Preparation method of optical active medicine intermediate

A technology for compounds and hydrochlorides, applied in the field of preparation of optically active intermediates, can solve the problems of low resolution efficiency, low selectivity, and many by-products, etc., so as to reduce the risk of process changes, shorten the reaction conditions, and save costs. Effect

Active Publication Date: 2014-02-12
PORTON FINE CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] The method uses 3-aminopyridine as a raw material, and directly obtains R-3-aminopiperidine through two steps of high-pressure hydrogenation and resolution of the pyridine ring. Although the total reaction steps are short, the reaction is not easy.
When hydrogenating the pyridine ring, when palladium carbon is used for catalysis, too many by-products are obtained, the selectivity of the reaction is small, and post-treatment purification is difficult. When rhodium carbon is used for catalysis, a high pressure of 3.0 MP is required to achieve better results, but A large amount of rhodium carbon is required, the cost is high, and it is difficult to apply industrially
In addition, when splitting with a resolving agent such as DBTA, the splitting efficiency is also quite low, and it is difficult to meet the requirements of high optical purity.

Method used

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  • Preparation method of optical active medicine intermediate
  • Preparation method of optical active medicine intermediate
  • Preparation method of optical active medicine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] In a 250mL dry hydrogenation kettle equipped with a thermometer and mechanical stirring, add 12.4g of the compound of formula II (n=1), 0.65g (dry basis) of 10% palladium carbon, 156g of methanol and 24.3g of concentrated hydrochloric acid in sequence. Install the reaction kettle, first replace it with nitrogen three times, then replace it with hydrogen three times, pressurize to 1.0MPa, raise the temperature to 50-60°C and stir for 15-25 hours, stop the reaction after the raw materials are completely reacted, and cool to 20-30°C After filtration, the filtrate was distilled under reduced pressure at 60-65°C and 0.09MPa until there was no fraction, then 20g*3 isopropanol was added, and the isopropanol was distilled off under the same conditions to obtain a yellow solid. Heat to dissolve, then slowly drop 46.6g of ethyl acetate into methanol, after the addition, cool down to -10~-5°C to crystallize, filter, wash the filter cake with ethyl acetate, and dry to obtain the R-c...

Embodiment 2

[0050] Add 34.6g of benzylamine into a dried three-necked flask equipped with a thermometer, heat it to 45-55°C, add 35g of the compound of formula III (n=1) into the benzylamine, and keep the temperature at 45-55°C until the reaction of the raw materials is complete , to stop the reaction, quickly add 290g of water to the reaction bottle, stir for 2 hours, filter, transfer the filter cake into a 500ml reaction bottle, add 180g of water, stir for 2 hours, filter, dry the solid under reduced pressure until the water content is less than 1%, and obtain Compound of formula II (n=1) crude product 25.3g, yield 92%, purity: 94.2%, set aside.

[0051] Add 180g of petroleum ether and 25.3g of the crude product obtained above into a dried three-necked flask equipped with a thermometer, heat to 80-90°C and stir to dissolve, filter while hot, transfer the filtrate into another 500ml three-necked flask, and cool down to 20-90°C. Crystallize at 25°C, then cool to 0-5°C in an ice-water bath...

Embodiment 3

[0053]In a dry three-neck flask equipped with a dropping funnel and a thermometer, add 80g of compound of formula IV (n=1), 520g of dichloromethane and 102.3g of triethylamine, stir and cool down to -5~0°C, at this temperature Add dropwise the mixed solution of 97.6g methanesulfonyl chloride and 104g dichloromethane, after the raw materials have reacted, add 280g water, be warming up to 15~25 ℃ of layering, organic layer has saturated salt water washing, organic phase decompression distillation ( lower than 40°C, -0.09MPa) to obtain a yellow oil, cooled to 15-20°C, added 128g of ethanol, cooled to -10--5°C to crystallize, and obtained 106.4g of a white solid compound of formula III, with a yield of 83.1%, chemical purity 95.2%, optical purity 99.1%.

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Abstract

The invention relates to a preparation method of an optical active compound, represented by formula I, or a hydrochloride of the optical active compound by taking a compound with optical activity as a starting material. Raw materials of the preparation method are cheap and easily available; no splitting is needed; the whole technological operation is simple and convenient; cost is low; pollution on environment is less; and the preparation method is suitable for industrialized production. In the formula I, n is 1 or 2 or 3.

Description

Technical field: [0001] The invention relates to the technical field of preparation of optically active intermediates, in particular to a method for preparing optically active 3-aminopiperidane, 3-aminopyridane and derivatives thereof. Background technique: [0002] Optically active 3-aminopiperidine and its derivatives are key intermediates in the synthesis of chiral drugs. For example, it can be used to synthesize Linagliptin and Alogliptin benzoate, the DPP-IV inhibitors developed by BI and Takeda respectively for the treatment of diabetes. In addition, the patent US7550485 filed by Wyeth in 2009 reported that 3-aminopiperidine can synthesize a class of monoamine reuptake inhibitors, which can be used to treat vasomotor symptoms or moderate depression. There are other literature reports that 3-aminopiperidine can be used to synthesize a class of histamine 4 receptor inhibitors, protein kinase inhibitors and the like. [0003] Optically active 3-aminopyrrolidine and its ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/14C07D211/56C07D223/12
CPCC07D207/14C07D211/56C07D223/12
Inventor 徐平洲覃军王科蒲慧杨坤于刘强
Owner PORTON FINE CHEM
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