JPS60116677A - Production of benzothiazepine derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as pharmaceuticals, with a simple reaction operation, in high yield, by carrying out the dehydrohalogenation reaction of a novel compound with 2-N-(2-dimethylaminoethyl)aminothiophenol, and heating the resultant compound. CONSTITUTION:The novel compound of formula II (X is halogen) is subjected to the dehydrohalogenation reaction with 2-N-(2-dimethylaminoethyl)aminothiophenol of formula III in an aprotic solvent, preferably in the presence of a basic catalyst, at 0-50 deg.C for 10min-2hr, and heating the resultant product of formula IV in a solvent at 50-150 deg.C for 1-10hr to obtain the objective 2-(4-methoxyphenyl)-3-acetoxy-5-( 2-dimethylaminoethyl )-2,3-dihydro-1,5-benzothiazepin-4( 5H )- one. The product may be converted to an acid addition salt such as hydrochloride. The derivative produced thereby can be used as a drug such as counterdepressant, tranquilizer, coronary vasodilator, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 2-(4-methoxypheny/l')-8-7 represented by the formula H2 1 H2 )Is"'OHs
Setoxy5-(2-dimethylaminoethyl)-2,
8-dihydro-1,5-benzothiazepine-4 (5H)
The present invention relates to a method for producing benzothiazepine derivatives, which are -one and its acid addition salt.

The compound of formula CD and its acid addition salts are particularly important pharmaceuticals among benzothiazepine derivatives, and are used as antidepressants,
It is used clinically as a nerve stabilizer, a coronary vascular tonic agent, etc.

An object of the present invention is to provide a novel method for producing the above-mentioned benzothiazepine derivatives with a high yield through simple reaction operations. According to the present invention, the compound of formula [1] is produced according to the following reaction process scheme.

<Reaction Scheme A> [In the above general formula [1], xFi represents a halogen atom. ]
That is, a compound produced by subjecting a compound represented by the general formula [2] and 2-N-(2-dimethyμaminoethyl/I/)aminothiophenol represented by the formula [layer] to a dehydrohalogenation reaction. By heating (ff), the desired compound of formula [[] is obtained. Compound (ff) has the formula [1
It is presumed that the compound [1] has the above N-acylated structure, and this is ring-closed by heating to form the target compound [1]
It is thought that this can be obtained.

The reaction conditions for the above dehydrohalogenation reaction are as follows:
The reaction may be carried out in an aprotic solvent, usually at a ratio of about 0.5 to 2 times 7μ. Examples of the aprotic solvent include methylene chloride, dioxane, acetonitrile, polyproform, and dimethyl sulfoxide, and at least four of these are used. Although the reaction proceeds without a catalyst, it is usually preferably carried out in the presence of a basic catalyst such as pyridine, collidine, or triethylamine. When using a catalyst, the amount used is the compound (
It is usually about 0.5 times mole or more, particularly preferably about 1 to 2 times mole, relative to 1). The reaction temperature is
Although not particularly limited, it is usually appropriate to set the temperature to 0 to 50"08 degrees. This reaction is usually completed in about 1 minute to 2 hours, and the compound (fV) is produced.

In the present invention, it is not necessary to particularly purify compound (IV), and it is sufficient to heat the compound (IV) to close the ring after the above-described dehydrohalogenation reaction is completed. The ring-closing reaction is usually carried out using 1-
What is necessary is to heat it for about 10 hours, usually at a temperature of about 50 to 150°C. Examples of the solvent include alcohols such as ethanol-μ, propatool, and getano/I/, and aromatic hydrogen subhydride in benzene, toluene, and xylene, and at least one of these is used.

The target compound [1] obtained in this way is
It can be easily isolated by purification methods such as recrystallization and various chromatography techniques.

In the present invention, the target compound (1) obtained above can be converted into an acid-added compound such as a hydrochloride by a conventional method.

Compound [x] in the above reaction scheme A is a known compound, but compound [■] is a new compound.

Compound (It) can be produced, for example, according to Reaction Scheme B below.

<Reaction Scheme B> [In the above general formula [1], X represents a halogen atom. That is, p-methoxyphenylpyruvic acid, a known compound represented by formula (V), is acetylated to form a compound (former), and then halogenated to obtain a compound (former). In addition, the compound [■
], that is, p-methoxy-α-acetoxycinnamic acid, is also a new compound.

The acetylation reaction is carried out using, for example, acetic anhydride, acetate chloride, etc. as the acetylating agent, and using the acetylating agent as it is as a solvent, or in the aprotic solvent described above. The amount of the acetylating agent to be used is usually at least 0.5 times the electric power μ, preferably at least the same times the amount of the compound CD.

The reaction proceeds even without a catalyst, but during the reaction, for example, p
-) A catalyst such as luenesulfonic acid is added to the mK of the compound at 0
．． It is preferable to use about 1 to 1016. The reaction temperature is not particularly limited, but may be generally about 0 to 200°C. The reaction time is usually 80 minutes to 24 degrees [111 degrees].

In addition, the above halogenation reaction uses, for example, oxalyl chlorphyte, thionyl chloride, phosphorus oxychloride, oxalyl prolide, etc. as a halogenating agent, and the halogenating agent is used as it is as a solvent, or in the aprotic solvent. , is carried out. The amount of the halogenating agent to be used is usually about 0.2 times or more, preferably 0.5 times or more by mole, relative to compound (Vl). The reaction temperature is
Although not particularly limited, the temperature may normally be about 0 to 200°C.

The reaction time is usually about 10 minutes to 12 hours.

In this way, compound [1] is obtained, which is used as the raw material for reaction scheme A above.

The method of the present invention is industrially advantageous because the target compound [1] can be obtained in good yield through simple reaction operations.

Moreover, if necessary, it can be made into an acid addition salt such as a hydrochloride.

Hereinafter, the present invention will be explained in more detail with reference to Reference Examples and Examples.

Reference Example 1 Synthesis of p-methoxy-α-acetoxycinnamic acid 2Ii of p-methoxyphenylpyruvate was clouded with 5 ml of acetic anhydride @ 0.1 g of p-)luenesulfonic acid was added, and the mixture was stirred for 2 hours.
Refluxed for an hour. After the reaction was completed, the mixture was cooled with air, and the precipitated crystals were taken off the ground, washed with ethyl acetate, and then dried. Yield:! 112Ii (yield 82.2%), mp, tso~tst<0>C, yellow crystals.

IR (am-'): 1765 (-0=O-0-00
-), 1710 (-00□H).

Elemental analysis value = C Otori 2HI 206, calculated value (%) O
:61. OL, H: 5. l 2 Experimental value (%) O: 6
1.11, H: 5.15゜Reference Example 2 Synthesis of p-methoxy-α-a-7toxycinnamic acid chloride 89 p-methoxy-a-acetoxycinnamic acid was added to oxalyl chloride loml and under stirring. Refluxed for 40 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure. Methylene chloride was added to further remove remaining oxalyl chloride, and the mixture was concentrated again under reduced pressure. N-hexane was added to the residue to crystallize it, and the crystals were collected. Yield 2.69
(Yield 8096) Sm, p, 124-1 27°C (decomposition), red needle-like crystals.

IR (am), 1810 (-Cool.

Elemental analysis value: c12u,, alo, calculated value (
%) C: 56.59, I(:4.85', experimental value (4
)(:!:56.70, H:4.40゜Example 1 2-(4-methoxyphenyl)-8-7 setoxy 5-
(2-dimethylaminoethyl/l/)-2,8-dihydro-1,5-benzothiacevin-4(5B)-one [[]
and its hydrochloride synthesis p-methoxy α-acetoxycinnamic acid chloride 2g
methylene chloride2. Dissolved in Om/. This was added to 2 ml of 2-N-(2-dimethylaminoethyl)aminothiophenol 1,55.9 in methylene chloride aomlK and pyridine at room temperature with stirring. The mixture was further stirred for 80 minutes, and after the reaction was completed, it was concentrated under reduced pressure. 20 ml of ethanol-yv was added to the residue, and the mixture was refluxed for 6 hours while stirring. The hakama and reaction solution were concentrated under reduced pressure. This crude product was purified by silica gel column chromatography (eluted with a chloroform/methanol-μ mixture). The obtained crystals were recrystallized from isopropyl ether. Yield 1.7g (Yield 5B, 1%'), m, p, 185-186
°C, white crystals.

IR (am): 1740-1215 (OOOH3)
, 1678 (-00-N:: ), 1250.1080
(0-8).

Elemental analysis value: Calculated value (4) 0: 68.75, K6.82, N: 6.76, as 022H2604N28
Experimental value (%”) 0: 6 B, 81. H: 6.8
4, N: 6.79° This was dissolved in amethane, hydrochloric acid and ethanol were added, and the solution was allowed to stand to precipitate the hydrochloride. This was dried several times. Yield jL1.5.9 (Yield 42.8
%), m, p.

190-191°C, white crystals.

■几(am-'): 1740.121B(OOOH3
), 1680 (-Co-N'C), 1250 1028
(0-8).

Elemental analysis value: 'a22H26o4y2s-mcl, calculated M(φ)C: 5g, 6o, H: 6.04, N
: (i, 21, experimental value (chi) 0:58.65.1(
:6. OL, N: 6.27° (or more)

Claims (1)

[Claims] ■ General formula % formula % [In the formula, X represents a halogen atom. ] The compound represented by the formula 2-N-(2-dimethyμaminoethyl/L/
) Aminothiophenol is dehydrohalogenated and the product obtained is heated to form 2-(4-methoxyphenyl)-8-acetoxy-5-(2 -dimethylaminoethyl)-2,8-
1. A method for producing a benzothiazepine derivative, which comprises obtaining dihydro-1,5-benzothiazepine-4(5H)-one and, if necessary, adding acid to it.