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Preparation method of (1r,4s)-(-)-2-azabicyclo[2.2.1]hept-5-en-3-one

A technology of azabicyclo and cyclopentene, applied in the field of preparation of (1R,4S)-(-)-2-azabicyclo[2.2.1]hept-5-en-3-one, can solve the problem of bottom The problems of low concentration of substances, large amount of biological cells, and low yield have been solved, and the effects of high raw material utilization, simple reaction operation, and good selectivity have been achieved.

Active Publication Date: 2020-09-11
SHANGHAI SYNTHEALL PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, among the reported research results, the technology of preparing enantiomerically pure (-)-Wens lactam by these biocatalysts requires a large amount of biological cells, low substrate concentration, and low yield, which brings great difficulties to the separation and purification of subsequent products. Come a lot of trouble, not easy to industrialized production
[0010] In addition, in the above-mentioned methods for obtaining (-)-Vence lactam from (±)-Vence lactam racemate by biocatalysis or enzymatic technology, there is no recovery and separation of (1S,4R)-( +)-4-Amino-2-cyclopentene-1-carboxylic acid, causing waste of this chemical raw material

Method used

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  • Preparation method of (1r,4s)-(-)-2-azabicyclo[2.2.1]hept-5-en-3-one
  • Preparation method of (1r,4s)-(-)-2-azabicyclo[2.2.1]hept-5-en-3-one
  • Preparation method of (1r,4s)-(-)-2-azabicyclo[2.2.1]hept-5-en-3-one

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] In a 500mL glass jacketed reaction flask, add 100mL water, 0.064g NaH 2 PO 4 and 1.344g Na 2 HPO 4 , stir until the solid dissolves; add 20g of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one racemate, stir until the solid dissolves; adjust and control the temperature of the reaction solution 30°C; add 0.4g Esterase-53 enzyme to the reaction solution, stir for 12 hours; add 10g of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one to the reaction solution Spin and continue stirring for 24 hours.

[0063]The reaction solution was extracted four times with dichloromethane, using 150 mL of dichloromethane each time. Combine all the extracted organic phases, and concentrate the organic phase to about 30mL by distillation under reduced pressure at 30°C; add 70mL of n-heptane to the concentrated solution, and concentrate the organic phase to about 30mL by distillation under reduced pressure at 50°C; filter; Under the protection of nitrogen flow, it was dried under reduced pressure for 12 hou...

Embodiment 2

[0066] In a 250mL reaction bottle, add 70mL water, 0.06g KH 2 PO 4 2H 2 O and 1.5 g K 2 HPO 4 , control the reaction temperature at 30°C, stir for 1 hour; add 12g (±)-2-azabicyclo[2.2.1]hept-5-en-3-one racemate, add 600mg Esterase-53 enzyme, control the temperature 30°C, stirring for 16 hours.

[0067] The reaction solution was extracted 4 times with dichloromethane; the extracted organic phase was concentrated by distillation under reduced pressure at 30°C until 20mL; 60mL of n-heptane was added, and concentrated by distillation under reduced pressure until 40mL; filtered; After drying under reduced pressure for 12 hours, 5.6 g of white crystalline powder was obtained by weighing, and the separation yield was 46.8%. After chiral HPLC analysis, the obtained solid was the product (1R,4S)-(-)-2-azabicyclo[2.2.1]hept-5-en-3-one, with an enantiomeric excess of 99.9%. HPLC analysis conditions are the same as HPLC condition 1.

[0068] Add 50mL of n-butanol to the remaining a...

Embodiment 3

[0070] Add 40mL of water, 20mL of methyl tert-butyl ether and 10g of racemate of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one into a 200mL glass flask, shake well Dissolve the solid until the solid is clear; dissolve 0.2g of Esterase-53 enzyme in 10mL of pure water, then mix the obtained enzyme solution with the reactant; stir at room temperature for 24 hours.

[0071] The reaction solution was extracted 6 times with methyl tert-butyl ether, using 50 mL of methyl tert-butyl ether each time. The extracted organic phases were combined and concentrated by distillation under reduced pressure until the solvent was completely evaporated to dryness. The obtained solid was dried under reduced pressure at 40° C. under the protection of nitrogen flow for 12 hours, and 4.4 g of white crystalline powder was obtained by weighing, with an isolation yield of 44%. After chiral HPLC analysis, the obtained solid was the product (1R,4S)-(-)-2-azabicyclo[2.2.1]hept-5-en-3-one, and the enantiomeric exc...

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Abstract

The invention provides a preparation method of (1R,4S)-(-)-2-azabicyalo[2.2.1]heptyl-5-ene-3-ketone and discloses a raceme applying an enzyme treatment compound (I), a formula (II) intermediate for preparing a pure enantiomer and a method for preparing a pure enantiomer hydrolysate (III) (shown in the description). According to the method, the compound (II), enzyme, a buffer solution or a water-organic solvent form a mixture, reaction is performed at the temperature of 15-60 DEG C for 3-168 hours, and a reaction formula is shown as a formula (IV). The method is simple in reaction operation, high in yield, good in selectivity and high in raw material utilization rate.

Description

technical field [0001] The present invention relates to an enantiomerically pure (1R,4S)-(-)-2-azabicyclo[2.2.1]hept-5-en-3-one and (1S,4R)-(+)- Process for the preparation of 4-amino-2-cyclopentene-1-carboxylic acid. Background technique [0002] (1R,4S)-(-)-2-azabicyclo[2.2.1]hept-5-en-3-one (as shown in formula (II), abbreviated as (-)-vins lactam, sniractone or (-)-γ-lactam) [0003] [0004] It is an important chiral precursor for the synthesis of carbocyclic nucleosides. It can be used to synthesize a variety of chiral drugs, such as the anti-AIDS drug Abacavir, the anti-influenza A and bird flu drug Peramivir, and the new hypoglycemic drug Melogliptin Wait. But in the chemical synthesis of this chiral compound, what generally obtain is racemic (±)-2-azabicyclo[2.2.1]hept-5-en-3-one, as shown in formula (I) Show. [0005] [0006] At present, among many methods (including physical methods, chemical methods and biological methods) for preparing enantiomerica...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P41/00C12P17/18C12P13/00
CPCC12P13/005C12P17/182C12P41/007
Inventor 孙丰来孟枭李杰董理
Owner SHANGHAI SYNTHEALL PHARM CO LTD