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Preparation method suitable for industrial production of empagliflozin

A technology of empagliflozin and compounds, applied in the design of organic synthesis routes and in the fields of medicine and chemical industry, to achieve the effects of reducing production costs, simplifying process steps, and simple preparation methods

Inactive Publication Date: 2019-07-09
XUZHOU WANBANG JINQIAO PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This medicine is not for use in people with type 1 diabetes or in people with diabetic ketoacidosis (elevated ketone bodies in the blood or urine)

Method used

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  • Preparation method suitable for industrial production of empagliflozin
  • Preparation method suitable for industrial production of empagliflozin
  • Preparation method suitable for industrial production of empagliflozin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Compound V 2 Preparation of:

[0042]

[0043] Under nitrogen protection, compound V 0 (10kg, 56mol) and 50L of pyridine were added into 80L of dichloromethane, cooled to -20°C, and stirred for 10 minutes to dissolve. Slowly add trimethylchlorosilane (50 L, 168 mol) dropwise, keep the internal temperature not exceeding 10°C, return to room temperature and stir for 7 hours. Add 5L of ice water to quench the reaction, evaporate the solvent at 30°C under vacuum, add 50L of methyl tert-butyl ether and 45L of water, extract and separate layers, wash the organic layer twice with 1M sodium dihydrogen phosphate aqueous solution, and then wash with anhydrous sulfuric acid Magnesium was dried for 2 hours, filtered, and the filtrate was concentrated and dried in vacuo to obtain 24kg colorless and transparent oily compound V 2 , the yield is about 92%.

Embodiment 2

[0045] Compound V 2 Preparation of:

[0046] Under nitrogen protection, compound V 0(10kg, 56mol) and DIPEA (50L) were added into 80L of dichloromethane, cooled to -20°C, and stirred for 10 minutes to dissolve. Slowly add trimethylchlorosilane (50 L, 168 mol) dropwise, keep the internal temperature not exceeding 10°C, return to room temperature and stir for 7 hours. Add 5L of ice water to quench the reaction, evaporate the solvent at 30°C under vacuum, add 50L of methyl tert-butyl ether and 45L of water, extract and separate layers, wash the organic layer twice with 1M sodium dihydrogen phosphate aqueous solution, and then wash with anhydrous sulfuric acid Magnesium was dried for 2 hours, filtered, and the filtrate was concentrated and dried in vacuo to obtain 18kg colorless and transparent oily compound V 2 , the yield is about 70%.

Embodiment 3

[0048] Compound V 2 Preparation of:

[0049] Under nitrogen protection, compound V 0 (10kg, 56mol) and pyridine (50L) were added into 80L of acetonitrile, cooled to -20°C, and stirred for 10 minutes to dissolve. Slowly add trimethylchlorosilane (50 L, 168 mol) dropwise, keep the internal temperature not exceeding 10°C, return to room temperature and stir for 7 hours. Add 5L of ice water to quench the reaction, evaporate the solvent at 30°C under vacuum, add 50L of methyl tert-butyl ether and 45L of water, extract and separate layers, wash the organic layer twice with 1M sodium dihydrogen phosphate aqueous solution, and then wash with anhydrous sulfuric acid Magnesium was dried for 2 hours, filtered, and the filtrate was concentrated and dried in vacuo to obtain 20kg of colorless and transparent oily compound V 2 , the yield is about 87%.

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Abstract

The invention belongs to the technical field of organic synthesis route design and medicine and chemical engineering, particularly relates to a synthesis method of a sodium-glucose cotransporter 2(SGLT2) inhibitor, and more particularly relates to a preparation method of empagliflozin. The empagliflozin is synthesized by taking (3S)-3-[4-[(2-chloro-5-iodophenyl) methyl] phenoxy] tetrahydrofuran and glucono delta-lactone as initial raw materials through a series of substep reactions such as protection, addition, substitution, deprotection and reduction. In the synthesis steps disclosed by the invention, a staged target product does not need to be separated and purified after each step of reaction, and the target product is finally obtained by directly subjecting a high-purity reaction intermediate to subsequent steps. The preparation method is simple in process, simple and convenient to operate and good in industrial prospect.

Description

technical field [0001] The invention relates to the design of organic synthesis routes and the technical fields of medicine and chemical industry, in particular to a method for synthesizing a sodium-glucose co-transporter 2 (SGLT2) inhibitor, more specifically an industrialized preparation method for empagliflozin. Background technique [0002] Empagliflozin (also known as empagliflozin) was jointly developed by Boehringer Ingelheim and Eli Lilly and Company. The drug is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that blocks the reabsorption of glucose by the kidneys, increases glucose excretion, and lowers blood sugar levels. A combination of diet and exercise in the treatment of adults with type 2 diabetes to improve glycemic control. This medicine is not for use in people with type 1 diabetes or in people with diabetic ketoacidosis (elevated ketone bodies in the blood or urine). [0003] Empagliflozin belongs to the glucopyranosyl-substituted phenyl derivative c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D407/12
CPCC07D407/12
Inventor 袁威乔德水董长青高雪芹
Owner XUZHOU WANBANG JINQIAO PHARMA
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