JPS60100564A - Preparation of 5-(n,n-dimethylaminoethyl)-benzo- thiazepine derivative - Google Patents

Abstract

PURPOSE:To obtain the titled substance, by acetylating 2-hydroxy-3-(2'-aminophenylthio)-3-(4''-methoxyphenyl)-propionic acid, subjecting the resultant compound to ring closure, reacting the reaction product with N,N-dimethylaminoethyl chloride. CONSTITUTION:1mol compound shown by the formula I is reacted with about 2mol acetyl chloride in a solvent such as chloroform, benzene, etc. at 0 deg.C-the reflux temperature for about 1hr to give a compound shown by the formula II, which is reacted with an equipmolar amount or a little excess amount of acetyl chloride at 90 deg.C-the reflux temperature of the solvent under heating, to give a compound shown by the formula III. 1mol of this compound and 2-3mol KHCO3 are suspended in methyl ethyl ketone, and reacted with ClCH2N(CH3)2 with stirring under reflux for 10-15hr, to give a compound shown by the formula IV. USE:A coronary vasodilator, or a stimulant for electroencephalogram.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing a 5-(N,N-dimethylaminoethyl)-benzothiazebin derivative represented by Formula 94 (1).

The compound of formula (1) obtained by the method of the present invention has excellent coronary vasodilating effect and electroencephalogram awakening effect, and is currently widely used in clinical practice.
-2-(4'-methoxyphenyl)-3-acetoxy-5-(N,N-zomethylaminoethyl)-2,3-dihydro-1,5-penzothiazepine-4(5H) monoone has particularly excellent effects. (Special public bean paste No. 53-18038)
.

Conventionally, as a method for producing this compound (i), for example, 2-hydroxy-3-
(2'-aminophenylthio)-1a-(4"-methoxyphenyl)-probion powder is chlorinated and then acetylated to produce 2-(4'-methoxyphenyl)-3-acetoxy expressed by formula (■) 2.3 -Dihydro-1,5-penzothiazebin-4(5H) monoone is prepared and then N-alkylated.

In particular, as a method for N-alkylation, a method is known in which the 5-position of a benzothiazepine fatty conductor (B) is made into an alkali metal salt and then this is reacted with KN,N-dimethylaminoethyl chloride. (q'f public error 46-4378
5) This method has an extremely low yield of about 23%, which is inevitably disadvantageous as a regular method.

Therefore, it is necessary to develop an industrial method with good water retention.
1 [This has been desired and many investigations have been made. For example, compound (1) is made into an alkali gold salt in the presence of silica dal and/or alumina in a non-grotonic polar solvent, and then N, A method of reacting N-dimethylaminoethyl chloride (%Kai No. 57-136581), and a method of reacting the compound (
IV) is reacted with N,N-dimethylaminoethyl chloride in the presence of sodium hydroxide in acetone or in the presence of acetone, acetone-water, vinegar lower alkyl ester, vinegar lower alkyl ester-potassium R acid in water. A method has been reported (%Kaisei No. 58-99471).

In the actual situation where Wf is present, the present inventor conducted further research and completed a new method that is different from the above method and has an extremely high yield.

The method of the present invention is shown by the following reaction formula.

The following margin C0CH5 (il (IV) That is, the present invention is based on 2-hydroxy-3-(2'-aminophenylthio)-3-(4''-methoxyphenyl)
2-acetoxy-3-(2'-N
-acetylaminophenylthio)-3-(4''-meth)oxyfer)-7'lobion& (1), which was then subjected to a heating reaction in the presence of acetyl chloride to form 2-
(4'-methoxyphenyl)-3-7 setoxy 2,
3-dihydro-1,5-benzothiazepine-4 (5H)
5-(N,
This is a method for producing N-dimethylamineethyl)-benzothiazepine derivative (1).

From compound (11), (lit) is 1, compound (
The reaction is carried out with 2 mol or slightly excess acetyl chloride relative to III. The reaction is preferably carried out in a hot medium such as chloroform, benzene, toluene, xylene, etc. at θ°C to reflux temperature for about 1 hour. This reaction is performed using a base, e.g. biricin,
& 2 Even if hydrogen chloride (r-) is present in the presence of aminecidal amines, carbonic acid, alkaline carbonate, etc., hydrogen chloride (r-) is present, and the aqueous chloride system is not removed from the reaction mixture as a force. You may go.

From compound (llll) to (1v) 7) l1tL I
r, L, Compound 'Ih (ta) Compound 9aGl) is reacted by heating in the presence of 1 equimolar to slightly excess acetyl chloride relative to vc at 90° C. or at the reflux temperature of the hot medium. Benzene, toluene, xylene, etc. are used as the heating medium.

The reaction ~ is completed in about 10 hours. The cyclization reaction can also be carried out by simply heating compound 0) in the absence of acetyl chloride, but this takes an extremely long time and is not industrially preferred.

To obtain (1) from compound (IV), compound (IV
) using 2 to 3 times the molar amount of returned acid water cord potassium,
Compound (IV) and potassium hydrogen carbonate to methyl ethyl ketone? The mixture becomes cloudy, and compound ① is added to it while stirring and allowed to react. The reaction is preferably carried out under reflux for 10 to 15 hours.

When the number is 1, the reaction progresses to 1, with a yield of 90% or more. (11 is swallowed.

Next, I will explain it with examples.

Reference example 1 (1) Cis-(...-2dihydroxy-3- (2'-
31.9 f (0.1 mol) of chloroform
19.8f (0.25 mol) of pyricine was added thereto, and the mixture was incubated at 0 to 10°C for about 10 minutes for 3 t++. Next, inject 17.7f (0,225 mol) of acetyl chloride and pray for seven hours for one hour. Reaction solution k 2 (J
Pour into ice water to loosen the organic layer, and add water to the top.
! j is extracted with chloroform 50-. Including the unfavorable layer, 200++ tl of water! After washing twice with 6), dry with anhydrous sodium sulfate and shrink under reduced pressure. When the residual liquid is recrystallized from toluene, cis-(++-2-acetoxy-3-(2'-N-acetylaminophenylthio)-
3-(4”-methoxyphenyl)-propionic acid 34f
(Yield 85%) is obtained. Optical rotation [α] Amako +19
5.8°c=0.3166, ethanol).

(ii)) -2-hydroxy-3-(2'-aminophenylthio)-3-'(4
”-methoxyphenyl)-teropionic acid 209 (0,
062'7 mol) and acetyl chloride 11, Oy (Q,
140 mol) and heated while stirring, the temperature reached approximately 8θ℃.
The reaction occurs while generating HCt gas. Stir for 1 hour. After cooling, the precipitated crystals are separated and dried.
The above diacetyl compound 21.1F (melting point i66-168°C)
A yield of 83.5%) is obtained. Optical rotation [α] 2δ = 2
02.2° (C=0.3220, ethanol) Example 2 cis-((1)-2-acetoxy-3-(2'-N-7
(cetylaminophenylthio)-3-(4''-methoxyphere)-zolopionic acid 4f (0.01 mol) is clouded with 40 tn1.V of xylene and heated to 90° C. with 0.0 ml of acetyl chloride. 99 (0,012 mol)
Let cool and incubate at temperature for 1 hour, followed by 1O2 incubation under reflux. The reaction solution 6 is densified under reduced pressure, and isozorobyl alcohol lO- is added to the residue, followed by cooling. Take the precipitated crystals,
Drying yields 2.59 crude products (73.55+6). This was recrystallized from isozorobyl alcohol,
cis-(4-2-(4'-methoxyphenyl)-3-acetoxy-2,3-dihydro-1, with a melting point of 150.7°C)
5-benzothiazepin-4(5H)-one was obtained.

Optical rotation [α) 2G = +40.3° (C = 0.3528
．． chloroform) Example 3 cis-(→-2-(4'-methoxyphenyl)=3-acetoxy-2,3-dihydro-1°5-benzothiazepin-4(5H)-one 5f (14,6 mmol ), potassium hydrogen carbonate 2.99 (29.0 mmol), potassium iodide 0.19 (0.6 mmol) were suspended in methyl ethyl ketone 5θ-, and while stirring, N,N-dimethylaminoethyl chloride 2.0f was suspended. (18.6 mmol)
and react under reflux for 12 hours. After cooling the reaction solution, it is filtered through a p-filter, and the F solution is pulverized under reduced pressure. ′! Toluene 3 in A residue
In addition, the organic layer was dissolved and washed three times with 50 g of water, and the organic layer was dried with anhydrous sodium sulfate. The solvent was erroneously reduced in diameter under reduced pressure, and the resulting crystals were collected and kept dry to form a composition 6.Of (yield: 919 g).

This was recrystallized from methanol-isonol/e-ethanol, with a melting point of 211.6°C (D cis-(4-)-2-(4'
-methoxyphenyl)-3-acetoxy-5-(N,N
-dimethylaminoethyl)-2+3-7hi)'low1.
5-pen"15-azepin-4(5H)-one hydrochloride was obtained.

Optical rotation & [(Z)20=+l l 6° (C= 1.00
5.

water) Reference example 1 cis-@-)-2-acetoxy-3 in 50 m of xylene
-(2'-N-acetylaminophenylthio)-3-(
4“-methoxyphenyl)-zolopionic acid 109 (0
,0248 mol) was added, and while stirring, 53 mol of
Allow time to react.

The reaction solution was evaporated under reduced pressure, and inzolobil alcohol 2 was added to the residue.
〇-Add and cool. The precipitated crystals are collected and dried to obtain 4.2f of crude product (yield: 49.5%). This was recrystallized from isozorobyl alcohol to obtain a cis-(+)-2-(4'-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiamine with a melting point of 151.3°. Azepin-4(5)1)-one was obtained.

Optical rotation [α)” = +40.7° (c = 0.4474
.

chloroform)

Claims (1)

[Scope of Claims] 1. About twice the mole of 2-hydroxy-3-(2'-aminenyltheo)-3-(4''-methoxyphenyl)-zolopione represented by the following formula (...) of acetyl chloride to form 2-acetoxy-3-(2'-N-acetylaminophenylthio)-3-(4"-methoxyphenyl)-zolopionic acid represented by formula (1), 0CHs, and then This was subjected to a heating reaction in the presence of acetyl chloride to form 2-(4'-methoxyphenyl)-3- of the formula (IV).
Acetoxy-2,3-zohydride μm1゜5-benzothiazepin-4(511)-one is prepared, and further reacted with N,N-dimethylaminoethyl chloride in the presence of potassium carboxyhydrogen in methyl ethyl ketone. 5-(N,N-dimethylaminoethyl)- represented by the following formula (I) characterized by
Method for producing benzothiacebin hlJ form.