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A novel process for the preparation of peramivir and intermediates thereof

A technology for a process and a compound is applied in the field of preparing peramivir or a pharmaceutically acceptable salt thereof, and can solve the problems of long synthesis route, low yield and high production cost

Active Publication Date: 2014-05-28
PHARMA SHANGHAI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The main disadvantages of this process are long synthetic route, low yield and high production cost

Method used

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  • A novel process for the preparation of peramivir and intermediates thereof
  • A novel process for the preparation of peramivir and intermediates thereof
  • A novel process for the preparation of peramivir and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0175] 1. (1S,4R)-methyl-4-(2,3-bis(tert-butoxycarbonyl)guanidino)cyclopent-2-ene-carboxylate (13)

[0176]

[0177] To a mixture of (1S,4R)-methyl-4-aminocyclopent-2-enecarboxylate tartrate 11 (7.29 g, 25 mmol) dissolved in dichloromethane (150 mL) at 0 °C was added ET 3 N (9 mL, 65 mmol) and the resulting mixture was stirred for 15 minutes. To this was added methyl tert-butyl(1H-pyrazol-1-yl)methylenedicarbamate 12 (7.38 g, 24 mmol). After the addition was complete, the completion of the reaction was monitored by TLC (PE:EtOAc=5:1). The organic phase was washed with water and brine, and anhydrous Na 2 SO 4 Dry overnight. The mixture was filtered and concentrated to give 13 as a white solid, which was used in the next step without purification.

[0178] MS(M+1): 384.

[0179] 1 H NMR (400MHz, CDCl 3 )δ11.49(s,1H),8.53(d,J=8.4Hz,1H),5.94-5.83(m,2H),5.38-5.31(m,1H),3.73(s,3H),2.60(dt , J=14.0, 8.5Hz, 1H), 1.94(dt, J=13.9, 4.7Hz, 1H), 1.50(d, J=7.4Hz, 18H) (see attac...

Embodiment 2

[0181] 2(3aR,4R,6S,6aS)-methyl-4-(2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pentan-3-yl)-4,5,6,6α- Tetrahydro-3αH-cyclopentano[d]isoxazole-6-carboxylate (5)

[0182]

[0183] a) Preparation of 2-ethyl-N-hydroxybutyrimyl chloride (14)

[0184] Hydroxylamine hydrochloride (7.2 g, 0.1 mol) was dissolved in water (7 mL). Toluene (27 mL) was added followed by 2-ethylbutanal (10.0 g, 0.1 mol). The biphasic mixture was vigorously stirred while cooling. Sodium hydroxide solution (approximately 30%, 14.6 g, 0.11 mol) was added slowly (addition was strongly exothermic) to maintain the temperature between 15-25°C. The mixture was stirred for 60 minutes, after which the layers were left to stand. The organic phase was washed with water and brine, Na 2 SO 4 Dry overnight and use directly in the next step.

[0185] N-Chlorosuccinimide (NCS) (13.3 g, 0.1 mol) was suspended in dimethylformamide (DMF) (17 mL) and cooled to about 10 °C. The toluene solution prepared above (3.15 mol) ...

Embodiment 3

[0192] 3. (1S,2S,3S,4R,1'S)-methyl-3-(1-acetamido-2-ethylbutyl)-4-(2,3-bis(tert-butoxycarbonyl)-guanidino )-2-hydroxycyclopentanecarboxylate (16):

[0193]

[0194] Compound 15 (from Example 2, 5.0 g, 10.08 mmol) and nickel chloride hexahydrate (2.5 g, 10.5 mmol) were dissolved in methanol (40 mL). The green solution was cooled to -15°C while forming a suspension. Sodium borohydride (0.456 g, 12 mmol) was added to the reaction mixture at -5--10°C (the reaction was highly exothermic). A black suspension formed with gas evolution. After complete addition of sodium borohydride solution, the reaction mixture was stirred until TLC showed complete consumption of 15. A solution of acetic anhydride (15 g, 0.13 mol) was added slowly and maintaining the reaction temperature at 0-5 °C, the reaction mixture was stirred at 0 °C for 2-12 hours (the black solution turned to a green solution). The pH of the mixture was adjusted to approximately 9 by the addition of 25% aqueous ammonia....

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Abstract

The present invention relates to a novel process for preparing peramivir formula (I) or a pharmaceutically acceptable salt thereof, and to intermediates used therein.

Description

technical field [0001] The present invention relates to a new process for preparing peramivir or a pharmaceutically acceptable salt thereof and a new intermediate thereof. In particular, the present invention relates to a more efficient process for preparing peramivir or a pharmaceutically acceptable salt thereof, including a highly diastereoselective reaction with fewer reaction steps to obtain peramivir. Background technique [0002] Peramivir chemical name is (1S,2S,3S,4R)-3-[1'S)-1-acetylamino-2-ethyl-butyl]-4-(diaminomethyleneamino)-2- Hydroxy-cyclopentane-1-carboxylic acid and has the following structural formula: [0003] [0004] Peramivir has now been developed as an antiviral drug and specifically for the treatment of influenza. As a neuraminidase inhibitor, peramivir effectively inhibits the replication of all types of influenza viruses. Peramivir can be administered by injection and is known to be well tolerated and cause only mild side effects. [0005] S...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C279/16C07C277/08C07C279/02
CPCC07C277/08C07B2200/07C07C279/16C07C2601/08C07C2601/10C07D261/20
Inventor 陈平李殷强彭少平蒋胜力蔡振威安荣苍王伟华董学军
Owner PHARMA SHANGHAI
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