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Preparing methods of ipragliflozin intermediates

A technology of methyl group and thiophene, which is applied in the field of preparation of pharmaceutical intermediates, can solve problems such as affecting the field of medicine, being unsuitable for the field of medicine, affecting the quality of raw materials of final products, etc.

Inactive Publication Date: 2018-01-05
SHANDONG CHENGCHUANG PHARMA R&D
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] (1) During the preparation of compound 3, a large amount of F ortho-substituted by-products will be produced;
[0007] (2) When compound 5 was prepared, pyridine was used, which was highly toxic;
[0008] (3) Trifluoromethanesulfonic acid was used in the preparation of compound 6 by demethoxylation, which may produce genotoxic substances and is not suitable for the field of medicine
[0009] And the purity of compound 6 will directly affect the obtained (1S)-1,5-anhydro-1-C-[3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl ]-D-glucitol purity, which in turn affects the quality of the final product API

Method used

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  • Preparing methods of ipragliflozin intermediates
  • Preparing methods of ipragliflozin intermediates
  • Preparing methods of ipragliflozin intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] (1S)-2,3,4,6-tetraacetoxy-1,5-anhydro-1-[3-(1-benzothiophen-2-ylmethyl)-4-fluorophenyl]-D -The preparation method of sorbitol, comprising steps:

[0051](1) Add 22 mL of tetrahydrofuran and 220 mL of toluene to the reaction flask, and add 22.0 g of 2-(5-bromo-2-fluorobenzyl)benzothiophene (compound 1) under stirring. Cool the reaction solution to -70°C, add 31.5mL of n-butyl lithium in n-hexane solution (2.5mol / L) dropwise under the protection of nitrogen, control the temperature of the reaction solution not higher than -60°C, and the dropping rate is 3 drops / second, After about 5 minutes of dripping, keep at -70°C for 1 hour.

[0052] Dissolve 36.8 g of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone (compound 2) in 20 mL of toluene, and add it dropwise to the above system, controlling the temperature of the reaction solution not to exceed -60°C, after about 10 minutes, the dripping was completed, and the reaction was continued at -70°C for 6 hours to obtain compound...

Embodiment 2

[0062] (1S)-2,3,4,6-tetraacetoxy-1,5-anhydro-1-[3-(1-benzothiophen-2-ylmethyl)-4-fluorophenyl]-D -The preparation method of sorbitol, comprising steps:

[0063] (1) Add 22 mL of tetrahydrofuran and 220 mL of toluene to the reaction flask, and add 22.0 g of 2-(5-bromo-2-fluorobenzyl)benzothiophene (compound 1) under stirring. Cool the reaction solution to -60°C, add 31.5mL of n-butyl lithium in n-hexane solution (2.5mol / L) dropwise under the protection of nitrogen, control the temperature of the reaction solution not higher than -60°C, and the dropping rate is 3 drops / second, After about 5 minutes of dripping, keep at -60°C for 1 hour.

[0064] Dissolve 36.8 g of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone (compound 2) in 20 mL of toluene, and add it dropwise to the above system, controlling the temperature of the reaction solution not to exceed -60°C, the dripping was completed in about 10 minutes, and the reaction was continued at -60°C for 5 hours to obtain compound 3....

Embodiment 3

[0074] (1S)-2,3,4,6-tetraacetoxy-1,5-anhydro-1-[3-(1-benzothiophen-2-ylmethyl)-4-fluorophenyl]-D -The preparation method of sorbitol, comprising steps:

[0075] (1) Add 2.2 L of tetrahydrofuran and 22 L of toluene to the reaction flask, and add 2,200 g of 2-(5-bromo-2-fluorobenzyl)benzothiophene (compound 1) under stirring. Cool the reaction solution to -70°C, add 3150mL of n-butyllithium n-hexane solution (2.5mol / L) dropwise under the protection of nitrogen, control the temperature of the reaction solution not higher than -60°C, the rate of addition is 3 drops / second, about After 1 hour of dripping, keep warm at -60°C for 1 hour.

[0076] Dissolve 3680g of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone (compound 2) in 2L of toluene and add it dropwise to the above system, controlling the temperature of the reaction solution not to exceed - 60°C, about 1 hour to complete the dripping, keep warm at -70°C and continue to react for 6 hours to obtain compound 3.

[0077] (2) A...

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Abstract

The invention discloses preparing methods of ipragliflozin intermediates. The methods includes preparing methods for 2-(3-benzo[B]thien-2-ylmethyl-4-fluorophenyl)-3,4,5-tris(trimethylsiloxy)-6-trimethylsiloxymethyl-tetrahydro-pyran-2-ol (a compound 3) and (1S)-2,3,4,6-tetraacetoxy-1,5-anhydro-1-[3-(1-benzothiophen-2-yl-methyl)-4-fluorophenyl]-D-glucitol (a compound 6). Under the premise of controlling the temperature of a reaction solution to be not higher than -60 DEG C, n-butyllithium should be added dropwise as soon as possible, and the higher the adding speed of the n-butyllithium is, theless F-ortho-position substituted side products of the compound 3 are, thus ensuring purity of the compound 3 and directly influencing the yield of the compound 6 finally prepared. Through scale-up, the methods are free of scale-up effects, and are suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate. It belongs to the field of medical technology. Background technique [0002] (1S)-2,3,4,6-tetraacetoxy-1,5-anhydro-1-[3-(1-benzothiophen-2-ylmethyl)-4-fluorophenyl]-D -Sorbitol is a key intermediate in the synthesis of Ipagliflozin L-Proline, which is an important representative drug of SGLT2 inhibitors and is mainly used for the treatment of type 2 diabetes. [0003] Patent application EP 2105442A1 discloses (1S)-2,3,4,6-tetraacetoxy-1,5-anhydro-1-[3-(1-benzothiophen-2-ylmethyl)-4- A kind of preparation method of fluorophenyl]-D-sorbitol, concrete steps are as follows: [0004] [0005] There are following problems in above-mentioned preparation method: [0006] (1) During the preparation of compound 3, a large amount of F ortho-substituted by-products will be produced; [0007] (2) When compound 5 was prepared, pyridine was used, which was highly toxic; [0008] ...

Claims

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Application Information

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IPC IPC(8): C07F7/18
Inventor 高长彬吕志涛姚松芝马亮
Owner SHANDONG CHENGCHUANG PHARMA R&D
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