JPH0354663B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the general formula (However, Ar is a phenyl group substituted with a lower alkoxy group,
R represents a lower alkyl group) The present invention relates to a new method for producing a 1,5-benzothiazepine derivative represented by

The above-mentioned 1,5-benzothiazepine derivative [ ] is a compound useful as a synthetic intermediate for pharmaceutical compounds, for example, as a synthetic intermediate for diltiazem hydrochloride, a coronary vasodilator.

Conventionally, as a method for producing the above compound, for example, 2-hydroxy-3-(2'-aminophenylthio)-3-
A method of ring-closing (4″-methoxyphenyl)propionic acid to form a thiazepine ring, and then acylating the 3-position hydroxy group (Japanese Patent Publication No. 43785/1983)
Manufactured by. This is because when the above propionic acid derivative is acylated and then ring-closed,
A compound in which the hydroxyl group at position 3 and the nitrogen site at position 5 of the thiazepine ring are simultaneously acylated is obtained, and it is difficult to selectively remove the acyl group at the nitrogen site at position 5 without cleaving the acyl group at position 3. By being.

As a result of intensive research, the inventors unexpectedly discovered a new method that can selectively remove the acylated acyl group at the 5-position nitrogen site of a compound [ ]. .

That is, according to the method of the present invention, the above general formula []
The compound represented by has the general formula (However, R and Ar have the same meanings as above)
It can be produced by treating the compound represented by with ammonia, hydrazine, primary amine or 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 includes a phenyl group substituted with a methoxy group or an ethoxy group.

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

An equivalent amount to the compound [] is sufficient, but an excess amount may be used.

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,
Examples include xylene and N,N-dimethylformamide.

The reaction proceeds suitably at room temperature, and according to this method, only the acyl group at the nitrogen site at the 5-position can be easily and almost quantitatively removed without affecting the acyloxy group at the 3-position.

According to another aspect of the present invention, the compound [ ] used in the above reaction is, for example, a compound of the general formula (However, Ar has the same meaning as above.) Either the propionic acid derivative represented by [] and the acid anhydride are reacted to perform the acylation reaction and the ring-closing reaction at once, or the propionic acid derivative [] and the acid anhydride or After reacting with an acid halide to acylate the 2′-position amino group or the 2′-position amino group and the 2-position hydroxy group,
It can be produced by further reacting this with an acid anhydride to perform a ring-closing reaction.

Examples of the acid anhydride used in the present invention include lower fatty acids such as acetic anhydride, propionic anhydride, butyric anhydride, and acetic anhydride is particularly preferred. These acid anhydrides are used in an amount of 3 equivalents or more relative to the compound [] when the acylation and ring-closing reactions are carried out at once.

Preferably, the reaction is carried out at about 100-150°C, preferably about 110-140°C.

This reaction is estimated to proceed as shown in the reaction formula below.

(However, Ar and R have the same meanings as above.) The solvent to be used is not particularly limited as long as it does not adversely affect the reaction, but examples include toluene, xylene, ethylbenzene, etc., and the acid anhydride used in the reaction. The substance may be used as a solvent as is.

In this reaction, if less than 3 equivalents of acid anhydride are used, or if the reaction is carried out at 100°C or less, the reaction will not be completed, resulting in a compound (hereinafter referred to as N -acyl compound) or a compound in which both the hydroxyl group at the 2-position and the amino group at the 2'-position are acylated is obtained.

Similar results can also be obtained by using other acylating agents such as lower fatty acid halides such as acetyl chloride, acetyl bromide, and propionyl chloride instead of acid anhydrides.

A compound [] in which both the hydroxyl group at the 2-position and the amino group at the 2'-position are acylated is cyclized to form a compound []
To obtain the compound, an equivalent amount of the compound may be reacted, or to obtain the N-acyl form as the compound, 2 equivalents of an acid anhydride may be reacted thereon at 110 to 140°C.

In addition, the raw material compound [] of the present invention is
It can be produced by the method described in No. 9383. That is, 2-aminothiophenol and the general formula (In the formula, Ar has the same meaning as above, and R ³ represents an ester residue.)
The reaction may be carried out at 140°C, followed by hydrolysis.

Example 1 2-(4'-methoxyphenyl)-3-acetoxy-5-acetyl-2,3-dihydro-1,5-
Synthesis of benzothiazepin-4(5H)-one (compound []) 1-1 2-Hydroxy-3-(2'-aminophenylthio)-3-(4″-methoxyphenyl)-propionic acid ( Add 3.19 g of compound []) and 6.12 g of acetic anhydride to 10 ml of xylene, and reflux for 2 hours while azeotropically distilling the acetic acid formed. After the reaction is complete, cool to room temperature, and precipitate crystals are collected by filtration, washed, and dried. Obtained 3.28 g of a compound with a mp of 158-160°C.Yield 85.2% When this product was recrystallized from xylene, a mp of 160-160°C was obtained.
A compound [] with a temperature of 161°C was obtained.

1-2 Compound [] 3.19g and acetic anhydride 1.22g
Add to 10 ml of xylene and stir at 50°C for 1 hour.
After the reaction, the precipitated crystals are collected by filtration, washed and dried to give 2-hydroxy-3-(2
-N-acetylaminophenylthio)-3-(4
3.43 g of -methoxyphenyl)-propionic acid were obtained. Yield 95.0% 3.0g of this product and 3.39g of acetic anhydride were mixed with xylene 10
ml and conduct the reaction in the same manner as in Example 1-1.
2.7 g of compound [] with mp 158-160°C was obtained. Yield 84.5% 1-3 Add 7.22 g of N-acetyl form of compound [] and 2.44 g of acetic anhydride to 20 ml of toluene, and heat at 80°C.
React for 1 hour. After cooling, the precipitated crystals are collected by filtration, washed and dried to give 2-acetoxy-3-(2′-N-acetylamino-phenylthio)-3-(4″-methoxyphenyl)- with a mp of 164 to 166°C.
7.40 g of propionic acid (compound ()) was obtained. Yield 91.8% 37.0g of this product and 1.87g of acetic anhydride were mixed with xylene 10
ml and conduct the reaction in the same manner as in Example 1-1.
3.0 g of compound [] with mp 158-160°C was obtained. Yield 84.9% Example 2 Synthesis of 2-(4'-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (compound []) 2 -1 2-(4'-methoxyphenyl)-3-acetoxy-5-acetyl-2,3-dihydro-
1,5-benzothiazepin-4(5H)-one (compound []) 1.93g and diethylamine 0.44
g to 20 ml of chloroform and stirred at room temperature for 1 hour. After distilling off the chloroform, add water and collect the resulting crystals by filtration, wash with water, and dry.MP198~
1.63 g of compound [] at 200°C was obtained. yield
94.8% 2-2 In Example 2-1, if 0.27 g of dimethylamine was used instead of diethylamine and 90 ml of benzene was used instead of chloroform, the reaction was carried out.
1.54 g of a compound with a mp of 196-9°C was obtained. Yield: 89.6% 2-3 Add 200 mg of compound [] and 63 mg of aniline to 10 ml of chloroform, and stir at room temperature for 2 hours. Concentrate the chloroform solution and perform thin layer chromatography using silica gel (developing solvent,
When fractionated with benzene: ethyl acetate = 1:1), 62 mg (yield 88.3%) and m.
159 mg of the compound [p.196-8°C] was obtained.
Yield 89.2%.

Claims (1)

[Claims] 1. General formula (However, R represents a lower alkyl group, and Ar represents a phenyl group substituted with a lower alkoxy group.) The compound represented by the formula is treated with ammonia, hydrazine, a primary amine, or a secondary amine to form an acyl group at the nitrogen site at the 5-position. General formula characterized by selective removal of groups (However, Ar and R have the same meanings as above.) A method for producing a 1,5-benzothiazepine derivative. 2 General formula (However, Ar represents a phenyl group substituted with a lower alkoxy group.) Either the propionic acid derivative represented by [] and an acid anhydride are reacted to perform an acylation reaction and a ring-closing reaction at once, or the propionic acid derivative [] and an acid anhydride are reacted together. After acylating the 2′-position amino group or the 2′-position amino group and the 2-position hydroxyl group by reacting with a substance or an acid halide,
This was further reacted with an acid anhydride to perform a ring-closing reaction, and then the general formula obtained in this way was (However, R represents a lower alkyl group, and Ar represents the same meaning as above.) The compound represented by is treated with ammonia, hydrazine, a primary amine or a secondary amine to remove the acyl group at the 5-position nitrogen site. General formula characterized by selective removal (However, Ar and R have the same meanings as above.) A method for producing a 1,5-benzothiazepine derivative.