JPS59231075A - Preparation of 1,5-benzothiazepine derivative - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as an intermediate of pharmaceuticals, economically, by treating a compound corresponding to the objective compound and having acyl group at the 5-N atom with ammonia, hydrazine or primary or secondary amine, thereby selectively removing said acyl group. CONSTITUTION:The objective compound useful as an intermediate of e.g. diltiazem hydrochloride (a coronary vasodilator) is prepared easily and quantitatively, at normal temperature, by treating the compound of formula I (R is lower alkyl; Ar is phenyl substituted with lower alkoxy) with ammonia, hydrazine or primary or secondary amine thereby selectively removing the acyl group of the 5-N site. The starting compound of formula I is obtained either by carrying out the acylation and cyclization of the compound of formula III with an acid anhydride in one step, or by reacting the compound of formula III with an acid anhydride or an acid halide to acylate the 2'-amino group or further 2-hydroxyl group,and cyclizing the product with an acid anhydride.

Description

[Detailed description of the invention] The present invention is based on the general formula (However, Ar is a lower alkoxy-distributed 44I phenyl group.

It represents a lower alkyl group.

The above 1,5-benzothiazepine derivative [1] is a compound useful as a synthetic intermediate for medical mulberry compounds.

For example, it is useful as a synthetic intermediate for diltiazem hydrochloride, a coronary vasodilator.

Conventionally, the above compound has been produced by ring-closing 2-hydroxy-3-(2'-aminophenylthio)-3-(4'-methoxyphenyl)propionic acid to form a thiazepine ring at f+7. After that, the 3-position hydroxy group is acylated (Japanese Patent Publication No. 46-43785). This is because when the above-mentioned propionic acid derivative is acylated and ring-closed, a compound is obtained in which the 31-position hydroxyl group of the thiazepine ring (and the nitrogen site at the 5th position are simultaneously acylated, and the acyl group at the 3rd position) This is because it is difficult to selectively remove the acyl group at the 5-position nitrogen site without cutting I411.

As a result of intensive research by the inventors, all (unexpectedly,
We have discovered a new method capable of selectively removing the acyl group at the 5-position nitrogen site of a compound (1) that has been acylated up to the 5-position nitrogen site.

That is, according to the method of the present invention, the compound represented by the above general formula (1) has the general formula (However, It and Ar have the same meanings as above)
It can be produced by treating the compound represented by with ammonia, hydrazine, a primary amine or a secondary amine to selectively remove the acyl group at the 5-position nitrogen site.

In the method of the present invention, the group represented by Ar is a methoxy group or an ethoxy group. Examples include substituted phenyl groups.

Specific examples of primary amines include aliphatic amines such as methylamine, ethylamine, and n-bunalamine, and aromatic amines such as aniline and toluidine. Examples include aliphatic secondary amines such as n-propylamine and di-n-butylamine, and cyclic amines such as morpholine, virol, and imidazole. Group secondary amines are preferred.

The amount used is sufficient for compound [1], but it may be used in excess.

The solvent used here is not particularly limited as long as it does not adversely affect the deacylation reaction, but examples include chloroform, benzene, toluene, xylene, N,N-dimethylformamide, and the like.

The reaction progresses in a suitable manner, and according to this method, 3
Shadow 4i on the acyloxy group! , without providing u, it is possible to easily and almost quantitatively remove only the acyl group at the 5-position (nitrogen)>co site.

Further, according to another aspect of the present invention, #, L, + jbeilζ, the compound [11] used in the above reaction has 1, for example, the general formula (
However, the acylation reaction and the ring-closing reaction may be carried out at once by reacting propionic acid, a kasumi conductor, and an acid anhydride shown as (# represents the same meaning as above), or ) and an acid anhydride or an acid halide to acylate the 2'-position amino group or the 2'-position amino group and the gold grain hydroxyl group, and then react the acid anhydride with the 2'-position amino group to perform a ring-closing reaction. It can be made by doing.

The acid anhydrides used in this reaction include lower fatty acids such as acetic anhydride, propionic anhydride, and acetic anhydride, with (jJl and glacial acetic acid being particularly preferred). When carrying out all at once, 3 equivalents or more are used relative to compound CI).

The reaction is carried out at about 100-150 uC, preferably about 110-14
Preferably, it is carried out at 0°C.

This reaction proceeds as shown in the following reaction formula: 411i
determined.

(1) (However, Ar and R have the same meanings as above.) There are no particular restrictions on the solvent used as long as it does not adversely affect the reaction.2 Examples include toluene, xylene, ethylbenzene, etc. The acid anhydride used in the above may be used as a solvent as it is.

In this reaction, if more than 3 equivalents of acid anhydride are used, or if the reaction is carried out at temperatures higher than 100°C, the reaction will not be completed, and only the amine group at the 2' position of the compound (ffl) will become acyl. The compound []■] is obtained.

In addition, the same result can be obtained by using a lower fatty acid halide such as acetyl chloride, acetyl bromide, propionyl chloride, etc., as an acylating agent of (11+) instead of the acid 11 (hydrate). (ff), 1 equivalent m of the compound is added, and the N-acyl form is added to the compound (ff).
If) can be obtained by reacting it with two 1' anhydrides at 110 to 140 uC.

2. The raw material compound [''] of the present invention is disclosed in Japanese Patent Application Laid-open No. 45-9383.
It can be manufactured by the method described in No. f.

That is, 2-aminothiophenol and the general formula (wherein k
r is the same as in item 11, and RF represents an ester residue. ) in t6 medium, 100 to 1
The reaction may be carried out at 40°C and then hydrolyzed.

Example 1 2-(4'-methoxyphenyl)-3-acetoxy-5
-Synthesis of acetyl-2,3-dihydro-1,5-benzothiazepin-4(5J-1)-one (compound (It)) 1-1,2-hydroxy-3-(2'-aminophe-1
-3-(4''-methoxyphenyl)-propionic acid (compound (III)) Reflux for 2 hours while distilling off. After reaction path T, cool to room temperature, precipitate crystals are collected by filtration, washed and dried to obtain a compound with m, p, l of 513 to 260oC [11]
3,289 was obtained. Yield: 85.2cm When this product is recrystallized from xylene, m, p, 160 ~
Compound (If) was incubated at 161°C.

1-2. Compound (Ji) 3.19 and anhydrous m,
acid 1.222 to xylene 10. In addition to d5. Oo(,'
I worshiped for 1 hour and 4Tt. After the completion of the reaction, the precipitated crystals are collected by filtration, and after drying, m, p, 2 at 170-1°C are obtained.
-Hydroxy-3-(2-N-acenalaminophenylthio)-3-(4-methoxyphenyl)-propionic acid 3.432 was obtained. Yield 95.0% This product 3.02 and anhydrous vinegar 1. Add 3.392 cm of helmet to 10 ml of xylene,
Example] When the reaction is carried out in the same manner as in -1, m, p, 158-1
Compound (II) 2.7y was obtained at 60°C. Yield 8
45i 1-3. Compound (N-acetyl form of lit"I 7.22
9 and 2.449 ml of acetic anhydride were added to 20 ml of toluene.

React at 80°C for 1 hour. After cooling, the precipitated crystals are washed and dried to a temperature of m, p, 164-166°C.
2-acetoxy3-(2'-N~acetylaminophenylthio)-3-(4'-methoxyphenyl)-
Propion I! 112 (Compound (IV)) 7.4 o
y was obtained. Yield 91.8% 3.70 g of quartz and 1.87 y of F'l'l acid anhydride were added to 10 ml of xylene and the reaction was carried out in the same manner as in Example 1-1. Compound (II)3.
07 was obtained. Yield 84.9% Example 2.2-(4'-Methoxyphenyl)-3-aceto-2,3-dihydro-1,5-benzothiazepin-4(5I-7)-one (compound [ I]) Synthesis 2-1
．． 2-(4'-methoxyphenyl)-3-acetoxy-5-acetyl-2,3-dihydro-1.5-benzothiazepin-4(5H)-one (compound (n)) 1.
939 and diethylamine 0.447 in chloroform 2
0 ml and stirred at room temperature for 1 hour. When the crystals obtained by adding chloroform distilled condensate are collected by filtration, soaked in water and dried, compound (1) with m and p of 198 to 200°C is obtained.
1.639 was obtained. Yield 94.8% 2-2. Example 2-1. When 0.27y of dimethylamine was used instead of diethylamine and 90ml of benzene was used instead of chloroform, m, p, 1
96-9°CO) Compound (1) 1.51' was obtained.

Yield 89.6% 2-3. Compound CI+) 200 Takumi and Aniline 6
3 ml of chloroform 10. mt and stir at room temperature for 2 hours. Chloroform solution /i1'1! Thin layer chromatography using silica gel (developing solvent,
When fractionated with benzene; ethyl acetate (1:1), acetanilide was 62% (yield: 88.3") and rn, p, 1
159 rng of compound 1:I) were obtained at 96-8°C. Yield 89.2″I

Claims (1)

[Scope of Claims] ) A compound represented by the general formula (1 (, represents a lower alkyl group, and Ar represents a lower alkoxy-substituted phenyl group) is ammonia, hydrazine, a primary amine or 1, 5 represented by the general formula (wherein )\r and R have the same meanings as above) characterized by selectively removing the acyl group at the 5-position nitrogen site by treatment with a secondary amine. -Production method of benzothiazepine derivatives 2) A propionic acid derivative represented by the general formula (1M represents a phenyl group substituted with a lower alkoxy group) is reacted with an acid anhydride to perform an acylation reaction and a ring-closing reaction at once. , or the propion Ii! The derivative [厘] is reacted with an acid hydrate or an acid halide to form an amino group at the 2' position or a 2'-position amino group.
After the amino group at the '' position and the hydroxyl group at the K position are acylated, this is further reacted with an acid anhydride to prevent a ring-closing reaction. Thereafter, the compound represented by the general formula thus obtained (where 几represents a lower alkyl group and Ar represents the same meaning as in Section IVJ) was mixed with ammonia, hydrazine, and
A general formula characterized by selectively removing the acyl group at the 5-position nitrogen site by treatment with k-amine or secondary amine (however, Ar and R are the same as in ftI (having a taste); Method for producing the indicated 1,5-benzothiazepine derivatives