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Synthesis method of rosuvastatin calcium intermediate

A technology for rosuvastatin calcium and a synthesis method, which is applied in chemical instruments and methods, compounds of Group 5/15 elements of the periodic table, and organic chemistry, etc., can solve the problem of easily generating side reactions, affecting product purity and product yield Low problems, to achieve good reaction yield and purity, reduce production costs, simplify the effect of synthesis steps

Inactive Publication Date: 2017-12-08
ZHEJIANG MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] In the methods for preparing the above-mentioned intermediates disclosed in the prior art, each step of the reaction is carried out independently and requires multiple separations and purifications. Not only the steps are cumbersome, the cost increases, but also directly leads to a low product yield. And because the medium used in the reaction process is not suitable, it is easy to produce side reactions and affect the purity of the product.

Method used

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  • Synthesis method of rosuvastatin calcium intermediate
  • Synthesis method of rosuvastatin calcium intermediate
  • Synthesis method of rosuvastatin calcium intermediate

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Embodiment 1

[0030] The synthetic method of rosuvastatin calcium intermediate in this embodiment, that is, the rosuvastatin calcium intermediate is [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N -methylsulfonyl amido)-5-pyrimidinyl] the synthetic method of triphenylphosphine bromide comprises the following steps:

[0031] (1) Under nitrogen protection, add 400mL tetrahydrofuran to a 1000mL dry four-necked reaction flask, add 40g anhydrous magnesium chloride and 40g potassium borohydride, heat and reflux for 1 hour; distill at atmospheric pressure, remove 300mL tetrahydrofuran, add 750mL toluene and 100g of compound 2 was refluxed for 7 hours; after the reaction was completed, cool to room temperature, filter, add dropwise 145mL of 1N hydrochloric acid to the filtrate to quench the reaction, stir and separate layers, dry the organic layer with anhydrous magnesium sulfate, filter, and transfer the obtained filtrate to 2000mL standby in the reaction flask;

[0032] (2) Add 27 mL of phosphorus...

Embodiment 2

[0035] The synthetic method of rosuvastatin calcium intermediate in this embodiment, that is, the rosuvastatin calcium intermediate is [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N -methylsulfonyl amido)-5-pyrimidinyl] the synthetic method of triphenylphosphine bromide comprises the following steps:

[0036] (1) Under nitrogen protection, add 400mL tetrahydrofuran to a 1000mL dry four-necked reaction flask, add 40g anhydrous magnesium chloride and 40g potassium borohydride, heat and reflux for 1 hour; distill at atmospheric pressure, remove 300mL tetrahydrofuran, add 750mL toluene and 100g of compound 2 was refluxed for 6 hours; after the reaction was completed, cool to room temperature, filter, add dropwise 145mL of 1N hydrochloric acid to the filtrate to quench the reaction, stir and separate layers, dry the organic layer with anhydrous magnesium sulfate, filter, and transfer the obtained filtrate to 2000mL standby in the reaction flask;

[0037] (2) Add 27 mL of phosphorus...

Embodiment 3

[0040] The synthetic method of rosuvastatin calcium intermediate in this embodiment, that is, the rosuvastatin calcium intermediate is [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N -methylsulfonyl amido)-5-pyrimidinyl] the synthetic method of triphenylphosphine bromide comprises the following steps:

[0041] (1) Under nitrogen protection, add 400mL tetrahydrofuran to a 1000mL dry four-necked reaction flask, add 40g anhydrous magnesium chloride and 40g potassium borohydride, heat and reflux for 1 hour; distill at atmospheric pressure, remove 300mL tetrahydrofuran, add 750mL toluene and 100g of compound 2 was refluxed for 8 hours; after the reaction was completed, cool to room temperature, filter, add dropwise 145mL of 1N hydrochloric acid to the filtrate to quench the reaction, stir and separate layers, dry the organic layer with anhydrous magnesium sulfate, filter, and transfer the obtained filtrate to 2000mL standby in the reaction flask;

[0042](2) Add 27 mL of phosphorus ...

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Abstract

The invention relates to a synthesis method of a rosuvastatin calcium intermediate. The rosuvastatin calcium intermediate is [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonamide)-5-pyrimidyl] triphenylphosphonium bromide.[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonamide)-5-pyrimidyl] triphenylphosphonium bromide is successfully prepared by a one-pot method by using a mixed organic solvent of tetrahydrofuran and methylbenzene to unify a reaction medium for a three-step reaction. Any separation and purification operation is not required in a reaction process; the synthesis steps are simplified; a feed ratio in the reaction process is reduced; raw materials are saved; a better reaction yield and purity are achieved; the total yield reaches above 80%; the purity is above 99.6%; the operating cost is saved; the production cost is lowered.

Description

technical field [0001] The invention relates to a method for synthesizing a rosuvastatin calcium intermediate. Background technique [0002] Rosuvastatin calcium, chemical name: bis-[E-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5 -yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt is a statin drug approved by AstraZeneca in Europe in 2002, and it is a "super statin" evaluated by the media. ", belonging to HMG-CoA reductase inhibitors, for the treatment of primary, familial hypercholesterolemia and mixed dyslipidemia. Its structural formula is as follows: [0003] [0004] Compound [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonamido)-5-pyrimidinyl]triphenylphosphine bromide (CAS: 885477- 83-8) is a key intermediate for the synthesis of rosuvastatin calcium, and its structure is shown in formula 1. [0005] [0006] In the methods for preparing the above-mentioned intermediates disclosed in the prior art, each step ...

Claims

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Application Information

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IPC IPC(8): C07F9/6512
CPCC07F9/6512
Inventor 余奎黄想亮沈琦邢玉龙余盛刚陈为人姚成志
Owner ZHEJIANG MENOVO PHARMA
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