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Preparation method for chiral piperylhydrazine compound and recycling method for chiral resolving agent

A technology of chiral resolution and piperidine amine, which is applied in the fields of organic chemistry and organic chemistry, and can solve the problems that are not conducive to large-scale industrial production, the use of chiral resolving agents is large, and the generation of industrial solid waste is large. , to achieve the effect of easy control of purity, easy operation and control of impurity content

Inactive Publication Date: 2018-12-11
NANTONG CHANGYOO PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This process has a long synthesis route, and it is applied to expensive reagents such as rhodium catalysts and high pressure for hydrogenation reaction; the amount of chiral resolving agent used is large, there is no recycling, a large amount of industrial solid waste is generated, and the production cost of the route is high, which is not conducive to large-scale industrial production

Method used

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  • Preparation method for chiral piperylhydrazine compound and recycling method for chiral resolving agent
  • Preparation method for chiral piperylhydrazine compound and recycling method for chiral resolving agent
  • Preparation method for chiral piperylhydrazine compound and recycling method for chiral resolving agent

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Preparation of intermediate TF-1: Add 1-benzyl-4-methyl-3-piperidinol (30.8g, 0.15mol) and 450mL dichloromethane to the reaction flask, stir to dissolve, cool to 0-5 ℃, then add thionyl chloride (71.4g, 0.6mol, 4.0eq), stir for 1h, then raise the temperature to 25-30℃ for reaction, and monitor the reaction by TLC. After the reaction is complete, add 500mL of water, then add potassium carbonate (41.4g, 0.3mol, 2.0eq), adjust the pH value to alkaline, let stand to separate the liquid, extract the aqueous layer with dichloromethane (200mL×2), and combine the organic phases , washed with saturated sodium chloride (500mL×1), dried over anhydrous sodium sulfate, filtered with suction, and evaporated to dryness under reduced pressure to obtain 31.2g of an oily product with a yield of 93%.

[0022] Preparation of intermediate TF-2: Add intermediate TF-1 (31.2g, 0.14mol) and 300mL ethanol to the reaction flask, stir to dissolve, then add potassium carbonate (19.3g, 0.14mol, 1.0q...

Embodiment 2

[0027] Preparation of intermediate TF-1: Add 1-benzyl-4-methyl-3-piperidinol (41g, 0.2mol) and 600mL dichloromethane into a reaction flask, stir to dissolve, and cool down to 0-5°C , and then add phosphorus oxychloride (61.32g, 0.4mol, 2.0eq), stir the reaction for 1h, then raise the temperature to 25-30°C for reaction, and monitor the reaction by TLC. After the reaction is complete, add 600mL of water, then add potassium carbonate (55.2g, 0.4mol, 2.0eq), adjust the pH value to alkaline, let stand to separate the liquid, extract the aqueous layer with dichloromethane (300mL×2), and combine the organic phases , washed with saturated sodium chloride (500mL×1), dried over anhydrous sodium sulfate, filtered with suction, and evaporated to dryness under reduced pressure to obtain 42.3g of an oily product with a yield of 95%.

[0028] Preparation of intermediate TF-2: Add intermediate TF-1 (42.3g, 0.19mol) and 400mL methanol to the reaction flask, stir to dissolve, then add sodium c...

Embodiment 3

[0033] Preparation of intermediate TF-1: Add 1-benzyl-4-methyl-3-piperidinol (21g, 0.1mol) and 200mL dichloromethane into a reaction flask, stir to dissolve, and cool down to 0-5°C , and then add hydrobromic acid (24.7g, 0.3mol, 3.0eq), stir the reaction for 1h, then raise the temperature to 25-30°C for reaction, and monitor the reaction by TLC. After the reaction is complete, add 300mL of water, then add potassium carbonate (28.6g, 0.2mol, 2.0eq), adjust the pH value to alkaline, let stand to separate the layers, extract the aqueous layer with dichloromethane (200mL×2), and combine the organic phases , washed with saturated sodium chloride (300mL×1), dried over anhydrous sodium sulfate, filtered with suction, and evaporated to dryness under reduced pressure to obtain 20.9g of an oily product with a yield of 92%.

[0034] Preparation of intermediate TF-2: Add intermediate TF-1 (20.9g, 0.09mol) and 300mL ethanol to the reaction flask, stir to dissolve, then add potassium carbon...

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Abstract

The invention discloses a preparation method for a chiral piperylhydrazine compound and a recycling method for a chiral resolving agent. In the invention, 1-benzyl-4-methyl-3-pipradrol is taken as aninitial raw material and is subjected to reactions of halogenation, methylamination, chiral resolution, and the like, so as to prepare a (3R, 4R)-N,4-dimethyl-1-(phenyl methyl)-3-piperylhydrazine dihydrochloride product, and meanwhile, a resolving mother solution is subjected to alkalization, refined, purified and recycled, so as to acquire a (2R,3R)-2,3-bi[(4-methyl benzoyl) oxo] succinic acid product meeting the reaction requirement. The invention has the beneficial effects of 1) short synthetic route, easily controlled intermediate purity and benefit to the control on impurity content, and2) simple and convenient technological operation in each step reaction, capability of recycling the high-dosage chiral resolving agent, capability of reducing production cost while reducing yield of solid wastes and suitability for large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of preparation of chiral piperidine amine compounds. Background technique [0002] Chiral piperidinamine compound: (3R,4R)-N,4-dimethyl-1-(phenylmethyl)-3-piperidinamine dihydrochloride, chemical structure formula is , is an important intermediate in the synthesis of Tofacitinib. Tofacitinib is a Janus kinase inhibitor developed by Pfizer. On November 6, 2012, the U.S. FDA approved the marketing of tofacitinib citrate (Xeljanz) for moderately to severely active rheumatoid arthritis (RA) with insufficient response or intolerance to methotrexate treatment. For the treatment of adult patients, it is a novel oral JAK inhibitor. [0003] Patent WO2007012953 reports a (3R,4R)-N,4-dimethyl-1-(phenylmethyl)-3-piperidinamine ((2R,3R)-2,3-bis[(4- The synthetic method of methylbenzoyl) oxygen group] succinate, concrete synthetic route is as follows: [0004] [0005] The route uses 3-amino-4-picoline as raw ma...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/56
CPCC07B2200/07C07D211/56
Inventor 李泽标丁海明张磊郭海峰马甜甜严军
Owner NANTONG CHANGYOO PHARMATECH CO LTD
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