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Preparation method of (R)-3-Boc-aminopiperidine

A -3-boc-, aminopiperidine technology, applied in the field of preparation of piperidine heterocyclic compounds, can solve the problems of complicated post-processing operation procedures, difficult purification, low overall yield and the like, and achieves good process stability, Mild reaction conditions and high yield

Active Publication Date: 2015-12-09
CANGZHOU SENARY CHEM SCI TEC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The problems existing in the preparation of this intermediate at this stage are mainly reflected in the following points: the reaction route is long and the overall yield is low; the process operation is relatively harsh; the post-treatment operation procedure is cumbersome and difficult to purify

Method used

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  • Preparation method of (R)-3-Boc-aminopiperidine
  • Preparation method of (R)-3-Boc-aminopiperidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Dissolve 26.3g of N-Cbz-3-piperidinecarboxylic acid in 55mL of methanol, stir and heat to 40-50°C, slowly add 9.7g of R-phenylethylamine in 13.5mL of methanol solution dropwise at this temperature, and keep stirring for 20 ~30min, slowly cool to 10~15℃, suction filter and dry to obtain carboxylate 16g; then 16g carboxylate Add 32mL of ethanol, heat to 70-75°C, keep warm for 15-20min, slowly drop to 10-15°C, filter with suction, and dry to obtain carboxylate 15.2g, repeat this operation 2 times to obtain carboxylate 13.5g, ee value 99.7%; finally 13.5g carboxylate Add it to 40mL of water, adjust the pH to 1-2 with concentrated hydrochloric acid, add 30mL of ethyl acetate to extract twice, combine the organic phases and concentrate until there is no distillate to obtain 9.2g of compound I.

Embodiment 2

[0036] Dissolve 26.3g of N-Cbz-3-piperidinecarboxylic acid in 105mL of acetone, stir and heat to 40-50°C, slowly add 10.3g of R-phenylethylamine in 50mL of acetone solution dropwise at this temperature, after dropping, keep stirring for 20-50°C 30min, slowly cool to 10~15℃, suction filter and dry to obtain carboxylate 15.4g; then 15.4g carboxylate Add 30mL of ethanol, heat to 70-75°C, keep warm for 15-20min, slowly drop to 10-15°C, filter with suction, and dry to obtain carboxylate 14.6g, repeat this operation 2 times to obtain carboxylate 12.9g, ee value 99.5%; finally 12.9g carboxylate Add it to 40mL of water, adjust the pH to 1-2 with concentrated hydrochloric acid, add 25mL of ethyl acetate to extract twice, combine the organic phases and concentrate until there is no distillate to obtain 8.8g of compound I.

Embodiment 3

[0038] Dissolve 26.3g of N-Cbz-3-piperidinecarboxylic acid in 150mL of ethyl acetate, stir and heat to 40-50°C, slowly add 9.2g of R-phenylethylamine solution in 50mL of ethyl acetate dropwise at this temperature, and dropwise, Insulate and stir for 20-30 minutes, slowly cool to 10-15°C, filter and dry to obtain carboxylate 15.7g; then 15.7g carboxylate Add 30mL of ethanol, heat to 70-75°C, keep warm for 15-20min, slowly drop to 10-15°C, filter with suction, and dry to obtain carboxylate 14.9g, repeat this operation 2 times to obtain carboxylate 13.2g, ee value 99.5%; finally 13.2g carboxylate Add it to 40mL of water, adjust the pH to 1-2 with concentrated hydrochloric acid, add 25mL of ethyl acetate to extract twice, combine the organic phases and concentrate until there is no distillate to obtain 9.0g of compound I.

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Abstract

The invention discloses a preparation method of (R)-3-Boc-aminopiperidine and relates to the technical field of preparation of piperidine heterocyclic compounds. The preparation method includes following steps: (1) with N-Cbz-3-piperidinecarboxylic acid as a raw material, performing chiral resolution with R-phenylethylamine to obtain a compound I; (2) performing an acid-amide condensation reaction to the compound I and ammonia gas to obtain a compound II; (3) performing a Hofmann degradation reaction to the compound II to obtain a compound III; (4) performing protection to the compound III with di-tert-butyl dicarbonate to obtain a compound IV; and (5) performing a hydrogenation and Cbz-removal reaction to the compound IV to prepare the (R)-3-Boc-aminopiperidine. The method is mild in reaction conditions, is safe and reliable, is excellent in process stability, is low in energy consumption, is high in yield, is green and environment-protective and is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of preparation of piperidine heterocyclic compounds. Background technique [0002] Type 2 diabetes is a polygenic hereditary disease, which is the result of the joint action of environmental factors and genetic factors. The etiology is related to insulin resistance and insufficient insulin secretion. Clinical statistics show that more than 90% of diabetic patients are type 2 diabetes. The treatment of type 2 diabetes is mainly to control blood sugar, and the general treatment is through some drugs that lower blood sugar or stabilize blood sugar. [0003] Linagliptin is a selective DPP-4 inhibitor, which inhibits the activity of the enzyme by reversibly binding to DPP-4, delays the degradation of GLP-1, enhances the activity of GLP-1, and stimulates the activity of GLP-1 in a glucose-dependent manner. Insulin secretion, and reduces circulating glucagon levels, thereby regulating blood glucose levels in type...

Claims

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Application Information

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IPC IPC(8): C07D211/56C07D211/60
CPCC07D211/56C07D211/60
Inventor 张少平王平周文峰张伟刘劲松于淑玲孙海丽
Owner CANGZHOU SENARY CHEM SCI TEC