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Improvement method of preparation technology of tert-butyl (E)-7-[3'-(4''-fluorophenyl)-1'-methylethyl-indol-2'-yl)-3-oxo-5-hydroxy-6-heptenoate

A preparation process, fluorophenyl technology, which is applied in the preparation of the cholesterol-lowering drug fluvastatin and the preparation of fluvastatin intermediate fluvasolone, which can solve the problems of high production cost, difficult recovery of solvent tetrahydrofuran, cumbersome operation, etc. , to achieve the effects of reducing production costs, improving recovery rates, and simplifying operating methods

Inactive Publication Date: 2014-12-31
SHANGHAI PUYI CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Traditional method is to be solvent with tetrahydrofuran, because this reaction must carry out strict control to moisture, just very difficult to the recovery of solvent THF; In this way, the operation is cumbersome and the production cost is relatively high.

Method used

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  • Improvement method of preparation technology of tert-butyl (E)-7-[3'-(4''-fluorophenyl)-1'-methylethyl-indol-2'-yl)-3-oxo-5-hydroxy-6-heptenoate
  • Improvement method of preparation technology of tert-butyl (E)-7-[3'-(4''-fluorophenyl)-1'-methylethyl-indol-2'-yl)-3-oxo-5-hydroxy-6-heptenoate
  • Improvement method of preparation technology of tert-butyl (E)-7-[3'-(4''-fluorophenyl)-1'-methylethyl-indol-2'-yl)-3-oxo-5-hydroxy-6-heptenoate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Add 450L of anhydrous 2-methyltetrahydrofuran into a dry nitrogen reactor, cool to 0°C, add 13.1 kg of 60% sodium hydride, and dropwise add 45.4 kg of tert-butyl acetoacetate, stir at 0°C for 30 minutes; then add dropwise 180 L of n-hexane solution of 1.6 mol / L n-butyllithium, continue stirring for 1 h; 84 kg (E)-3-[3'-(4''-fluorophenyl)-1'-isopropyl Indol-2'-yl]-2-propenal (II) in 100L of 2-methyltetrahydrofuran was slowly dropped into the reaction system, and the reaction was completed at -10°C for 2 hours.

[0027] The reaction solution was pumped into 250L hydrochloric acid of 1 mol / L, separated into layers, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was evaporated to dryness under reduced pressure, and about 80% of 2-methyltetrahydrofuran was recovered to obtain The orange oil was dissolved in an appropriate amount of absolute ethanol, cooled and crystallized under stirring, and dried to...

Embodiment 2

[0032] Add 450L of anhydrous tetrahydrofuran into a reaction kettle with dry nitrogen, cool to 0°C, add 13.1 kg of 60% sodium hydride, and dropwise add 45.4 kg of tert-butyl acetoacetate, stir at -78°C for 30 minutes; then add dropwise 1.6 mol / L of n-butyl lithium in n-hexane solution 180 L, continue stirring for 1 h; 84 kg (E)-3-[3'-(4''-fluorophenyl)-1'-isopropylindole-2 The 100L tetrahydrofuran solution of '-yl]-2-propenal (II) was slowly dripped into the reaction system, and the reaction was completed at -10°C for 2 hours.

[0033] The reaction solution was pumped into 250L of 1 mol / L hydrochloric acid, most of the tetrahydrofuran was evaporated under reduced pressure, and about 50% was recovered, and the remaining reaction solution was extracted with 300L ethyl acetate, and the ethyl acetate layer was separated and washed with saturated chlorine Wash with sodium chloride solution, dry over anhydrous magnesium sulfate, evaporate the solvent to dryness under reduced pressu...

Embodiment 3

[0037] Add 105 L of anhydrous 2-methyltetrahydrofuran into a reaction kettle with dry nitrogen, cool to 0°C, add 3.4 kg of 60% sodium hydride, and dropwise add 11.4 kg of tert-butyl acetoacetate, and stir at -15°C for 30 minutes; Add 45 L of n-butyllithium n-hexane solution of 1.6 mol / L, and continue stirring for 1 h; A solution of indol-2'-yl]-2-propenal (II) in 25 L of 2-methyltetrahydrofuran was slowly dropped into the reaction system, and the reaction was completed at -10°C for 2 hours.

[0038] The reaction solution was pumped into 60L hydrochloric acid of 1 mol / L, separated into layers, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was evaporated to dryness under reduced pressure, and about 80% of 2-methyltetrahydrofuran was recovered to obtain The orange oil was dissolved in an appropriate amount of absolute ethanol, cooled and crystallized under stirring, and dried to obtain 26.4 kg of a browni...

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Abstract

The invention relates to a fluvastatin intermediate tert-butyl (E)-7-[3'-(4''-fluorophenyl)-1'-methylethyl-indol-2'-yl)-3-oxo-5-hydroxy-6-heptenoate, and relates to improvement of a preparation technology of tert-butyl (E)-7-[3'-(4''-fluorophenyl)-1'-methylethyl-indol-2'-yl)-3-oxo-5-hydroxy-6-heptenoate (I). 2-methyl tetrahydrofuran as a solvent is adopted to replace tetrahydrofuran in the original process, so that not only is the reaction yield increased, but also the solvent recovery rate is greatly improved, and the production cost is reduced. The method is used for producing fluvastatin ketone, the reaction yield is increased by about 15%, the solvent recovery rate is increased from 50% to 80%, and the overall production cost is reduced by more than 30%.

Description

[0001] technical field [0002] The invention relates to the field of preparation of the cholesterol-lowering drug fluvastatin, in particular to the field of preparation of the fluvastatin intermediate fluvasolone. Background technique [0003] Fluvastatin Sodium (Fluvastatin Sodium) (as shown in formula (0)) is the first fully synthetic HMG CoA reductase inhibitor hypolipidemic drug developed by Swiss Novartis Pharmaceuticals. It is marketed as a pair of enantiomers with two hydroxyl groups in the same direction, of which (3R,5S)-type has pharmacological activity, while (3S,5R)-type has no pharmacological activity. In 1994, the FDA approved its capsules for marketing, and in 2001, it approved its sustained-release tablets for marketing, which is used to treat primary hypercholesterolemia and primary mixed dyslipidemia that are ineffective in dietary regulation. Among them, fluvasolone (E)-7-[3'-(4''-fluorophenyl)-1'-isopropylindol-2'-yl]-3-oxo-5-hydroxy- tert-butyl 6-hept...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/24
CPCC07D209/24
Inventor 王博
Owner SHANGHAI PUYI CHEM CO LTD
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