Synthetic method of empagliflozin intermediate

A technology of intermediates and mixed solvents, which is applied in the field of synthesis of empagliflozin intermediate-3-[4-[methyl]phenoxy]tetrahydrofuran, which can solve the problems of low yield, short synthetic route and unfavorable industrial production and other problems, to achieve the effect of high yield, short reaction steps and mild conditions

Inactive Publication Date: 2022-03-22
山东鲁宁药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] The synthetic route is shorter, but the yield is low, which is unfavorable for industrial production

Method used

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  • Synthetic method of empagliflozin intermediate
  • Synthetic method of empagliflozin intermediate
  • Synthetic method of empagliflozin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Step 1) Preparation of (S)-3-phenoxytetrahydrofuran

[0037] In THF (200 mL) were added phenol (4.70 g, 50 mmol), BINAP (32.4 g, 52 mmol) and (R)-3-hydroxytetrahydrofuran (4.58 g, 52 mmol), and MTAD (5.65 g, 50 mmol) was added dropwise. The solution was stirred overnight at room temperature (reaction completion monitored by HPLC). After the reaction, 6.90 g of (S)-3-phenoxytetrahydrofuran was obtained after filtration, concentration, extraction and purification, with a yield of 84.6% and a purity of 99.5%.

[0038] Step 2) Preparation of 2-3(5-iodo-2-chlorophenyl)[4-[[(3S)-tetrahydro-3-furyl]oxy]phenyl]methanone

[0039] In 150ml of tetrahydrofuran and dimethyl sulfoxide mixed solution (ratio 2:1), add 2-chloro-5-iodobenzoic acid (11.30g, 40mmol) and (S)-3-phenoxytetrahydrofuran (6.57 g, 40mmol), then TsCl (0.3g, 1.6mmol) was added, stirred at room temperature, slowly added dropwise 8ml EDTA, TLC showed that the reaction was completed after 1h, at room temperature the...

Embodiment 2

[0043] Step 1) Preparation of (S)-3-phenoxytetrahydrofuran

[0044]In THF (300 mL) were added phenol (7.05 g, 75 mmol), BINAP (46.73 g, 75 mmol) and (R)-3-hydroxytetrahydrofuran (6.61 g, 75 mmol), and MTAD (8.48 g, 75 mmol) was added dropwise. The solution was stirred overnight at room temperature (reaction completion monitored by HPLC). After the reaction was completed, 10.53 g of (S)-3-phenoxytetrahydrofuran was obtained after filtration, concentration, extraction and purification, with a yield of 84.6% and a purity of 99.5%.

[0045] Step 2) Preparation of 2-3(5-iodo-2-chlorophenyl)[4-[[(3S)-tetrahydro-3-furyl]oxy]phenyl]methanone

[0046] In 240ml of tetrahydrofuran and dimethyl sulfoxide mixed solution (ratio 2:1), add 2-chloro-5-iodobenzoic acid (16.95g, 60mmol) and (S)-3-phenoxytetrahydrofuran (9.86 g, 60mmol), then add TsCl (0.4g, 2.1mmol), stir at room temperature, slowly add dropwise 10ml EDTA, TLC shows that the reaction is completed after 1h, at room temperature ...

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Abstract

The invention discloses a synthesis method of an empagliflozin key intermediate. The preparation method comprises the following steps: generating (S)-3-phenoxy tetrahydrofuran from (S)-3-hydroxytetrahydrofuran and phenol under the action of BINAP and MTAD, then carrying out acylation reaction on the (S)-3-phenoxy tetrahydrofuran and 2-chloro-5-iodobenzoic acid to obtain 2-3 (5-iodo-2-chlorphenyl) [4-[[(3S)-tetrahydro-3-furyl] oxy] phenyl] ketone, and finally reducing to obtain the (S)-3-(4-(5-iodo-2-chlorobenzyl) phenoxy) tetrahydrofuran. Compared with the prior art, the method has the advantages of short reaction steps, mild conditions, simple post-treatment and high product yield.

Description

technical field [0001] The invention relates to a synthesis method of an empagliflozin intermediate (3S)-3-[4-[(5-iodo-2-chlorophenyl)methyl]phenoxy]tetrahydrofuran, belonging to the technical field of organic synthesis. Background technique [0002] Empagliflozin is a sodium-glucose co-transporter (SGLT2) inhibitor jointly developed by Boehringer Ingelheim and Eli Lilly. It was first approved by the European Medicines Agency in May 2014 and launched in August 2014 It was approved for marketing by the FDA in the United States, and was approved for marketing by the Japan Pharmaceuticals and Medical Devices Administration in December 2014. It was approved for marketing in China in September 2017 and can be used for the treatment of type 2 diabetes. As a highly selective SGLT2 inhibitor, Empagliflozin has a unique insulin-independent hypoglycemic pathway, that is, it directly excretes glucose from the urine by reducing the reabsorption of glucose in the kidney, besides having a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/20
CPCC07D307/20
Inventor 孙钊孙宁闫志刚金浩马传振徐增强
Owner 山东鲁宁药业有限公司
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