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Preparation method of chiral side chain intermediate of rosuvastatin

A technology of rosuvastatin and chiral side chains, which is applied in organic chemistry, fermentation, bulk chemical production, etc., can solve the problems of multi-manual intervention control reaction, large amount of three wastes treatment, harsh conditions, etc., to achieve process stability, The effect of low energy and material consumption and mild reaction conditions

Pending Publication Date: 2022-08-09
HUBEI XUNDA PHARMA +1
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Problems solved by technology

[0003] At present, the industrial synthesis of rosuvastatin chiral side chain intermediates mainly relies on the traditional total chemical synthesis process using expensive borane reagents and catalysts. The conditions are harsh, the total yield is low, the steps are cumbersome, and more manual intervention is required to control the reaction. , a large amount of waste treatment

Method used

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  • Preparation method of chiral side chain intermediate of rosuvastatin
  • Preparation method of chiral side chain intermediate of rosuvastatin
  • Preparation method of chiral side chain intermediate of rosuvastatin

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Experimental program
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Effect test

Embodiment 1

[0033](1) 5.6L of tetrahydrofuran solution of S-4-chloro-3-trimethylsilyl butyronitrile 2.56kg (13.4mol), nano zinc 1.56kg (24.1mol) is pumped into the first mixer ①, the flow rate of pump A For 2.56mL / min, the tetrahydrofuran solution 2.8L of methanesulfonic acid 23g (0.24mol) was pumped into the first mixer ①, the flow rate of pump B was 1.28mL / min, tert-butyl bromoacetate 3.41kg (17.5mol) Pump into the first mixer ①, the flow rate of pump C is 1.18mL / min. After fully mixing, the reaction was carried out in the first microchannel reactor. The volume of the first microchannel reactor I was 45.5 mL, the reaction residence time was 9 min, and the reaction temperature was 80°C. The reaction effluent was filtered, 10% hydrochloric acid was added to the filtrate, pH was adjusted to 3±0.5, the layers were separated, the aqueous layer was extracted with 2.0 L of ethyl acetate, the organic layers were combined, and the pH was adjusted to neutrality with 10% sodium bicarbonate solutio...

Embodiment 2

[0044] The operation is the same as that of Example 1, the only difference is:

[0045] In step (1), the concentration of the tetrahydrofuran solution of S-4-chloro-3-trimethylsilyl butyronitrile is 3mol / L, the concentration of the tetrahydrofuran solution of nano-zinc is 5.3mol / L, and the concentration of the methanesulfonic acid tetrahydrofuran solution is 0.08mol / L, the molar ratio of S-4-chloro-3-trimethylsilylbutyronitrile to nano-zinc, methanesulfonic acid and tert-butyl bromoacetate is 1:1.5:0.008:1. The flow rates of pump A, pump B, and pump C were 1.0 mL / min, respectively, the flow rate of pump B was 0.5 mL / min, and the flow rate of pump C was 0.5 mL / min. The volume of the first microchannel reactor I was 36.4 mL, the reaction residence time was 20 min, the reaction temperature was 70°C, and the yield was 92%.

[0046] In step (2), the concentration of phosphate buffer is 0.05mol / L, the concentration of sodium hydroxide solution is 6.0mol / L; S-6-chloro-5-hydroxy-3-ox...

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Abstract

The invention provides a preparation method of a rosuvastatin chiral side chain intermediate, which organically combines enzyme engineering, a biological catalysis technology and a microchannel reactor production technology, the name of the chiral side chain intermediate is (4R, cis)-6-chloromethyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate, and the chiral side chain intermediate has a structural formula shown in the description. The invention provides a green and efficient rosuvastatin chiral side chain intermediate production mode, the use of expensive borane reagents and catalysts is avoided, the transfer of materials in different reaction kettles is reduced, and the labor cost is reduced; the industrialization level and the product quality of rosuvastatin are improved, the problems of low yield, complicated procedures, three-waste emission and the like which restrict the industry are solved, and the method has relatively high market competitiveness.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical and chemical production, in particular to a production of rosuvastatin chiral side chain intermediate (4R,cis)-6-chloromethyl-2,2- Method for tert-butyl dimethyl-1,3-dioxane-4-acetate. Background technique [0002] Rosuvastatin is a selective HMG-CoA reductase inhibitor for the treatment of hyperlipidemia and hypercholesterolemia. Compared with other statins, it has high lipid-lowering effect and safety, and the market demand for it continues Increase, but its production cost is on the high side, and the high price limits its promotion. Rosuvastatin is prepared from a main ring and a chiral side chain. The main ring synthesis process is mature. Relevant researchers focus more on the synthesis of the chiral side chain. Research has achieved certain results, but there are still many deficiencies. [0003] At present, the industrial synthesis of rosuvastatin chiral side chain intermediates ...

Claims

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Application Information

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IPC IPC(8): C07D319/06C12P7/62
CPCC07D319/06C12P7/62C07B2200/07Y02P20/55
Inventor 李亮卢翠芬杨桂春
Owner HUBEI XUNDA PHARMA
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