JPH0680641A - Production of optically active 5-hydroxybenzoazepine derivative - Google Patents

Abstract

PURPOSE:To obtain an optically active 5-hydroxybenzoazepine derivative in high purity and in high yield by a safe and simple operation under a mild reaction condition without carrying out resolution operation. CONSTITUTION:A benzoazepine of formula I (R<1> is H, halogen, lower alkoxy or lower alkyl; R<2> is lower alkyl or halogen) is reduced with a hydrogenating reducing agent (e.g. diborane or boron methyl sulfide) in the presence of an oxazoborolidine catalyst such as B-methyl-S-(-)-(diphenylhydroxymethyl) pyrrolidino-N,O-borolidine to give an optically active 5-hydroxybenzoazepine derivative of formula III. The compound of formula III has excellent vasopressin antagonism and is useful as a basodilator, hypotensor, water diuretic, inhibitor of blood platelet aggregation, etc.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a process for producing an optically active 5-hydroxybenzazepine derivative.

[0002]

[Prior Art and its Problems] Conventional formula

[0003]

[Chemical 3]

[In the formula, R ¹ represents a hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkyl group. R ² represents a lower alkyl group or a halogen atom. ] Represented by 5
-Hydroxybenzazepine derivatives can be prepared according to a known method, for example, the method described in International Patent Publication No. 9105549, by the general formula

[0005]

[Chemical 4]

[Wherein R ¹ and R ² are the same as above. ] It is manufactured by reducing the benzoheterocyclic compound represented by these. However, according to this method, only racemic or diastereomeric products are obtained,
In order to obtain an optically active product, further work for resolving racemates or diastereomers is required, and therefore, the loss of the product is large, and the yield and the purity are not satisfactory.

[0007]

The 5-hydroxybenzazepine derivative represented by the general formula (1) and a salt thereof have an excellent vasopressin antagonism, and have a vasodilator, an antihypertensive agent, a diuretic agent, and a platelet. It is useful as a coagulation suppressor, etc.

[0008]

[Chemical 5]

[R ¹ and R ² are the same as above. R ³ and R
⁴ is the same or different and represents a lower alkanoyl group which may have a hydrogen atom, a lower alkyl group or a halogen atom. ] It is also an important compound as an intermediate for synthesizing a useful compound having a vasopressin antagonistic action.

The object of the present invention is to produce an optically active 5-hydroxybenzazepine derivative (1) by a safe and simple operation without separation work, under a mild reaction condition, in good purity and in good yield. To provide a possible method.

In the present specification, the halogen atom includes
For example, chlorine atom, bromine atom, iodine atom, fluorine atom and the like can be mentioned. Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy groups. it can. As a lower alkyl group,
For example, carbon number 1 such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl group
The straight-chain or branched-chain alkyl group of ~ 6 can be mentioned. Examples of the lower alkanoyl group include linear or branched alkanoyl groups having 1 to 6 carbon atoms such as acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl and hexanoyl groups. Examples of the lower alkanoyl group which may have a halogen atom include 2,2,2-trifluoroacetyl, 2,2,2-trichloroacetyl and 2-
Chloroacetyl, 2-bromoacetyl, 2-fluoroacetyl, 2-iodoacetyl, 2,2-difluoroacetyl, 2,2-dibromoacetyl, 3,3,3-trifluoropropionyl, 3,3,3-trichloropropionyl , 3-chloropropionyl, 2,3-dichloropropionyl, 4,4,4-trichlorobutyryl, 4-fluorobutyryl, 5-chloropentanoyl, 3-chloro-
2-methylpropionyl, 6-bromohexanoyl,
As a substituent such as a 5,6-dibromohexanoyl group, there may be mentioned a linear or branched alkanoyl group having 1 to 6 carbon atoms which may have 1 to 3 halogen atoms.

According to the invention, the general formula (1a)

[0013]

[Chemical 6]

[R ¹ and R ² are the same as above. The optically active 5-hydroxybenzazepine derivative represented by the general formula (4) is the same as the benzazepine derivative represented by the general formula (2).

[0015]

[Chemical 7]

[Wherein R ⁵ represents a hydrogen atom, a phenyl group, a lower alkyl group or a halogen atom, and R ⁶ and R ⁷ are the same or different and represent a lower alkyl group, a phenyl group, a halogen atom or a naphthyl group. ] It is manufactured by reducing with a hydrogenation reducing agent in the presence of an oxazoborolidine catalyst represented by the following formula.

The compound of the general formula (2) used as a starting material can be easily produced according to the method described in International Patent Publication No. 91055549. Also, the general formula (4)
The oxazoborolidene catalyst of J. Am. Chem.
Soc. It can be easily produced according to the method described in 1987, 109, 7925-7926.

In the above reduction reaction, the hydrogenation reducing agent used is, for example, borane-tetrahydrofuran,
Examples thereof include diborane and borane methyl sulfide. Such a hydrogenating / reducing agent is usually used in an amount of at least equimolar, preferably 1.5 to 3 times the molar amount of the compound of the general formula (2). Specific examples of the oxazoborolidene catalyst represented by the general formula (4) include B-methyl-S-(-).
-2- (diphenylhydroxymethyl) pyrrolidino-
N, O-borolidin, Bn-butyl-S-(-)-
2- (diphenylhydroxymethyl) pyrrolidino-N,
O-borolidin, B-methyl-S-(-)-2- (di-β-naphthylhydroxymethyl) pyrrolidino-N, O
-Bororidin etc. can be illustrated. The amount of such a catalyst to be used is usually 0.05 to 0.05 based on the compound of the general formula (2).
It is preferable that the molar amount is about 0.2 times. Examples of the solvent include ethers such as tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether and diglyme, and mixed solvents thereof. The reaction is-
The reaction proceeds at 70 ° C to around room temperature, preferably at -10 ° C to around room temperature, and the reaction is generally completed in about 1 to 5 hours.

General formula (1b)

[0020]

[Chemical 8]

[R ¹ and R ² are the same as above. ] The optically active 5-hydroxybenzodiazepine derivative represented by the above formula is produced by subjecting the compound represented by the above formula (1a) to a stereo-inversion reaction.

The steric inversion reaction is carried out by using an organic acid such as benzoic acid, acetic acid or formic acid and a compound represented by the general formula (1a), for example, a dialkylazodicarboxylate such as diethyl azodicarboxylate or dibutyl azodicarboxylate. , 1,1'-azodicarbonyldi (piperidine)
Is carried out by reacting in the presence of a dialkylazodicarboxamide such as trialkylphosphine such as triethylphosphine, a phosphoric acid compound such as triarylphosphine such as triphenylphosphine, and then hydrolyzing the resulting compound. . As the solvent used in the reaction of, for example, tetrahydrofuran, 1,2-
Examples thereof include ethers such as dimethoxyethane, diethyl ether, diisopropyl ether and diglyme, aromatic hydrocarbons such as benzene and toluene, and mixed solvents thereof. The amount of the dialkylazodicarboxamides and the phosphoric acid compound to be used is usually at least equimolar, preferably equimolar to 1.5 times the molar amount of the organic acid. The reaction proceeds normally at about -20 to 150 ° C, preferably at about -20 to 50 ° C.
Generally, the reaction is completed in about 1 to 30 hours. The subsequent hydrolysis reaction is carried out in the presence of an inorganic base such as sodium hydroxide, potassium hydroxide or lithium hydroxide. As the solvent at this time, methanol, ethanol, lower alcohols such as isopropanol, water, dioxane, ethylene glycol dimethyl ether, ethers such as tetrahydrofuran, acetone,
Examples include ketones such as methyl ethyl ketone and mixed solvents thereof.

The compound of the general formula (1a) obtained in the present invention can be produced by the general formula (3-1) according to the method shown in the following reaction formula-1.
It can be derived to the compound of b) and the compound of general formula (3-2b).

[0024]

[Chemical 9]

[In the formula, R ¹ and R ² are the same as defined above. R ^{3 '}
And R ^{4 ′} are the same or different and each represents a hydrogen atom or a lower alkyl group. X represents a halogen atom. ] Compound (3-
1b) is obtained by converting the compound (1a) into dialkylazodicarboxylates such as diethylazodicarboxylate and dibutylazodicarboxylate, and dialkylazodicarboxamides such as 1,1′-azodicarbonyldi (piperidine). And a trialkylphosphine, triarylphosphine or the like in the presence of a phosphoric acid compound, and then reacted with an azidating agent, and then reducing the resulting compound.

Examples of the azidating agent used in the reaction (1) include hydrazoic acid and diphenylphosphoryl azide (DPPA). Examples of the solvent used include tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether,
Examples thereof include ethers such as diglyme, aromatic hydrocarbons such as benzene and toluene, and mixed solvents thereof.
The dialkylazodicarboxylates, phosphoric acid compound and azidating agent are each used in an amount of at least about equimolar, preferably about 1 to 1.5 times the molar amount of the compound (1a). The reaction usually proceeds at −20 to 100 ° C., preferably −20 to 50 ° C., and generally the reaction is completed in 1 to 30 hours.

The reduction reaction (1) is carried out using a catalytic reduction catalyst in a suitable solvent. Examples of the catalytic reduction catalyst include palladium, palladium black, palladium carbon, platinum, platinum oxide, copper chromite, Raney nickel, etc., and these catalysts are contained in an amount of 0.01 to 0.01 with respect to the raw material compound to be reduced.
It is preferable to use about 10% by weight. Examples of the solvent include alcohols such as methanol, ethanol and isopropanol, hydrocarbons such as hexane and cyclohexane, ethers such as dioxane, tetrahydrofuran, diethyl ether and ethylene glycol dimethyl ether, esters such as ethyl acetate and methyl acetate, dimethylformamide. , Glacial acetic acid, a mixed solvent thereof, and the like. The reaction is usually −20 to 150 ° C., preferably 0 to 100.
The reaction proceeds at 1 ° C and hydrogen pressure of 1 to 10 atm, and generally the reaction is completed in 1 to 15 hours.

The compound (3-2b) is the compound (3-1)
It is produced by reacting b) with compound (5) or compound (6).

In the reaction of the compound (3-1b) with the compound (5), examples of the solvent used include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and ethylene glycol dimethyl ether. , Dichloromethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, methanol, ethanol, isopropanol, butanol, te
Examples thereof include lower alcohols such as rt-butanol, acetic acid, ethyl acetate, acetone, acetonitrile, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, and mixed solvents thereof. Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydride, potassium, sodium and sodium amide. Metal alkoxides such as sodium methylate and sodium ethylate, pyridine,
N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, 1,5-diazabicyclo [4.3.0] nonene-5 (DBN), 1,8-diazabicyclo [5.4.0] undecene-7 (DBU),
1,4-diazabicyclo [2.2.2] octane (DA
Examples thereof include organic bases such as BCO). Examples of the compound (5) include methyl iodide and methyl bromide. The ratio of the compound (3-1b) to the compound (5) to be used is not particularly limited and may be appropriately selected within a wide range, but the latter is at least about equimolar amount, preferably equimolar to 10 with respect to the former. It is preferable to use a double molar amount. An alkali metal halide such as sodium iodide or potassium iodide may be added to the reaction system. The reaction is usually performed at about -30 to 200 ° C, preferably at about -30 to 170 ° C, and generally for 30 minutes to
The reaction is completed in about 30 hours.

In the reaction of the compound (3-1b) with the compound (6), examples of the solvent used include water, alcohols such as methanol, ethanol and isopropanol, acetonitrile, formic acid, acetic acid, dioxane, tetrahydrofuran and diethyl. Examples thereof include ethers such as ether and diglyme, aromatic hydrocarbons such as benzene, toluene and xylene, and mixed solvents thereof.
The reaction is carried out in the presence of a reducing agent. Examples of the reducing agent used include formic acid, fatty acid alkali metal salts such as sodium formate, sodium borohydride, sodium cyanoborohydride, hydride reducing agents such as lithium aluminum hydride, palladium-black, palladium-carbon, and oxidation. Examples thereof include catalytic reducing agents such as platinum, platinum black and Raney nickel. The compound (6) is usually used at least in equimolar amounts, preferably in equimolar to large excess amount based on the compound (3-1b).

When formic acid is used as the reducing agent, the reaction temperature is usually room temperature to 200 ° C., preferably 50 to 150.
It is suitable to set the temperature to around C, and the reaction is completed in about 1 to 10 hours. The amount of formic acid used is preferably a large excess amount with respect to compound (3-1b).

When a hydrogenation reducing agent is used, the reaction temperature is usually about -30 to 100 ° C, preferably 0 to 70 ° C.
The degree is appropriate, and the reaction is completed in about 30 minutes to 12 hours. The amount of the reducing agent used is usually an equimolar to 20 times molar amount, preferably 1 to 6 times molar amount with respect to the compound (3-1b). Particularly when lithium aluminum hydride is used as the reducing agent, it is preferable to use ethers such as diethyl ether, dioxane, tetrahydrofuran and diglyme, and aromatic hydrocarbons such as benzene, toluene and xylene as the solvent.

When a catalytic reducing agent is used, it is usually in a hydrogen atmosphere at atmospheric pressure to 20 atm, preferably atmospheric pressure to 10 atm, or a hydrogen donor such as formic acid, ammonium formate, cyclohexene and hydrazine hydrate. In the presence of, the reaction is usually carried out at a temperature of about -30 to 100 ° C, preferably about 0 to 60 ° C, and the reaction is usually completed in about 1 to 12 hours. The amount of the catalytic reducing agent used is usually 0.1 to 40% by weight, preferably 1 to 20% by weight, based on the compound (3-1b).

The compound of the general formula (3-1b) obtained above is prepared according to the method shown in the following reaction formula-2.
3b), compounds of general formula (3-4b) and compounds of general formula (3-5b).

[0035]

[Chemical 10]

[In the formula, R ¹ , R ² and X are the same as defined above.
R ⁸ represents a lower alkanoyl group which may have a halogen atom. R ^3a represents a lower alkyl group. For the reaction between the compound (3-1b) and the compound (7), known conditions for amide bond formation reaction can be easily applied. For example, (a) a mixed acid anhydride method, that is, a method of reacting a carboxylic acid (7) with an alkylhalocarboxylic acid to form a mixed acid anhydride, and reacting this with a compound (3-1b), (b) an active ester method That is, carboxylic acid (7) is converted into p-nitrophenyl ester, N-hydroxysuccinimide ester, 1
-A method of reacting a compound (3-1b) with an active ester such as hydroxybenzotriazole ester, and (c) a carbodiimide method, that is, a compound (3-1b) is added to a carboxylic acid (7) by dicyclohexylcarbodiimide, carbonyldiimidazole. A condensation reaction in the presence of an activator such as, (d) other methods, for example, carboxylic acid (7) is converted to a carboxylic acid anhydride by a dehydrating agent such as acetic anhydride, and the compound (3-1b) is added thereto. Method of reacting, method of reacting compound (3-1b) with ester of carboxylic acid (7) and lower alcohol under high pressure and high temperature, acid halide of carboxylic acid (7), that is, compound (3-) with carboxylic acid halide. Examples thereof include a method of reacting 1b).

The mixed acid anhydride used in the above mixed acid anhydride method (a) is obtained by a usual Schotten-Baumann reaction, and it is usually compounded without isolation.
-1b) to produce the compound of the present invention of the general formula (1). The Schotten-Baumann reaction is carried out in the presence of a basic compound. Examples of the basic compound used include compounds commonly used in the Schotten-Baumann reaction such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,
5-diazabicyclo [4.3.0] nonene-5 (DB
N), 1,8-diazabicyclo [5.4.0] undecene-7 (DBU), 1,4-diazabicyclo [2.2.
2] Organic bases such as octane (DABCO), inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, and the like. The reaction is usually
It is carried out at about 20 to 100 ° C., preferably about 0 to 50 ° C., and the reaction time is about 5 minutes to 10 hours, preferably about 5 minutes to 2 hours. The reaction of the obtained mixed acid anhydride with the compound (3-1b) is usually carried out at about -20 to 150 ° C, preferably about 10 to 50 ° C, and the reaction time is about 5 minutes to 10 hours, preferably 5 minutes. It is about 5 minutes to 5 hours. The mixed acid anhydride method is generally performed in a solvent. As the solvent used, any solvent commonly used in the mixed acid anhydride method can be used, and specifically, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene. , Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dimethoxyethane, esters such as methyl acetate and ethyl acetate, N, N
-Aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile, and hexamethylphosphoric triamide, and mixed solvents such as these.
Examples of the alkylhalocarboxylic acid used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate and the like. Carboxylic acid (7), alkylhalocarboxylic acid and compound (3-1b) in the method
It is usually preferable to use each of them in an equimolar amount, but within a range of about 1 to 1.5 times the molar amount of the alkylhalocarboxylic acid and the carboxylic acid (7) with respect to the compound (3-1b). Can be used.

When the method of reacting the compound (3-1b) with a carboxylic acid halide is adopted among the above-mentioned other methods (d), the reaction is carried out in the presence of a basic compound in a suitable solvent. Be done. As the basic compound used, known compounds can be widely used, and for example, in addition to the basic compound used in the Schotten-Baumann reaction, for example, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride and the like. It can be illustrated. Examples of the solvent used include alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, pyridine, in addition to the solvent used in the mixed acid anhydride method. Acetone, water, etc. can be illustrated. Compound (3-1b)
The use ratio of carboxylic acid halide and carboxylic acid halide is not particularly limited and can be appropriately selected within a wide range. Usually, the latter is used in at least an equimolar amount, preferably an equimolar to 5 times molar amount. . The reaction is usually -20 to 18
It is carried out at about 0 ° C, preferably about 0 to 150 ° C,
Generally, the reaction is completed in about 5 minutes to 30 hours.

Further, in the above amide bond formation reaction, carboxylic acid (7) and compound (3-1b) are combined with triphenylphosphine, diphenylphosphinyl chloride, phenyl-
By a method of reacting in the presence of a condensing agent for a phosphorus compound such as N-phenylphosphoramide chloride, diethyl chlorophosphate, diethyl cyanophosphate, diphenylphosphate azide, and bis (2-oxo-3-oxazolidinyl) phosphinic chloride. Can also be implemented.

The reaction is usually carried out at about -20 to 150 ° C. in the presence of a solvent and a basic compound used in the method of reacting the carboxylic acid halide with the compound (3-1b).
The reaction is preferably carried out near 0 to 100 ° C., and the reaction is generally completed in about 5 minutes to 30 hours. The condensing agent and the carboxylic acid (7) are used at least in equimolar amounts, preferably in equimolar to 2-fold molar amounts with respect to the compound (3-1b).

The reaction between the compound (3-3b) and the compound (8) is carried out under the same reaction conditions as the reaction between the compound (3-1b) and the compound (5).

The hydrolysis of compound (3-4b) is carried out in a suitable solvent or without solvent in the presence of an acid or a basic compound. Examples of the solvent used include lower alcohols such as water, methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, ethers such as dioxane, tetrahydrofuran and ethylene glycol dimethyl ether, fatty acids such as formic acid and acetic acid or the like. Examples thereof include mixed solvents. Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, and organic acids such as formic acid, acetic acid and aromatic sulfonic acid, and examples of the basic compound include sodium carbonate and potassium carbonate. And the like, and metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide. The reaction is usually at room temperature to 20
The process proceeds suitably at about 0 ° C., preferably at room temperature to about 150 ° C., and generally ends in about 0.05 to 25 hours.

[0043]

[Chemical 11]

[Wherein R ¹ , R ² , R ^{3 ′} , R ^{4 ′} and X are the same as defined above. ]

[0045]

[Chemical 12]

[In the formula, R ¹ , R ² , R ^3a , R ⁸ and X are the same as defined above. ] From compound (1b) to compound (3-1a)
The reaction leading to compound (1a) is converted to compound (3-1).
It is carried out under the same reaction conditions as the reaction leading to b). The reaction for converting the compound (3-1a) to the compound (3-2a) is
The reaction is conducted under the same reaction conditions as the reaction for converting compound (3-1b) to compound (3-2b). In addition, the compound (3-1
The reaction leading from a) to compound (3-5a) is
-1b) to the compound (3-5b), which is carried out under the same reaction conditions.

[0047]

According to the method of the present invention, the desired optically active 5-hydroxybenzazepine derivative (1) can be purified by a safe and simple operation without division work and under mild reaction conditions. It can be produced in good yield.

[0048]

EXAMPLES The present invention will be further clarified with reference to Examples and Reference Examples below.

Example 1 Synthesis of 5-R-(+)-hydroxy-1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzazepine S- ( -)-Α, α-Diphenyl-2-pyrrolidinemethanol (337 mg) was dissolved in benzene (14 ml) under a nitrogen stream, 4 angstrom 1/16 molecular sieves (2.7 g) were added, and methaneboronic acid (80 mg) was further added at room temperature. Then, the mixture was stirred at the same temperature for 4 hours, and benzene was distilled off at 40 ° C. 5 ml of anhydrous tetrahydrofuran was added to the residue under a nitrogen stream, the mixture was cooled to 0 ° C., 27 ml of borane-tetrahydrofuran solution (1.0 N) was added, and the mixture was stirred for 20 minutes. A solution prepared by suspending 5.0 g of 1- {4- (2-methylbenzoylamino) benzoyl} -1,2,3,4-tetrahydrobenzazepin-5-one in 35 ml of anhydrous tetrahydrofuran was added to this over 40 minutes. Dropped. Then, the mixture was stirred at 0 ° C for 1.5 hours. After reaction 1
10 ml of N-hydrochloric acid was added, and the mixture was extracted with methylene chloride-water. The organic layer was dried and concentrated, and the residue was subjected to silica gel column chromatography (methylene chloride: methanol = 50:
The pale yellow oily substance obtained was separated and purified by 1) and recrystallized from ethanol-diethyl ether to obtain 2.15 g (43%) of the above target compound as white granular crystals.

M. p. 210 to 212 ° C. [α] _D = + 140 ° (C = 0.1, 99% methanol) When the optical purity was determined by HPLC analysis, it was 95%.
e. e. Met. The HPLC analysis conditions are as follows.

Column: CHIRALCEL OD, eluent: n-hexane; isopropanol: diethylamine = 700: 300: 1, detector: UV254 nm, flow rate: 1.0 ml / min, retention time: 8.6 min (S): 1
7.7 minutes (R) = 2.5: 97.5.

Reference Example 1 Synthesis of 5-S-(-)-hydroxy-1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzazepine Example 1 5-R-(+)-hydroxy-1- obtained in
[4- (2-methylbenzoylamino) benzoyl]-
1.0 g of 2,3,4,5-tetrahydro-1H-benzazepine, 660 mg of triphenylphosphine and 310 mg of benzoic acid were placed in a 100 ml eggplant flask and dissolved in 20 ml of anhydrous tetrahydrofuran under a nitrogen stream. Diethyl azodicarboxylate 44 at room temperature
A solution of 0 mg dissolved in 7 ml of anhydrous tetrahydrofuran was added, and the mixture was stirred at the same temperature for 20 hours. After completion of the reaction, tetrahydrofuran was distilled off, and the residue was directly subjected to silica gel column chromatography (methylene chloride: ethyl acetate =
The crude product was purified by a short column of 50: 1), 1.2 g of the obtained oil was dissolved in 50 ml of methanol, and 1N-
After adding 24 ml of sodium hydroxide, the mixture was heated and reacted at room temperature for 15 hours and at 60 ° C. for 1 hour. After completion of the reaction, extraction with methylene chloride-water, saturated aqueous sodium chloride solution was added and washed, the organic layer was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (methylene chloride: methanol = 50: 1). Then, the target compound was obtained as a colorless oily substance. This was solidified from ethanol-diethyl ether and recrystallized to give 430 mg (42 mg) of white granular crystals.
%) Was obtained.

HPLC analysis: (S) :( R) = 95:
5, 90% e. e. (Rich in S-(-) form) m. p. 209 to 211 ° C. [α] _D = −135 ° (C = 0.1, 99% methanol).

Reference Example 2 Synthesis of 5-S-(-)-amino-1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzazepine Example 1 5-R-(+)-hydroxy-1- obtained in
[4- (2-methylbenzoylamino) benzoyl]-
200 mg of 2,3,4,5-tetrahydro-1H-benzazepine and 131 mg of triphenylphosphine were dissolved in 4.0 ml of anhydrous tetrahydrofuran, and 87 mg of diethylazodicarboxylate was dissolved in 0.5 ml of anhydrous tetrahydrofuran and diphenylphosphoryl at room temperature. 138 mg of azide and 0.5 of anhydrous tetrahydrofuran
A solution dissolved in ml was added. Then, the mixture was stirred at the same temperature for 15 hours. After completion of the reaction, tetrahydrofuran is distilled off,
After dissolving the residue in methylene chloride, silica gel column chromatography (methylene chloride: methanol = 80:
Crude purification was performed by the short column of 1), and 100 mg of the obtained colorless oily substance was used as a solution of 8 ml of ethanol. Separately, 50 mg of 5% palladium-carbon was added to ethanol 2.
To the solution suspended in 0 ml, 8 ml of the above ethanol solution
Was added and hydrogenation was carried out at room temperature and normal pressure for 7 hours. After completion of the reaction, palladium-carbon was filtered off, the mother liquor was concentrated, and the residue was isolated and purified by silica gel TLC plate (methylene chloride: methanol = 20: 1). The obtained oily substance was solidified from hexane-ethyl acetate and recrystallized to obtain 30 mg (15%) of the above target compound as white granular crystals.

M. p. 119 to 121 ° C. [α] _D = −223 ° (C = 0.1, 99.7% methanol) When the optical purity was determined by HPLC analysis, it was 89%.
e. e. Met. The HPLC analysis conditions are as follows.

Column: ULTRON ES-OVM, eluent: ethanol: 20 mM KH ₂ PO ₄ aqueous solution =
3:97, detector; UV280 mm, flow rate; 1.0 ml
/ Min, holding time; 9.0 minutes (S): 11.8 minutes (R) =
94.5: 5.5.

Reference Example 3 Synthesis of 5-R-(+)-amino-1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzazepine Reference Example 1 5-S-(-)-hydroxy-1- obtained in
[4- (2-methylbenzoylamino) benzoyl]-
After 341 mg of 2,3,4,5-tetrahydro-1H-benzazepine and 223 mg of triphenylphosphine were dissolved in 6.0 ml of anhydrous tetrahydrofuran, 0.5 ml of a benzene solution of hydrogen azide (2.0 N) was added, and the mixture was stirred at room temperature. A solution of 148 mg of diethyl azodicarboxylate in 2.5 ml of anhydrous tetrahydrofuran was added dropwise. Then, the mixture was stirred at the same temperature for 20 hours. Thereafter, 110 mg of triphenylphosphine, 0.3 ml of a benzene solution of hydrogen azide, and 70 mg of diethylazodicarboxylate were added, and the mixture was stirred for 3 hours. After completion of the reaction, the same post-treatment as in Reference Example 2 was carried out to obtain 300 mg of a colorless oily substance. This was dissolved in 20 ml of an ethanol solution in which 150 mg of 5% palladium-carbon was suspended, and hydrogenated at room temperature,
It was carried out at normal pressure for 15 hours. After the completion of the reaction, the same treatment as in Reference Example 2 was carried out to obtain 98 mg (29%) of the above target compound in the form of white granular crystals.

HPLC analysis; 86.7% e. e. m. p. 124 to 126 ° C. [α] _D = + 239 ° (C = 0.1, 99.7% methanol).

Reference Example 4 5-S-(-)-Dimethylamino-1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5
-Synthesis of tetrahydro-1H-benzazepine 5-S-(-)-amino-1- [4 obtained in Reference Example 2
-(2-Methylbenzoylamino) benzoyl] -2,
3,4,5-Tetrahydro-1H-benzazepine 60
mg was dissolved in 1.0 ml of methanol, cooled to 0 to 5 ° C., 120 μl of 37% formalin aqueous solution was added, and further 28 mg of NaBH ₃ CN was added. 80 μ of acetic acid
1 was gradually added dropwise. Then, it stirred at room temperature for 1 hour.
After the reaction was completed, an aqueous potassium carbonate solution was added to make the mixture alkaline, and the mixture was extracted with methylene chloride. After drying and concentrating the organic layer, the residue was applied to a silica gel TLC plate (methylene chloride:
The product was collected and purified by methanol = 30: 1), and the obtained oily substance was solidified from ethyl acetate-hexane and recrystallized to obtain 35 mg (55 mg of the above target compound of white granular crystals).
%) Was obtained.

M. p. 235 to 237 ° C. [α] _D ²⁰ = −178 ° (C = 0.1, 99.7% methanol) When the optical purity was determined by HPLC analysis, it was 100%.
e. e. Met. The HPLC analysis conditions are as follows.

Column: CHIRALCEL OD, eluent: n-hexane: ethanol: diethylamine = 95
0: 50: 1, detector; UV280 mm, flow rate; 1.0
ml / min, retention time; 33 minutes (R): 37 minutes (S) =
0: 100.

Reference Example 5 5- (R)-(+)-dimethylamino-1- [4- (2
-Methylbenzoylamino) benzoyl] -2,3
Synthesis of 4,5-tetrahydro-1H-benzazepine 5-R-(+)-amino-1- [4 obtained in Reference Example 3
-(2-Methylbenzoylamino) benzoyl] -2,
Using 3,4,5-tetrahydro-1H-benzazepine, in the same manner as in Reference Example 4, the above target compound was obtained as white granular crystals.

M. p. 233-235 ° C. [α] _D ²⁰ = + 182 ° (C = 0.1, 99.7% methanol) HPLC analysis; 100% e. e. .

Reference Example 6 5-S-(-)-Methylamino-1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-
Synthesis of tetrahydro-1H-benzazepine 5-S-(−)-amino-1- [4 obtained in Reference Example 2
-(2-Methylbenzoylamino) benzoyl] -2,
3,4,5-Tetrahydro-1H-benzazepine 52
After dissolving 0 mg in 6.0 ml of methylene chloride and cooling to 0 ° C., 160 mg of triethylamine and 330 mg of trifluoroacetic anhydride were added. After stirring at the same temperature for 3 hours,
Silica gel column chromatography (eluent; methylene chloride: methanol = 30: 1) fractionation and purification,
Obtained 5-S-(-)-(2,2,2-trifluoroacetylamino) -1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H -Benzazepine (white amorphous crystal) 51
0 mg was made into a solution of 5.0 ml of dimethylformamide. This was cooled to 0 ° C., 42 mg of sodium hydride was added, and the mixture was stirred for 20 minutes, then 65 μl of methyl iodide was added, and the mixture was stirred at the same temperature for 4 hours. After the reaction was completed, 2.2 ml of 1N-hydrochloric acid was added, and the mixture was extracted with methylene chloride-water. The organic layer was dried over magnesium sulfate and concentrated, and the residue was subjected to silica gel column chromatography (eluent; methylene chloride:
5-S-(-)-[N- (2,2,2-trifluoroacetyl) -N-methylamino] -1- [4- (2-Methylbenzoylamino) benzoyl] -2,3,4,5-
Tetrahydro-1H-benzazepine (colorless oil)
0.5 g was used as a 17 ml solution of ethanol. 5N to this
1.03 ml of sodium hydroxide was added, and the mixture was stirred at 40 ° C. for 4 hours. After completion of the reaction, 1.0 ml of 1N hydrochloric acid aqueous solution was added, and the mixture was extracted with methylene chloride-water. The organic layer was dried over magnesium sulfate and concentrated, the residue was dissolved in methylene chloride,
It was fractionated and purified by silica gel column chromatography (eluent; methylene chloride: methanol = 50: 1 → 20: 1). This was further purified by a silica gel thin layer plate (eluent; methylene chloride: methanol = 15: 1, developed 4 times) to obtain a colorless oil. This was solidified from ethyl acetate-hexane and recrystallized to obtain 31.2 mg (7.3%) of the above target compound as white granular crystals.

M. p. 197 to 199 ° C. [α] _D ²³ = −208 ° (C = 0.1, 99.7% methanol) When the optical purity was determined by HPLC analysis, it was 100%.
e. e. Met. The HPLC analysis conditions are as follows.

Column: ULTRON ES-OVM, solution: ethanol: 20 mM KH ₂ PO ₄ = 3: 9.
7, detector; UV280 mm, flow rate; 1.0 ml / min,
Retention time; 7.3 minutes (S): 10.2 minutes (R) = 10
0: 0.

Reference Example 7 5-R-(+)-methylamino-1- {4- (2-methylbenzoylamino) benzoyl} -2,3,4,5-
Synthesis of tetrahydro-1H-benzazepine 5-R-(+)-amino-1- [4 obtained in Reference Example 3
-(2-Methylbenzoylamino) benzoyl] -2,
Using 3,4,5-tetrahydro-1H-benzazepine, in the same manner as in Reference Example 5, 5-R-(+)-(2,2,2
2-trifluoroacetylamino) -1- [4- (2-
Methylbenzoylamino) benzoyl] -2,3,4
5-Tetrahydro-1H-benzazepine is obtained, which is subsequently reacted similarly with methyl iodide to give 5-R-(+)-
[N- (2,2,2-trifluoroacetyl) -N-methylamino] -1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1
H-benzazepine was obtained and further hydrolyzed to obtain the above target compound as white granular crystals.

M. p. 197-199 ° C. [α] ^{_{D 20 = + 208 ° (C}} = 0.1,99.7% methanol) HPLC analysis; 100% e. e. .

Pharmacological test example Test 1) V ₁ receptor binding assay (V ₁ recepler binding assai) Method of Akira Ichihara [J. Bio. C
hem., 258, 9283 (1983)], using a rat liver membrane preparation, [ ³ H] -Arg-vasopressin 50,000 dpm (2 x
10 ^-10 M) membrane preparation 100 ng test drug (10 ^-7 or 10
^-4 M) for 10 minutes in a total volume of 250 μl of 100 mM Tris-HCl buffer (pH = 8.0) containing 5 mM MgCl ₂ , 1 mM EDTA and 0.1% BSA for 10 min.
Incubated at ° C. Then, using a glass filter (GF / F), filtration was performed three times to separate the membrane sample bound to vasopressin, and the membrane was washed with 5 ml of a buffer solution. The glass filter was taken out, mixed with a cocktail for liquid scintillation, the amount of [ ³ H] -vasopressin bound to the membrane was measured with a liquid scintillation counter, and the inhibition rate was calculated by the following formula.

Inhibition rate (%) = {100 − [(C ₁ −
B ₁ ) / (C ₀ -B ₁ )]} × 100 C ₁ ; The amount of [ ³ H] -vasopressin bound to the membrane in the presence of a known amount of a reagent and [ ³ H] -vasopressin C ₀ ; when excluding the test drug ^[3 H] - bond amount B ₁ with respect to the film of vasopressin; excess vasopressin (10 ^-6 M) in the presence of ^[3
Amount of [H] -vasopressin bound to the membrane The concentration of the reagent agent at which the inhibitor calculated above was 50% was determined and used as the IC ₅₀ value.

The results are shown in Table 1.

Test 2) V ₂ receptor binding assay O.HECHTER method [J. Bio. Chem., 253, 321
1 (1978)], using a rat kidney membrane preparation, [ ³ H] -Arg-vasopressin 1000 was prepared.
00 dpm (4 × 10 ⁻¹⁰ M) membrane preparation 0.6 mg test drug (10 ⁻¹⁰ to 10 ⁻⁵ M), 5 mM MgCl ₂ , 1 m
Incubated for 3 hours at 4 ° C. in a total volume of 250 μl of 100 mM Tris-HCl buffer (pH = 8.0) containing M EDTA and 0.1% BSA. Then, using a glass filter (GF / F), filtration was performed to separate the membrane sample bound to vasopressin, and the membrane sample was washed twice with 5 ml of a buffer solution. Take out this glass filter,
The amount of [ ³ H] -vasopressin bound to the membrane was measured with a liquid scintillation counter after mixing with a liquid scintillation cocktail, and the inhibition rate was calculated by the following formula. The results are also shown in Table 1.

Inhibition rate (%) = {100 − [(C ₁ −
_{B 1) / (C 0 -B} 1) ]} × 100 C _1, C ₀ and B ₁ is as defined above.

Test compound 1: 5-R-(+)-hydroxy-1- [4- (2-
Methylbenzoylamino) benzoyl] -2,3,4
5-Tetrahydro-1H-benzazepine 2: 5-S-(−)-hydroxy-1- [4- (2-
Methylbenzoylamino) benzoyl] -2,3,4
5-Tetrahydro-1H-benzazepine 3: 5-S (−)-amino-1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzazepine 4: 5-R-(+)-amino-1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-
Tetrahydro-1H-benzazepine 5: 5-S-(−)-dimethylamino-1- [4-
(2-Methylbenzoylamino) benzoyl] -2,
3,4,5-Tetrahydro-1H-benzazepine 6: 5-R-(+)-dimethylamino-1- [4-
(2-Methylbenzoylamino) benzoyl] -2,
3,4,5-Tetrahydro-1H-benzazepine 7: 5-S-(−)-methylamino-1- [4- (2
-Methylbenzoylamino) benzoyl] -2,3
4,5-Tetrahydro-1H-benzazepine 8: 5-R-(+)-methylamino-1- [4- (2
-Methylbenzoylamino) benzoyl] -2,3
4,5-Tetrahydro-1H-benzazepine

[0075]

[Table 1]

Claims (1)

[Claims] 1. A general formula: [In the formula, R ¹ represents a hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkyl group. R ² represents a lower alkyl group or a halogen atom. ] The optically active general formula characterized by reducing the benzazepine derivative represented by [Wherein R ¹ and R ² are the same as defined above. ] Represented by]
A process for producing a hydroxybenzazepine derivative and a salt thereof.