 81%) was obtained.

Example 6:

 (I) —Compound A obtained in accordance with Example 1 above—Bursin salt (2.60 kg; 3.18 mol) was added to toluene (25 L), and concentrated hydrochloric acid (2 L) and water (9 L). This solution was separated, and the toluene layer was washed twice with 10% hydrochloric acid (10 L), and further twice with water (10 L). The toluene layer was subjected to decolorizing carbon treatment / drying with activated carbon (78 g) and anhydrous sodium sulfate (1 kg), followed by celite filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate (20 L) was added twice more and azeotropic distillation was performed. Then, the solvent was distilled off, and crude oil containing ethyl acetate (0.51 kg) was added.

(-) — Compound A (1.86 kg) was obtained.

 Next, the obtained crude (-)-compound A (1.86 kg) was dissolved in a mixed solution of ethyl acetate (20 L) -hexane (20 L) and filtered. Further ethyl acetate

The filtrate obtained by washing with a mixed solution of (0.7 L) -hexane (0.7 L) was stirred at room temperature for 1 hour. Hexane (0.68 L) and (-) compound A (1.35 g) were added to the solution, and the mixture was stirred at room temperature for 4 hours. Further, (-)-compound A (1.35 g) was added, and the mixture was stirred at room temperature for 2.5 hours. Next, hexane (6.8 L) was added to the solution, and the mixture was heated to 45 ° C to melt a part of the precipitated crystals, loosened the lump crystals, and stirred at room temperature for 0.5 hours. Hexane (16.8 L) was further added dropwise over 2 hours, the solution was stirred for 0.5 hour, and then cooled to 0 to 5 ° C. Left for 1 hour. The crystals were collected by filtration and washed with ethyl acetate / hexane (10: 1) (6.8 L). The crystals were dried at 50 ° C for 18 hours to obtain (1) -Compound A (1.25 kg). The crystals were pulverized using an atomizer (mesh: 3 mm) and dried at 50 ° C for 23 hours to obtain a white crystalline powder (1) —Compound A (1.21 kg).

Yield: 1.2 kg (Total yield from compound (A): 71.7%)

Optical purity: 98.81% e e, Chemical purity: 99.8% or more

Melting point: 102-105 ° C

Optical rotation: [H] D-39.6 ° (c = l, methanol)

Elemental analysis: C Hu FsNzOg Ss

Calculated values: C, 50.94; H, 2.61; N, 6.60

 Found: C, 50.83; H, 2.71; N, 6.55

Residual solvent: 0.096% of ethyl acetate, 0.011% of hexane (measured by gas chromatography)

Example 7:

(A) — Compound A (10.0 g; 23.6 mmol) was suspended in 2% aqueous ethyl acetate (153 mL), and (1) one brucine 2H ₂ 0 (5 Then, the mixture was heated under reflux for 2 hours and then stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration to obtain (1) one compound A · (—)-brucine salt (8.88 g; optical purity 96.8% de, yield 46%). The crystals (8.88 g) were heated to reflux in 2% aqueous ethyl acetate (153 mL) for 1 hour, and stirred for 1 hour under water cooling. The precipitated crystals were collected by filtration to give (1) —Compound A · (—) — brucine salt (8.55 g; optical purity 99.5% de, total yield 44%).

Example 8:

(H) — Compound A (4.24 g; lOmmol) and dehydroabiethylamine (2.85 g; lOmmol) were dissolved in methanol (21 mL) by heating, and then room temperature for 2 hours. The mixture was stirred at 45 to 50 ° C for 2 hours and further at room temperature for 1 hour. Precipitation The crystals thus obtained were collected by filtration to obtain (1) -Compound A • dehydroabiethylamine salt (1.43 g; optical purity 85.0% de, yield 20.2%). The crystals (1.43 g) were heated and refluxed in ethyl acetate (14.3 mL) for 2 hours, and then stirred for 1 hour under water cooling and 1 hour under ice cooling. The precipitated crystals were collected by filtration to obtain (1) -Compound A. dehydroabiethylamine salt (0.75 g; optical purity 98.8% de, total yield 11%).

Example 9:

 (Earth) —Compounds A (20.0 g; 47 mmol) and D— (_) — 2-Amino-1- (p-nitrophenyl) 1-1,3-propanediol (5.0 g; 24 mmo1) ) Was dissolved in a mixed solvent of ethyl acetate Z methanol (160 mL / 40 mL) by heating, and the mixture was stirred at 50 ° C for 2.5 hours and at room temperature for 3 hours, and then left overnight. The precipitated crystals are collected by filtration, and (1) one compound A'D — (—) one 2-amino

(p-Nitrophenyl) -1,3-propanediol salt (11.6 g; optical purity 86.0% de, yield 38.6%) was obtained. The crystals (11.6 g) were recrystallized using a mixed solvent of ethyl acetate / methanol (116 mL / 116 mL).

(I) —Compound A'D — (—) — 2-Amino-1— (p-Ditrophenyl) 1-1: 3-propanediol salt (9.69 g; optical purity 99.8% de, total yield) Rate 3 3%).

Example 10:

 (M) One compound A (84.8 g; 0.20 mo 1) and cinchonine (40.6 g; 0.14 mo 1) were suspended in ethyl acetate (848 mL) and dissolved by heating under reflux for 10 minutes. did. The temperature of the solution was maintained at 55 to 60 ° C, and the mixture was stirred for 1 hour.After stirring at 20 to 25 ° C for 2 hours, the solution was cooled to 0 to 5 ° C and stirred for 12 hours. I went. The precipitated crystals were collected by filtration to obtain (-) one compound A · cinchonine salt (66.4 g; optical purity 98.9% de, yield 46.5).

The resulting (-) compound A 'cinchonine salt (2.0 g; 2.8 mmo 1) was dissolved in methanol (14 mL), and concentrated hydrochloric acid (0.5 mL; 5.6 mmo 1) was added. Subsequently, water (5 mL) and further water (22.5 mL) were sequentially added, and the mixture was stirred at 10 to 20 ° C for 1 hour. The crystals were collected by filtration, washed with water (50 mL), and dried to obtain (-) mono-compound A (1.0 g; optical purity 99.1% ee, yield 43.3%). Was.

 Industrial applicability

 According to the present invention, the (I) -one enantiomer of the (P)-(1,4) -benzothiazin-2-acetic acid derivative represented by the above general formula (I) in high yield and high optical purity is obtained. A method of obtaining the body can be provided. Further, according to the present invention, there is provided a salt of an optically active amine with an (-1,4-) benzodiazine-2-acetic acid derivative represented by the above-mentioned general formula (I), which has not been known before. Can be. Further, according to the present invention, a (1) _1,4-benzothiazine-2-acetic acid derivative represented by the general formula (I) having an optical purity higher than 98.5%, which has not been obtained so far, and a drug therefor A physically acceptable salt can be provided. This application is based on a patent application No. 167447 filed in Japan, filed in Japan, the contents of which are incorporated in full herein.

Claims

The scope of the claims  1. General formula (I)

(In the formula, R ¹ and R ² may be the same or different, show it it hydrogen atom, C androgenic atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, triflate Ruoromechiru group or Torifuruorome butoxy group, R ³ Represents a carboxyl group which may be esterified; R ⁴ , ⁵ , R ⁶ and R ⁷ may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or X represents an oxygen atom or a sulfur atom.) A 1,4-benzothiazine-2-acetic acid derivative is reacted with an optically active substance in acetonitrile. The racemization of the (+)-enantiomer of the derivative and the formation of a salt between the (1) enantiomer of the derivative and the optically active substance (1) A method for producing 1,1-benzothiazine-12-acetic acid derivatives.  2. The method according to claim 1, further comprising heat-treating the salt of the (I) monoenantiomer of the derivative and the optically active substance in a solvent. A method for producing a nzothiazine 1-2-acetic acid derivative. 3. General formula (I):

(In the formula, R ¹ and R ² may be the same or different, show it it hydrogen atom, Nono androgenic atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, triflate Ruoromechiru group or Torifuruorome butoxy group, R ³ Represents a carboxyl group which may be esterified, and R ⁴ , R ⁵ , R ⁶ and: R ⁷ may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group. Or X represents an oxygen atom or a sulfur atom.) (±) — 1,4-Ben V Thiazine-12-acetic acid derivative in an optically active substance and solvent under heating conditions And performing optical resolution by forming a salt of the (−) — enantiomer of the derivative with the optically active substance. (1) — Method for producing 1,4-benzothiazine-12-acetic acid derivative. 4. The method according to claim 3, further comprising heat-treating the resulting salt of the derivative with the (1) one enantiomer and the optically active substance in a solvent. Benzothiazine-a method for producing 2-acetic acid derivatives.  5. The (±) — 1,4— ^ ^ nzothiazine-12-acetic acid derivative represented by the general formula (I) is (±) _3,4-dihydro-13-oxo-1 4-— ((4 , 5,7-Trifluoro-2-benzothiazolyl) methyl] -12H-1, 4-benzothiazine-12-acetic acid according to any one of claims 1 to 4, (-)-Method for producing 1,4-benzothiazine-12-acetic acid derivative. 6. The method according to any one of claims 1 to 5, wherein an (−) monoenantiomer of the derivative having an optical purity higher than 98.5% is obtained. 4—be A method for producing a monoacetic acid derivative. 7-General formula (I)

(In the formula, R ¹ and R ² may be the same or different, show it it hydrogen atom, C androgenic atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, triflate Ruoromechiru group or Torifuruorome butoxy group, R ³ Represents a carboxyl group which may be esterified; R ⁴ , R ⁵ , R ⁶ and R ⁷ may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or Represents a trifluoromethyl group, and X represents an oxygen atom or a sulfur atom.) And has an optical purity higher than 98.5%. (-) 1,4-benzothiazine-2-acetic acid derivative or its pharmacology Above acceptable salts. 8. —Formula (I) (1) — 1,4-Benzothian-2-acetate derivative is (1) 1,3,4-dihydro-3-3-oxo-1 4-— ((4 (1,7-trifluoro-2-benzothiazolyl) methyl] —2H 1,4-benzothiazine-12-acetic acid according to claim 7, wherein the (1-) 114-benzothiazine-12-acetic acid derivative or a derivative thereof is described. Pharmacologically acceptable salt. 9. General formula (I):

(Wherein R ¹ and R ² may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a trifluoromethyl group or a trifluoromethoxy group, ³ represents a carboxyl group which may be esterified; R ⁴ , R ⁵ , R ⁶ and R ⁷ may be the same or different, and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group; Or X represents an oxygen atom or a sulfur atom.) (-) 1,4-benzothiazine-2-acetic acid derivative, cinchonine, dehydroabiethylamine and D — (—) A salt with an optically active amine selected from the group consisting of 1-2-amino-1_ (p-ditrophenyl) —1,3-propanediol.  10. The (1) —1,4—benzothiazine—2—acetic acid derivative represented by the general formula (I) is represented by (1) 1,3,4-dihydro-1-3-oxo-4—— ((4, 10. The salt according to claim 9, wherein the salt is 5,7-trifluoro-2-benzothiazolyl) methyl] —2H-1,4-benzothiazine-monoacetic acid.