MXPA97001396A

MXPA97001396A - Procedure for preparing 1,5-benzotiazep derivative

Info

Publication number: MXPA97001396A
Application number: MXPA/A/1997/001396A
Authority: MX
Inventors: Shibatani Takeji; Yamada Shinichi; Yoshioka Ryuzo
Original assignee: Tanabe Seiyaku Co Ltd
Priority date: 1996-02-23
Filing date: 1997-02-24
Publication date: 1998-04-01

Abstract

A method is described for preparing a 1,5-benzothiazepine derivative [II] :( See Formula) wherein ring A and ring B are a substituted or unsubstituted benzene ring, and R 3 is H, dialkylamino lower-alkyl lower or piperazinyl-substituted or unsubstituted lower alkyl, or a salt thereof, in high yield and in a single step from a novel compound of phenylpropionamine 3- (2-amino-phenylthio-substituted or unsubstituted) -2 -hydroxy-3-substituted or unsubstituted. Said 1,5-benzothiazepine derivative [II] is useful as an exchange to prepare medicaments such as diltiaz hydrochloride

Description

PROCEDURE FOR PREPARING 1, 5-BENZOTIAZEPINE DERIVATIVE TECHNICAL CflMPO The present invention relates to a novel process for preparing a 1,5-benzothαzepine derivative which is useful as an intermediate for preparing drugs.

BACKGROUND OF THE INVENTION Diltiazem hydrochloride has been widely used (chemical name: (2S, 3) -3-acetox -5-C2- (d? Rnet? Larn? No) e +? L_I -? / 3-d? 2- (4-rnetox? Phen? L) - 1,5-benzot? Azep? N-4 (5H) -one, as a calcium channel blocker in the treatment of angina pectoris, essential hypertension, etc. and it is usually prepared by means of dimethylammonylation of position 5 and acetylation of the 3-hydroxyl group of c-s-3-h? drox? -2,3-d? h? dro-2- (4- methox? phen? l) -l, 5-benzot? aze? n- (5H) -one (see USP Nos. 356225? and 4438035). Up to now, a process for preparing c? s ~ 3-h is known Drox? -2 3-d? -hydro-2- (4-methox? in? l) -l, 5-benzot? aze? n-4 (5H) -one, an intermediate for diltiazern hydrochloride, which comprises the reaction of the methyl ester of 3- (4-ethoxyphenyl) -2,3-epoxypic acid ico with 2-arn? ot? phenol, hydrolyzing the methyl ester of the acid 3- (2-arninophenyl) - 2-H? Drox? -3- (4 ~ methox? Feml) resulting propionic, and subjecting the product to cyclization reaction in a molecular [see Chemical and Pharmaceuticals Bulletm, p 2028, 1 < 370]. Alternatively, the following procedures are known as procedures for preparing c? S-3-h? Drox? -2,3 -dihi ro- 2- (4-rnetox? Feml) -l, 5-benzot? Azepm-4 (5H) -one by the use of a sulphonic acid without the hydrolyzation of the acid ester 3- (2 -am? o-fen? lt? o) - -h? drox? -3 ~ (4-? netox? fen? l) propioruco. (1) A process comprising the reaction of 2-arnmothiophenol with the methyl ester of the acid (~) - (2R, 3S) -, 3-epox? -3- (4-methox? Phen? L)? Oxygen, and subjecting the methyl ester of the acid (2S, 3S) -3- (2-arn? nofen? lt? o) -2-h? drox? -3 ~ (4-methoxy eml) propionic to intramolecular cyclization reaction in the presence of methanesulonic acid, etc., in a chlorinated organic solvent having a boiling point of more than 70 ° C (see USP 510299B). (2) A process comprising subjecting the 3- (2-aminophemoxide) -2-hydroxyl-3- (4-ethoxy-phenyl-D-propionic) intramolecular cyclization reaction in the presence of methanesulfuric acid single, etc., in a non-halogenated organic solvent (see USP 5294706). (3) A process comprising subjecting the (IR, S) -2-phen? lc? clohex? -es (2S, 3S) acid ester -3- (2-ami ofemitió) - 2-h? Dro? - - (4-rnetox? E? L)? Ropion? Co to intramolecular cyclization reaction in the presence of p-toluensul phonic acid monohydrate Cvease Japanese Patent First Publication (Kokai) No. 17170/1990.] The following procedures are known as a procedure for the preparation of 5- 2- (d? Met? Lam? No) et? Ll-2, 3 ~ dh? Dro-3- h? drox? 2- (4-inetoxife i 1) -1,5-benzothiazepi -4 (5H) -one, another intermediate for diltiazem hydrochloride, by intramolecular cyclization reaction using a base. (1) A pf ' It is understood that the methyl ester of 3- (2-amino) acid is ofemltium) -2-hydroxy-3- (4- ethoxyphene Dpr opioni co to intramolecular cyclization reaction by reaction with N, Nd? rnet? larn? noetlo chloride or an acid addition salt thereof in presence of a solid alkali metal hydroxide in an ether solvent [see Japanese Patent First Publlcatlon (Kokai) No. 202013/19931. (2) A process comprising subjecting the methyl ester of the acid 3- (2-ammophenolyl) -2-hydroxyl-3- (4-methoxyphenyl) ropioni to an intramolecular cyclization reaction in the presence of an alkali metal alkoxide in an aprotic polar solvent, and then introducing the 2- (dirnetiiarnino) ethyl group at the 5-position of the product [see Japanese Patent First Publication (Kokai) No. 221376/19921. However, it is well known among organic chemists that an amide is less easily attacked by a nucleophile than is an ester [see Hendrick on, Crarn, Hammond, Organic Chernistry the 3rd. edition, Cap 13-1, pp 501-516, etc, and to form the nucleus of 1,5-benzot? azepma, only one intramolecular cyclization reaction of (~) -4-? sopropil -3- [3 - (2-amidophenolithine) -2-? Nexax? Ethoxy ethoxy? -3- (4-methoxy eml) prop? On? Ll-2-oxazole? Doneone having N-acyl lamide group activated by treatment with trirnethylaluminum in methylene chloride [see Tetrahedron Letters, 32, pp 3516-3552 (1991) 1. In addition, USP 4959359 discloses that trans-3- (4-methoxyphenyl) -2,3-epoxyrronamide is prepared by treating the ester of trans-3- (4-ethoxy fem) -2.3 -epox? prop? onam? da with ammonium hydroxide; and UO 95/7359 discloses that the trans-3- (4-methox? fem) -2,3-epox? propiomco methyl ester is treated with ammonia between the presence of Lipase SP 523 whereby it is only stereoselectively amidated ( 2S, 3R) -isomer of the same.

BRIEF DESCRIPTION OF THE INVENTION An object of the present invention is to provide an improved process for preparing a 1,5-benzothiazepma core in high yield and in a single step from a novel compound of 3- [2-amino- (substituted or non-substituted emltium. substituted) -2-h? drox? -3- (substituted or unsubstituted phenyl) prop? onam? to.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, a 1,5-benzothiazepine derivative of the formula [II]: wherein ring A and ring B are substituted or unsubstituted benzene anion and R3 is a hydrogen atom, a lower (di-lower alkylamino) -alkyl group or a substituted or unsubstituted piperazinyl group- lower alkyl, is prepared by subjecting a propion derivative ida of the formula [11 to in vitro molecular cyclization reaction, wherein R 1 and 2 are the same or different and each is a hydrogen atom, a carbamoyl group, a lower alkyl group, an inferred alkanoyl group, a lower alkyl amylcarbonyl group, an amino acid residue, or a group optionally having a substituent, or combination thereof in its terminal group together with the adjacent nitrogen atom to which they are attached to form a heterocyclic group optionally having a substituent, and ring A, ring B and R3 they are the same as defined above, or a salt thereof. Ring A and / or ring B in the propionamide derivative of formula [II] can be either an unsubstituted benzene ring or benzene rings having a substituent selected from a lower alkyl group, a lower alkoxy group and a halogen atom and a lower femloalkyl group at any position (Jel itself) Suitable examples of ring A are f-ornule groups: wherein R * is a hydrogen atom, a halogen atom, a lower alkyl group or a phenyl-lower alkyl group and suitable examples of the B ring are a lower 4-alkyl group and a 4- lcox group ? fem the inferior. Among these examples of ring A and ring B, preferred combinations of ring A and ring B are: (a) ring A is a partial structure of formula [VI] (R * ee a hydrogen atom, a halogen atom or a phenyl-lower alkyl group) and ring B is an inner 4-alkoxyl group, and (b) ring A ee a partial structure of formula [VI] (RA is a lower alkyl group), and ring B it is a lower 4-alkyl group. The amino acid residue for R1 and R2 includes a residue that is produced by removing an amino group from an amino acid, wherein the hydroxyl groups, mercapto groups, mo groups and / or carboxyl groups may optionally be protected by a protecting group. The amino acid includes amino acids whether natural or synthetic amino acids and must have at least one arnino group and a carboxyl group in the molecule thereof, for example natural amino acids or antipodes of the same D- or (.-Synthetic amino acids or racemic mixtures of Preferred amino acids are α-arninoacids and β-ammo acids These amino acids can be either neutral amino acids, acidic amino acids or basic amino acids, and neutral amino acids and amino acids having arnino groups and carboxyl groups in the same numbers such as alamna, ísoleucma, leucma, etc., amino acids that have a hydroxyl group such as senna, threonine, tyrosma, etc. Amino acids containing sulfur such as cysteine, cystine, ethionine, etc. Acid amino acids are amino acids that have more groups carboxyl that arnino groups, such as glutamic acid, aspartic acid, and the basic amino acids are amino acids that have more mood groups carboxyl groups, such as arginine, ornithma, lysine, etc. When the hydroxyl groups, mercapto groups, mo groups and / or carboxyl groups of the amino acids are protected, they can be protected by a conventional protecting group. The protective group for the hydroxyl group is the benzyl group, t-butyl group, benzyloxycarbonyl group, etc. The protective group for the mercapto group is benzyl group, benzyloxycarbomlo group, etc. The protective group for the arnmo group is benzyloxycarbonyl group, t-butoxycarbonyl group, etc. The protective group for the carboxyl group is methyl group, ethyl group, rnetoxyethyl group, methoxyethoxyethyl group, arnine group, etc. The group aplo for Rl and R2 includes any aromatic hydrocarbon groups such as a phenyl group or naphthyl group. The substituent for the aryl group includes a lower alkyl group, a lower alkoyl group or a halogen atom. The heterocyclic group which is formed by combining * and R2 in its terminal part together with the nitrogen atom adjacent to which they are attached, can be either a heterornonocyclic group or a heterobicyclic group and may contain heteroatom selected from an atom. of nitrogen, an atom of oxygen and? n volume of sulfur, in addition to the nitrogen atom that forms an amide group. The heterocyclic group includes, for example, a 5 to 6-membered aromatic monocyclic group partially saturated or more saturated (for example pyrrolyl group, pipdyl group, pyrazinyl group, pyriridyl group, pyridazinyl group, iridazolyl group, pyrazolyl group, thiazolyl group, tetrazoli lo), an aliphatic 5-6 membered noncyclic group (eg, pyrrolidinyl group, pipepdimel group, piperazmyl group, norlyolinyl group, oxazolidyl group, thiazolidyl group), a partially saturated or unsaturated cyclic aromatic b group that is formed by condensing a group cyclic of 5 to 6 members and a cyclic group of 5 to 6 members (for example, qumolyl group, ndolyl group, indazolyl group, benzoxazolidimide group, benzothiazolidinyl group, benzoxazinyl group, benzothiazimone group) or an aliphatic bicyclic group that is formed by condensing a group cyclic of 5 to 6 members and a cyclic group of 5 to 6 members (for example quinolyl group, octahydro-lH-i ndol group ilo). The above heterocyclic groups may optionally have a substituent, and the substituent includes an electron donor group (e.g., arnino group, hydroxyl group, lower alkyl group, lower alkoxy group, cycloalkyl group) or electron withdrawing group (e.g. oxo group, nitro group, a halogen atom, carboxyl group, a lower alkoxycarbombo- group). The preferred heterocyclic group is a heterocyclic group which has an electron attracting group. Suitable examples of the group het oei cl i co that is formed by combining Rl and R2 in their terminal parts together with the nitrogen atom adjacent to which they are attached, are the groups of the following formulas.

- - Vi -N I Among the examples of the substitutes R * and R2, preferred combinations of R1 and R2 are: (a) each of them is a hydrogen atom, and (b) one of them is a hydrogen atom, and the other is a lower alkyl group. The combination wherein each of R1 and R2 is a hydrogen atom is most preferred. The substituent on the lower piperazimidoalkyne group for R3 may be a phenylene group or a phenyl group substituted with a group selected from a lower alkyl group, a lower alkoxy group, a lower alkyndiioxy group and a halogen atom. The substituted piperazyl-lower alkyl group for R3 is for example the group 3- [4 - (2-methox i te i 1)? perazim 1] propí 1 o. The group (lower di-alkylammo) -low alkyl lower alkyl is, for example, the 2- (dimethylammonium) ethylene group. E-11 preferred example of R3 is a hydrogen atom. Among the propionide derivatives (I) preferred are the compounds of formula I wherein ring A is a partial structure of formula VI (R * is a hydrogen atom, a chlorine atom, a methyl group or a benzyl group ), ring B is a 4-methylene group or group 4-rnetox i phen i lo, R3 is a hydrogen atom, a 2-di ethylammoetiio group or? n group 3 ~ [4- (2- methox? phen?) peraz? ml] -propyl, and each of R1 and R2 is a hydrogen atom or one of RI and R2 is a hydrogen atom and the other is a methyl group. Among the proponarnide derivatives (I), preferred are the compounds of formula I wherein: (i) ring A ee a partial structure of formula VI (R * is a hydrogen atom or a chlorine atom) , the ring of B is a 4-methoxyl group, R3 is a hydrogen atom or a group 2- (dimet i lammo) et i lo. (n) ring A is a partial structure of formula VI (R * is? n methyl group), ring B is a 4-methylphenyl group, R3 is a hydrogen atom or a 2- (d? rnet) group ? iam? no) et? io. (m) ring A is a partial structure of formula VI (R4 is a volume of chlorine), ring B is a group 4-rnetox? phenol, R3 is a hydrogen atom or a group 3- [ 4- (2- rnetoxy eniDpiperazinylpropyl. (LV) ring A is a partial structure of formula VI (R * is a benzyl group), ring B is a 4-10 methoxypheme group, R3 is a hydrogen atom or a 2- (dirnethylamine) ethyl group and R 1 and R 2 both a hydrogen atom, some of R 1 and R 2 is a hydrogen atom and the other is a methyl group The onarnide ppp derivative (I) can be used in the form of a salt thereof in the cyclisation reaction of the present invention The salt of the mixture includes, for example, a salt with an inorganic acid or organic acid (for example, hydrochloride, sulfate, phosphate, brornhydrate, methanesulfonate, p toluensul fonate, acetate, fumarate, maleate, oxalate, fonnal benzene sulphite, etc. The intramolecular cyclization reaction of the present invention can evade out in the presence or absence of an acid or a base, but preferably is carried out in the presence of an acid. ? R The acid can be any Bronsted acids or Lewis acids. The Bronsted acid may be either an inorganic acid or an organic acid, for example a mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, prechloric acid, etc.), a lower alkanoic acid (eg formic acid, acetic acid, ico-acid, butyric acid, etc.), a hydroxy-substituted lower alkanoic acid (eg citric acid etc.), a lower halogenated alkanoic acid (eg phoreoacetic acid, etc.), an interior alkanesulphonic acid (eg methanesulfon acid co, etc.), an aryl acid (eg p-toluensulonic acid, benzensulonic acid, etc.), oxic acid, etc. Lewis acid includes titanium tetrachloride, aluminum chloride, boron tri fluoride, tin chloride, etc. Among these acids, a mineral acid, a lower alkyl alkanol acid and an arisulonic acid are preferred, and preferred examples are methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, hydrochloric acid and bromidic acid. The base may be either inorganic base or organic base, for example inorganic bases (eg, alkali metal bicarbonates, alkaline metal carbonates, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal hydrides, alkali metal amides). , alkali metal alkoxides, alkali metal alkoxides, alkali metals, lcali noterreos metals, etc.), and organic bases (for example 1, 8-d? Azab? C? Clo [5.4.0] -unde-7-queno, d? Isoprop? Let? Iam? Na, tnet iiarnina, pipdina, etc.). The amount of the acid or base is not critical, but it is usually on the scale of 0 to 300 mole%, for the amount of compound I .. That is, the present process can be preferably carried out using a Bronsted acid, in an amount of 0 to 100 moles, preferably in an amount of 0 to 50 moles% or using a Le? acid in an amount of 0 to 300 moles%, preferably in an amount of 50 to 200 moles, or using a bae in an amount of 0 to 300 mole%, for the amount of compound I. The acids or bases can be added to the reaction mixture either in one portion or in several portions. However, it may be preferable to add the acids or bases in several portions in order to decrease the reaction time. The solvent used in the present invention can be any that does not affect the reaction, for example, water, alcohols (for example methanol, ethanol, propanol, etc.), ketones (for example acetone, rnet-l-ii-ketone, etc. .), esters (eg ethyl acetate, etc.), aromatic hydrocarbons (for example benzene, naphthalene, chlorobenzene, o-dichlorobenzene, rn-dichlorobenzene, p-d? chlorobenzene, o-, m- or pt p-chlorobenzene, toluene, estylene, xylene, etc.), halogenated hydrocarbons (for example, methylene chloride) , chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.), aliphatic hydrocarbons (for example n-hexane, n-heptane, etc.), alicyclic hydrocarbons (for example cyclohexane, etc.), polar aprotic solvents ( example N, N-dirnetiiformami a, dirnetyl sfoxide, etc.), ethers (for example dioxane, tetrahydrofuran, etc.), and mtrilos (for example acetonitplo, etc.), preferably the solvents are those that have? n high boiling point of more than 100 ° C, such as dioxane, neeitylene, xylene, toluene, chlorobenzene, dichlorobenzene, or tpclorobenzene, from the point of view of the reaction rate. These solvents can be used alone, but can be used in the form of a mixture of two or more solvents in a suitable ratio, in a single phase or in two phases. Alcohols, aromatic hydrocarbons, ethers and mixtures thereof are preferred, and preferred examples are chlorobenzene, dichlorobenzene, toluene, xylene, and stryiene. The amount of the solvent can be on the scale of the amount at which the reagent can be dissolved. However, it is preferable to use a smaller quantity of solvent in the above scale (ie, to decrease the time.) The reaction of nontranocular cyclization is preferably carried out in a solvent at a temperature between 0 and 250 °. C, preferably at a temperature of between 80 and 200 ° C. The propionate derivative (I) used in the present invention can be optically active or a racemic mixture of the same When an optically active compound (I) is used in the present invention, the desired optically active compound can be obtained without racemization The desired compound (II) can optionally be treated with an acid or a base to be converted to an acid addition salt such as hydrochloride, sulfate, phosphate, bro hydrate, methanesulfonate, p-toluenesulfonate, acetate, furnarate, maleate, oxalate, benzenesulfonate, etc. or in an alkali metal salt (for example sodium salt, potassium salt, etc.), an alkali metal salt ore (for example, magnesium salt, calcium salt, etc.) ). The thus obtained 1,5-benzot? Azep? Na (II) derivative or a salt thereof can be converted to a derivative of 3-alkanoyloxy? Nfer? Or-5- (d? Alkylamino-lower alkyl or substituted or unsubstituted piperazimino-lower alkyl) -2, 3-d? h? dro-2- (substituted phenyl) -1,5-benzot? azep? na, formul: where R3 * is a group (di -alqu larnmo in fepor) -al qu? or a lower piperazine lo-alkyl group which optionally has a substituent, R 5 is a lower alkanoyl group, and ring A and ring B are the same as previously defined by a method described in the Second Japanese Patent Publication (Kokot'u) Nos. 43785/1971, 18038/1978, USP Nos. 3562257, 4438035, 4567175 , 5134139, 5378698, etc., the description of which is incorporated in the present reference, and if necessary, is additionally converted into a pharmaceutically acceptable salt thereof. That is, when R3 of the compound (II) is a hydrogen atom, a lower (di-alkylamino) -lower alkyl group or a substituted or unsubstituted p-perazyl group-lower alkyl, is introduced in the 5-position. of the derivative of 1,5-benzothiazepine na (II), and the group 3-h? drox? it is acylated with a lower alkanoyl group, and if required, the product thus obtained is converted into a pharmaceutically acceptable salt (J or m) The pharmaceutically acceptable salt can be an acid addition salt with an inorganic acid or an acid organic, for example, hydrochloride, sulfate, phosphate, bromide, methanesulfonate, p-toluenesulfonate, acetate, smoking-ato, maleate, oxalate and benzene-fonate When the intramolecular cyclization reaction of the present invention is carried out using the propionamide derivative (I) wherein R3 is a hydrogen atom, and a reactant which may be capable of introducing a lower (dialkylanone) -lower alkyl group or a piperazinyl-lower alkyl group optionally having a substi The extender (for example (dialkyl) not lower alkyl halide, or a lower alkyl piperazinyl halogen optionally having a substituent, etc.) is added simultaneously to the Reaction system, a derivative of 1,5-benzothiazepine (TI) can be obtained in substantially a single step wherein the 5-position of the 1,5-benzothiazepine nucleus is replaced with a group d? ~ alk? lower alkyl-lower alkyl or a piperazyl-lower alkyl group optionally having a substituent. The initial propionide derivative (I) used in the present invention is a novel compound, and a derivative of 2-ammonotide of Formula IV can be prepared, for example, by refluxing: SH A [IV] NHR wherein ring A and R3 are the same as defined above, with a 2,3-epo? prop? onamide derivative of formula V: wherein the ring B, R 1 and R 2 are the same as defined above, in a suitable solvent in the presence or absence of a catalyst (F iron), solvent may be methanol, benzene, toluene, ile, estylene, chlorobenzene, dichlorobenzene , trichlorobenzene or naphthalene, and methanol, xylene, chlorobenzene and dichlorobenzene are preferred.The iron catalyst can be inorganic or organic salts or complexes having a bivalent or trivalent iron ion, for example ferric nitrate, iron oxyhydroxide, ferric chloride, ferrous chloride, ferrous sulfate, ferrous iodide, ferrous sulphide, 4-c-clohexyl-butyrate (iron, ferric oxide, ferric bromide, ferrous fluoride and ferric fluoride, and ferric chloride, ferrous sulfate and ferric nitrate are the preferred examples: Among the proponarnide derivatives (I), the compound of formula I wherein R and R2 are the same or different and are each a hydrogen atom,? n lower alkyl group , a R Amino acid residue, or an aplo group optionally having a substituent, or combination thereof at its terminal part together with the nitrogen atom adjacent to which it is attached to form a heterocyclic ring optionally having a substituent, can be prepared by reaction of an ester derivative of propionic acid of formula VII: where R ee a lower alky group, and Ani l A, Ani l, B and R3 are the same as defined above, with a compound of the formula [VlII- al: LOR u / HN [VHI-a] R 21 wherein RH and R2 * are the same or different and each is a hydrogen atom, a lower alkyl group, an amino acid residue or an aryl group optionally having a substituent, or combine with each other at their terminals together with the adjacent volume of nitrogen to which they are bonded to form a heterocyclic ring having optionally 0 its value, in a suitable solvent at a temperature of between 0 and 80 ° C. The solvent may be methanol, ethanol, tetrahydrofuran, toluene, xylene, mesitylene, chlorobenzene, etc. If necessary, the amino group of the compound [HIV can be protected by a protecting group such as a benzyloxycarbonyl group, etc., and used in the above reaction, if said protecting group is furthermore separated by a conventional method after the reaction . In the derivatives of 2, -epo ipropionapuda [V],? N composed of the (2R, 3S) -2, 3-e? Ox? Prop? Onam? Da of the formula [V-al: wherein the ring B, R1 and R2 are the same as defined above, a compound of the (2S, 3R) ~ 2, 3-epox? prop? onam? da (He formula [V-bl: wherein the ring Bl is a benzene ring which is substi ted by a lower alkyl group, and R1 and R2 are the same as defined above, are both novel compounds. The compounds [V-al and [V-bl where R 1 and R 2 are each a hydrogen atom or of R * and R 2 is a hydrogen atom and the other is a lower alkyl group are very preferred, and the examples even more preferred are the compounds [V-al and [V-bl where R1 and R2 each is a hydrogen atom.

In the derivatives of 2,3-epox? Prop? Onam? Da [VI, the compound of the formula [V] wherein R1 and R2 are the same or different and each is a hydrogen atom, a carbamoyl group, a lower alkyl group, an amino acid residue, or an aplo group optionally having a substituent, or combine with each other at their terminals together with the adjacent nitrogen atom to which they are linked to form a heterocyclic group optionally having an Substituent can be prepared by reacting a compound of the formula [1X1: wherein ring B is the same as defined above, with compound [VI II -al in a solvent such as methanol, tetrahydrofuran, dimethylformamide, toluene, xylene, etc., at a temperature between 0 and 100 ° C. The compound TV] can be prepared by reacting a reactive derivative (for example acid chloride, acid anhydride, etc.) of a compound of the formula [XI: CH = CH-CO2H [X] wherein ring B is the same as defined above, with a compound of formula [VIII]: R1 / [VIII] HR R¿ wherein R * and R2 are the same as defined above, in the presence of a base (e.g. potassium carbonate, sodium hydroxide, sodium acid carbonate, diethyla ine, pipdin, etc.), in a solvent such as chloride of rnetylene, tetrahydrofuran, toluene, xylene, etc., at a temperature between 0 and 100 ° C, and reacting the resulting product of the formula [XI]: where the ring B, Rl and R2 are the same as. defined above, in the presence of an oxidizing agent such as a peroxide compound (eg, aqueous hydrogen peroxide, hydroperoxy or tert-butyl, etc.) or a peracid (eg, peracetic acid, m-chloroperbenzoic acid), in a suitable solvent such as ethylene chloride, tetrahydrofuran, chlorobenzene, etc. at a temperature between 0 and 100 ° C. In the description and claims herein, the lower alkyl group means a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, and the lower alkoxy group means a straight chain or branched chain alkoxy group having from 1 to 6 carbon atoms. The lower alkylenedioxy group means a straight chain or branched chain alkylenedioxy group having from 1 to 6 carbon atoms, and the lower alkanoyl group means a straight chain or r-linked alkanoyl group having from 1 to 7 atoms of carbon. The cycloalkyl group means a cycloalkyl group having from 3 to 8 carbon atoms, and the lower alkanoic acid means a straight chain or branched chain alkanoic acid having from 1 to 7 carbon atoms. The halogen atom is an atom of chlorine, bromine atom, fluorine atom or iodine atom. The present invention is illustrated in more detail in the following examples and reference examples, but should not be construed as being limited thereto.

EXAMPLES EXAMPLE 1 A mixture of (2S, 3S) -3- (2-arn? Nofen? Lt? O) -2-h? Drox? -3- (4-rnetox? -fenj 1 is refluxed for 11 hours. ) -propionamide (1.59 g), xylene (8 ml) and methanesulfonic acid (24 rng) after allowing to cool to room temperature, the mixture is stirred until crystallized. The precipitated crystals are collected by filtration, washed with cooled methanol and dried at 50 ° C to give (2S, 3S) -2,3-d? H? Dro ~ 3-h? Drox? -2- (4- rnetox? phen? l) -l, 5 ~ benzot? azep? n-4 (5H) -one (1.41 g).

P.f. ? 03-205? C [allo25: * -H4.3 ° (c = 0.5, dimet and Lforrna ida) 1H-NMR (DMSO-dβ, d): 3.76 (3H, s), 4.30 (lH, dd), 4.74 ( lH, d), 5.05 (lH, d), 6.87-7.62 (8H, m), 10.32 (lH, s) Optical purity (HPLC): > 99.9% ee Condition for HPLC: Column: CHIRALCEL 0D (4.6x250 inrn). manufactured by Daicel Chemical Industries, Ltd. Solvent: n-Hexane: ethanol-85: l5 Flow rate: 0.5 rnl / min. UV detector: 254 n Column temperature: 35 ° C EXAMPLE 2 A mixture of reflux is carried out for 29 hours. (2S, 3S) -3- (2-amnoferoferum) -2-hydrox -3- (4-methox? -phen?) -propionarnide (159 rng) and xylene (3 ml). After allowing it to cool to room temperature, the mixture is stirred until crystallized. The precipitated crystals are collected by filtration, washed with xylene and dried at 60 ° C to give (2S, 3S) -2,3-d? H? Dro-3-h? Drox? -2 (4-methox? Phen?) -l, 5-benzo-t? Aze? N ~ 4 (5H -one (115 ng). The physical properties of this product are identical to those of the compound of Example 1.

EXAMPLE 3 A mixture of (2S, 3S) -3- (2-arn? Ofen? Lt? O) -2-h? Drox? -3- (4-metho? -fen? L) -N is brought to reflux. -methylpropionamide, chlorobenzene and p-toluene phonic acid monohydrate. The reaction mixture is subjected to HPLC analysis to confirm the production of (2S, 3S) -2,3-d? H? Dro-3-h? Drox? -2 - (4-rnetoxy -fe il) - 1 , 5-benzot? Azep? N-4 (5H) -one. Conditions for HPLC: Column: Uaters Puresil 5 μ C18 120 A (4.6 x 150 rnrn), manufactured by Uaters, Tnc. Solvent: Acetomtrile: 10 mM potassium dihydrogen phosphate (pH 3) -50: 50 Flow rate: 0.5 rnl / rnin. UV detector: 254 nrn Column temperature: 40 ° C EXAMPLE 4 (2E, 3R) -3- (2-Arn? No-5-rnet? Lfen? Lt? O) -2-h? Dro? -3- (4-rnet-ilphenyl) -prop? Onam? Da try the same way as in example 1 to give (2R, 3R) -2,3-d? h? dro-3-h drox? -2 ~ (4-ef ll eni I) -8-me ii-i, 5-benzot? aze? n-4 (5H) -one. P.f. 212-214 ° C «ID25: - 129.2O (C-1.0, dimethyl forrnarnide) 1 H-NMR (DMS0-d6, d): 2.29 (6H, s) .29 (IH, d), 4.67 (lH, d) , 5.03 (LH, d), 7.02-7.42 (7H, m), 10.20 (lH, s) EXAMPLE 5 A mixture of (2R, 3S) -3 - (-rnetoxyphenyl) -2,3-e is refluxed. ? ox? prop? onam? da (966 ing) and xylene (10 rnl) with heating under a nitrogen atmosphere. When the reflux is started, a mixture of 2-arninothiophenol (689 g) and ferrous sulfate heptahydrate (0.11 rng) in methanol (0.1 rnl) is immediately added to the reaction system, and the mixture is reacted at the same temperature during the reaction. 5 minutes. (-) The reaction mixture is added with rnetanosulonic acid (48 rng) and the mixture is refluxed for 13 hours. The mixture is cooled with ice (for 2 hours and the precipitated crystals are collected by filtration, washed with methanol and dried at 50 ° C to give (25.3S) -2, 3-d? H? Dro-3 -h? drox? -2- (-metox? -feml) l, 5-benzot? aze? n-4 (5H) ona (1.07 g) .The physical properties of this product are identical to those of the compound of the example l.

EXAMPLE 6 A mixture of (2S, 3S) -3 2-arninophenylthio) -2-hydrox was refluxed? -3- (-rnetox? In? L) pro ?? onarn? da, tri-boron fluoride complex - diethyl ether and 1,4-d-oxano. A mixture of the reaction is subjected to HPLC analysis to confirm the production of (2S, 3S) -2,3-d? H? Dro ~ 3-h? Drox? -2- (4-rnetoxy phenyl) -1, 5-benzot? Azepm-4 (5H) -one. Conditions for HPLC: Column: Uaters Puresil 5 u C18 120 8 (4.6 X 150 rnrn), manufactured by Uaters, Inc. Solvent: Acetonitrile: 10 nm (Phosphate diacid of potassium (pH 3) = 50: 50 Flow rate : 0.5 ml / min UV detector: 254 nrn Column temperature: 40 ° C.

EXAMPLES 7-31 Compounds [I] as listed in Tables 1-4 are treated in the same manner as in Example 1 -6 or 32-36 to give the corresponding compounds [III of enclosed intramolecular ring.

CUODRO 1 CHART 2 3. 1 FIGURE 3 -? P.lJflDRO 4, EXAMPLE 32 Mix (2S, 3S) -3- (2-f.rn? Nofen? Lt? O) -2-h? Drox? -3 ~ (4 ~ rnetoxy-phenyl) -N- phenylpropionamide (582 mg) with chlorobenzene (10 ml) and the mixture is refluxed for 25 hours during which time it is added to the rnor.oh? Phytonic acid-toluensul draic acid (112 mg) in 8 portions (14 mg x 8) at 3 hour intervals. The reaction mixture is cooled to room temperature and concentrated under reduced pressure to remove chlorobenzene. The residue is added methanol (5 ml) and the mixture is refluxed for 1 hour. The mixture is allowed to cool to room temperature and is stirred until crystallized, and then cooled with ice. The precipitated crystals are collected by filtration, washed with chilled methanol and dried at 50 ° C to give (2S, 3S) -2,3-d? -hydro-3-hydrox? -? - (4- etox? femD-1, 5-enzot azepm-4 (5H) -one (243 rng) .The physical properties of this product are identical to those of the compound of example 1., EXAMPLE 33 The mixture of (2R, 3S) -3- (- ethoxyphenyl) -2, 3-epox? Prop? Onamide (3.86 g) and chlorobenzene (77 nm) with reflux under a nitrogen atmosphere is refluxed. . When reflux is initiated, a solution of 2-aminotenol (2.75 g) and ferric chloride hexahydrate (0.54 mg) in methanol (0.1 ml) is immediately added to the reaction mixture, and the mixture is reacted to the reaction mixture. the same temperature for 5 minutes.

Bring the reaction mixture to the HPLC analysis to confirm the production of 3- (2-arn? Nofeml-.10) -2-hydrox? -3- (4-nitro-diethenyl-propionamide (6.09 g)) (2S , 3S) / (2S, 3R) = 91.5 / 8.51. P-Toluensulonic acid monohydrate (0.76 g) is added to the reaction mixture, and the mixture is refluxed for 32 hours and concentrated under pressure The mixture is reduced to remove the chlorobenzene, the residue is added to methanol (25 ml) and the mixture is brought to a reflux for 1 hour and cooled with ice overnight.The precipitated crystals are collected by filtration, washed with methanol and dry at 50 ° C to give (2S, 3S) -2,3-d? H? Dro-3-h? Drox? -2- (4-methox? Phen?) -l, 5-benzot? Aze? N-4 (5H) -one (4.76 g). The physical properties of this product are identical to that of the compound of Example 1. Conditions for HPLC: Column: Ua + ers Puresil 5 u C18 120 A (4.6 X 150 inm), manufactured by Waters, Inc. Solvent: ficetomt rilo: 10 mM of potassium dihydrogen phosphate (pH 3) 30: 70 Flow velocity: LO rnl / rnin. UV detector: 254 nm. Column temperature: 40 ° C.

EXAMPLE 34 The mixture of (2R, 3S) -3 ~ (-rnetoxyphenyl) -2, 3-epox? Prop? Onam? Da (9.66 g) and chlorobenzene (193 rng) is brought to reflux with heating under a nitrogen atmosphere . When the reflux starts, a solution of 2-arn? Not? Ofenol (6.89 g) and ferric chloride hexahydrate (1.35 mg) in methanol (Q.L rnl) are added to the reaction mixture, and the mixture is stirred at the same temperature for 5 minutes. The reaction mixture containing (2S, 3S) -3- (2-aminophen-1-yl) -2-hydroxy -3- (4-methoxy-fem-1) proponam is refluxed. gives during hours during which p-tolueneulonic acid rnonohydrate (2.88 g) is added thereto in 6 portions (0.48 g x 6) at 2.5 hour intervals to separate the chlorobenzene. The remaining chlorobenzene is evaporated and methane L (50 rnl) is added to the residue. The mixture is refluxed for 1 hour, cooled to room temperature and continued to cool at 3 ° C overnight. The precipitated crystals are collected by filtration, washed with cooled methanol and dried at 50 ° C to give (2, 3S) -2,3-dh? Dro-3-hydrox? -2 ~ (4 -rnetox. phenyl) -, 5-benzot? azep? n-4 (5H) -one (11.73 g). The physical properties of this product are identical to those of the compound of Example 1.

EXAMPLE 35 The mixture of (2R, 3S) -3- (4-rnetox? Phen?) -2,3-epoxyrronamide (L.93 g) and chlorobenzene (39 nm) is refluxed. ) with heating under a nitrogen atmosphere. When reflux is started, a solution of 2-arnmot® ofenol (1.38 g) and ferric chloride hexahydrate (0.27 rn) in methanol (0.05 rnl) is immediately added to the reaction mixture, and the mixture is stirred at the same temperature for 5 minutes to give a reaction mixture containing 3- (2-arn? nofemlt? o) -2-hydroxy-3- (4-methoxy-phene Dpropionamide (3.08 g) The resulting reaction mixture is concentrated to 16 g The concentrated mixture is refluxed for 13 hours during which metanephonic acid (38 mg) is added in 5 portions (38 mg x 5) at intervals of 2-3 hours, the remaining chlorobenzene is evaporated. of the mixture and methanol (10 ml) is added to the residue, the mixture is refluxed for 1 hour, allowed to cool to room temperature and continued cooling at 8 ° C for 40 hours.The precipitated crystals are collected by filtration. , washed with cooled methanol and dried at 50 ° C to give- (2S, 3S) -2, 3-d? h? dro-3-h? drox? -2- (4-methox? fe ml) -l, 5-benzot? azep? n-4 (5H) -one (2.38 g). The specific properties of this product are identical to that of the compound of Example 1.

EXAMPLE 36 A mixture of (2R.3S) -3- -methoxyphenol) -2,3-e? Ox? Propranone (15.46 g) and chlorobenzene (309i) is heated under reflux under a nitrogen atmosphere. When reflux is initiated, a solution of 2-arnmotio phenol (11.02 g) and ferric chloride (2.16 g) hexahydrate in methanol (0.1 ml) is immediately added to the reaction mixture, and the mixture is stirred at the temperature for 5 minutes to give a reaction mixture containing 3 - (2 ~ arn? no-phen? lt? o) - 2-h? drox? -3- (4-methox? phen? l) prop? onam? da (24.24 g) C (2S, 3S) (2S, 3R) = 91.3 / 8.7]. One quarter of the mixture is obtained and 35% hydrochloric acid (1.04 g) is added thereto. The mixture is refluxed for 13 hours to remove the solvent. The remaining chlorobenzene is evaporated from the mixture and methanol (25 ml) is added to the residue. The mixture is refluxed for 1 hour, allowed to cool to room temperature and continued to cool at 3 ° C overnight. The precipitated crystals are collected by precipitation, washed with chilled methanol and dried at 50 ° C to give (2S, 3S) -2.3 ~ d? H? Dro-3? H? Drox? -2- (4 - met oxy phenyl il) -l, 5-benzot? azep? n- (5H) -one (4. 9 g). The physical properties of this product are L to the compound of Example 1.

EXAMPLE 37 The (2R, 3S) -3- (4-Methoxyphenyl) -2,3-epoxypropion ida is treated in the same manner as in Example 36 except for using hydrobromic acid instead of hydrochloric acid to give (2S) , 3S) -2, 3-d? H? Dro-3-h? Drox? -2- (4-methox? Phen?) -l, 5 ~ benzot? Azepm-4 (5H) -one. The physical properties of this product are identical to that of the compound of Example 1 EXAMPLE OF REFERENCE 1 1) fi the mixture of (2R, 3S) -3- (4-rnetox? Feml) -2,3-e? Ox? Prop? Ón? Co (2.08 g) and N, methyl ester. N-dirnetiiformamide (3 ml) is added 28% aqueous ammonia (6.1 g) under cooling with ice. The mixture is reacted at room temperature for 2 hours, and the precipitated crystals are collected by filtration, washed with water and dried at 50 ° C to give (2R, 3S) -3-4rnetox? Phen? L) - 2, 3-epo Lpropionamide (1.64 g). Mp: 14? -144 ° C HC.] D25: -163.7 ° (C = 1.0, rnet ano l) 1H-NI1R (DMS0- (J6, d: 3.49 (lH, d), 3.75 (3H, s), 3.96 (lH, d), 6.94 (2H, d), 7.24 (2H, d), 7.41 (lH, s), 7.56 (lH, s) 2) A mixture is brought to reflux in (2R, 3S) -3 -4-rnetoxifeni 1) -2, 3-e? Ox? Rop? Onarn? Amide (1.93 g) and xylene (15 nl) with heating under a nitrogen atmosphere. When reflux is initiated, a solution of 2-arn? Not? Ofenol (1.38 g) and ferrous sulfate heptahydrate (0.28 mg) in methanol (0.2 ml) is immediately added to the reaction mixture, and the Mix at the same temperature for 5 minutes and cool to room temperature. The reaction mixture is subjected to HPLC analysis to confirm the production of 3- (2-arn? O-phen? Lt? O) -2-h? Drox? -3- (4-rnetox? In? L) ? ro? onarn? da (2.69 g, (2S, 3S) / - (2S 3R) = 91/9). The reaction mixture or concentrated pressure is concentrated to remove the solvent and the residue is dissolved with heating in ethanol (3 ml) and water (3 ml). The mixture is gradually mixed at 0 ° C with stirring until it crystallizes. The precipitated crystals are collected by filtration, washed with ethanol cooled to 50 ° C and dried 50 ° C to give (2S, 3S) -3- (2-am? Nofen? L? T? O) -2-h? Drox? -3- (4-rnetoxifeml) pro? Nam? a (0.84 g). Mp: 110-112 ° C GW] D25: + 506 ° (C = 1.0, methanol) lH-NMR (DMS »0-6, or: 3.70 (3H, s), 4.11 (1H, d), 4.44 (IH , d), 5.35 (H, d), 6.0 (1H,), 6.25 -7.28 (8H, m), 7.39 (2H, s) Conditions for HPLC: Column: Waters Puresil 5 JJ C18 120 fi (4.6 x 150 rnrn) manufactured by Waters, Inc. Solvent: Acetonitplo: 1 OM potassium dihydrogen phosphate (pH 3) = 30: 70 Flow rate: 1.0 rnl / rnin UV detector: 254 nrn Column temperature: 40 ° C REFERENCE EXAMPLE 2 (1) Methyl ester of (2R, 3S) -3- (4-Methoxyphenyl) -2, 3-e? Ox? Pypiomco acid (2.08 g) is mixed with methanol (10 ml), and The same is added dropwise to a 40% aqueous methylamine solution (1.44 g) in methanol (10 ml) under cooling with ice. The reaction mixture is stirred at 10-15 ° C for 2 hours and concentrated under reduced pressure to remove the methanol. Ether is added to the residue and the precipitated crystals are collected by filtration, washed and dried under reduced pressure at 50 ° C to give (2R, 3S) -3- (4-methox? Phen?) -2 , 3-epox? -N-rneti lpropionar í dad .70 g). Mp: L35 ~ 136 ° CG «3D 5: -145.3 ° (C = LO, methanol) 1 H-NMR (CDCl 3, 6: 2.86 (3H, d), 3.53 (lH, d), 3.81 (3H, s), 3.83 (lH, d), 6.26 (lH, < _), 6.84-7.26 (4H, m) (2) A mixture of (2R, 3S) -3 ~ (-rnetox? Phen? L) is refluxed. -2.3-epox ?, N-Met? L-? Rop? Onam? Da (829 ing) and xylene (10 ml) with heating under a nitrogen atmosphere.

When reflux is initiated, a solution of 2-arn? Not? Ofenol (551 rng) and anhydrous ferric chloride (0.065 mg) in rnetanol (0.08 ml) is immediately added to the reaction mixture, and the mixture is reacted at the same temperature for 5 minutes and cooled to room temperature. The precipitated crystals are collected by filtration, washed with xylene and dried at 60 ° C to give (2S, 3S) -3- (2-am? Nofemlt? O) -2-h? Drox? -3- (4-rnetox? Feml) -N-met? Lprop? Onam? Da (1.06 rng) Pf: 145-147 ° C Ca3D25: + 433 ° (c = 10, methanol) 1 H-NMR (DMSO-d? , &): 2.63 (3H, d), 3.70 (3H, s), 4.14 (lH, dd), 4.45 (lH, d), 5.33 (2H, s), 6.11 (1H < J) 6.25-7.29 (8H, rn), 7.93 (lH, d) REFERENCE EXAMPLE 3 (1) is a mixture of methyl ester of acid (2S, 3R) ~ 3- (4-met? Lfeml) -2, 3-epox? Prop? Ón? Co (3.84 g) and methanol (25 rnl) is added dropwise a solution of 28% aqueous ammonia (6.1 g) in methanol (10 ml) under cooling with ice. The reaction mixture is gradually heated to room temperature and stirred for 2 hours, and the mixture is stirred for 1 hour or cooled with ice. The precipitated crystals are collected by filtration, washed and dried at 50 ° C to give (2S, 3R) -3- (4-rnet? Lfen? L) -2, 3-epox? Prop? On-arn? a (2.71 g). Mp: 183-185 ° C [Or] D25: +17? .5 ° (c = 1.0, rnet nol) 1H-NMR (CDC13 and DMS0d6.6): 2.35 (3H, s), 3.47 (lH, d) , 3.93 (LH, d), 6.52 (2H, d), 7.16 (4H, s) (2) It is treated (2S, 3R) -3-Met? Lfen? L) 2 -, 3-epoxypropionnide and 2 -arn? no-5-rnetLlteophenol in the same manner as in the reference example l- (2) to give (2R, 3R) -3- (2-arn? no-5-met ifenjl? o) -2- h? drox? -3- (4-rnetiifeml) pro? onam? da. Mp: 145-1456C f 3D 5: -410o (c = 1.0, methanol) iH-NMR (DMS0d6, 6): 1.96 (3H, s), 2.24 (3H, s), 4.11 (lH, dd, 4.46 (lH, d), 5.13 (2H, s), 5.99 (1H, s), 6.51-7.26 (7H, rn), 7.37 (2H, s) REFERENCE EXAMPLE 4 (1) is a mixture of methyl ester (2S, 3R) -3 ~ (4-methexenol) -2, 3-epox? propylene ion (1.92 g) and methanol (10 ml) is added dropwise a solution of aqueous rhamlanilin 40% (2.37 g) in methanol (10 ml) under ice-cooling The reaction mixture is stirred under ice-cooling for 1 hour and concentrated under reduced pressure, the residue is added with ether and the filtrate is collected by filtration. crystals precipitated, washed and dried at 50 ° C to give (2S, 3R) -3- (4-inetiifeml) -2,3-e? ox? -N-met? lprop? onam? da (1.75 g) Mp 152-153 ° C CW] D25: + 153.7 ° (C = 1, rnetanol) 1 H-RNN (CDCl 3 d): 2.34 (3H, s), 2.86 (3H, d), 3. 52 (lH, d), 3.83 (2H, d), 6.27 (lH, s), 7.15 (4H, s) (2) (2S, 3R) -3- (4-Met? Lfen? L) -2, 3-epox? -N-rnet-il-propionami and 2-am? No-5-met? Lt? Ofenol are treated in the same manner as in reference example l- (2) to give (2R, 3R) -3- (2) -2- H? drox? -3- (4-rnet? lfen? l) -N-rneti lpropíarnida. P. f ".lf) 8-170 ° C rof] D25: -379 ° (cl, methanol) 1H-NMR (DMSO-de, 6): 1-97 (3H, s), 2.25 (3H, s) , 2. 62 (3H, d), 4.13 (lH, dd), 4.47 (lH, d), 5.12 (2H, s), 6.10 (lH, d) 6.51- 7.27 (7H,? N), 7.94 (lH, d) REFERENCE EXAMPLE 5 a mixture of methyl ester acid of (25,35) -3- (2-arninophenylthio) -2-hydroxyl- (4-methox? -femDpropionic acid and rnetanol is added dropwise aqueous low ammonia cooling with ice The reaction mixture is reacted at room temperature and the precipitated crystals are cooled by filtration, washed with water and dried to give (25.35) -3- (2-arnide not f) 2-h? Drox? -3- (4-rnetox? Phen? L)? Rop? Onarn da.

REFERENCE EXAMPLE 6 Potassium carbonate is added to dichloride sulfoxide and the mixture is stirred at 70 ° C. The mixture is cooled to room temperature and is added (S, 3S) -3- (2-arn? Nofen lt? O) -2-h? Drox? -3- (4-methox? Phen?)? The mixture is stirred, and the reaction mixture is added dropwise with 2-direthylaminoethyl chloride, and the mixture is stirred at room temperature. The reaction mixture is poured into the ice water, and extracted with ethyl acetate. The extract is dried and concentrated under reduced pressure to remove the solvent for d (25, 35) -3- C2- (2-dírnet? Lam? Noet? Iam? No) femlt? O] -2-h? Drox ? -3- (4 -methyl) -propion ida.

REFERENCE EXAMPLE 7 A mixture of (2R, 3S) -3- (4-? Netox? Phen? L) -2,3-epox? ~ Propionamide and xylene is refluxed with heating under a nitrogen atmosphere. When the reflux starts, a solution of 2 A2-d? Rnet? Lam? Noet? Larn? no) t-ofenol and ferrous sulfate eptahydrate in methane is added immediately into the reaction mixture, and the mixture is reacted at the same temperature and cooled to room temperature. The reaction mixture is concentrated under reduced pressure and the residue is dissolved with heating in ethanol and water. The mixture is allowed to cool to 0 ° C, and the precipitated crystals are collected by filtration, washed with cooled 50% ethanol and dried to give (25.3S) -3-C2. (2.d? Met? L-am? Noet? Lam? No) fe itió] -2-hydroxy-3- (4-methox? Phen? L) rop? Onarn? to.

REFERENCE EXAMPLES 8-30 The corresponding starting compounds are treated in the same manner as in Reference Examples 1-7 or 31-33 to give the compounds listed in Tables 5-8.

TABLE 5 TABLE 6 TABLE 7 TABLE a REFERENCE EXAMPLE 31 (1) To a mixture of sodium hydride (oil dispersion at 62.5%, 0.46 g) and dimethyl sulfoxide (3 ml) is added an aniline solution (1.02 g) in dimethyl sulfoxide (1 ml). ) at room temperature under nitrogen atmosphere, and the mixture is stirred for 30 minutes, and the mixture is added a solution of methyl ester of (2R, 3S) -3- -rnetox? l) -, 3-epox? prop? ón? co (2.08 g) in dunetyl sulfoxide (4 rnl) at room temperature for a period of 5 minutes. The mixture is subsequently stirred at the temperature for 1 hour, and water (50 ml) is added thereto. The precipitated yellow crystals are collected by filtration, and recps-talized from ethyl acetate (60 rnl) to give (2R, 3S) -3- (-rnetox -feml) -2, 3-epox-N-phenylpropionnide (1.50 g). P.f. 162-1 fi3 ° C rof] D25: -223.7 ° (c = 1.0 / diinet ll form »» da) 6): 3.77 (3H, s), 3.7B (lH, d), 4.13 (lH, d) , 6.95 ~ 7.69 (9H, rn), 10.25 (lH, s) (2) A mixture of (2R, 3S) -3- (4-methox? Phen?) -2, -epoxy-N-phenylpropionnide (539 rng) and chlorobenzene (5 rnl) is refluxed under low heating nitrogen atmosphere. When reflux is started, a solution of 2-am? Not? Ofenol (275 mg) and ferric chloride hexahydrate (0.054 mg) in methanol (0.1 ml) is immediately added to the reaction mixture. The mixture is stirred at the same temperature for 5 minutes and cooled to room temperature. The precipitated crystals are collected by filtration, washed with chlorobenzene and dried at E0 ° C to give (2S, 3CA -3- (2-arn? NofemlUo) -2-h? Drox? -3- (4-rnetox? fen? l) -N-femlprop? onam? da (582 rng) .Pf 215-217 * 0 dimethyl form i da) 6) _3.69 (3H, s), 4.35 (lH, d), 4.51 (lH, d), 5.3l (2H, s), 6.24-7.69 (13H,? n) /6.52(lH,s), 9.83 (lH, s) REFERENCE EXAMPLE 32 Acid methyl ester (2R, 35) -3- (-Metox? Phen?) -2, 3-epoxypyrronic acid (10.4 g) is mixed with a solution of ammonia in methanol. 15.3% by weight (56 g), and the mixture is reacted at 15 ° C for 2.5 hours. The mixture is concentrated under reduced pressure until the total weight of the mixture becomes 44 g. The mixture is added water with ice (112 < j., And the mixture is stirred for 2 hours under ice cooling.) The precipitated crystals are collected by filtration, washed with water and dried at 50 ° C to give ( 2R, 5) - - (.-Rethoxyphenyl) -2,3-epox? -propione i da (8.99 y).

REFERENCE EXAMPLE 33 Acid methyl ester (2S, 3S) - 3 - (2-yninopheni 1 lio) - -h? Drox? -3- (4-methox? Feml) -propionic and aniline are treated in the same way as in reference example 5 to give (2S, 3S) -3- (2-flm? Nofen? Lt? O) -2-h? Drox? -3- (4-methox? Phen?) -N- femlpropione ida. EFFECTS OF THE INVENTION According to the present invention, the 1,5-benzot [azepma] derivative [II, which is an intermediate for preparing drugs such as diltiazem hydrochloride, can be obtained in high yield by an intramolecular crystallization reaction of the derivative of propione ida ["13 q? e has group 2-h? drox? desprot-eg? do. Especially, when Substi? entes in the portion amida of the derivative of propionani a TI] (ie R * and R2) are both hydrogen atom, the ammonia that is generated during the intramolecular ecular crystallization reaction can be removed in the form of gas from the reaction system and therefore the intramolecular crystallization reaction of the compound [13 can be carried It is easy to heat the reaction mixture without using an acid or base, and after the reaction of the 2-arni derivative not ofenol [IV] and the derivative of 2,3-e? ox? propionate CV3, the resulting propionamide derivative [I] can be used in the prese the intramolecular crystallization reaction without isolating it from the reaction system. In this case, the desired compound [II] can be obtained from the derivative of 2,3-epoxypropion ida [V.1 in high yield in a single step without complicated procedures.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. A process for preparing a 1,5-benzothiazepine derivative of the formula [II]: wherein ring fl and ring B are substituted or unsubstituted benzene ring, and R 3 is a hydrogen atom, a lower (lower alkyl) group or a piperazimyl-alkyl group substituted or unsubstituted lower, or a salt of the ism, is meant to subject a propionamide derivative of the formula CI3: wherein R and R2 e, the same or different and each are a hydrogen atom, a carbamoyl group, a lower alkyl group, a lower alkanoyl group, a lower alkylamino carbomyl group, an amino acid residue or an appropriate group It has optionally substituting, or commingling, with one another at its termination along with the hydrogen atom adjacent to which they join to form a heterocyclic group which optionally has substiuent, and ring fl, Ring B and R3 are the same as defined above, to the intramolecular crystallization reaction, and if necessary, convert the product into a salt of the same. 2.- A procedure to prepare a 3-alkane? Lox? mfenor ~ 5 ~ [d? non-lower alkylaryn-lower alkyl or a substituted or unsubstituted lower alkyl substituted piperazimyl] -1,5-benzothiazine of the formula [III]: wherein ring fl and ring B are a substituted or unsubstituted benzene ring, R31 is a lower (di-lower alkylamino) -lower alkyl group or a substituted or unsubstituted lower piperazinyl-lower alkyl group, and R5 is a lower alkanoyl group, or a pharmaceutically acceptable salt thereof, comprising subjecting an ida derivative derivative of the formula [I]: page 45 where Rl and R2 on the same or different and each are a hydrogen atom, a carbarnoyl group, a lower alkyl group, a lower alkanoyl group, a lower alkylaminocarbonyl group, an amino acid residue or an aplo group optionally having a substituent, or combining with one another at its termination together with the hydrogen atom adjacent to which they join to form a heterocyclic group optionally having a substituent, R3 is a hydrogen atom, a group (dial qui lower) -lower alkyl "or a substituted or unsubstituted piperazinyl-lower alkyl group, and ring fl and ring B are the same as defined above, or a salt thereof, to the reaction of intramolecular crystallization to give a 1,5-benzothiazepine derivative of the formula L "IT 1: wherein the ring fl, ring B and R3 are the same as defined above, and wherein R3 of the compound [TT] is a hydrogen atom, introducing a group (di lower alkyl) -lower alkyl or a piperazyl group -substituted or unsubstituted lower alkyl at the 5-position of the compound [II], isolating the 3-hydroxy group of the resulting compound with _ '. A lower alkanoyl group and, if necessary, converting the product to a pharmaceutically acceptable salt of the same. 3. A process according to any of claims 1 and 2, further characterized by the propionide derivative of the formula [Ti: wherein the ring fl and ring B are a substituted or unsubstituted benzene ring, R1 and R2 are the same or different and each is a hydrogen atom, a carbamoyl group, a lower alkyl group, an alkanoyl group lower, a lower alkylammocarbomyl group, an amino acid residue, or an indigo group optionally has a s? bstituent, or combine with each other at its termination together with the adjacent nitrogen atom to which they are attached to form a heterocyclic group optionally having a substituent, and R3 is a hydrogen atom, a group (non-lower dialkylamino) -lower alkyl or a substituted or unsubstituted or substituted pipercyl or lo-alkyl group, or a salt of the same is the compound that is prepared by reacting n derivative of 2-am? not? ofenol of the formula [IV]: SH [IV] NHRJ where the ring fl and R3 are the same as defined above, with a derivative of 2,3-e? ox? prop? onar? da of the formula TV !: wherein ring B, R1 and R2 are the same as defined above. 4. A method according to any of claims 1 and 2, further characterized in that the compound of the formula [I] is a propionide derivative of the formula [I-al: ring fl and ring B are a substituted or unsubstituted benzene ring, RH and R2i are a hydrogen atom, a lower alkyl group, an amino acid residue, or an aplo group optionally having a substituent, or combining one with another at its termination together with the nitrogen atom adjacent to which they join to form a heterocyclic group optionally having a substituent, and R3 is a hydrogen atom, a group (dialkyl or lower) -low alkyl or a substituted or unsubstituted piperazinyl-lower alkyl group, or a salt thereof, which is prepared by reacting a propionic acid ester derivative of the formula [HIV: where R is a lower alkaline group, and the ani lo lo, ani l l B and R3 are the same as defined above, with a compound of the formula [Vl II -a] .- R n / [VIII-a] HN. R 21 where Rll and R2i are the same as defined above. 5. A process according to any of claims 1, 2, 3 and 4, further characterized in that R3 is a hydrogen atom. b. ~ A procedure in accordance with any of Claims 1, 2, 3, and 4, further characterized in that each of R and R is a hydrogen atom or one of R and R2 is a hydrogen atom and the other is a lower alkyl group. 7. A method according to claim 6, further characterized in that each of Rl and R2 is a hydrogen atom. 8. A process according to any of claims 1, 2, 3 and 4, further characterized in that each of R1 and R2 is a hydrogen atom or one of R and R2 is a hydrogen atom and the other is? n lower alkyl group, and R3 is a hydrogen atom. 9. A method according to claim 8, further characterized in that each of R and R3 is a hydrogen atom. 10. A method according to any of claims 1, 2, 3, 4, 5, 6, 7, 8 and 9, further characterized in that the ring fl is a benzene ring of the formula: R4 is a hydrogen atom, a halogen atom, a lower alkyl group or a lower 1-methyl group, and in a B-ring a lower 4-alkyl group or a 4-alkoxy group ? femlo i ferior-. 11. A process according to claim 10, further characterized in that R * is a hydrogen atom, a halogen atom or a phenyl-lower alkyl group, and ring B is a 4-alkoxy group. lower femlo. 1

2. A process according to claim 10, further characterized in that R * is a lower alkyl group and ring B is a 4-alkylene lower group. 1

3. A method according to any of claims 1, 2, 3 and 4, further characterized in that the ring fl is a benzene ring of the formula: R * is a hydrogen atom, a chlorine atom, a methyl group or a benzyl group, ring B is a 4-mephilel group or a 4-rnetoxy-femlo group, each of R and R2 is an atom of hydrogen or one of Ri and R2 is a hydrogen atom and the other is a methyl group, and R3 is a hydrogen atom, a 2- (d? rnet? larn?) group or a group 3- C4-Í 2-methox? Phen? L) -p ?? erax? Ml]? Rop? the. 1

4. - A method according to claim 13, further characterized in that R? Is a hydrogen atom or a chlorine atom, ring B is a 4-rnetoxy fem 1 group, and R3 is a hydrogen atom or a group 2-de i rnet 11 am and noet 11 o. 1

5. A method according to claim 13, further characterized in that 4 is a met L Lo group, ring B is a group 4-rnet? lfen? l, and R3 is? n hydrogen atom or a group 2-d ?? net? iarnmoet i lo. 1

6. A process according to claim 13, further characterized in that R * is a chlorine atom, ring B is a 4-rnetox group? phenyl, and R3 is a hydrogen atom or a 3- [4- (2-rnetox? fem 1) -? peraz? n? l] prop? l group. 1

7. A process according to claim 13, further characterized in that R * is a benzyl group, ring B is a 4-methox group? feni 1, and R3 is a hydrogen atom or a 2-d? met? la? p? noet? io group. 1

8. A process according to any of claims 13, 14, 15, 16 and 17, further acted because R3 is a hydrogen atom 1

9. A method according to claim 18, characterized also because each of R1 and R2 is a hydrogen atom 20. A method of any one of claims 1, 2, 3, 4, 5, 6, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 and 19, further characterized in that the intramolecular cyclization reaction is carried out in an alcohol, an aromatic hydrocarbon, an ether or a mixture of the same. 21. A process according to claim 20, further characterized in that the intramolecular cyclization reaction is carried out in chlorine benzene, dichlorobenzene, toluene, xylene and rnexit i le or. 22. A method according to any of claims 1, 2, 3, 4, 5, 6, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 21, further characterized in that the intramolecular cyclization reaction is carried out in the presence of an acid. 23. A process according to claim 22, further characterized in that the reaction of intramolecular cyclization is carried out in the presence of a mineral acid, a lower alkanesulonic acid or a p-sulfoic acid. 24. A process according to claim 23, further characterized in that the intramolecular cyclization reaction is carried out in the presence of ethalosulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, hydrochloric acid or hydrobromic acid co .. 25.- A derived from propionamide of the formula [I]: wherein ring 0 and ring B are a substituted or unsubstituted benzene ring, R and R2 are the same or different and each are a hydrogen atom, a carbamoyl group, a lower alkyl group, a lower alkanoyl group , a lower alkylaminocarbombo group, an ammo acid residue or an aplo group optionally having a substituent, or combining with one another in its termination together with the atom (nitrogen adjacent to which they join to form a heterocyclic group). optionally has a substituent, and R3 is a hydrogen atom, a non-lower dialkyl-lower alkyl group or a substituted or unsubstituted lower alkyl-substituted piperazinyl group, or a salt thereof. according to claim 25, further characterized in that the ring fl is a benzene ring of the formula: R * is an atom of hydrogen, a halogen atom, a lower alkyl group or a phenyl-lower alkyl group, and ring B is a 4-alkyllophene group; the lower or lower 4-alkoxyl group. 27. A compound according to claim 26, further characterized in that R "is a hydrogen atom, a halogen atom or a phenyl-lower alkyl group, and ring B is a 4-alkoxyl group. lower. 28. A cornp? Is or in accordance with claim 26, further characterized in that R is a lower altulo group, and ring B is? N group k -alq? I 1 feni lo lower. 29. A compound according to any of claims 25, 26, 27 and 28, further characterized in that the ring fl is a benzene ring of the formula: R * is a hydrogen atom, a chlorine atom, a methyl group or a benzyl group, ring B is a 4-methyl group or a 4-methoxyl group, each of R 1 and R 2 is a hydrogen atom or one of R and R2 is a hydrogen atom and the other is a methyl group, and R3 is a hydrogen atom, a group 2-dj metí lami no or a group 3- [4- (2 -rnetox? feml) p? peraz? nil]? rop? l. 30. A compound according to claim 29, further characterized in that R * is an atom of hydrogen or a chlorine atom, ring B is a 4-rnetoxy phenol, and R3 is a hydrogen atom or a group 2- (< J? Rnet? Iarn? No) ot io. 31. A compound according to claim 29, further characterized in that R is a methyl group, ring B is a 4-methox? Phenol group, and R3 is a hydrogen atom or a group 2- dirnetilaini noeti Lo . 32. A compound according to claim 29, further characterized in that R4 is a chlorine atom, ring B is a 4-methoxyl group, and R3 is a hydrogen atom or a 3- group. - (2-inet oxi phenol) perax? Mlo] prop? Lo. 33. A compound according to claim 29, further characterized in that R is a benzyl group, ring B is a 4-methoxyl group, and R3 is a hydrogen atom or a 2-drnet group. ? iarn? noet? The. 34. A compound according to any of claims 29, 30, 31, 32 and 33, further characterized in that R3 is a hydrogen atom. 35.- A derivative of (2R, 3) -, 3-epox? Rop? Onam? Da of the formula [V-aA wherein ring B is a substituted or unsubstituted benzene ring, and R and R2 are the same or different and each is a hydrogen atom, a carbamoyl group, a lower alkyl group, a lower alkanoyl group, a group lower alkylammocarbonyl, an acid arnino residue or a ryl group having optionally? ns? bsti tenant, or combine with one another at their terminations together with the nitrogen atom adjacent to which they are attached to form a heterocyclic group optionally having an substudent or a salt thereof. 36. A compound according to claim 35, further characterized in that ring B is a lower 4-benzene group, and each of R and R2 is hydrogen atom or one of R1 and R2 is one hydrogen atom and the other is a lower alkyl group. 37. A compound according to claim 36, further characterized in that the ring B is group 4-meto? Femlo, and each of Rl and R2 is a hydrogen atom »38.- A derivative of (2R, 35) -2, 3-e? O? propionar í da de La formula [V-b] .- wherein the ring is a benzene ring which has a lower alkyl radical, and R1 and R2 are the same or different and each are a hydrogen atom, a carbamoyl group, a lower alkyl group , a lower alkanoyl group, a lower alkoxycarbonyl group, an acidic arnino residue or an optional group has optionally? nstitute, or combine with each other at their termini together with the nitrogen atom adjacent to which is n joined together to form a heterocyclic group having optionally a substituent or a salt thereof. 39.- A compound according to claim 38, further characterized in that the ring B is a lower 4-alkyl-lower group, and each of R1 and R2 is a hydrogen atom or one of R1 and R2 is an atom of hydrogen and the other is a lower alkyl group. 40. A compound according to claim 39, further characterized in that the ring Bl is 4-methox-femlo group, and each of R and R2 is a hydrogen atom.