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Pitavastatin calcium intermediate preparation method

A technology for pitavastatin calcium and intermediates, applied in the field of preparation of pitavastatin calcium intermediates, can solve problems such as not easy to completely remove, dimethyl sulfoxide waste water, triphenoxyphos solid waste, etc., and achieve beneficial The protection of the ecological environment, the maximum application value, the effect of reducing solid waste and liquid waste

Pending Publication Date: 2019-11-05
安庆恩聚生物医药科技有限公司
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0004] The object of the present invention is to provide a kind of preparation method of pitavastatin calcium intermediate, to solve the Wittig reaction of the preparation method currently on the market that proposes in the above-mentioned background technology to produce a large amount of triphenoxyphos solid waste, aftertreatment purification It is not easy to completely remove, requires multiple crystallization, and produces a large amount of wastewater containing dimethyl sulfoxide

Method used

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  • Pitavastatin calcium intermediate preparation method

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Embodiment 1

[0019] 2-((4R,6S)-6-((E)-2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)ethenyl)-2,2-dimethyl Preparation of (1,3-dioxan-4-yl) tert-butyl acetate compound V:

[0020] Pump 700 kg of methylene chloride into a 2000-liter reactor, then add 100 kg of (2-cyclopropyl-4-(fluorophenyl)quinolin-3-yl)methanol, start stirring, and cool down to 0 to 5°C; Take 90 kg of phosphorus tribromide to the high level tank, start dropping, keep the reaction temperature at 0 to 5 °C during the dropping process, keep the temperature at 0 to 5 °C for one hour after the addition; add 100 kg of water to quench the reaction, keep the temperature at 0 to 5°C, stirred for 1 hour, added dropwise 15% sodium hydroxide aqueous solution to adjust the pH to 8, separated the dichloromethane layer, washed three times with water; concentrated most of the dichloromethane under reduced pressure, added 500 liters of tetrahydrofuran, and reduced pressure Concentrate 50 liters of tetrahydrofuran to obtain a tetrahydro...

Embodiment 2

[0022] 2-((4R,6S)-6-((E)-2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)ethenyl)-2,2-dimethyl Preparation of (1,3-dioxan-4-yl) tert-butyl acetate compound V:

[0023] Add 200 milliliters of tetrahydrofuran into a 3-liter three-necked flask, then add 23 grams of active zinc powder, 0.5 grams of iodine, replace with nitrogen three times, heat to 50 to 60 ° C under stirring and keep for 30 minutes until the color of iodine disappears; 121 grams of 3-(methyl bromide Base)-2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline was dissolved in 450 milliliters of tetrahydrofuran, and then added dropwise to the reaction flask, and the rate of addition was controlled so that the reaction temperature was between 50 and 60°C. After completion of the heat preservation reaction for 2 hours, the temperature of the reaction system was lowered to 10 to 20°C, and 88 grams of 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4 - Base) tetrahydrofuran (250 ml) solution of tert-butyl acetate was added dropw...

Embodiment 3

[0025] 2-((4R,6S)-6-((E)-2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)ethenyl)-2,2-dimethyl Preparation of (1,3-dioxan-4-yl) tert-butyl acetate compound V:

[0026]Add 200 milliliters of toluene to a 3-liter there-necked flask, then add 23 grams of active zinc powder, 0.5 gram of iodine, replace with nitrogen three times, heat to 60 to 70 ° C under stirring and keep for 30 minutes until the color of iodine disappears; 121 grams of 3-(methyl bromide Base)-2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline was dissolved in 600 milliliters of toluene, and then added dropwise to the reaction flask, and the rate of addition was controlled so that the reaction temperature was between 60 and 70°C. After completion of the heat preservation reaction for 2 hours, the temperature of the reaction system was lowered to 10 to 20°C, and 88 grams of 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4 - Base) toluene (400 ml) solution of tert-butyl acetate is added dropwise to the reaction flask, th...

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Abstract

The invention discloses a pitavastatin calcium intermediate preparation method, and relates to the technical field of preparation of pitavastatin calcium intermediates. In the prior art, the Wittig reaction can generate a large amount of solid waste triphenyl phosphorus oxychloride, and the solid waste is difficult to completely remove through post-treatment purification. A purpose of the presentinvention is to solve the problem in the prior art. The preparation method comprises: 1, carrying out a reaction on (2-cyclopropyl-4-(fluorophenyl)quinoline-3-yl)methanol I and phosphorus tribromide in dichloromethane to form 3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline II, and extracting with dichloromethane; 2, carrying out a Reformatsky reaction on the 3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline II and 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl)tert-butyl acetate to obtain an alcohol VII; and 3, adding p-toluenesulfonyl chloride in a dropwise manner to obtain p-toluenesulfonate VIII, treating the reaction liquid with potassium tert-butoxide, and carrying out an elimination reaction to obtain 2-((4R,6S)-6-((E)-2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl) tert-butyl acetate V, or directly treating with a sodium carbonate aqueous solution to obtain the product V.

Description

technical field [0001] The invention relates to the technical field of preparation of pitavastatin calcium intermediates, in particular to a preparation method of pitavastatin calcium intermediates. Background technique [0002] Pitavastatin Calcium is the first fully synthetic HMG-CoA reductase inhibitor developed by Nissan Chemical Co. ", according to the existing clinical trial results and the comparison with foreign similar listed products, its lipid-lowering effect is very good, and it is the most powerful lipid-lowering drug so far. In the preparation method of pitavastatin, 2-(( 4R,6S)-6-((E)-2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)vinyl)-2,2-dimethyl-1, 3-dioxan-4-yl) tert-butyl acetate is an important intermediate for the synthesis of pitavastatin calcium API. [0003] Scheme 1 in the prior art: US2013 / 72688 reported that (2-cyclopropyl-4-(fluorophenyl) quinoline-3-yl)methanol I was brominated with phosphorus tribromide, bromide II and triphenyl The quat...

Claims

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Application Information

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IPC IPC(8): C07D405/06
CPCC07D405/06
Inventor 邵建勇杨宁王慧宾王伟强栾义黄英豪李小鹏
Owner 安庆恩聚生物医药科技有限公司
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