Preparation method of Rayleigh bactam intermediate

A technology for intermediates and compounds, applied in the field of pharmaceutical synthesis, can solve the problems of special raw materials, low reaction conversion rate, increase cost, etc., and achieve the effects of mild reaction conditions, improved reaction yield, and reduced preparation cost.

Pending Publication Date: 2020-09-01
JIANGXI FUSHINE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In the existing reported methods, some raw materials are special and difficult to prepare, some impurities are difficult to control, which affects the quality of the final product, and some reaction conversion rates are low, which increases the cost.

Method used

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  • Preparation method of Rayleigh bactam intermediate
  • Preparation method of Rayleigh bactam intermediate
  • Preparation method of Rayleigh bactam intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: (R1 is benzyl)

[0033] Put 30ml of toluene, 0.7g (5.3mmol) of anhydrous aluminum chloride, 7.0g (35mmol) of compound III, 5g (14.7mmol) of compound II into the reaction bottle, keep warm at 50°C until the reaction is complete (about 3 hours), add 50% Sodium hydroxide aqueous solution 2.0g, filter, separate layers, depressurize the organic phase to dryness, crystallize with petroleum ether, filter with suction, rinse and dry the filter cake with petroleum ether to obtain 5.6g of compound I, yield: 88%, Content: 98.5%. 1 H NMR (400MHz, CDCl 3 )δ7.40–7.27(m,5H),6.75(d,J=8.0Hz,1H),4.66(s,2H),4.00(s,2H),3.93–3.82(m,1H),3.29(dd ,J=11.8,2.4Hz,1H),3.16(dd,J=10.4,2.8Hz,1H),2.96(t,J=10.0Hz,1H),2.84(t,J=11.5Hz,2H),2.53 –2.42(m,1H),2.15–2.05(m,1H),1.88(dd,J=23.3,8.8Hz,3H),1.44(d,J=3.5Hz,10H),1.38–1.20(m,3H ). Ms: M+1=433.28.

[0034] Reduce the mother liquor to dryness, add 30ml of toluene, 3.8g (19mmol) of compound III, 0.7g (5.3mmol) of anhydrous aluminum chl...

Embodiment 2

[0035] Embodiment 2: (R1 is benzyl)

[0036] Put 30ml of acetonitrile, 0.7g (5.3mmol) of anhydrous aluminum chloride, 7.0g (35mmol) of compound III, 5g (14.7mmol) of compound II into the reaction bottle, keep warm at 50°C until the reaction is complete, add 2.0% 50% sodium hydroxide aqueous solution g, filter, decompress the filtrate to dryness, crystallize with cyclohexane, filter with suction, rinse the filter cake with pure water, and dry to obtain 5.5g of compound I, yield: 86%, content: 99.0%.

[0037] Reduce the mother liquor to dryness, add 30ml of acetonitrile, 3.8g (19mmol) of compound III, 0.7g (5.3mmol) of anhydrous aluminum chloride, 5g (14.7mmol) of compound II, keep warm at 50°C until the reaction is complete, add 50% hydroxide Sodium aqueous solution 2.0g, filtered, separated, the organic phase was decompressed to dryness, crystallized with cyclohexane, filtered with suction, and the filter cake was rinsed and dried with cyclohexane to obtain 6.0g of compound I,...

Embodiment 3

[0038] Embodiment 3: (R1 is benzyl)

[0039] Put 30ml of toluene, 1.02g (7.5mmol) of anhydrous zinc chloride, 7.0g (35mmol) of compound III, 5g (14.7mmol) of compound II into the reaction bottle, keep warm at 50°C until the reaction is complete, add 2.0% 50% sodium hydroxide aqueous solution g, filter, separate layers, decompress the organic phase to dryness, crystallize with petroleum ether, filter with suction, and dry to obtain 5.08g of compound I, yield: 80%, content: 97.0%.

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Abstract

The invention discloses a preparation method of a Rayleigh bactam intermediate. (2S, 5R)-5-[(benzyloxy) amino] piperidine-2-formate II is used as a raw material and reacts with Boc-4-aminopiperidine III in the presence of an accelerant to generate 4-((2S, 5R)-((benzyloxy) amino) piperidine-2-formamide) piperidine-1-tert-butyl formate I. The method has the advantages of readily available raw materials, mild reaction conditions, high reaction selectivity, high reaction speed, few impurities and the like.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, and in particular relates to a preparation method of tert-butyl 4-((2S,5R)-((benzyloxy)amino)piperidine-2-carboxamido)piperidine-1-carboxylate. Background technique [0002] Relebactam is a new type of β-lactamase inhibitor with non-β-lactam structure, its structure is similar to that of avibactam, relebactam and imipenem-cilastatin Sodium combination drugs have shown good performance in the second clinical phase, and it is of great significance to study their synthesis and action. Its chemical name is mono[(1R,2S,5R)-7-oxo-2-[(4-piperidinylamino)carbonyl]-1,6-diazabicyclo[3.2.1]octyl-6 sulfate -base] ester, the specific structure is as follows: [0003] [0004] Wherein, 4-((2S, 5R)-((Bian oxy) amino) piperidine-2-carboxamido) piperidine-1-carboxylic acid tert-butyl ester I is the key intermediate for the synthesis of relibactam, Its structure is as follows: [0005] [0006] Regardin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/60
CPCC07D211/60C07B2200/07
Inventor 龚杰周忠波胡涛谢永居郑裕义曹敏
Owner JIANGXI FUSHINE PHARMA CO LTD
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