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Preparation method of rosuvastatin side chain intermediate

A technology for rosuvastatin and intermediates, which is applied in the field of preparation of rosuvastatin side chain intermediates, can solve problems such as unfavorable industrial production, affecting product quality, strong corrosion, etc., and achieves environmentally friendly and easy-to-scale up production Formation and mild reaction conditions

Active Publication Date: 2020-08-11
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] U.S. Patent US4970313A and Chinese Patent CN1876644A (Application No. CN200610052219.1) reported the Swern oxidation method, which uses oxalyl chloride as an activator, and oxalyl chloride is easily decomposed at room temperature to generate hydrogen chloride gas, which is highly corrosive to equipment
In addition, this reaction needs to be carried out at an ultra-low temperature of -78°C, which requires high energy consumption and produces a foul-smelling by-product of dimethyl sulfide, which pollutes the atmospheric environment.
[0007] Chinese patent CN102617540A (application number CN201210117031.6) reported the preparation of (4R-Cis)-6 aldehyde-2,2-dimethyl-1,3-dioxane- The method of 4-tert-butyl acetate, the cost of pyridine sulfur trioxide complex used in this method is relatively high, and has strong corrosiveness
The reaction is carried out in a two-phase system of organic solvent and water. If the system is highly alkaline, it will cause hydrolysis of tert-butyl ester and affect the yield.
Therefore, it is necessary to adjust the NaClO solution to a specific pH value in advance and slowly add it dropwise to the reaction system, which is cumbersome to operate and is not conducive to industrial production.
[0009] Most of the (4R-Cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester obtained by the above method is an oily substance with poor stability and is difficult to maintain for a long time deposit
And the above process is easy to produce over-oxidized carboxylic acid impurities (general formula as shown below), which are difficult to remove and affect product quality

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1: Preparation of (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester

[0048] (1) Dissolve 260.3g of Compound I, 1.6g of TEMPO, and 16.1g of tetrabutylammonium bromide in 2600mL of dichloromethane, add 2600mL of potassium carbonate / sodium bicarbonate buffer solution with a pH of 7.5, and add 186.9g of it at 10°C N-chlorosuccinimide (NCS), stirred for 5h. Stand still for liquid separation, extract the aqueous phase with 300 mL of dichloromethane, combine the organic phases, add 200 mL of saturated saline to the organic phase, stir and wash, and stand for liquid separation. The organic phase was dried over anhydrous sodium sulfate. Filtration and concentration gave 256.9 g of a light yellow oil, which was the crude product of (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester, HPLC Purity: 97.4%, carboxylic acid impurity: 0.76%.

[0049] (2) Add 540 mL of ethanol into the flask containing the crude compound II above...

Embodiment 2

[0050] Example 2: Preparation of (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester

[0051] (1) Dissolve 260.3g of compound I, 3.9g of 4-BzO-TEMPO, and 3.2g of tetrabutylammonium bromide in 1600mL of ethyl acetate, add 1600mL of sodium carbonate / potassium bicarbonate buffer solution with a pH of 8.0, at 15°C Add 160.2g of N-chlorosuccinimide (NCS), and stir the reaction for 5h. Stand still for liquid separation, extract the aqueous phase with 300 mL of dichloromethane, combine the organic phases, add 200 mL of saturated saline to the organic phase, stir and wash, and stand for liquid separation. The organic phase was dried over anhydrous sodium sulfate. Filtration and concentration gave 255.8 g of a light yellow oil, which was the crude product of (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester, HPLC Purity: 97.12%, carboxylic acid impurity: 0.87%.

[0052] (2) Add 270 mL of acetone into the flask containing the above-mentio...

Embodiment 3

[0053] Example 3: Preparation of (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester

[0054] (1) Dissolve 260.3g of compound I, 1.1g of 4-AcNH-TEMPO, and 18.2g of benzyltriethylammonium chloride in 3900mL of toluene, add 3900mL of sodium carbonate / sodium bicarbonate buffer solution with a pH of 8.5, at 20°C Add 213.6g of N-chlorosuccinimide (NCS), and stir the reaction for 5h. Stand still for liquid separation, extract the aqueous phase with 300 mL of dichloromethane, combine the organic phases, add 200 mL of saturated saline to the organic phase, stir and wash, and stand for liquid separation. The organic phase was dried over anhydrous sodium sulfate. Filtration and concentration gave 257.4 g of a light yellow oily substance, which was the crude product of (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester, HPLC Purity: 96.80%, carboxylic acid impurity: 0.93%.

[0055] (2) Add 540 mL of methanol into the flask containing the ab...

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Abstract

The invention belongs to the technical field of medicines, and particularly provides a preparation method of a rosuvastatin side chain intermediate. The method comprises the following steps: (1) dissolving a compound I, an oxidation catalyst and a phase transfer catalyst in an organic solvent A, respectively adding a buffer solution of alkali and an oxidant, and reacting to obtain a compound II; and (2) dissolving the compound II crude product in an organic solvent B, heating for dissolving, adding purified water, separating out a solid, filtering and drying to obtain a compound II refined product. The yield of the rosuvastatin side chain intermediate prepared by the technology is higher than 95%, the HPLC purity is higher than 99.70%, and the generated carboxylic acid impurity is lower than 0.2%. The method has the advantages of mild reaction conditions, no need of ultralow temperature, no water and other harsh reaction conditions, no foul gas generation in the reaction process, environmental protection, easy amplification generation, easy realization of the reaction temperature, and facilitation of industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a preparation method of a rosuvastatin side chain intermediate. Background technique [0002] Rosuvastatin (rosuvastatin) was developed by AstraZeneca. It was first approved for marketing in the Netherlands in November 2002. It was approved for marketing by the US FDA in August 2003. It was approved and launched in China in 2006. It has been marketed in many countries. is one of the most widely used statins. [0003] (4R-cis)-6-aldehyde-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate (compound II) is a synthetic rosuvastatin, pitavastatin and other statins The key intermediate of similar APIs, which can be obtained by oxidation of (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester (compound I) . The reaction equation is as follows: [0004] [0005] Currently, the preparation of (4R-cis)-6- Aldehyde-2,2-dimethyl-1,3-dioxane-4...

Claims

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Application Information

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IPC IPC(8): C07D319/06
CPCC07D319/06
Inventor 黄文波王学应
Owner LUNAN PHARMA GROUP CORPORATION