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Method for synthesizing forxiga intermediate

A synthesis method and intermediate technology, which are applied in the field of dapagliflozin synthesis, can solve the problems of high impurity content, low total yield and low product purity, and achieve the effects of reducing impurity content and improving purity and yield.

Active Publication Date: 2014-10-08
安徽联创生物医药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] In order to overcome the technical problems of low product purity, high impurity content, and low total yield in the prior art, the inventors have completed the present invention after conducting a large number of in-depth studies.

Method used

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  • Method for synthesizing forxiga intermediate
  • Method for synthesizing forxiga intermediate
  • Method for synthesizing forxiga intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] This embodiment relates to compound (5), namely 5-bromo-2-chloro-4 ′ -A kind of synthetic method of ethoxy diphenylmethane, comprises the steps:

[0031] Step 1, add 5-bromo-2-chlorobenzoic acid (23.5 g, 0.1 mol) and 120 mL of dry dichloromethane in sequence in the flask, stir at room temperature, add 12.8 mL of oxalyl chloride (0.15 mol) in 3 times within 8 hours ), continue to stir at room temperature for 2 hours until the reaction solution is clarified and there is no more gas to be released, then evaporate the solvent and excess oxalyl chloride under reduced pressure to obtain the concentrated solution of 5-bromo-2-chlorobenzoyl chloride, that is, the compound ( 2), MS-EI(m / z): 253[M + ];

[0032] Step 2, dissolve 26 g of the above red transparent liquid (containing about 0.1 mol of 5-bromo-2-chlorobenzoyl chloride) in 40 mL of dry dichloromethane, cool to -7 °C, add phenetole (15.8 mL, 0.125 mol), and then added anhydrous aluminum trichloride (14.7 g, 0.11 mol) ...

Embodiment 2

[0035] This example relates to a compound (5) that is 5-bromo-2-chloro-4 ′ -A kind of synthetic method of ethoxy diphenylmethane, comprises the steps:

[0036] Step 1: Add 5-bromo-2-chlorobenzoic acid (23.5 g, 0.1 mol) and 120 mL of dry dichloromethane in sequence in the flask, stir at room temperature, add 8.5 mL of oxalyl chloride (0. 1 mol), after the addition, continue to stir at room temperature for 2 hours until the reaction solution is clarified and there is no more gas emission, then evaporate the solvent and excess oxalyl chloride under reduced pressure to obtain the concentrated solution of 5-bromo-2-chlorobenzoyl chloride, Namely compound (2), MS-EI (m / z): 253 [M + ];

[0037] Step 2, dissolve 26 g of the above red transparent liquid (containing about 0.1 mol of 5-bromo-2-chlorobenzoyl chloride) in 40 mL of dry dichloromethane, cool to -7 °C, add phenetole (18.9 mL, 0.15 mol), and then added anhydrous aluminum trichloride (14.7 g, 0.11 mol) in three batches, duri...

Embodiment 3

[0040] This example relates to a compound (5) that is 5-bromo-2-chloro-4 ′ -A kind of synthetic method of ethoxy diphenylmethane, comprises the steps:

[0041] Step 1: Add 5-bromo-2-chlorobenzoic acid (23.5 g, 0.1 mol) and 120 mL of dry dichloromethane in sequence in the flask, stir at room temperature, add 17 mL of oxalyl chloride (0. 2 mol l), after the addition, continue to stir at room temperature for 2 hours until the reaction solution is clear and no gas is released, then evaporate the solvent and excess oxalyl chloride under reduced pressure to obtain the concentrated solution of 5-bromo-2-chlorobenzoyl chloride , namely compound (2), MS-EI (m / z): 253 [M + ];

[0042] Step 2, dissolve 26 g of the above red transparent liquid (containing about 0.1 mol of 5-bromo-2-chlorobenzoyl chloride) in 40 mL of dry dichloromethane, cool to -7 °C, add phenetole (12.6 mL, 0.1 mol), and then added anhydrous aluminum trichloride (14.7 g, 0.11 mol) in three batches, during which the t...

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Abstract

The invention relates to a method for synthesizing a forxiga intermediate. The method comprises the following steps: step 1, by taking dichloromethane as a solvent, reacting a compound (1) and oxalyl chloride under stirring conditions, performing reduced pressure distillation to remove the dichloromethane, and obtaining a concentrated solution of a compound (2); step 2, by taking the dichloromethane as a solvent, reacting the compound (2) and a compound (3) under the condition that aluminum trichloride serves as a catalyst, wherein the reaction temperature is 20 DEG C below zero to 10 DEG C below zero, the reaction time is 2-4 hours, and obtaining a compound (4); and step (3) by taking THF as a solvent, carrying out a reduction reaction on the compound (4), sodium borohydride and aluminum chloride anhydrous, thereof obtaining a compound (5), namely 5-bromine-2-chloro-4'-ethyoxydiphenylmethane. According to the method, the content of impurities can be reduced, the purity is improved, the yield is improved, and the method is suitable for synthesizing the forxiga intermediate in a large scale.

Description

technical field [0001] The invention relates to the technical field of dapagliflozin synthesis, in particular to a dapagliflozin intermediate 5-bromo-2-chloro-4 ′ - Synthetic method of ethoxydiphenylmethane. . Background technique [0002] Dapagliflozin (dapagliflozin) is a sodium-glucose cotransporter 2 (SGLT2) inhibitor used to treat type 2 diabetes, and can be used as an important choice in diabetes drug treatment. The structural formula of dapagliflozin is shown below. [0003] [0004] Currently, Dapagliflozin can be used as compound (5), namely 5-bromo-2-chloro-4 ′ -Ethoxydiphenylmethane is a starting material, which is synthesized by the following steps: [0005] [0006] Therefore, 5-bromo-2-chloro-4 ′ -Ethoxydiphenylmethane as an important intermediate in the synthesis of dapagliflozin, research on 5-bromo-2-chloro-4 ′ -The synthetic method of ethoxydiphenylmethane is of great significance. [0007] Yu Yankun et al. ("Synthesis of Dapagliflozin", "China ...

Claims

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Application Information

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IPC IPC(8): C07C41/18C07C43/225
CPCC07C41/18C07C45/46C07C51/60C07C43/225C07C49/84C07C63/70
Inventor 葛德培吴其华
Owner 安徽联创生物医药股份有限公司
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