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Method for synthesizing rosuvastatin calcium intermediate by using continuous flow microchannel reactor

A technology of rosuvastatin calcium and channel reactor is applied in the field of synthesis of rosuvastatin calcium intermediates, which can solve the problems of low product yield and complicated post-processing process, and achieve simple post-processing and short reaction time. , Environmentally friendly effect

Pending Publication Date: 2022-05-06
JIANGSU ALPHA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The preparation methods disclosed in the above-mentioned patents are all carried out in existing kettle-type reaction bottles. Most of the feeding methods are multiple step-by-step feeding, and the reaction time is as long as several hours. Isomer impurities are easily produced during the reaction process, resulting in The treatment process is more complicated and the product yield is not high

Method used

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  • Method for synthesizing rosuvastatin calcium intermediate by using continuous flow microchannel reactor
  • Method for synthesizing rosuvastatin calcium intermediate by using continuous flow microchannel reactor
  • Method for synthesizing rosuvastatin calcium intermediate by using continuous flow microchannel reactor

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Effect test

Embodiment 1

[0035]

[0036] combine Figure 1-2 Shown, a kind of method utilizing continuous flow microchannel reactor to synthesize rosuvastatin calcium intermediate comprises the following steps:

[0037] (1) Preparation of material A: Compound II (952g, 5.7mol) is added to tetrahydrofuran, diluted to 1.5L, stirred and dissolved, and placed in raw material tank A (the bottom of the raw material tank is fed through a valve corresponding to the microchannel reactor. Pipeline connection), nitrogen protection stand-by.

[0038] (2) Preparation of material B: Lithium diisopropylamide (2.14Kg, 20mol) is added to tetrahydrofuran, diluted to 10.28L, stirred and dissolved, and placed in raw material tank B (the bottom of the raw material tank passes through the valve and the microchannel reactor Corresponding feed pipelines are connected), nitrogen protection stand-by.

[0039] (3) Preparation of material C: tert-butyl acetate (2.58Kg, 22.2mol) was added to tetrahydrofuran, diluted to 11.67...

Embodiment 2

[0043] combine Figure 1-2 Shown, a kind of method utilizing continuous flow microchannel reactor to synthesize rosuvastatin calcium intermediate comprises the following steps:

[0044](1) Preparation of material A: Compound II (952g, 5.7mol) is added in ether, diluted to 1.5L, stirred and dissolved, and placed in raw material tank A (the bottom of the raw material tank is fed through a valve corresponding to the microchannel reactor. Pipeline connection), nitrogen protection stand-by.

[0045] (2) Preparation of material B: Lithium diisopropylamide (1.83Kg, 17.1mol) was added to diethyl ether, diluted to 7.2L, stirred and dissolved, and placed in raw material tank B (the bottom of the raw material tank reacted with the microchannel through a valve) connected to the corresponding feed pipeline of the device), nitrogen protection is for standby.

[0046] (3) Preparation of material C: tert-butyl acetate (2.97Kg, 25.6mol) is added in ether, diluted to 7.5L, stirred and dissolv...

Embodiment 3

[0050] combine Figure 1-2 Shown, a kind of method utilizing continuous flow microchannel reactor to synthesize rosuvastatin calcium intermediate comprises the following steps:

[0051] (1) Preparation of material A: Compound II (952g, 5.7mol) is added to toluene, diluted to 1.5L, stirred and dissolved, and placed in raw material tank A (the bottom of the raw material tank is fed through a valve corresponding to the microchannel reactor. Pipeline connection), nitrogen protection stand-by.

[0052] (2) Preparation of material B: Lithium diisopropylamide (2.44Kg, 22.8mol) is added to toluene, diluted to 12L, stirred and dissolved, and placed in raw material tank B (the bottom of the raw material tank passes through the valve and the microchannel reactor Corresponding feed pipelines are connected), nitrogen protection stand-by.

[0053] (3) Preparation of material C: tert-butyl acetate (2.33Kg, 20mol) is added in toluene, diluted to 15L, stirred and dissolved, and placed in raw...

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Abstract

The invention relates to the technical field of drug intermediate synthesis, in particular to a method for synthesizing a rosuvastatin calcium intermediate by using a continuous flow microchannel reactor, which comprises the following steps: 1) mixing a compound II with a solvent, stirring and dissolving to obtain a material A; 2) mixing lithium diisopropylamide with a solvent, stirring and dissolving to obtain a material B; 3) mixing tert-butyl acetate with a solvent, and stirring for dissolving to obtain a material C; 4) respectively pumping the material B and the material C into a micro-channel reactor, uniformly mixing, and then pumping the material A for chemical reaction; and after the reaction is finished, quenching with hydrochloric acid, adjusting the pH value to 3-4, and carrying out liquid separation, extraction, washing and drying to obtain a target product. By adopting the method, the reaction time is extremely short, the reaction condition is mild, the target product yield is high, the yield reaches 90% or above, the purity reaches 99% or above, the cost is low, resources are saved, the product aftertreatment is simple, and the method is environmentally friendly.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a method for synthesizing rosuvastatin calcium intermediates. Background technique [0002] Rosuvastatin calcium, the chemical name is 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 (2:1), CAS No. 147098-20-2, is a selective HMG-CoA reductase inhibitor Drug, developed by AstraZeneca, has been listed in the United States, Japan, Europe, China and other countries and regions. Its structural formula is as follows: [0003] [0004] Rosuvastatin calcium can be used to treat hyperlipidemia. In the production process, it is often prepared with (S)-6-chloro-5-hydroxy-3-carbonylhexanoic acid tert-butyl ester, etc. as intermediates. [0005] At present, the following process route is commonly used in the method for preparing (S)-6-chloro-5-hydroxy-3-carb...

Claims

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Application Information

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IPC IPC(8): C07C67/343C07C67/58C07C69/716B01J19/00
CPCC07C67/343C07C67/58B01J19/0093C07C69/716
Inventor 陈本顺石利平江涛李大伟尹强张凌怡魏巍朱萍
Owner JIANGSU ALPHA PHARM CO LTD
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