JPS61229874A - Production of benzothiazine derivative - Google Patents

Abstract

PURPOSE:To obtain the titled substance useful as a synthetic intermediate for vasodilator, at a low cost, by treating the cis-l-isomer of 2-(4-methoxyphenyl)-3- hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one with an organic sulfonic acid chloride. CONSTITUTION:The objective compound of formula II can be produced by reacting the cis-l-isomer of the 2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5- benzothiazepin-4(5H)-one of formula I (R is H, lower alkyl or 2-dimethyl aminoethyl) or its N-substituted derivative with an organic sulfonic acid chloride [preferably tosyl chloride (p-toluenesulfonyl chloride)]. The starting compound of formula I can be synthesized by reducing the nitro group of cis-2-hydroxy-3-(4- methoxyphenyl)-3-(2-nitrophenylthio)prop-ionic acid and cyclizing the resultant cis-2-hydroxy-3-(4-methoxyphenyl)-3-2-aminophenylthio)propi-onic acid.

Description

Detailed Description of the Invention The present invention provides 2-(4-methoxyphenylmethylidene) represented by the general formula (n) (wherein R represents hydrogen, lower alkyl, or 2-dimethylaminoethyl group) −
The present invention relates to a method for producing 2H-1°4-benzothiazin-3(4H)-one and its N-substituted product.

Diltiazem hydrochloride, which is currently frequently used as a vasodilator to improve exertional angina and angina in old myocardial infarction, is useful only in the cis-6 form among the optically active forms represented by the formula. It is. Therefore, in producing diltiazem hydrochloride, it is necessary to perform asymmetric synthesis from optically active raw materials or to perform optical resolution somewhere in the synthesis process. The former method is known, for example, as disclosed in JP-A-59-196863, but the synthesis requires expensive reagents and multi-step reaction operations, and is hardly practical. Among the latter methods, several methods are known for optical resolution, but
There is no known method for isomerizing and reusing the cis-isomer produced as a by-product during optical resolution. The present inventors have discovered that 2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine represented by the general formula (N (wherein R is the same as above) −
An isomerization reaction based on deriving the cis-1 form of 4(5H)-one and its N-substituted product to Compound (II) was carried out to convert it into the cis-d1 form of Compound (1), which was then treated with hydrochloric acid again. The present invention was completed by discovering a method for using diltiazem as a synthetic intermediate.

The present invention is extremely useful industrially because not only can diltiazem hydrochloride be produced at low cost, but also production can be done without disposing of large amounts of valuable resources.

7-membered ring compound (1) (R=H) is pyridine-9OC1,
The six-membered ring compound (I[)
It is known to give (H, Kugita, ,
H, I noue, , M, I kezaki.

,S,Takeo, ,ChetPharm,Bull,
, 18.2028 (1970)] is of little practical use.

The present inventors have discovered that compound (If) can be obtained in high yield by treating compound (1) with an organic sulfonic acid chloride. Examples of the organic sulfonic acid chloride include benzenesulfonyl chloride and naphthalenesulfonyl chloride, but the purpose can be achieved most preferably by using tosyl chloride (p-toluenesulfonyl chloride), which is industrially easily available and inexpensive. I can do it. This reaction proceeds via the organic sulfonic acid ester of the 2-hydroxy group of compound (1), and the intermediate can also be isolated as shown in the examples.

It is known that when the 6-membered ring compound (II) obtained in this way is treated with hydrogen peroxide and then reduced with sodium borohydride, it selectively gives the cis-61 form of compound (1). (Special Publication No. 59-20273). In particular, although there is no prior knowledge regarding the N-unsubstituted compound (R=H) of compound (1), it has been found that the same reaction proceeds more easily than in the case of the N-substituted compound.

l-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5- which is a raw material of the present invention
Benzothiazepine-4(5H)-one (CI) was obtained when optical resolution was performed at the stage of cis-2-hydroxy-3-(4-methoxyphenyl)-3-(2-aminophenylthio)propionic acid ( It can be obtained according to Japanese Patent Application No. 59-97606 and Japanese Patent Application Laid-open No. 59-231065), Japanese Patent Publication No. 53-18018 (method of heating in xylene while removing water), and others. In addition, when optical resolution was performed with cis-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylthio)propionic acid (Japanese Patent Publications No. 49-27576 and No. 53-18038) ) also reduces the nitro group to form the above cis-2-hydroxy-3-
After deriving into (4-methoxyphenyl)-3-(2-aminophenylthio)propionic acid, the compound of formula (1) can be obtained by subjecting it to a ring-closing reaction in the same manner. Furthermore, this compound is a cis-2 synthetic intermediate of diltiazem hydrochloride.
-(4-methoxyphenyl)-3-acetyloxy-2
,3-dihydro-1,5-benzothiazepine-4 (5H
)-one by treatment with a dilute aqueous alkali solution.

On the other hand, compound (1) after isomerization can be easily treated with an alcoholic alkali to easily form the 2-hydroxy-3
-(4-Methoxyphenyl)-3-(2-aminophenylthio)propionic acid can be returned to optical resolution (see reference example), and 2-(4-methoxyphenyl)-3-acetoquine -5-(2-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepine-4
After induction into (5H)-one, the desired diltiazem hydrochloride can be obtained by optical resolution (for example, JP-A-58-32872 or JP-A-59-20273).

As described above, the method of the present invention is capable of converting the cis-1 form of compound (1) having two asymmetric carbon atoms into the da form while retaining the cis structure through short steps and simple operations. This is greatly beneficial to the production of diltiazem hydrochloride, and by repeating this step, substantially all of the cis-61 form can be converted to the cis-6 form. Further, if desired, converting the cis-6 form into the cis-1 form can be carried out within the scope of the present invention without any need for chemical changes.

This reaction will be explained in more detail by giving examples below.

Example ! ! -cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine-
A solution of 15 ml of pyridine containing 5.7 g of p-toluenesulfonyl chloride was added dropwise to a mixed solution of 6.04 g of 4(5H)-one and 20 ml of pyridine over 30 minutes at 5°C.

- ■ at 75°C after being left overnight.

After heating and stirring for 5 hours, pouring into 0.71 g of water and stirring at room temperature for 2 hours, the precipitated crystals were collected by filtration and dried to give 2-(4-methoxyphenylmethylidene)-28-1,4-benzothiazine-3.
3.75 g of pale yellow needle crystals of (4H)-one were obtained.

m, p, 205-208℃ IR (KBr) 3200, l 655cn-'NM
R (da DMSO, ppm) 3 , 85 (s
, 3H), 7.00-7.08(8)(), 7.8
0(s, IH) Example 2 1-cis-2-(4-methoxyphenyl)-3-hydroxy-5-(2-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepine- Dissolve 1.1 g of 4(5H)-one in 1.5+nl of pyridine, and add 1.5 ml of pyridine and 0 p-toluenesulfonyl chloride under water cooling.
．． 64 g of the solution was added, and the mixture was stirred for 3 hours under water cooling and for 2 hours at room temperature. Next, 10+1 water was added and stirred for 30 minutes, ethyl acetate was added, washed with water, dried, and concentrated. Next, 6 ml of pyridine was added, heated at 100°C for 20 hours, ethyl acetate was added, washed with water, dried and concentrated, then benzene was added and the remaining pyridine was distilled off. This operation was repeated until the pyridine odor disappeared. This was purified by column chromatography and 2-(4-methoxyphenylmethylidene)-4(2
660 mg of pale yellow needle crystals of -dimethylaminoethyl)-2H-1,4-benzothiazin-3(4H)-one were obtained.

m, p, 102-104℃ IR (KBr) 1635cm-'NMR (CDC
Is, ppm) 2.38 (s, 6H), 2.70 (
t, 2H), 3.85 (s, 3H), 4.22 (t, 2
H), 6.95-7.70 (8H), 7.82 (s,
IH) Example 3! -2.29 g of cis-2-(4-methoxyphenyl)-3-hydroxy-5-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one in pyridine 2
p-Toluenesulfonyl chloride 2.
9 g was added and stirred overnight. Next, water was added, extracted with chloroform, washed sequentially with dilute hydrochloric acid, aqueous sodium bicarbonate solution, and water, dried over magnesium sulfate, concentrated to dryness,
l-cis-2-(4-methoxyphenyl)-3-p-toluenesulfonyloxy-5-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one3.
Obtained 0g.

m, p, 148.5-150℃ IR (KBr) 1170.1685cm-'NMR
(CDCl2.1)l)m) 2.48(s, 3H)
, 3.40 (s, 3H), 3.88 (s, 3H), 5.
12 (d, J = 7 Hz.

IH), 5.24 (d, J=7Hz, IH), 6.80
~7.80 (8H) 1.8 g of the compound obtained above was dissolved in 10 ml of pyridine, and the mixture was heated and stirred at 100° C. for 15 hours. Ethyl acetate was added to this reaction solution, washed sequentially with water, diluted hydrochloric acid, and water, dried over magnesium sulfate, concentrated, and purified by column chromatography.
2-(4-methoxyphenylmethylidene)-4-methyl-2H-1,4-benzothiazin-3(4H)-one 0
．． 97g was obtained.

m, p, 85-90°C IR (KBr) 1650 cm' NMR (CD Cla, ppm) 3, 55 (s
, 3 H), 3.85 (s.

3H), 7.00-7.70 (8H), 7, '85
(s.

IH) Reference example 1 2-(4-methoxyphenylmethylidene)-2H-1,
Dissolve 0.14 g of 4-penzothiazin-3 (4H)-one in 10 ml of THF, add 30% hydrogen peroxide 0,1
ml of concentrated hydrochloric acid were added under water cooling, and the mixture was left at room temperature for 24 hours. Next, water 5a+1 was added, and after 2 hours, it was made into I) H7,O with ammonia water, an excess amount of sodium borohydride was added, and after 20 minutes, it was extracted with ethyl acetate, washed with water, dried, concentrated, and d
l-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine-
0.1 g of 4(5H)-one was obtained.

m, p, 166-167℃ (dl body) I R (K
Br) 1670cm-'NMR (CDC1a, I)
pa+) 2,00 (d, J= 91(z, l
H), 3°80 (s, 3H), 4.50 (^Bq, J
= 7Hz, 9Hz, IH), 5.10(d, J=7
Hz, lH), 6.90-7°70 (8H), 8. ,
54 (s, IH) Reference example 2 2-(4-methoxyphenylmethylidene)-2H-1,
2836 g of 4-benzothiazin-3(4H)-one was added to T
0.15 ml of 30% hydrogen peroxide and 0.38 ml of trimethylsilyl chloride dissolved in 20 ml of HF at -10°C.
1 was added and left overnight at room temperature. Next, 5 ml of water was added and after stirring for 2 hours, an appropriate amount of sodium borohydride was added. After 30 minutes, it was extracted with ethyl acetate, washed with water, dried and concentrated to give dl-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine-4(5 )()-one 0.21 g was obtained.

Reference Example 3 dl-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 0.9 g, water 5II111 ethanol 5ml and Mix 0.3g of sodium hydroxide,
The mixture was heated and stirred at 70°C for 4 hours.

After cooling and pouring into 50ml of water, the pH was adjusted to 2.8 with 6N hydrochloric acid, the precipitated crystals were collected by filtration, dried, and dl-2-hydroxy-
0.9 g of 3-(4-methoxyphenyl)-3-(2-aminophenylthio)propionic acid was obtained.

Claims (1)

[Claims] A compound [I] represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [I] (In the formula, R represents hydrogen, lower alkyl, or 2-dimethylaminoethyl group) General formula ▲ characterized by reacting the cis-l form with an organic sulfonic acid chloride
There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] (In the formula, R is the same as above) Method for producing the compound [II].