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Method for synthesizing intermediate through statins

A technology for drug synthesis and intermediates, which is applied in the field of preparation of statin drug synthesis intermediates, can solve the problems of high cost, complex process equipment, and many by-products, and achieves production cost reduction, easy purification steps, and few by-products Effect

Active Publication Date: 2014-11-19
NANJING OCEAN PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0020] Aiming at the defects such as high cost, complicated process equipment and many by-products existing in the existing synthesis process, the present invention provides a new preparation method for statin drug synthesis intermediate, comprising the following steps:

Method used

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  • Method for synthesizing intermediate through statins
  • Method for synthesizing intermediate through statins
  • Method for synthesizing intermediate through statins

Examples

Experimental program
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Effect test

Embodiment 1

[0053] Put 8.4 g, that is, 55.2 mmol of R-mandelic acid (compound IV) into a glass reaction bottle with a capacity of 250 mL, add 40 mL of ethyl acetate (the first solvent) and stir to dissolve, then put 100 mL of toluene (the second solvent) and 10 g of 3-tert-butyldimethylsiloxoglutaric anhydride (compound III) 40.9 mmol. The mixture was stirred and heated, and refluxed for 48 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain an oily concentrated product. Add 40 mL of toluene solution to the oily concentrated product, heat to dissolve fully, then cool down to -20°C, crystallize unreacted R-mandelic acid, filter with suction, and discard the solid. Concentrate the filtrate under reduced pressure in vacuo until there is no solution, then add 30 mL of toluene, heat until fully dissolved, cool down to -20°C and keep crystallization for 48 hours, filter and dry to obtain 3.4 g of white solid, namely (3R)-3-tert Butyldimethylsiloxy...

Embodiment 2

[0055] In a glass reaction bottle with a capacity of 500 mL, 12.4 g, namely 80.8 mmol of S-mandelic acid (compound VII), and 20 g of 80.8 mmol of 3-tert-butyldimethylsiloxoglutaric anhydride (compound III ), and a total of 250 mL of tetrahydrofuran was added. The mixture was stirred and heated, and refluxed for 20 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain an oily concentrated product. Add 50 mL of toluene solution to the oily concentrated product, heat to dissolve fully, then cool down to 15°C, keep it for 12 hours, then place it in a freezer at -20°C for 48 hours, filter and dry to obtain 27.0g of white solid , namely (3R)-3-tert-butyldimethylsiloxyglutaric acid-1-(S)-mandelate and (3S)-3-tert-butyldimethylsilyloxyglutaric acid- A mixture of 1-(S)-mandelic acid esters. By HPLC, refer to standard compounds, respectively calibrate (3R)-3-tert-butyldimethylsilyloxyglutarate-1-(S)-mandelate and (3S)-3-tert-butyldimethyl ...

Embodiment 3

[0057] Into a glass reaction bottle with a capacity of 250 mL, 6.22 g, namely 40.9 mmol of R-mandelic acid (compound IV), and 10 g of 40.9 mmol of 3-tert-butyldimethylsiloxoglutaric anhydride (compound III ), a total of 150 mL of tetrahydrofuran was added. The mixture was stirred and heated, and refluxed for 20 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain an oily concentrated product. Add 25mL of toluene solution to the oily concentrated product, heat, dissolve fully, cool down to 15°C, keep for 12 hours, then freeze at 0°C for 48 hours, filter and dry to obtain 9.5g of white solid, namely ( 3R)-3-tert-butyldimethylsiloxyglutaric acid-1-(R)-mandelate and (3S)-3-tert-butyldimethylsilyloxyglutaric acid-1-( R) - a mixture of mandelic acid esters. By HPLC, with reference to standard compounds, respectively calibrate (3R)-3-tert-butyldimethylsilyloxyglutarate-1-(R)-mandelate and (3S)-3-tert-butyldimethyl Siloxyglutaric acid-1...

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Abstract

The invention relates to the field of organic chemistry, and particularly relates to the organic pharmaceutical field. More specifically, the invention relates to a method for synthesizing an intermediate through statins, aiming at overcoming the defects of high cost, complex process equipment, many by-products and the like in the prior art. According to the new method, 3-tertiary butyl dimethyl silica glutaric acid-1-mandelic acid ester is prepared by a one-step method, and cooperated with recrystallization, the intermediate synthesized by the statins is simply obtained at low cost, so that the method is suitable for industrialized production.

Description

technical field [0001] The present invention relates to the field of organic chemistry, in particular to the field of organic pharmacy, and more specifically relates to a preparation method of a statin drug synthesis intermediate. Background technique [0002] Cardiovascular disease is a type of disease that seriously endangers human health. In recent years, the morbidity and mortality of such diseases have shown a clear upward trend worldwide. Statins can significantly slow down the disease progression in patients with low risk of subclinical atherosclerosis, and thus are effective for the primary and secondary prevention of cardiovascular and cerebrovascular events. [0003] The Chinese chemical name of compound (I) is: (3R)-3-tert-butyldimethylsiloxy glutaric acid-1-(R)-(-)-mandelate, molecular formula: C19H28IO7Si; CA registration number : 131466-61-0, the chemical structure is shown in formula (I): [0004] [0005] As an intermediate in the synthesis of statins, t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F7/18
Inventor 陈本顺周长岳陈凯戚陈陈
Owner NANJING OCEAN PHARMA TECH
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