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Preparation method of hepatitis C and novel coronavirus drug intermediate and salt thereof

A technology for hepatitis C and intermediates, applied in the field of drug synthesis, can solve the problems of poor reaction selectivity, high production cost, low yield and the like, and achieve the effects of short reaction steps, short production time, and easily available raw materials

Active Publication Date: 2022-02-18
NANJING CHEMPION BIOTECHNOLOGY CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The raw material of this synthetic method still needs to be synthesized by carronic anhydride, and the reaction selectivity of the second step is poor at the same time, and needs to be separated and purified by crystallization, the yield is low, and the production cost is high

Method used

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  • Preparation method of hepatitis C and novel coronavirus drug intermediate and salt thereof
  • Preparation method of hepatitis C and novel coronavirus drug intermediate and salt thereof
  • Preparation method of hepatitis C and novel coronavirus drug intermediate and salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: (1 R ,2 S ,5 S )- N Synthesis of -tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3,1,0]hexyl-2-carboxylic acid methyl ester

[0042]

[0043] (S)- N -tert-butoxycarbonyl-2,5-dihydro-1 H -Methyl pyrrole-2-carboxylate can be conveniently prepared in high yield by a published method (document US2008 / 0027262).

[0044] Under nitrogen protection, the (S)- N -tert-butoxycarbonyl-2,5-dihydro-1 H -Methyl pyrrole-2-carboxylate (1.00 eq, 34.2 g) was dissolved in 800 mL of dry dichloromethane, cooled to –78 °C in a dry-ice acetone bath, and then a diethyl ether solution of 2-diazopropane was added dropwise (according to literature Org. Synth., 1970, 50, 27. Preparation) until the conversion of raw materials monitored by TLC was complete. After the system was heated to 20-25 °C to continue the reaction for 2 h, the solvent was concentrated and replaced with methyl tert-butyl ether, and then cooled in an ice-water bath. Maintain at 0-5°C, irradiate with a 30...

Embodiment 2

[0045] Embodiment 2: (1 R ,2 S ,5 S )- N Synthesis of -Benzyloxycarbonyl-6,6-dimethyl-3-azabicyclo[3,1,0]hexyl-2-carboxylic acid methyl ester

[0046]

[0047] (2 S ,4 R )- N -Benzyloxycarbonyl-4-hydroxyproline methyl ester can be conveniently prepared in high yield by the disclosed method (document CN112930350A).

[0048] Under nitrogen protection, 48.1 g of 1-propyl cyclophosphoric anhydride in ethyl acetate solution (50% w / w, 1.32 eq.) was added to the reactor, cooled to 0 °C under stirring, and 15.9 g ( 2 S ,4 R )- N - Benzyloxycarbonyl-4-hydroxyproline methyl ester (1.00 eq.) in 50 mL of ethyl acetate. After the dropwise addition, the reaction was incubated until the reaction of the raw materials was monitored by TLC, and the reaction solution was washed with 50 mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound (S)- N -Benzyloxycarbonyl-2,5-dihydro-1 H - Methyl pyrrole-2-carboxylate.

[0049] Under ni...

Embodiment 3

[0050] Embodiment 3: (1 R ,2 S ,5 S )- N Synthesis of -tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3,1,0]hexyl-2-carboxylic acid methyl ester

[0051]

[0052] Under nitrogen protection, add (S)- N -tert-butoxycarbonyl-2,5-dihydro-1 H - Methyl pyrrole-2-carboxylate (1.00 eq., 11.5 g) and 2,2-dibromopropane (3.00 eq., 30.6 g), cooled to -78 °C in a dry ice acetone bath. A solution of n-butyllithium in n-hexane (2.00 eq.) was then slowly added dropwise. After the dropwise addition was completed, the temperature was raised to 20-25° C. to continue the reaction for 12 hours, then a saturated ammonium chloride solution was added, and the organic phase was washed with water and dried over anhydrous sodium sulfate, concentrated to remove the solvent and used column chromatography (petroleum ether / acetic acid Ethyl ester) was purified to obtain slightly oily compound (1 R ,2 S ,5 S )- N - methyl tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3,1,0]hexyl-2-carboxylate (6....

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Abstract

The invention relates to the technical field of drug synthesis, in particular to a preparation method of a hepatitis C and novel coronavirus drug intermediate and a salt thereof. The preparation method comprises the following steps: step 1, dissolving a compound shown in expression IV in a solvent, adding with 2-diazopropane or reacting with 2, 2-dihalogenated propane under the action of a metal reagent, and performing subsequent treatment and purification to obtain a compound as shown in expression V; 2, dispersing the compound as shown in expression V prepared in the step 1 in a solvent, and performing deprotection to obtain a compound as shown in expression I, namely (1R, 2S, 5S)-6, 6-dimethyl-3-azabicyclo [3, 1, 0] hexyl-2-carboxylate. Compared with the prior art, the synthesis method has the advantages of short reaction steps, easily available raw materials, simple reaction conditions, short production time and lower production cost.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for preparing a hepatitis C and new crown drug intermediate and a salt thereof. The intermediate is specifically (1 R ,2 S ,5 S )-6,6-dimethyl-3-azabicyclo[3,1,0]hexyl-2-carboxylate. Background technique [0002] (1R,2S,5S)-6,6-Dimethyl-3-azabicyclo[3,1,0]hexyl-2-carboxylate (compound represented by formula (I)) and its corresponding salts are An important class of pharmaceutical intermediates, which are used as key intermediates in the synthesis of various antiviral drugs. Boceprevir (compound represented by formula (II)), developed by Schering Corporation of the United States and launched in 2011 for the treatment of chronic hepatitis C in some adult patients, can be efficiently synthesized through the compound of formula (I) ( WO2005 / 107745). Its Covid-19 treatment drug Paxlovid (PF-07321332, the compound represented by formula (III)) disclosed by Pfizer o...

Claims

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Application Information

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IPC IPC(8): C07D209/52
CPCC07D209/52C07B2200/07
Inventor 陈剑余长泉顾榕夏威邱亚涛祝俊李丹李斌
Owner NANJING CHEMPION BIOTECHNOLOGY CO LTD
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