Preparation method of 2-(4-methoxyphenyl)-3-hydroxy-2, 3-dihydro-1, 5-benzothiazepine ketone
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A technology of methoxyphenyl and benzothiazide, which is applied in the field of chemical pharmaceuticals, can solve the problems of high cost and achieve the effects of high yield, high product purity and high yield
Active Publication Date: 2021-01-29
SUZHOU KAIYUAN MINSHENG SCI & TECH CORP
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Embodiment 1
[0048] Intermediate 1:
[0049] 1000ml reaction flask, under nitrogen protection, add o-aminothiophenol (62.6g, 0.5mol, 1.0eq), toluene 500ml, triethylamine (10.1g, 0.1mol, 0.2eq), cool down to -18°C, add acetone dropwise Methyl alkynoate (46.2g, 0.55mol, 1.1eq), control the temperature at -18°C, stir well, keep warm for half an hour, until the reaction of o-aminothiophenol is complete, heat up, evaporate the low boiling point substances, and then heat up to toluene Reflux, react for 2 hours, cool, wash with water, concentrate and cool, precipitate crystals, filter with suction, and dry to obtain intermediate product 1, 69.9g, with a yield of 78.9% and a purity of 99.2%.
Embodiment 2
[0051] Intermediate 2:
[0052] In a 1000ml reactor, add 500ml of dichloromethane, catalyst 1 (10g, a mixture of titanium tetraisopropoxide and L-(+)-diisopropyl tartrate in a mass ratio of 1:1), and intermediate 1 (53g , 0.3mol, 1.0eq), cooled to 0°C, controlled the internal temperature to 0°C, then added dropwise tert-butanol peroxide (28.4g, 0.315mol, 1.05eq) to react for half an hour, filtered, washed with water, concentrated to obtain the intermediate product 2 (44.1g, 0.228mol), yield 76%, purity 98.5%.
Embodiment 3
[0054] In a 1000ml reaction flask, under the protection of nitrogen, add 300ml of tetrahydrofuran, 12g of magnesium chips, 0.1g of iodine, and a small amount of 4-methoxybromobenzene. -Methoxybromobenzene (39.3g, 0.21mol), refluxed for 1 hour to obtain a solution of (4-methoxyphenyl)magnesium bromide in tetrahydrofuran.
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Abstract
The invention provides a preparation method of 2-(4-methoxyphenyl)-3-hydroxy-2, 3-dihydro-1, 5-benzothiazepine ketone. The preparation method comprises the following steps: taking o-aminothiophenol and methyl propiolate as raw materials to synthesize an intermediate product 1, carrying out selective epoxidation to obtain an intermediate product 2, reacting the intermediate product 2 with 4-methoxyphenyl anions, carrying out Mitsunobu reaction to obtain an intermediate product 3, and hydrolyzing to obtain the product. In the cyclization process of the intermediate product 1, the tension of Z-structure olefin is small so that the yield is high, subsequent epoxidation is an asymmetric epoxidation reaction, the obtained intermediate product 2 is high in optical purity and high in yield, the intermediate product 2 and 4-methoxyphenyl anions are subjected to SN2 reaction, configuration inversion is carried out in an ortho-position, and the product is obtained. The whole reaction process doesnot need to be split, the total yield of the route is high, and the method is economical.
Description
technical field [0001] The invention relates to a preparation method of a compound, in particular to a preparation method of a diltiazem chiral intermediate, and belongs to the technical field of chemical pharmacy. Background technique [0002] Diltiazem (diltiazem) is a benzothiazepine calcium antagonist, a selective calcium channel blocker, the chemical name is cis-(+)-5-[(2-dimethylamino)ethyl]-2- (4-Methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4-(5H)-one hydrochloride. Diltiazem was developed and marketed by Japan Tanabe Company in the early 1970s. At present, the route of synthesizing diltiazem is mainly to first synthesize D-cis-2-(4-methoxyphenyl)-3-hydroxyl-2,3-dihydro-1,5-benzothiazepine-4(5H) -ketone (i.e. 2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepinone), followed by N-alkylation, O-acetyl A two-step reaction yields the product. [0003] As the key chiral intermediate in the synthesis of diltiazem, the existing synthetic methods of 2-...
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