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Novel method for synthesizing dapagliflozin intermediate compound

A new method and technology for intermediates, applied in the field of synthesizing dapagliflozin intermediates, can solve the problems of inconvenient transportation of oxalyl chloride, incomplete reaction of raw materials, troublesome tetrahydrofuran, etc., and achieve the effects of easy recovery of tetrahydrofuran, clean reaction and simple raw materials

Inactive Publication Date: 2017-12-01
上海常丰生物医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Among them, step 1 uses oxalyl chloride, but the transportation of oxalyl chloride is inconvenient, the protection requirements are high, the toxicity is large, the odor is high, and the price is high, and no catalyst is used, resulting in insufficient yield and incomplete reaction of raw materials; step 2 uses aluminum chloride As a catalyst, a large amount of waste water and waste gas will be produced, and post-processing is troublesome; step 3 uses aluminum chloride as a catalyst, which produces more by-products, and saturated brine quenching reaction uses organic solvents, such as ethyl acetate, dichloromethane and other solvents Extraction makes it troublesome to recover THF, the concentration consumes a lot of energy, and the solvent cost is high

Method used

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  • Novel method for synthesizing dapagliflozin intermediate compound
  • Novel method for synthesizing dapagliflozin intermediate compound
  • Novel method for synthesizing dapagliflozin intermediate compound

Examples

Experimental program
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Effect test

Embodiment 1

[0031] Step 1. Dissolve 5-bromo-2-chlorobenzoic acid (100g, 0.43mol) in 500ml of dichloromethane, add 1g of pyridine for catalysis, add thionyl chloride (60.5g, 0.51mol) dropwise at room temperature, and heat up to Reflux at 40°C for 3.5 hours, use TLC to detect that the reaction is complete, and concentrate the dichloromethane under reduced pressure to obtain 104 g of crude 5-bromo-2-chlorobenzoyl chloride (yield 97%), which is directly used in the next step without further purification;

[0032] Step 2: Using 500ml of dichloromethane as a solvent, add 10g of solid acid catalyst (preparation method of solid acid attached below) into the reaction kettle, add phenetole (50g, 0.41mol) at room temperature, stir for 2h after the dropwise addition, and then dropwise add The concentrated solution of 5-bromo-2-chlorobenzoyl chloride obtained in step 1 was reacted at a temperature of 30°C for 3-4 hours. After the reaction was completed, it was filtered and concentrated to obtain 5-brom...

Embodiment 2

[0035] Step 1, 5-bromo-2-chlorobenzoic acid (100g, 0.43mol) was dissolved in 500ml of dichloromethane, catalyzed by adding 1g of pyridine, and thionyl chloride (76.1g, 0.645mol) was added dropwise at room temperature, and the temperature was raised to Reflux at 40°C for 3 hours, use TLC to detect that the reaction is complete, and concentrate the dichloromethane under reduced pressure to obtain 102.5 g of crude 5-bromo-2-chlorobenzoyl chloride (yield 95%), which is directly used in the next step without further purification ;

[0036] Step 2. Using 500ml of dichloromethane as a solvent, add 10g of solid acid catalyst (preparation method of solid acid attached below) into the reaction kettle, add phenetole (59.6g, 0.49mol) at room temperature, stir for 2h after the addition, and then drop Add the concentrated solution of 5-bromo-2-chlorobenzoyl chloride obtained in step 1, and react at a temperature of 30°C for 4 hours. After the reaction is completed, filter and concentrate to...

Embodiment 3

[0039]Step 1. Dissolve 5-bromo-2-chlorobenzoic acid (100g, 0.43mol) in 500ml of dichloromethane, add 1g of pyridine to catalyze, add thionyl chloride (101.5g, 0.86mol) dropwise at room temperature, and heat up to Reflux at 40°C for 5 hours, use TLC to detect that the reaction is complete, and concentrate the dichloromethane under reduced pressure to obtain 103 g of crude 5-bromo-2-chlorobenzoyl chloride (yield 96%), which is directly used in the next step without further purification;

[0040] Step 2: Using 500ml of dichloromethane as a solvent, add 10g of solid acid catalyst (preparation method of solid acid attached below) into the reaction kettle, add phenetole (50g, 0.41mol) at room temperature, stir for 1h after the dropwise addition, and then dropwise add The 5-bromo-2-chlorobenzoyl chloride concentrate obtained in step 1 was reacted at a temperature of 35°C for 5 hours. After the reaction was completed, it was filtered and concentrated to obtain 5-bromo-2-chloro-4-ethoxy...

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Abstract

The invention discloses a novel method for synthesizing a dapagliflozin intermediate compound. The method comprises the following steps: (1) by taking dichloromethane as a solvent and pyridine as a catalyst, reacting 5-bromo-2-chlorobenzoic acid and thionyl chloride to obtain 5-bromo-2-chlorobenzoyl chloride; (2) by taking dichloromethane as a solvent and solid acid as a catalyst, reacting phenetole and the 5-bromo-2-chlorobenzoyl chloride to obtain 5-bromo-2-chloro-4-ethoxydiphenylketone; and (3) by taking THF as a solvent, adding the 5-bromo-2-chloro-4-ethoxydiphenylketone concentrated solution obtained in the step (2); by taking acetic acid and aluminum trichloride as catalysts, adding sodium borohydride, and performing a reduction reaction; and after the reaction is completed, adding a saturated saline solution, and performing quenching at 25 DEG C or below to obtain 5-bromo-2-chloro-4-ethoxydiphenylmethane. The novel method disclosed by the invention has the advantages of cheap and available raw materials, simple and easy operation, no discharge of three wastes, high reaction yield and the like.

Description

technical field [0001] The invention belongs to the technical field of dapagliflozin synthesis, and in particular relates to a new method for synthesizing a dapagliflozin intermediate. Background technique [0002] Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, is a new type of antidiabetic drug indicated for use as an adjunct to diet and exercise to improve blood sugar control in adults with type 2 diabetes. [0003] At present, the synthesis method of dapagliflozin is: 5-bromo-2-chlorobenzoic acid undergoes acyl chlorination, reacts with phenetole, and reduces carbonyl to obtain 5-bromo-2-chloro-4'-ethoxydi Benzene, then condensed with 2,3,4,6-tetra-O-trimethylsilyl-D-glucopyranosic acid-1,5-lactone, etherified the anomeric carbohydroxyl group, and deprotected to obtain 2-chloro -5-(1-methoxy-D-glucopyranose-I-yl)-4'-ethoxydiphenylmethane, then with Et 3 SiH / BF 3 ·OEt 2 Reductive removal of methoxyl group, esterification of acetic anhydride, and hydrolysis ...

Claims

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Application Information

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IPC IPC(8): C07C51/60C07C63/70C07C45/46C07C49/84C07C41/18C07C43/225
CPCC07C41/18C07C45/46C07C51/60C07C63/70C07C49/84C07C43/225
Inventor 张博王伟王东任永远
Owner 上海常丰生物医药科技有限公司
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