JPS60204776A - 1,5-benzothiazepine derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula 1 (Ar is phenyl wherein at least one H is substituted with lower alkoxy; R1 is H or acetyl; R2 is lower alkylene; X is halogen) and its salt. EXAMPLE:2-( 4-Methoxyphenyl )-3-acetoxy-5-( 2-chloroethyl )-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. USE:Useful as a synthetic intermediate of the compound of formula 2 (R3 and R4 are lower alkyl) having coronary vasodilating and psychoneurotic activities, etc. and useful as an excellent drug, and its salt. It can be prepared in high yield and purity. PREPARATION:The compound of formula 1 can be prepared by reacting the compound of formula 3 with the compound of formula 4 (Z is halogen) in an aprotic solvent in the presence of a base such as NaOH, at -5-+50 deg.C.

Description

Detailed Description of the Invention The present invention is based on the following formula (1) (where Ar is a phenyl group in which one or more hydrogen atoms are substituted with a lower alkoxy group, R1 is a hydrogen atom or an acetyl group, and R2 is a lower alkylene group) , X represents a halogen atom, respectively) and salts thereof.

Conventionally, the following formula (2) (However, Ar represents a phenyl group substituted with a lower alkoxy group, R4 represents a hydrogen atom or an acetyl group, R2 represents a lower alkylene group, and R3 and R4 represent a lower alkyl group, respectively.) 1,5-benzothiazepine derivatives selected from the compounds represented by and salts thereof, especially 2 represented by the following formula (2a)
-(4-methoxyphenyl)-3-acetoxy-5-(
2-(dimethylamine)ethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and its salts have coronary vasodilatory effects, psychotropic effects, etc., and are excellent medicines. It is known to be used as

Conventionally, various methods have been proposed as methods for producing the compound of formula (2) above, but the compound of formula (2) and the compound of formula (2a) have been proposed in a higher yield and with higher purity. It is further desired to develop a method for obtaining the same.

In view of the above circumstances, the present inventor has developed formula (2), particularly formula (2a
) As a result of intensive research into efficient synthesis methods for compounds represented by formula (4), for example, when a compound represented by formula (4) is reacted with a compound represented by formula (3), which will be described later, '! ``1'')
B["(1)E"'""ahlF[(Re4m"46), and the new compound of formula (1) has the formula (
By reacting the compound represented by 7), the compound of the formula (2), especially the formula (2a), can be obtained in high yield and purity, and therefore this new compound of the formula (1) can be obtained. by passing through as an intermediate, formula (2), especially formula (2a
) was found to be able to be efficiently synthesized, leading to the present invention.

The present invention will be explained in more detail below.

The novel compound 1,5-benzothiazepine derivative according to the present invention has the above-mentioned formula (1) (where Ar is a phenyl group in which one or more hydrogen atoms are substituted with a lower alkoxy group, R1 is a hydrogen atom or Acetyl group, R2 represents a lower alkylene group, and X represents a halogen atom.

In addition, here, the lower alkoxy group has 1 to 5 carbon atoms,
Examples of the lower alkylene group include those having 1 to 5 carbon atoms, especially those having 1 to 3 carbon atoms, and examples of the halogen atom include CL + Br.

Furthermore, examples of the salt of the compound of formula (1) include hydrochloride.

The compound represented by the above general formula (1) is, for example, the following formula (
3) (However, Ar represents a phenyl group in which one or more hydrogen atoms are substituted with a lower alkoxy group, and R1 represents a hydrogen atom or an acetyl group, respectively.) The compound represented by the following formula (4) % formula % (4 ) (However, R2 represents a lower alkylene group, and X and 2 each represent a halogen atom.) It can be obtained in high yield and high purity by reacting the compound represented by (see reaction 2 A below). .

(1) The above reaction is preferably carried out in an aprotic solvent in the presence of a base. In this case, it is preferable to react 1 to 3 molar equivalents, particularly 1.2 to 2 sole equivalents, of the compound of formula (4) with respect to 1 molar equivalent of the compound of formula (3). In addition, as the aprotic solvent, dimethyl sulfoxide, N, N-dimethylformamide, acetone (toluene, etc.) can be used, but dimethyl sulfoxide, N,
-Dimethylformamide is particularly preferably used. Further, as a base, potassium hydroxide, sodium hydroxide, potassium carbonate, potassium carbonate, etc. are preferably used.
It is usually preferable to use this base in a molar ratio of about 1 to 2 to the compound of formula (3). The reaction temperature is not particularly limited and varies depending on the solvent, the base, the type of compounds of formulas (3) and (4), etc., but is usually -5 to 50°C, particularly 0 to 50°C.
The temperature is preferably 25°C. Obtained in the above reaction (
The compound of formula 1) can be isolated, for example, by pouring the reaction solution into ice water, separating the precipitated crystals in a furnace, and drying them.

In particular, among the compounds represented by the above general formula (1), the 2-
(4-methoxyphenyl)-3-acetoxy-5-(2
-halogenoethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one can be synthesized, for example, by the following method (see Reaction Scheme B below).

That is, 2-hydroxy-3-(4-methoxyphenyl)
-'3-'(2-aminophenylthio)furopionic acid (formula (5) below) t-acetylated 2-acetoxy-3-(4-methoxyphenyl) -3-(2-aminophenylthio)propionic acid This is ring-closed in a solvent such as dimethylformamide in the presence of pyridine and acetic anhydride to obtain 2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1 ,5-
Benzothiazepine-4(5H)-one (formula (3a)
). Next, the following formula (
4&)ZCH2CH2X ・= (4m) (wherein, 2-halogenoethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (formula (1m)) is obtained. In this way, by first acetylating the compound of formula (5) and then ring-closing it, the compound of formula (1a) can be obtained in good yield. In addition, 2-hydroxy- of formula (5),
When 61 units of 3-(4-methoxyphenyl)-3-(2-aminophenylthio)propionic acid are present, this is optically resolved to give d-2-hydroxy-3-(4-methoxyphenyl)-3-( 2-aminophenylthio)propionic acid was obtained, which was acetylated and then ring-closed, to which (4a)
By reacting a compound of formula p,d-2-(4-methoxyphenyl)-3-acetoxy-5-(2-halogenoethyl)-2,3-dihydro-1,5-benzothiazepine-4 (5H)-one (formula (1m)) can be obtained in high yield and purity.

(5) (6) (3a) 0H・CH,X, la.

Kao, the salt of the compound of the above formula (1) or (1a) is,
It can be produced from the corresponding compound by a known method.

In addition, the compound of formula (1) or formula (1a) above can be obtained as a pal1 compound unless optically resolved, but if 6 or 1 compound is used as a raw material, 6 compounds can be obtained by dividing an intermediate substance. Alternatively, by using one compound, six, six, or one target compound can be obtained.

In this case, of course, 6 or 1 target compound can be obtained by dividing the a1 target compound. In addition,
The dividing method can follow a conventional method.

The compound represented by the formula (1) and its salt is the compound represented by the formula (2) above.
) It can be suitably used as a raw material in producing the compound represented by the formula and its salt.

In this case, for example, the compound of the present invention of formula (1) may be added to the compound of the following formula (7
) (However, R6 and R4 each represent a lower alkyl group.) By reacting the compound represented by (2), the compound of formula (2) can be obtained in high yield and high purity (see reaction formula 〇 below) ).

2 - This is preferably carried out by adding a secondary amine of formula (7) to this. In this case, a base such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, etc. can be added to promote the reaction. In addition, in the above reaction, the hydrochloride of the secondary amine of formula (7) is added and neutralized in the reaction solution to generate the secondary amine of formula (7), which is then reacted. There is no problem. Note that the reaction temperature is not particularly limited, and the solvent, base, (1), (7
) varies depending on the type of compound, etc., but usually -5 to 5
The temperature is preferably 0°C, particularly 0 to 30°C.

In particular, among the compounds represented by the above general formula (2), 2-(4-methoxyphenyl)-3=acetoxy-5-(2-(dimethylamine)ethyl)-2 represented by the following formula (2a) ，
3-dihydro-1,5-benzothiazepine-4 (5H)
-one can be obtained, for example, by reacting the compound of formula (1a) with dimethylamine under the reaction conditions described above (see the reaction formula below).

CH2CH2X (la) (2a) Here, by using 6 compounds as the compound of formula (1a), 6 compounds of formula (2a) can be obtained. I will explain in detail.

[Example 1] 2-(4-methoxyphenyl)-3-7 setoxy 2
,3-dihydro-1,5-benzothiazepine-4(5)
t)-on30. It is dissolved in 250 d of i-dimethyl sulfoxide, and 8 g of pulverized potassium hydroxide and 14 ml of ethylene chlorpromide are added thereto at a liquid temperature of 20 DEG C. while stirring. After reacting at 20 to 25° C. for 3 hours, the reaction solution is poured into ice water, and the crystals are separated and dried. Next, the present compound 2-(4-methoxyphenyl)-3-acetoxy-5- was washed with methanol.
(2-chloroethyl) -2,3-dihydro-1,5-
Benzothiazepine-4(5H)-one 27.85. ! i
' was obtained as pale yellow crystals. The yield, melting point, M, S, and IR and NMR analysis results of the target compound are as follows.

Yield 79% Melting point 156-157°C M, S-%/e: 405.5 (M+) Engineering R (KBr
,z-”) 1738.1670,1603,1578
．． 1505NMR (CDC63, ppm) 1.8 (
3H, s, ), 3.5-4.8 (7H, m).

5.1 (2H, d), 6.8-8.0 (8H, m) In addition, 2.0 g of the above target compound was separated by column, and 2-(4
1.99 g of -methoxyphenyl)-3-acetoxy-5-(2-chloroethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was obtained as colorless crystals. The melting point and column separation conditions of the above colorless crystalline substance are as follows: Melting point: 156-157°C Column separation conditions: Stationary phase: Wakogel C-200; Developer: Hensen: Chloroform: Ethyl acetate - 4:1:
1 [Example 2] 2-(4-methoxyphenyl)-3-7 setoxy 2
+3-dihydro-1,5-benzothiazepine-4 (5H
)-one 40 g 1 dimethylformamide 300 d and 10.4. ! Add iil and 1,2-diprometa 720-. After reacting this at 0 to 5°C for 3 hours, the reaction solution is poured into ice water, and the crystals are collected and dried. Next, the present compound 2-(4-methoxyphenyl)-3-7setoxy5-
(2-bromoethyl)-2,3-dihydro-1,S
46.90 g of -benzothiazepine-4(5H)-one was obtained as pale yellow crystals. The yield, melting point, M, S, and IR and NMR analysis results of the target compound are as follows.

Yield 89% Melting point 157-158°C M, S, rTI/e: 450 (M+)IR (KB
r, cm) 1750, 1680.1670.1605
,1580.151ONMgCDC9,,ppn) 1
．． 8(3)1. +a), 3.5-4.8 (7H, m)
.

5.1 (2H, d), 6.8-8.0 (8H, m) In addition, the above target compound 2.0y was separated by column under the same conditions as in Example 1, and 2-(4-methoxyphenyl)- 3-acetoxy-5-(2-bromoethyl)-2,3-dihydro-
1,5-benzothiazepine-4(5H)-one 1.93
9 was obtained as colorless crystals.

The melting point of the colorless crystalline substance was 157 to 158°C.

[Example 3] 2-(4-methoxyphenyl)-3-hydroxy-2
,3-dihydro-1,5-benzothiazepine-4 (5H
)-one as a raw material by the same method as in Example 2,
92-(4-methoxyphenyl)-3-hydroxy-5
-(2-bromoethyl) -2,3-dihydro-1,5
-benzothiazepine-4(5H)-one was obtained.

Reference examples are shown below.

[Reference Example 1] 2-(4-methoxyphenyl)-3-acetoxy-5
-(2-bromoethyl) -2,3-dihydro-1,5
-Dissolve 1 g of benzothiazepine-4(5H)-one in 10-dimethyl sulfoxide, and add 1 g of potassium carbonate.
g and 0.5 d of diethylamine were added, and the mixture was stirred overnight at a liquid temperature of 20°C. Thereafter, the reaction solution was poured into ice water, and the precipitate was collected and extracted with benzene. After the benzene layer is washed with water, 10% hydrochloric acid is added thereto to separate the 10% hydrochloric acid soluble portion, and the mixture is made alkaline using sodium carbonate.

After extraction with ethyl acetate and drying, the ethyl acetate was distilled off and the residue was crystallized by adding a small amount of ether to give 2-(4-methoxyphenyl)-3-acetoxy-5. -(2-(diethylamine)ethyl) -2,
3-dihydro-1,5-benzothiazepine-4 (5H)
-one O,'1ll (yield 71%) was obtained.

In addition, 0.79% of the above target compound was dissolved in ether, 10% HC1/acetone was added thereto to make the liquid acidic, the solvent was distilled off, and the residue was recrystallized with ethanol-ether to obtain the above compound. hydrochloride 0.74g (yield 98%
) was obtained.

[Reference Example 2] 2-(,4-methoxyphenyl)-3-7setoxy5-(2-bromoethyl)-2,3-,dihydro-1
, 15 g of 5-benzothiazepin-4(5H)-one and 20 g of dimethylamine are mixed at 0°C in a closed autoclave, stirred to dissolve the contents, and then left at 15°C for 2 days. Thereafter, excess dimethylamine was removed, and the reaction mixture was made acidic by adding 10% hydrochloric acid while cooling with water, and the insoluble matter was removed. Then, after neutralizing with potassium carbonate, it is extracted with ether. After drying this,
Convert to hydrochloride using hydrogen chloride gas. After distilling off the solvent, the residue was recrystallized from ethanol-ether to give 2-(4-
methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl)-2,3-dihydro-1,5
-Benzothiazepine-4(5H)-one hydrochloride 13.6
8 g (yield: 91 g) was obtained.

[Reference Example 3] 2-(4-methoxyphenyl')-3-acetoxy-
5-(2-chloroethyl)-2,3-dihydro-1,
15 g of 5-benzothiazepin-4(5H)-one and 20 g of dimethylamine were mixed at 0° C. in a closed autoclave and stirred to give contents 1! After dissolving, leave it at 20°C for 4 days. Thereafter, it was treated in the same manner as in Reference Example 2 to obtain 2-(4-methoxyphenyl)-3-acetoxy-5
-(2-(dimethylamino)ethyl)-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride 13.36 g (yield: 80%) was obtained.

[Reference Example 4] 2-(4-methoxyphenyl)-3-human0roxy5-(2-bromoethel)-2,3-dihumano1
, 2-(4-methoxyphenyl)-3-hydroxy-5-(2-(dimethylamino)ethyl) - by the same method as in Reference Example 2 using 5-benzothiazepin-4(5H)-one as a starting material. 2,3-dihydro-1,5-benzothiazepine-4(5)I)-one hydrochloride 15.5.9(
A yield of 95% was obtained (Reference Example 5) 2-(4-methoxyphenyl)-3-acetoxy-5
-(2-bromoethyl)-2,3-dihydrol,
Dissolve 5 g of 5-benzothiazepin-4(5H)-one in 200 d of dimethylformamide and add 9.6 g of dimethylamine hydrochloride and 16 Ii of potassium carbonate to D under water cooling. After the reaction, 10-dihydrochloric acid was added to the reaction solution under ice cooling,
Acidify with hydrochloric acid. After washing this with benzene 50d and making the aqueous layer alkaline using potassium carbonate, the precipitate is extracted with benzene 50d. Next, the benzene layer was washed with water, dried, and the solvent was distilled off to give an oily 2-(4-methoxyphenyl)-3-acetoxy-5-(2-(dimethylamino)ethyl)-2,3-dihydrochloride. 3.73 g of 1,5-benzothiazepin-4(5H)-one (yield 82%)
) was obtained.

In addition, the above target compound was crystallized with inpropyl ether to give colorless crystals of 2-(4-methoxyphenyl)-3-acetoxy-5-(2-(dimethylamino)ethyl) -
2,3-dihydro-1,5-benzothiazepine was obtained.

[Reference Example 6] 2-(4-methoxyphenyl/)-3-human0roxy5-(2-bromoether)-2,3-dihydro-1
, 1 g of 5-benzothiazepine-4(5H)-one in 10 WLl of dimethylformamide! and add 50 tidimethylamine aqueous solution 2- into the solution at a temperature of 5°C. After this was left at 5° C. overnight, 10% hydrochloric acid was added to the reaction solution while cooling with water to make it acidic. Next, after removing the insoluble matter, it is made alkaline using potassium carbonate, and the precipitated crystals are extracted with chloroform. After drying this, chloroform is distilled off and the residue is dissolved in acetone. Add hydrochloric acid and ethanol to this and leave it
The precipitate was collected, washed with ethanol, and dried to give 2-(4-methoxyphenyl)-3-hydroxy-5-
0.77 g (yield: 85 g) of (2=(dimethylamino)ethyl)-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride was obtained.

Applicant: Toho Pharmaceutical Research Institute Co., Ltd. Agent: Patent Attorney Takashi Kojima

Claims (1)

[Claims] 1. The following formula (1) (However, Ar is a phenyl group in which one or more hydrogen atoms are substituted with a lower alkoxy group, R1 is a hydrogen atom or an acetyl group, R2 is a lower alkylene group, and X is a lower alkylene group. 1,5-benzothiazepine derivatives selected from compounds and salts thereof, each representing a halogen atom.