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

Synthesis method of avibactam intermediate (I)

A synthesis method and a technology for intermediates, which are applied in the field of synthesis of avibactam intermediates, can solve the problems of expensive raw materials, complicated synthesis steps and the like, and achieve simple operation, high chemical yield and optical purity, and good enantioselectivity. Effect

Pending Publication Date: 2021-12-28
无棣融川医药化工科技有限公司 +1
View PDF1 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the existing reports on the synthesis of avibactam, the synthetic routes all adopt chiral sources as starting materials, such as the use of 2-allyl 1-(tert-butyl) (2S ,5S)-5-hydroxypiperidine-1,2-dicarboxylate as the starting material, both Novexel and AstraZeneca use benzyl pyroglutamate as the starting material, and there is no asymmetric synthesis report , the existing route raw materials are expensive and the synthesis steps are cumbersome

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
  • Synthesis method of avibactam intermediate (I)
  • Synthesis method of avibactam intermediate (I)
  • Synthesis method of avibactam intermediate (I)

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0033] A kind of synthetic method of avibactam intermediate (I), comprises steps:

[0034] Dissolving the rhodium metal catalyst and the chiral bisphosphine ligand in a solvent to obtain a mixed solution, adding compound (II) and hydrogen gas to the mixed solution for an asymmetric hydrogenation reaction to prepare the avibactam intermediate (I);

[0035] The synthetic route of Avibactam intermediate (I) is as follows:

[0036]

[0037] in:

[0038] Compound (II) is 6-bromo-2-((tert-butoxycarbonyl)amino)-5,5-dimethoxyhex-2-enoic acid methyl ester, and the chemical structural formula of compound (II) is In the formula, X is halogen, R2 is any one of C1-C5 alkyl, aralkyl, and aryl, and R3 is various alkoxycarbonyl groups;

[0039] Avibactam intermediate (I) is (S)-6-bromo-2-((tert-butoxycarbonyl)amino)-5,5-dimethoxyhexanoic acid methyl ester, Avibactam intermediate The chemical structural formula of (I) is

[0040] In this method, the enamine substrate, compound (II), ...

Embodiment 1

[0062] Preparation of Compound (Ia)

[0063] Dissolve 106 mg of bis(1,5-cyclooctadiene) rhodium tetrafluoroborate, 617 mg of ligand (R)-(-)-DTBM-SegPhos and 15 mL of degassed methanol in a dry reaction flask, stir for 30 min, and then Add 1g of 6-bromo-2-((tert-butoxycarbonyl)amino)-5,5-dimethoxyhex-2-enoic acid methyl ester in the reaction flask, place it in the autoclave, replace with hydrogen for 3 Once, hydrogen gas was introduced to 40atm, and stirred at 25°C for 48h. Hydrogen was released slowly, the solvent was removed under reduced pressure, and the white solid obtained by separation with a silica gel column was the avibactam intermediate (Ia) (83% yield, 98% ee).

[0064] figure 1 is compound (Ia) hydrogen spectrogram; figure 2 It is the carbon spectrum of compound (Ia).

[0065] 1 H NMR (400MHz, Chloroform-d) δ5.11(d, J=5.2Hz, 1H), 4.33(m, 1H), 3.74(s, 3H), 3.35–3.27(m, 2H), 3.19(s, 6H), 1.89–1.76(m,3H), 1.66–1.59(m,1H), 1.43(s,9H).

[0066] 13 C NMR (100MHz...

Embodiment 2

[0068] Preparation of compound (Ib)

[0069] Dissolve 20mg of bis(1,5-cyclooctadiene)rhodium tetrafluoroborate, 29mg of ligand (R,R)-QuinoxP* and 6mL of degassed methanol in a dry reaction flask, stir for 30min, and then pour into the reaction flask Add 200 mg of (S)-4-(2-(bromomethyl)-1,3-dioxolan-2-yl)-2-((tert-butoxy) and stir at room temperature for 48 hours at 25°C. Release slowly Hydrogen, the solvent was removed under reduced pressure, and the white solid obtained by recrystallization was the avibactam intermediate (Ib) (87% yield, 98% ee).

[0070] image 3 is compound (Ib) hydrogen spectrogram; Figure 4 It is the carbon spectrum of compound (Ib).

[0071] 1 H NMR (600MHz, DMSO-d6) δ8.91(s, 1H), 7.43–7.28(m, 5H), 6.32(t, J=7.2Hz, 1H), 5.07(s, 2H), 4.04–3.96( m,2H),3.96–3.90(m,2H),3.65(s,3H),3.53(s,2H),2.69(d,J=7.2Hz,2H).

[0072] 13 C NMR (151MHz, DMSO-d6) δ164.59, 154.23, 136.62, 129.28, 129.13, 128.37, 127.92, 127.73, 107.35, 65.90, 65.32, 52.03, 36.05, 33.83...

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 invention provides a synthesis method of an avibactam intermediate (I). According to the method, an enamine substrate is subjected to asymmetric hydrogenation in an organic solvent in a hydrogen environment under the catalysis of a rhodium complex formed by a rhodium metal catalyst and a chiral diphosphine ligand to prepare the avibactam intermediate (I). The method has the advantages of mild reaction conditions, excellent enantioselectivity and diastereoselectivity, high chemical yield and potential industrial application value.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a method for synthesizing an avibactam intermediate (I). Background technique [0002] Avibactam (avibactam, NXL-104) belongs to the diazabicyclooctone compound and is currently the most promising non-β-lactam β-lactamase inhibitor. Penem antibiotics have broad-spectrum antibacterial activity when used in combination. [0003] In the existing reports on the synthesis of avibactam, the synthetic routes all adopt chiral sources as starting materials, such as the use of 2-allyl 1-(tert-butyl) (2S ,5S)-5-hydroxypiperidine-1,2-dicarboxylate as the starting material, both Novexel and AstraZeneca use benzyl pyroglutamate as the starting material, and there is no asymmetric synthesis report , the existing route raw materials are expensive and the synthesis steps are cumbersome. Contents of the invention [0004] The purpose of the present invention is to overcome the deficiencies of...

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 Applications(China)
IPC IPC(8): C07C227/16C07C229/22
CPCC07C227/16C07C229/22
Inventor 陈芬儿唐培杨智蒋龙李亚玲
Owner 无棣融川医药化工科技有限公司
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