Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

A preparation method for synthesizing 3-azabicyclo[4.1.0]heptane-2-carboxylic acid and its hydrochloride

A compound and a range of technology, applied in the field of synthesis of pharmaceutical intermediates, can solve problems such as low yield, unfriendly environment, and large irritation

Active Publication Date: 2022-04-26
PHARMABLOCK SCIENCES (NANJING) INC
View PDF4 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] This route has synthesized (1S, 2S, 6R)-5-benzyloxyamino-3-azabicyclo[4.1.0]heptane-2-carboxylic acid benzyl ester (compound XXVII), and this route has the following problems: The starting material is not easy to obtain, and the second step reaction uses benzyl bromide, which is more irritating and environmentally unfriendly; the whole route is through 6 steps of reaction, the total yield is 16.5%, the yield is low, and the process cost is high ,Not environmentally friendly

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • A preparation method for synthesizing 3-azabicyclo[4.1.0]heptane-2-carboxylic acid and its hydrochloride
  • A preparation method for synthesizing 3-azabicyclo[4.1.0]heptane-2-carboxylic acid and its hydrochloride
  • A preparation method for synthesizing 3-azabicyclo[4.1.0]heptane-2-carboxylic acid and its hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Preparation of compound III:

[0036]

[0037] Sodium tert-butoxide (58.45g, 608.2mmol, 2.0e.q.) was dissolved in 600mL DMSO, under nitrogen protection, trimethylsulfoxide iodide (133.86g, 608.2mmol, 2.0e.q.) was added in batches, and the reaction was stirred at 0°C for 1 hour , at this temperature, 50 mL THF solution of compound II (60.00 g, 304.2 mmol, 1.0 e.q.) was added dropwise, and the reaction was stirred at 0°C for 6 h after the addition. TLC showed that the raw materials were completely reacted. , the organic phase was washed with saturated brine, and purified by sand column chromatography to obtain 17.20 g of compound III as a light yellow liquid with a yield of 26.8%.

[0038] Preparation of Compound IV:

[0039]

[0040] Compound III (15.18g, 71.9mmol, 1.0e.q.) was dissolved in 150mL THF, cooled to -50°C in dry ice acetone, and triethylsodium borohydride (1N) THF solution (158.2mL, 158.2mmol, 2.2e.q.) was added dropwise, Stir the reaction for 1 h, TL...

Embodiment 2

[0049] Preparation of compound III:

[0050]

[0051] Potassium tert-butoxide (34.14g, 304.2mmol, 1.0e.q.) was dissolved in 600mL DMSO, under nitrogen protection, trimethylsulfoxide iodide (66.95g, 304.2mmol, 1.0e.q.) was added in batches, and the reaction was stirred at 25°C for 1 hour , cooled to below 20°C, dropwise added 50mL of THF solution of compound II (60.00g, 304.2mmol, 1.0e.q.), stirred and reacted at 30°C for 1h after the addition, TLC showed that the raw materials were completely reacted, the reaction solution was poured into 500mL of ice water, ethyl acetate Ester was extracted, the organic phase was washed with saturated brine, and purified by sand column chromatography to obtain 30.04 g of compound III as a light yellow liquid with a yield of 46.8%.

[0052] Preparation of Compound IV:

[0053]

[0054] Compound III (15.18g, 71.9mmol, 1.0e.q.) was dissolved in 150mL THF, cooled to -78°C with dry ice acetone, and THF solution (71.9mL, 71.9mmol, 1.0e.q.) w...

Embodiment 3

[0063] Preparation of compound III:

[0064]

[0065] Sodium hydrogen (60%) (36.79g, 912.4mmol, 3.0e.q.) was dissolved in 600mL DMSO, under nitrogen protection, trimethylsulfoxide iodide (200.78g, 912.4mmol, 3.0e.q.) was added in batches, and the reaction was stirred at 25°C After 1 hour, cool to below 20°C, add compound II (60.00g, 304.2mmol, 1.0e.q.) dropwise in 50mL of THF solution, and stir at 30°C for 1h after the addition, TLC shows that the raw materials are completely reacted, and the reaction solution is poured into 500mL of saturated bicarbonate In sodium solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, and purified by sand column chromatography to obtain 39.05 g of compound III as a light yellow liquid with a yield of 60.8%.

[0066] Preparation of Compound IV:

[0067]

[0068] Compound III (15.18g, 71.9mmol, 1.0e.q.) was dissolved in 150mL THF, cooled to -78°C in dry ice acetone, and triethylpotassium borohydride (1...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The present invention discloses for the first time a preparation method for synthesizing 3-azabicyclo[4.1.0]heptane-2-carboxylic acid and its hydrochloride, comprising the following steps: using 2-oxo-5,6-dihydro Pyridine-2H-1-carboxylate tert-butyl ester (compound II) is used as raw material, first react with sulfur ylide reagent to obtain compound III by [1+2] cycloaddition reaction; compound III is reduced to obtain compound IV; Silane reaction to obtain compound V; finally, hydrolysis of cyano group and deamination of protecting group to obtain 3-azabicyclo[4.1.0]heptane-2-carboxylic acid and its hydrochloride (compound I).

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method for synthesizing 3-azabicyclo[4.1.0]heptane-2-carboxylic acid and its hydrochloride. Background technique [0002] 3-Azabicyclo[4.1.0]heptane-2-carboxylate hydrochloride is an important intermediate in pharmaceutical synthesis. As pipecolic acid homologues, it is widely used in peptide chemistry and has broad market prospects. [0003] There is no bibliographical report about the synthesis of 3-azabicyclo[4.1.0]heptane-2-carboxylic acid and its hydrochloride (compound I) at present, the analog of compound I pipecolic acid class azabicyclo[4.1. 0] The synthesis of heptane is also rare. [0004] The following synthesis method is reported in the patent CN104302636A: [0005] [0006] Reagents and conditions: (a) NaBH 4 , ethanol, room temperature, overnight; (b) DIPEA, DMAP, tert-butyldiphenylchlorosilane, DCM, 0 ℃ ~ room temperatu...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): C07D221/04
CPCC07D221/04
Inventor 刘文博欧阳浩
Owner PHARMABLOCK SCIENCES (NANJING) INC
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com