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Method for synthesizing irregular glucitol

A synthesis method and technology of glucitol are applied in the synthesis field of pharmaceutical grade compounds, and can solve the problems of low total yield, long route, low yield and the like, and achieve the effects of mild reaction conditions, shortened reaction steps and easy operation.

Active Publication Date: 2017-12-19
SHANGHAI SHYNDEC PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The compound 6 obtained in the patent US6515117B2 is only used as an intermediate, and the impurities in the synthesis process are difficult to be completely removed, so its product quality is difficult to meet the drug quality standard
In addition, the process route will go through the protection and deprotection reaction of hydroxyl, the route is longer, and the yield is lower (the inventor has tested many times according to the process, and its total yield is 7.57%~16.8%), which is not conducive to industrial production
[0015] In 2012, the synthesis method reported in patent CN102627676B was similar to the method reported in patent US6515117B2. The process route also required the protection and deprotection of hydroxyl groups. The route was long and the yield was low, which was not conducive to industrial production. Compound 6 was also used as a The use of intermediates, the product quality is difficult to meet the pharmaceutical standards
[0019] In summary, the 6 obtained in the prior art is basically obtained by alkaline hydrolysis of the acetylated compound 5-2, and the overall yield is low, which is not conducive to industrial production, and the quality of the finally obtained 6 is difficult to achieve pharmaceutical standard

Method used

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  • Method for synthesizing irregular glucitol
  • Method for synthesizing irregular glucitol
  • Method for synthesizing irregular glucitol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1. Preparation of amorphous (1S)-1,5-anhydro-1-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol

[0053] 1), the synthesis of compound 3

[0054] Under the protection of nitrogen, sequentially add toluene (500.0ml), tetrahydrofuran (400.0ml) and compound 1 (200.00g, 614.19mmol) into the reaction flask, cool to below -70°C with liquid nitrogen, and dropwise add 2.5M n-butyl Lithium n-hexane solution (270.25ml, 675.61mmol), after dripping, keep stirring for 10min, add dropwise the toluene solution (500.0ml) of compound 2 (344.10g, 737.03mmol), continue to keep stirring for 30-60min after dropping, TLC Monitor the response. After completion of the reaction, a solution of methanol (500.0 ml) of methanesulfonic acid (80.0 ml, 1.23 mol) prepared in advance was added dropwise, and reacted at 20-30° C. after the drop was completed. The reaction was monitored by TLC. After the reaction was completed, the pH of the reaction solution was adjusted to be ≥ 7 using sa...

Embodiment 2

[0063] Example 2. Preparation of amorphous (1S)-1,5-anhydro-1-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol (Dag net)

[0064] 1), the synthesis of compound 3

[0065] Under nitrogen protection, toluene (430.0ml), tetrahydrofuran (400.0ml) and compound 1 (200.00g, 614.19mmol) were successively added to the reaction flask, cooled to below -70°C with liquid nitrogen, and 2.5M n-butyl Lithium n-hexane solution (294.81ml, 737.03mmol), after dropping, keep stirring for 10min, add dropwise the toluene solution (370.0ml) of compound 2 (344.10g, 737.03mmol), continue to keep stirring for 30-60min after dropping, TLC Monitor the response. After the reaction was completed, a pre-prepared methanol (600.0 ml) solution of methanesulfonic acid (80.0 ml, 1.23 mol) was added dropwise, and reacted at 20-30° C. after the drop was completed. The reaction was monitored by TLC. After the reaction was completed, the pH of the reaction solution was adjusted to be ≥ 7 using saturated aque...

Embodiment 3

[0074] Example 3. Preparation of amorphous (1S)-1,5-anhydro-1-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol

[0075] 1), the synthesis of compound 3

[0076]Under the protection of nitrogen, sequentially add toluene (500.0ml), tetrahydrofuran (400.0ml) and compound 1 (200.00g, 614.19mmol) into the reaction flask, cool to below -70°C with liquid nitrogen, and dropwise add 2.5M n-butyl Lithium n-hexane solution (270.25ml, 675.61mmol), after dripping, keep stirring for 10min, add dropwise the toluene solution (500.0ml) of compound 2 (344.10g, 737.03mmol), continue to keep stirring for 30-60min after dropping, TLC Monitor the response. After completion of the reaction, a solution of methanol (500.0 ml) of methanesulfonic acid (80.0 ml, 1.23 mol) prepared in advance was added dropwise, and reacted at 20-30° C. after the drop was completed. The reaction was monitored by TLC. After the reaction was completed, the pH of the reaction solution was adjusted to be ≥ 7 using sat...

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Abstract

The invention relates to a method for synthesizing irregular glucitol (1S)-1,5-dehydration-1-[4-chlorine-3-[(4-ethyoxyl phenyl) methyl] phenyl]-D-glucitol. The reaction formula of the compound is as shown in the specification. The method is gentle in process reaction condition, simple and convenient to operate, applicable to industrial production and relatively high in total product yield, that is, the total product yield is 43-53%, and medicine-grade irregular glucitol 6 is easily prepared.

Description

technical field [0001] The present invention relates to a synthetic method of a pharmaceutical grade compound, in particular to an amorphous (1S)-1,5-anhydro-1-[4-chloro-3-[(4-ethoxyphenyl)methyl ]Phenyl]-D-glucitol (dapagliflozin) synthetic method. Background technique [0002] Diabetes is one of the top ten leading causes of death in the United States. About 25 million people have diabetes, and this number is increasing due to aging and obesity. At present, there are about 382 million people suffering from diabetes in the world. According to statistics, by 2035, this number is expected to become 592 million people, accounting for about 10% of the world's total population. [0003] Type 2 sodium-glucose cotransporter 2 (SGLT2) is a new target for the treatment of diabetes, which consists of 672 amino acids. SGLT2 is distributed in the kidney and is the main protein that controls the absorption of glucose from the primary urine and returns it to the blood. Therefore, inh...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/10
CPCC07D309/10
Inventor 张广沈钢邹凌燕傅民吴渺渺
Owner SHANGHAI SHYNDEC PHARMA CO LTD
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