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Preparation methods for canagliflozin and intermediate thereof and intermediate

A technology for canagliflozin and intermediates, which is applied in the field of preparing canagliflozin and its intermediates, can solve problems such as complex reaction routes, and achieve the effects of simple reaction routes, product purity and high yield

Inactive Publication Date: 2016-03-30
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with bromoglucose derivatives, gluconolactone is cheaper and has higher reactivity, so this method can reduce production costs to a certain extent, but this method requires acetyl protection of the crude product of canagliflozin and deacetylation protection, the reaction route is more complicated

Method used

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  • Preparation methods for canagliflozin and intermediate thereof and intermediate
  • Preparation methods for canagliflozin and intermediate thereof and intermediate
  • Preparation methods for canagliflozin and intermediate thereof and intermediate

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preparation example Construction

[0033] The invention provides a preparation method of canagliflozin, comprising the following steps:

[0034] The structural compound shown in formula (I) carries out debenzylation reaction, obtains canagliflozin;

[0035]

[0036] In the present invention, the compound represented by the formula (I) undergoes a debenzylation reaction to obtain canagliflozin. The structural compound shown in the formula (I) is preferably prepared according to the following steps:

[0037] The structural compound shown in the formula (II) is reduced in the presence of a reducing agent to obtain the structural compound shown in the formula (I);

[0038]

[0039] In formula (II), R is selected from hydrogen or methyl.

[0040] The structural compound represented by the formula (II) has a structure of formula (II-I) or formula (II-II);

[0041]

[0042] In the present invention, the compound of formula (II) undergoes a reduction reaction in the presence of a reducing agent to obtain th...

Embodiment 1

[0073] Under the protection of argon, add 300mL of tetrahydrofuran and 90.4g (250mmol) of 2-(2-methyl-5-bromobenzyl)-5-(4-fluorobenzene)thiophene into a 1000mL three-necked flask , use an acetone / dry ice bath to control the temperature of the mixed system at -78°C, add 100mL (2.5mol / L, 250mmol, 1eq) of n-butyl lithium dropwise to the three-necked flask, and control the temperature of the reaction system during the dropwise addition At -78°C, after the dropwise addition was completed, it was left to stand at -78°C for 1 hour. To the reaction system, dropwise add a THF solution of 2,3,4,6-tetra-O-benzyl-D gluconolactone (2,3,4,6-tetra-O-benzyl-D gluconolactone 135.6g, tetrahydrofuran 150mL), stirred while adding dropwise, removed the dry ice / acetone bath after the dropwise addition, slowly returned the temperature of the reaction system to room temperature and reacted for 3 hours. NaHCO 3 The solution quenched the reaction, and the quenched reaction product solution was sequen...

Embodiment 2

[0077] Under the condition of argon protection, 150mL of tetrahydrofuran after dehydration, 300mL of toluene and 114.8g (280mmol) of 2-(2-methyl-5-iodobenzyl)-5-(4-fluorobenzene)thiophene were added to 1000mL In the three-necked flask, use an acetone / dry ice bath to control the temperature of the mixed system at -78°C, add 146mL (2.5mol / L, 364mmol, 1.3eq) of n-butyllithium dropwise to the three-necked flask, and control The temperature of the reaction system does not exceed -40°C. After the addition is complete, let it stand at -78°C for 1 hour, and add 2,3,4,6-tetra-O-benzyl-D gluconic acid to the reaction system dropwise Tetrahydrofuran / toluene solution of lactone (196.2g of 2,3,4,6-tetra-O-benzyl-D gluconolactone, 100mL of tetrahydrofuran, 200mL of toluene), stirring while adding dropwise, withdraw after dropwise addition Dry ice / acetone bath, slowly return the temperature of the reaction system to room temperature and react for 3 hours. After the reaction is stopped, use s...

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Abstract

The invention belongs to the field of medicine, and particularly relates to preparation methods for canagliflozin and an intermediate thereof and the intermediate. The preparation method for canagliflozin comprises the following steps: a compound having the structure represented by the formula (I) is subjected to a debenzylation reaction to obtain canagliflozin. The preparation methods provided by the invention have simple reaction route, the intermediate has no need for purification, and the products have high purity and high yield. Experimental results indicate that when the method provided by the invention is used for preparing canagliflozin, the product yield is greater than 88%, and the purity is greater than 99.5%.

Description

technical field [0001] The invention belongs to the field of medicines, and in particular relates to a method for preparing canagliflozin and its intermediates and the intermediates. Background technique [0002] Diabetes mellitus is a series of clinical syndromes caused by absolute or relative insufficiency of insulin in the body. The main clinical manifestations of diabetes are polydipsia, polyuria, polyphagia, weight loss, high blood sugar and glucose in urine. Diabetes is mainly divided into type I diabetes and type II diabetes. Among them, type I diabetes is generally caused by the destruction of insulin-producing β cells by the autoimmune system; type II diabetes is caused by tissue cell insulin resistance and β cell function decline. or a variety of other reasons. At present, the treatment for type II diabetes is mainly through diet control and the use of hypoglycemic drugs. [0003] Canagliflozin is an oral drug used to treat type 2 diabetes in adult patients. Can...

Claims

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Application Information

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IPC IPC(8): C07D409/10
Inventor 陈新亮宓鹏程刘建马亚平袁建成
Owner HYBIO PHARMA
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