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A kind of synthetic method of amorphous glucitol

A synthetic method and amorphous technology, applied in organic chemistry and other directions, can solve the problems of low total yield, low yield and long route, and achieve the effects of shortening reaction steps, easy operation and mild reaction conditions.

Active Publication Date: 2020-05-26
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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  • A kind of synthetic method of amorphous glucitol
  • A kind of synthetic method of amorphous glucitol
  • A kind of synthetic method of amorphous 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) Synthesis of compound 3

[0054] Under the protection of nitrogen, toluene (500.0ml), tetrahydrofuran (400.0ml) and compound 1 (200.00g, 614.19mmol) were added to the reaction flask, the liquid nitrogen was cooled to below -70℃, and 2.5M n-butyl was added dropwise. Lithium n-hexane solution (270.25ml, 675.61mmol), after dropping, keep stirring for 10min, add dropwise the toluene solution (500.0ml) of compound 2 (344.10g, 737.03mmol), keep keeping keeping warm and stirring for 30-60min after dropping, TLC Monitor the reaction. After the reaction is completed, the pre-prepared methanol (500.0ml) solution of methanesulfonic acid (80.0ml, 1.23mol) is added dropwise, and the reaction is carried out at 20-30°C after the drop. TLC monitors the reaction. After the reaction is completed, use saturated sodium carbonate aqueous solution or sodium bicarbonate aqueo...

Embodiment 2

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

[0064] 1) Synthesis of compound 3

[0065] Under the protection of nitrogen, toluene (430.0ml), tetrahydrofuran (400.0ml) and compound 1 (200.00g, 614.19mmol) were sequentially added to the reaction flask, the liquid nitrogen was cooled to below -70℃, and 2.5M n-butyl was added dropwise. Lithium n-hexane solution (294.81ml, 737.03mmol), after dripping, keep stirring for 10min, add compound 2 (344.10g, 737.03mmol) in toluene solution (370.0ml) dropwise, continue to keep heating and stirring for 30-60min after dripping, TLC Monitor the reaction. After the reaction is completed, the pre-prepared methanol (600.0ml) solution of methanesulfonic acid (80.0ml, 1.23mol) is added dropwise, and the reaction is carried out at 20-30°C after the drop. TLC monitors the reaction. After the reaction is completed, use saturated sodium carbonate aqueous solution o...

Embodiment 3

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

[0075] 1) Synthesis of compound 3

[0076] Under the protection of nitrogen, toluene (500.0ml), tetrahydrofuran (400.0ml) and compound 1 (200.00g, 614.19mmol) were added to the reaction flask, the liquid nitrogen was cooled to below -70℃, and 2.5M n-butyl was added dropwise. Lithium n-hexane solution (270.25ml, 675.61mmol), after dropping, keep stirring for 10min, add dropwise the toluene solution (500.0ml) of compound 2 (344.10g, 737.03mmol), keep keeping keeping warm and stirring for 30-60min after dropping, TLC Monitor the reaction. After the reaction is completed, the pre-prepared methanol (500.0ml) solution of methanesulfonic acid (80.0ml, 1.23mol) is added dropwise, and the reaction is carried out at 20-30°C after the drop. TLC monitors the reaction. After the reaction is completed, use a saturated sodium carbonate aqueous solution or sodium bicarbonate aqu...

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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 invention relates to a method for synthesizing a pharmaceutical grade compound, in particular to an amorphous (1S)-1,5-dehydrate-1-[4-chloro-3-[(4-ethoxyphenyl)methyl ]Phenyl]-D-glucitol (dapagliflozin) synthesis method. Background technique [0002] Diabetes is one of the top ten deaths in the United States. Approximately 25 million people suffer from diabetes, and this number is gradually increasing due to the effects of aging and obesity. At present, there are about 382 million people living with 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 cooperating protein 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 in the original urine and returns it to the blood....

Claims

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Application Information

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Patent Type & Authority Patents(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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