B crystal form epalrestat and preparation method thereof

A technology of epalrestat and crystal form, applied in the field of preparation of crystal form B epalrestat, can solve the problems of long reaction time, complicated operation, poor product purity of crystal form B epalrestat, etc.

Active Publication Date: 2018-06-22
SHIJIAZHUANG NO 4 PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In the above method for preparing epalrestat, the operation is cumbersome, the reaction time is long, and the refining yield is low, and the purity of the B crystal form epalrestat product is also poor

Method used

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  • B crystal form epalrestat and preparation method thereof
  • B crystal form epalrestat and preparation method thereof
  • B crystal form epalrestat and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0035] For illustrating epalrestat of the present invention and its synthetic method

[0036] Step 1: The crude product preparation process, add 10L ethanol to the 20L reaction kettle, add 1kg (5.229mol) rhodanine acetic acid, add 1.22L (7.844mol) ammonia water, stir for 18min, add 946ml (6.798mol) α-methyl For cinnamaldehyde, heat up to 70°C, keep warm for 30 minutes, monitor the reaction with TCL (dichloromethane: methanol: acetic acid = 10:1:0.1), the spots of the reactant disappear, cool down to 25°C, and the crude product is not separated.

[0037] Step 2: In the preparation process of the crude product, directly add 1.31 L of concentrated hydrochloric acid (calculated as 1.0 moles of rhodanine acetic acid, and the relative mole number of HCl is 3.0) to the aforementioned crude product, raise the temperature to 50°C, stir for 2 hours, centrifuge, and purify water The filter cake was washed (until the pH of the cleaning waste liquid was 6), and dried to obtain 1078 g of cr...

Embodiment 2

[0044] For illustrating epalrestat of the present invention and its synthetic method

[0045] Step 1: The crude product preparation process, with reference to Example 1, the solvent is changed from ethanol to methanol, the amount of α-methylcinnamaldehyde added is changed from 1.3 to 1.0 in relative moles (calculated with the moles of rhodanine acetic acid being 1.0), the type of alkali From ammonia water to triethylamine, the reaction time is 40min.

[0046] Step 2: The preparation process of the crude fine product, referring to Example 1, the acid type is changed from hydrochloric acid to sulfuric acid, the amount of sulfuric acid added is changed from 3.0 to 4.0 relative moles (calculated as 1.0 moles of rhodanine acetic acid), and the reaction temperature is changed from 50°C Changed to 55°C, the yield was 63wt%.

[0047] Step 3: the finished product preparation process, add 10 times of ethanol 10L (calculated based on the mass of the crude product) to the 20L reactor, ad...

Embodiment 3

[0050] For illustrating epalrestat of the present invention and its synthetic method

[0051] Step 1: The crude product preparation process, with reference to Example 1, the amount of α-methylcinnamaldehyde added is changed from 1.3 to 1.1 in relative moles (calculated based on 1.0 moles of rhodanine acetic acid), and the type of alkali is changed from ammonia to diisopropylamine , The reaction time is 30min.

[0052] Step 2: the preparation process of the crude fine product, with reference to Example 1, the acid type is changed from hydrochloric acid to acetic acid, the amount of acetic acid added is changed from 3.0 to 4.5 relative moles (calculated with rhodanine acetic acid moles as 1.0), and the yield is 67wt% .

[0053] Step 3: the finished product preparation process, add 10 times of methanol 10L (calculated on the basis of the mass of the crude product) in the 20L reactor, add 1 kg of the crude product (prepared in step 2), at room temperature, first drop 732ml of amm...

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Abstract

The invention provides B crystal form epalrestat and a preparation method thereof. The method comprises the following steps: taking rhodanine acetic acid and alpha-methylcinnamaldehyde as raw materials and reacting to generate epalrestat crude product suspension; adding a first acid solution into the epalrestat crude product suspension; then heating and melting, carrying out centrifugal treatment,washing a filter cake and drying to obtain an epalrestat crude fine product, wherein the mole ratio of an acidic substance in the first acid solution to the rhodanine acetic acid is (3 to 4.5) to 1;adding low-carbon alcohol into the epalrestat crude fine product; after heating and melting, keeping for pre-set time; then cooling to 20 to 30 DEG C; carrying out the centrifugal treatment and dryinga filter cake to obtain an epalrestat fine product. According to the B crystal form epalrestat and the preparation method thereof, provided by the invention, the yield and purity of B crystal form epalrestat products are easy to improve and the content of 2Z-isomer impurities is reduced.

Description

technical field [0001] The invention relates to the field of drug synthesis, and specifically relates to a B crystal form epalrestat, and also relates to a preparation method of the B crystal form epalrestat. Background technique [0002] With the rapid economic development and the acceleration of industrialization, diabetes has become one of the non-communicable diseases that threaten human health in today's world. Diabetes is increasing at an alarming rate worldwide, especially in developing countries. According to the statistics of the International Diabetes Federation (IDF), there were 151 million diabetic patients in the world in 2000, and currently there are 285 million diabetic patients in the world. If the current growth rate is used, it is estimated that by 2030, nearly 435 million people will suffer from diabetes worldwide. Diabetes and its complications pose a great threat to the life and quality of life of patients, and bring heavy economic burdens to families a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/36
CPCC07D277/36C07B2200/13
Inventor 殷殿书孙立杰刘玉扑张伟丽印杰李彪
Owner SHIJIAZHUANG NO 4 PHARMA
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