JPH0573746B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula ()

The present invention relates to a method for producing a 1,5-benzothiazepine derivative represented by the following formula: (wherein, Ar represents a phenyl group substituted with a lower alkoxy group, and R represents a lower alkyl group.) For more details, see the general formula ()

It is characterized by subjecting a 1,5-benzothiazepine derivative represented by the following formula to a condensation reaction with dimethylaminoethyl chloride in the presence of a fluoride. Concerning a method for producing compound (). Japanese Patent Publication No. 46-43785 and JP-A No. 57-136581 are known as methods for producing compound () by alkylating the compound () at the 5-position nitrogen site; It is characterized by converting the nitrogen moiety into an alkali metal salt and then reacting it with an alkylating agent, and in order to form the alkali metal salt, a dangerous reagent such as sodium hydride is used. Furthermore, since the reaction is carried out under strong alkalinity, the acyl group at the 2-position oxygen site is likely to be eliminated. The present invention improves the above drawbacks and is characterized by using a fluoride as a catalyst. The fluoride used is preferably one containing an alkali metal ion such as potassium, or a fluoride of tetraalkylammonium such as tetrabutylammonium. When using tetrabutylammonium fluoride, the difference between the reaction via an alkali metal salt is
This can be clarified by NMR. (Measurement conditions: in dimethyl sulfoxide- _d6 , TMS standard).
Even if tetrabutylammonium fluoride is added to a dimethyl sulfoxide solution of compound (), 6,
Although the chemical shift of the proton on the benzene ring bonded to the 7-position is almost unchanged, the sodium salt of compound () is prepared by reacting compound () with sodium hydride in dimethyl sulfoxide according to Japanese Patent Publication No. 46-43785. , the chemical shift of the corresponding proton on the benzene ring moves to the high magnetic field side, and its value is almost equal to the chemical shift of the corresponding proton of the compound ().

[C] becomes more beautiful. This indicates that the conjugation of the nitrogen atom in the 7-membered ring was cleaved due to the formation of the sodium salt of compound (). Since potassium fluoride has low solubility in various solvents, it is usually used spread on various carriers. The present inventors also studied this point and found that a method using Celite, that is, a method in which an aqueous solution of potassium fluoride and Celite are mixed, water is distilled off, and the dried product is used as a catalyst.
It has been found that the purpose can be suitably achieved. A simple mixture of solid potassium fluoride and celite had low activity. The reaction consists of a compound () in an apronto polar solvent,
This is done by adding dimethylamine ethyl chloride and fluoride and stirring at room temperature. As the aprotic polar solvent, acetonitrile gives particularly suitable results. After the reaction, the solvent is distilled off, extracted with benzene, and the resulting crude product is recrystallized from isopropyl ether to obtain a pure compound (). A more detailed explanation will be given below with reference to Examples. Example 1 10.25 g of dl cis-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was suspended in 300 ml of acetonitrile. Ta. Separately, Celite 545
Add a solution of 17.4 g of potassium fluoride dissolved in 400 ml of water to 26.1 g, concentrate at 50-60℃, and reduce to 75-80 g.
It was dried under reduced pressure at °C and added to the above suspension. After stirring for 10 minutes, 4.19 g of β-dimethylaminoethyl chloride was added and stirred at room temperature for 26 hours, and further 1 g of β-dimethylaminoethyl chloride was added and stirred for 15 hours. Thereafter, the solid was separated and washed with acetonitrile, and the liquid and washing liquid were combined and concentrated under reduced pressure. This residue was dissolved in benzene, washed with aqueous sodium carbonate and water,
The benzene layer was dried and concentrated, and the residue was recrystallized with isopropyl ether to give colorless needle crystals mp135-6℃.
9.8g was obtained. The infrared spectrum of this substance is
dlcis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-
2,3-dihydro-1,5-benzothiazepine-
It matched with the standard specimen of 4(5H)-one. Example 2 686 mg of dl cis-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was suspended in 20 ml of acetonitrile, Tetrahydrofuran solution (8 ml) containing 2 g of tetrabutylammonium fluoride and 260 mg of β-dimethylaminoethyl chloride.
was added and stirred at room temperature for 2 days. Thereafter, the solvent was distilled off, benzene was added to the residue, dissolved, washed with an aqueous sodium carbonate solution and water, and after drying, benzene was distilled off, and the residue was recrystallized from isopropyl ether. methoxyphenyl)-3-
654 mg of colorless needles of acetoxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one were obtained.

Claims (1)

[Claims] 1. A 1,5-benzothiazepine derivative represented by the general formula [Formula] (wherein, Ar represents a phenyl group substituted with a lower alkoxy group, and R represents a lower alkyl group) is subjected to a condensation reaction with dimethylaminoethyl chloride in the presence of a fluoride supported on Celite. A method for producing a 5-benzothiazepine derivative.