JPH0645611B2 - Process for producing 1,5-benzothiazepine derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel method for producing an 8- or 9-chloro-1,5-benzothiazepine derivative.

[Prior art]

2- (4-Methoxyphenyl) -3-alkanoyloxy (or hydroxy) -5- [2- (dialkylamino) ethyl] -8-chloro-2,3-dihydro-1,5
-Benzothiazepin-4 (5H) -one has an excellent antihypertensive effect and / or cerebral / coronary vasodilatory effect, and the above benzothiazepine derivative is the corresponding N-unsubstituted N-position at the 5-position of the thiazepine ring. It is known that the compound can be produced by reacting it with a dialkylaminoethyl halide (JP-A-59-225174).

[Object of the Invention]

The object of the present invention is to provide a new process for producing 8- or 9-chloro-1,5-benzothiazepine derivatives.

[Structure and Effect of Invention]

As a result of various studies, the inventors of the present invention disclosed in Japanese Patent Laid-Open No. 59-22517.
A general formula in a completely different method from the method described in No. 4 (However, R ¹ , R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a lower alkyl group, R ² represents a hydrogen atom or a lower alkanoyl group, and ^one of X ¹ and X ² is a hydrogen atom. , Which means that the other is a chlorine atom), and the present invention has been completed.

In the above compound [I], a compound in which R ³ and R ⁴ are both lower alkyl groups is useful as a hypotensive agent and / or a cerebral / coronary vasodilator, and R ³ and R ⁴ are both hydrogen atoms or A compound in which one is a lower alkyl group and the other is a hydrogen atom is a useful pharmaceutical compound which exhibits a strong and long-lasting platelet aggregation inhibitory action even when orally administered. For example, (-)-cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (N-
Methylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one.hydrochloride and (+)-cis-2- (4-methoxyphenyl)
-3-hydroxy-5- [2- (N-methylamino) ethyl] -9-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one hydrochloride was added to SD rats When administered orally (dose: 10 mg / kg), all compounds showed 50% collagen-induced rat platelet aggregation.
The above is suppressed.

According to the present invention, the compound represented by the general formula [I] or a salt thereof has the general formula (However, R ⁶ represents a lower alkyl group, and R ¹ , R ³ ,
R ⁴ , X ¹ and X ² have the same meanings as defined above) or a salt thereof is subjected to intramolecular ring closure to give a compound of the general formula [II] (Provided that R ¹ , R ³ , R ⁴ , X ¹ and X ² have the same meanings as described above) or a salt thereof, and then the compound is reduced to give a compound of the general formula [IA] (However, R ¹ , R ³ , R ⁴ , X ¹ and X ² have the same meanings as described above) or a salt thereof, and if necessary, a compound [IA] or a salt thereof is generally used. Formula [III] R ⁵ COOH [III] (wherein R ⁵ represents a lower alkyl group) is condensed with a compound or a reactive derivative thereof to give a compound of the general formula [IB] (However, R ¹ , R ³ , R ⁴ , R ⁵ , X ¹ and X ² have the same meanings as described above), and if necessary, the compound [IA]
Alternatively, it can be produced by using [IB] as its salt.

The details will be described below.

[IV] → [II] The intramolecular ring closure reaction of the compound [IV] can be carried out in the presence of a base in a suitable solvent.

Examples of the base include lithium diisopropylamide,
Examples thereof include lithium isopropylcyclohexylamide, lithium hexamethyldisilazide, and butyllithium. As the solvent, for example, ether, tetrahydrofuran, hexamethylphosphoric triamide, dioxane, or a mixed solution thereof can be preferably used. The reaction suitably proceeds at -70 ° C to -25 ° C, especially at -60 ° C to -20 ° C.

The reduction reaction of [II] → [IA] diketone compound [II] can be carried out by treating compound [II] with a reducing agent or by catalytic reduction.

The reaction of treating the diketone compound [II] with a reducing agent can be carried out in a suitable solvent, and as the reducing agent, for example, an alkali metal borohydride such as sodium borohydride, potassium borohydride or lithium borohydride is preferable. can give. Examples of the solvent include lower alkanols such as methanol, ethanol and propanol, a mixed solution of lower alkanol and water, tetrahydrofuran or dioxane.

The catalytic reduction of the diketone compound [II] can be carried out in the presence of a catalyst in a suitable solvent.

As the catalyst, for example, palladium carbon, palladium black or the like can be used, and as the solvent, those used in the reaction between the diketone compound [II] and the reducing agent can be suitably used. The reaction suitably proceeds at about 0 to 40 ° C in both cases of using a reducing agent and catalytic reduction.

The hydroxy compound [IA] thus obtained is obtained as a racemate, and the racemate can be optically resolved by a conventional method to produce an optically active form of the hydroxy compound [IA]. For example, a racemate of a hydroxy compound [IA] is reacted with an optical resolving agent such as P-hydroxyphenylglycine ester, cinchonidine, camphorsulfonic acid, etc. in a suitable solvent (acetone, methyl ethyl ketone, ethyl acetate, methanol, etc.), Two diastereomeric salts are formed, and then the diastereomeric salts are fractionally crystallized, and the diastereomeric salt obtained is taken as an acid ( For example, the optically active hydroxy compound [IA] can be produced by treatment with hydrochloric acid. Further, the optically active compound of the hydroxy compound [IA] is obtained by reacting a racemic compound of the hydroxy compound [IA] with an optically active 1- (2-naphthylsulfonyl) pyrrolidine-2-carbonyl chloride. It can also be produced by forming a stereomer, separating the diastereomer by fractional crystallization or column chromatography, and hydrolyzing.

The hydroxy compound [IA] can be converted to its salt by subjecting it to a salt-forming reaction according to a conventional method.

[IA] + [III] → [IB] Hydroxy compound [IA] and carboxylic acid compound [II]
The condensation reaction of I] with the reactive derivative can be carried out in a solvent in the presence or absence of a deoxidizing agent. Examples of the reactive derivative of the carboxylic acid compound [III] include acid anhydrides (eg acetic anhydride, propionic anhydride, butyric anhydride) and acid halides (eg acetyl chloride, propionyl chloride, butyryl chloride). Examples of the solvent include pyridine, tetrahydrofuran, dioxane, benzene, toluene, methylene chloride or acetic acid. Examples of the deoxidizing agent include pyridine, triethylamine, N-methylpiperidine, N-methylmorpholine, N-methylpyrrolidine or N-ethyl-
Examples thereof include N, N-diisopropylamine. In the reaction, when excess acetic anhydride is used as the reactive derivative of the carboxylic acid compound [III], it also serves as a solvent, so that it is not always necessary to use a solvent. The reaction is preferably carried out at about 20 to 130 ° C when an acid anhydride is used as the reactive derivative of the carboxylic acid compound [III], and at about -10 to 60 ° C when an acid halide is used.

In this method, the condensation reaction between the carboxylic acid compound [III] (free carboxylic acid) and the hydroxy compound [IA] or a salt thereof can be carried out in a solvent in the presence of a condensing agent. Examples of the condensing agent include dicyclohexylcarbodiimide, N, N'-carbonyldiimidazole, 1-methyl-2-halopyridinium iodide (for example, 1-methyl-2-bromopyridinium iodide), methoxyacetylene or triphenylphosphine-tetrachloride. Examples thereof include carbon, and examples of the solvent include methylene chloride, chloroform, 1,2-dichloroethane, benzene, toluene, tetrahydrofuran, dioxane and the like.

The reaction is preferably carried out at about 0-50 ° C, especially about 0-25 ° C.

Since this reaction proceeds without racemization, an optically active alkanoyloxy compound [IB] can be produced by using an optically active hydroxy compound [IA]. Alkanoyloxy compound [IB]
Can be converted to its salt by subjecting it to a salt formation reaction according to a conventional method.

The diketone compound [II] is a novel compound and is a useful synthetic intermediate in the present invention.

Diketone compound (II) as, for example R ^1, R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a methyl group, an ethyl group, a such lower alkyl groups propyl or butyl group, of X ¹ and X ² One of them is a compound in which one is a hydrogen atom and the other is a chlorine atom.
Among these, preferred compounds are R ¹ is a lower alkyl group, R ³ is a hydrogen atom or a lower alkyl group, R ⁴ is a lower alkyl, ^one of X ¹ and X ² is a hydrogen atom, and the other is a chlorine atom. Compounds. Further more preferred compounds are R ¹ is a methyl group, R ³ is a hydrogen atom, or a methyl group, an ethyl group, a propyl group or a butyl group, and R ⁴ is a methyl group, an ethyl group or a butyl group,
Examples thereof include compounds in which one of X ¹ and X ² is a hydrogen atom and the other is a chlorine atom. The most preferable compound is the compound represented by the general formula [II] in which R ¹ is a methyl group and R ^{3 is}
Is a hydrogen atom or a methyl group, R ⁴ is a methyl group,
Examples thereof include a compound in which X ¹ is a chlorine atom and X ² is a hydrogen atom, or X ¹ is a hydrogen atom and X ² is a chlorine atom.

The compound of the present invention [II] can form a salt, and examples of such a salt include salts with inorganic salts such as hydrochloric acid and perchlorate, salts with organic acids such as oxalic acid, fumaric acid and maleic acid. can give.

The compound [II] of the present invention has one asymmetric carbon atom and 2
Although there are some optical isomers, the present invention includes any of these optical isomers or racemates.

The starting compounds [IV] of the present invention are all novel compounds and can be produced, for example, according to the following reaction formula.

Reaction formula (However, X ³ to X ⁵ are each a halogen atom,
R ¹ , R ³ , R ⁴ , R ⁶ , X ¹ and X ³ have the same meanings as described above. That is, the reaction between the compounds [VI] and [VII] is carried out by using a deoxidizing agent (alkali metal carbonate) in a suitable solvent (lower alkanol, tetrahydrofuran, dioxane, acetonitrile, benzene, toluene, dimethylformamide or a mixture thereof). Salt, alkali metal hydrogen carbonate, alkali metal hydroxide, alkali metal hydride, pyridine, organic base such as triethylamine, alkali metal alkoxide)
Can be carried out at 0 to 80 ° C., especially at 20 to 60 ° C. in the presence of to produce compound [VIII]. Compound [VI
The reduction reaction of [II] can be carried out by catalytic reduction in a solvent (lower alkanol, tetrahydrofuran, dioxane, etc.) in the presence of a catalyst (palladium carbon, palladium black, etc.), and a compound [IX] can be produced. The reaction between the compound [IX] and the compound [X] is carried out in the presence of a deoxidizing agent (alkali metal carbonate, alkali metal hydrogen carbonate, alkali metal hydroxide, organic base, etc.) in a solvent (methylene chloride, chloroform, acetic acid). Ethyl, tetrahydrofuran,
Dioxane, acetone or a mixture of these and water)
It can be carried out at 0 to 40 ° C., especially 0 to 25 ° C. to produce the compound [XI]. Compound [XI] and [XI
I] in the presence of a deoxidizing agent (alkali metal carbonate, alkali metal hydrogen carbonate, alkali metal hydroxide, sodium hydride, etc.), a solvent (acetone, ethyl acetate, acetonitrile, dimethylformamide, dioxane, It can be carried out in dimethylsulfoxide, etc.) at 20 to 100 ° C., especially at 20 to 70 ° C. to produce compound [IV].

Example 1 (1) N- {4-chloro-2-[(4-methoxybenzyl) thio] phenyl} -N- [2- (dimethylamino)
Ethyl] oxamic acid ethyl ester (reference example (4)))
A mixture of 0.2 g, 65 ml tetrahydrofuran and 0.075 g hexamethylphosphoric triamide is cooled to -60 ° C. Lithium diisopropylamide (prepared by a conventional method using 0.103 g of diisopropylamine, 0.64 ml of n-butyllithium (1.6 mol-hexane solution) and 3 ml of tetrahydrofuran) is added dropwise thereto.
After stirring at the same temperature for 10 minutes, the reaction solution is poured into a saturated ammonium chloride aqueous solution. This is extracted with ethyl acetate,
Wash with water, dry and evaporate the solvent. The residue was purified by silica gel chromatography (solvent; chloroform: ethanol = 20: 1) to give 8-chloro-5- [2- (dimethylamino) ethyl] -2- (4-methoxyphenyl) -1,
0.102 g of 5-benzothiazepine-3,4 (2H, 5H) dione is obtained as a pale yellow oil. Yield: 56.
7% IR (CHCl ₃ ) cm ⁻¹ : 1720,1660 NMR (CDCl ₃ ) δ: 2.20 (6H, SN (C
_{H 3) 2), 3.75 (} 3H, S, OCH 3), 5.3
8 (broad peak 1H, CH) oxalate M.I. P. 110 to 113 ° C. (decomposition) (recrystallization from ethanol) (2) To a solution of the compound (free) 0.1 g obtained above, ethanol 5 ml and water 1 ml was added 0.01 g of sodium borohydride under ice cooling. Add and stir at room temperature for 1 hour. Then, the reaction solution is diluted with water and extracted with ethyl acetate. The extract is washed with saturated saline and dried, and then the solvent is distilled off. By recrystallizing the residue with ethanol, cis-8-chloro-5-
[2- (dimethylamino) ethyl] -3-hydroxy-
2- (4-methoxyphenyl) 2,3-dihydro-1,
5-benzothiazepine-4 (5H) -one 0.081 g
Are obtained as needle crystals.

Yield: 80.6% M.I. P. : 169.5-170 ° C Hydrochloride / 1/2 ethanol M.I. P. 136-139 ° C. (recrystallized from a mixed solution of chloroform-ethanol-ether) (3) 1 g of the compound (hydrochloride) obtained in (2) above, 2 ml of acetic anhydride
And a mixture of 2 ml of acetic acid is stirred at 110 ° C. for 4 hours. The reaction mixture is concentrated under reduced pressure and the solvent is distilled off. Ether was added to the residue, and the precipitated crystals were collected by filtration to give cis-8.
-Chloro-5- [2- (dimethylamino) ethyl] -3
-Acetoxy-2- (4-methoxyphenyl) -2,3
-Dihydro-1,5-benzothiazepine-4 (5H)-
1.08 g of on hydrochloride is obtained. This product is chloroform,
When recrystallized from a mixed solution of ethanol and ether, it becomes needle crystals (ethanol adduct).

M. P. 159-161 ° C. Example 2 (1) 9-chloro-5- [2- (dimethylamino) ethyl] -2- (4-made from 2-chloro-6-nitrothiophenol in the same manner as in Reference Example. Methoxyphenyl) 1,
By treating 5-benzothiazepine-3,4 (2H, 5H) -dione in the same manner as in Example 1- (2), cis-9 was obtained.
-Chloro-5- [2- (dimethylamino) ethyl] -3
-Hydroxy-2- (4-methoxyphenyl) -2,3
-Dihydro-1,5-benzothiazepine-4 (5H)-
Get on

M. P. : 143-144 ° C Hydrochloride monohydrate M.I. P. : 228 to 230 ° C. (decomposition) (wet from 143 ° C.) (recrystallized from methanol) (2) The compound (free) obtained in the above (1) is optically active 1- (2)
(+)-Cis-9 obtained by optical resolution using -naphthylsulfonyl) pyrrolidine-2-carbonyl chloride.
-Chloro-5- [2- (dimethylamino) ethyl] -3
-Hydroxy-2- (4-methoxyphenyl) -2,3
-Dihydro-1,5-benzothiazepine-4 (5H)-
The same procedure as in Example 1- (3) was carried out using onone to give the hydrochloride salt of (+)-cis-9-chloro-5-.
[2- (dimethylamino) ethyl] -3-acetoxy-
2- (4-methoxyphenyl) -2,3-dihydro-
1,5-Benzothiazepine-4 (5H) -one hydrochloride salt hydrate is obtained.

M. P. : 140 to 143 ° C. [α] _D ²⁰ : + 13.0 ° (C = 0.347, methanol) Examples 3 to 39 By treating in the same manner as in Example 1 or 2, the compounds shown in the following table are obtained.

Reference Example (1) 3.3 g of 3-chloro-6-nitrothiophenol,
To a mixed solution of 50 ml of ethanol and 20 ml of tetrahydrofuran was added 5.3 g of sodium ethylate under ice cooling to prepare 1
Stir for 0 minutes. Then, 3 g of paramethoxybenzyl chloride is added, and the mixture is stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, water was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give 1- (4-methoxybenzylthio) -3-chloro-6-nitrobenzene. 5 g
As yellow needles.

M. P. : 122-123.5 ° C. (2-1) 1 g of the compound obtained in (1) above was added to 40 m of ethanol.
Suspend in 1 l, add 3.8 g of stannous chloride dihydrate 7
Stir at 0 ° C. for 1.5 hours. After the reaction, the mixture is cooled, the reaction solution is poured into ice water, and sodium bicarbonate is added to adjust the pH to 7-8. Extract with chloroform and dry the extract. The solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; benzene: hexane = 2: 1) to give 1- (4-methoxybenzylthio) -3-chloro-6-aminobenzene 0.78 g. To get

M. P. : 84-85.5 ° C. (2-2) 1 g of the compound obtained in (1) above, 15 m of methanol
l, tetrahydrofuran 15 ml, concentrated hydrochloric acid 1 ml and 10
% Palladium-carbon 0.2 g mixture is catalytically reduced at room temperature under atmospheric pressure. After the reaction, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue was recrystallized from a mixed solution of ethyl acetate-ethanol to give 1- (4-methoxybenzylthio) -3.
0.84 g of -chloro-6-aminobenzene.hydrochloride is obtained.

M. P. : 191-193 ° C. (3) 1.53 g of the compound (free) obtained in the above (2-1),
1.36 g of chloroglyoxalic acid ethyl ester (ClCOCOOC ₂ H ₅ ) are added dropwise with vigorous stirring of a mixture of 0.92 g of sodium bicarbonate, 20 ml of water and 30 ml of methylene chloride. After stirring for 30 minutes, methylene chloride is collected. The aqueous layer is extracted with methylene chloride. The methylene chloride layers are combined, washed with water and dried, and then the solvent is distilled off. By recrystallizing the residue from isopropanol, 1.81 g of N- {4-chloro-2-[(4-methoxybenzyl) thio] phenyl} oxamic acid ethyl ester is obtained as colorless needle crystals.

M. P. : 99.5-100 ° C (4) A mixture of 1.5 g of the compound obtained in the above (3), 1.27 g of dimethylaminoethyl chloride, 1.64 g of potassium carbonate and 30 ml of acetonitrile is stirred at 50 ° C for 3 hours. After the reaction, the mixture is cooled, poured into 50 ml of water and extracted with ethyl acetate. The extract is washed with water and dried, and the solvent is distilled off. By purifying the residue by silica gel column chromatography (solvent; chloroform: ethanol = 10: 1),
1.7 g of N- {4-chloro-2-[(4-methoxybenzyl) thio] phenyl} -N- [2- (dimethylamino) ethyl] oxamic acid ethyl ester are obtained as a yellow oil.

IR (CHCl ₃ ) cm ⁻¹ : 1740, 1670 NMR (ppm, CDCl ₃ ) δ: 1.04 (3H,
t. J = 7 Hz, CH ₂ CH ₃ , 2.17 (6H, S, N
(CH ₃ ) ₂ ), 3.79 (3H, S, OCH ₃ ),
3.97 (2H, q, J = 8Hz, OCH 2 CH 3),
4.11 (2H, S, S- CH 2)

Continuation of front page (56) Reference JP-A-60-32779 (JP, A) JP-A-59-20273 (JP, A) JP-A-59-104373 (JP, A) JP-A-59-225174 (JP , A) Japanese Patent Publication Sho 47-813 (JP, B1)

Claims (1)

[Claims] 1. A general formula [IV] (However, R ¹ , R ³ and R ⁴ are the same or different and represent a hydrogen atom or a lower alkyl group, R ⁶ represents a lower alkyl group, and ^one of X ¹ and X ² is a hydrogen atom, and the other is Represents a chlorine atom) and a salt of the compound represented by the general formula (Wherein R ¹ , R ³ , R ⁴ , X ¹ and X ² have the same meanings as described above) or a salt thereof, and then the compound is reduced to give a compound of the general formula (However, R ¹ , R ³ , R ⁴ , X ¹ and X ² have the same meanings as described above) or a salt thereof, and if necessary, a compound [IA] or a salt thereof is generally used. The compound represented by the formula R ⁵ COOH [III] (wherein R ⁵ represents a lower alkyl group) or a reactive derivative thereof is condensed with the general formula (However, R ¹ , R ³ , R ⁴ , R ⁵ , X ¹ and X ² have the same meanings as described above), and if necessary, the compound [IA]
Or a general formula characterized by using [IB] as a salt thereof (Wherein R ² represents a hydrogen atom or a lower alkanoyl group, and R ¹ , R ³ , R ⁴ , X ¹ and X ² have the same meanings as described above). -A method for producing a benzothiazepine derivative or a salt thereof.