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Method for preparing (R)-or(S)-3-aminopiperidine dihydrochloride

A technology of bishydrochloride and aminopiperidine, which is applied in the field of synthesis of pharmaceutical intermediates, can solve problems such as difficult realization and unguaranteed supply of starting materials

Active Publication Date: 2015-12-02
SHANGHAI HOBOR CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] There are different degrees of defects in the above methods, for example: the supply of starting materials cannot be guaranteed, and they need to be synthesized by themselves; the split method requires the use of biological enzymes, which is difficult to implement in the laboratory; or requires ultra-low temperature reactions and strong alkaline ion exchange resins

Method used

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  • Method for preparing (R)-or(S)-3-aminopiperidine dihydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Synthesis of N-Boc-3-(R)-tert-butylsulfinimide piperidine:

[0029] Under the protection of nitrogen, add 220 mL of dichloromethane, (R)-tert-butylsulfinamide (13.3 g, 0.11 mol) and N-Boc-3-piperidine in sequence into a 500 mL reaction flask equipped with a mechanical stirring and reflux device Ketone (19.9g, 0.1mol), dissolved completely under stirring. Then 100 g of 4A molecular sieve and tetrahydropyrrole (0.71 g, 0.01 mol) were added, stirred at room temperature for 30 minutes, and then heated to reflux for 8 hours. TLC detected that the reaction did not change, and the reaction was stopped. After cooling, diatomaceous earth was filtered, and the filter cake was washed by adding 50 mL of dichloromethane. The filtrate was rotary evaporated to dryness with a water pump, and the obtained solid (25.3 g, crude product yield 84%) was recrystallized from n-hexane to obtain a solid product, and 160 mL of methanol was added to form a solution that was directly used in the n...

Embodiment 2

[0033] Synthesis of N-Boc-3-(S)-tert-butylsulfinimide piperidine:

[0034] Under nitrogen protection, 200 mL of tetrahydrofuran, (S)-tert-butylsulfinamide (18.2 g, 0.15 mol) and N-Boc-3-piperidone ( 19.9g, 0.1mol), completely dissolved under stirring. Then, 90 g of 5A molecular sieve and tetrahydropyrrole (0.71 g, 0.01 mol) were added, stirred at room temperature for 30 minutes, and then heated to reflux for 6 hours. TLC detected that the reaction was complete, and the reaction was stopped. After cooling, diatomaceous earth was filtered, and the filter cake was washed by adding 40 mL of tetrahydrofuran. The filtrate was rotary evaporated to dryness with a water pump, and the obtained solid (27.5 g, crude product yield 91%) was recrystallized from n-heptane to obtain a solid product, and 180 mL of ethanol was added to form a solution that was directly used in the next reaction.

[0035] Synthesis of (R)-3-aminopiperidine dihydrochloride:

[0036] Under the protection of nitr...

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Abstract

The invention discloses a method for preparing (R)-or(S)-3-aminopiperidine dihydrochloride. The method includes the steps of taking N-Boc-3-piperidone as the raw material, making N-Boc-3-piperidone have a condensation reaction with enantiomerically pure (S)-or(R)-tert-butanesulfinyl amide under the existence of the catalytic amount of pyrrolidine, then conducting low-temperature reduction through a reducing agent, obtaining an enantiomerically pure intermediate after ethyl alcohol / heptane recrystallization, and obtaining (R)-or(S)-3-aminopiperidine dihydrochloride after removing the protection of Boc and tert-butanesulfinyl amide in hydrochloric acid at the same time.

Description

technical field [0001] The invention relates to a method for preparing (R)- or (S)-3-aminopiperidine dihydrochloride, which belongs to the field of synthesis of pharmaceutical intermediates. Background technique [0002] As a single optical isomer, (R)-3-aminopiperidine dihydrochloride has a wide range of applications in the fields of organic synthesis and medicine, and is an important raw material and intermediate for preparing medicines. For example: Japan's Takeda Pharmaceutical developed alogliptin (Alogliptin) through structural design and optimization. As a 2-peptidyl peptidase-IV (DPP-IV) inhibitor, the drug has shown exciting high activity in the treatment of type II diabetes, and has been approved for marketing in China in 2013. [0003] [0004] As the key intermediate of the drug, the synthesis methods of R-3-aminopiperidine dihydrochloride mainly include: 1) taking 3-aminopyridine as the starting material, after hydrogenation reduction, resolution and salt fo...

Claims

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Application Information

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IPC IPC(8): C07D211/56C07D211/72C07B57/00
CPCC07B57/00C07B2200/07C07B2200/13C07D211/56C07D211/72
Inventor 帅小华洪伟李大鹏
Owner SHANGHAI HOBOR CHEM CO LTD
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