Method for preparing compound

A technology of compounds and alkaline conditions, applied in the field of medicine, to achieve the effects of increased efficiency, high yield, and low toxicity

Inactive Publication Date: 2018-02-06
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Yet, the preparation technology of daclatasvir still needs further improvement

Method used

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  • Method for preparing compound
  • Method for preparing compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054]

[0055] The preparation process is as follows:

[0056] Add DSV206 (500mg), pinacol borate (854mg), potassium acetate (629mg), PdCl 2 (P(tBu) 2 Ph) 2 (40mg), ethylene glycol dimethyl ether (DME) (5ml), nitrogen replacement 3 times, react at 80°C for 5h, cool down, add DSV205 (1.45g), potassium carbonate (538mg), PdCl 2 (P(tBu) 2 Ph) 2 (100mg), water (1ml), DME (10ml), nitrogen replacement 3 times, react at 80°C for 18h. Add 10ml of ethyl acetate and 10ml of water, stir for 15min, separate the liquids, add 10ml of ethyl acetate to the aqueous phase, stir for 15min, separate the liquids, combine the organic phases, concentrate the organic phases under reduced pressure to obtain a yellow turbid oily liquid, and separate by column chromatography to obtain 620 mg off-white solid DSV103, yield 62.5%, purity 98.2%.

[0057] ESI-MS[m+H]+:625.3499; 1H NMR(400MHz,DMSO-d6)δ13.00-11.00(s,2H),7.90-7.75(m,4H),7.75-7.60(m,4H), 7.60-7.30(s,2H),4.92-4.72(m,2H),3.65-3.49(m,2H)...

Embodiment 2

[0059]

[0060] The preparation process is as follows:

[0061] Add DSV206 (1.00g), pinacol borate (1.86g), potassium acetate (1.72g), PdCl 2 (dppf) (0.11g), 1,4-dioxane (10ml), nitrogen replacement 3 times, reacted at 100°C for 22h, lowered the temperature, separated by column chromatography to obtain 1.22g solid, added DSV208 (2.00g), carbonic acid Sodium hydrogen (1.26g), PdCl2 (P(tBu)2Ph)2 (94mg), water (3ml), Dioxane (12ml), nitrogen replacement 3 times, 80 ℃ for 24h. The temperature was lowered to crystallize and separated by column chromatography to obtain 1.50 g of off-white solid DSV103 with a yield of 75.3% and a purity of 95.4%.

Embodiment 3

[0063]

[0064] The preparation process is as follows:

[0065] Add DSV210 (270mg), pinacol diborate (371mg), potassium phenate (KOPh) (351mg), Pd(PPh3)4 (80mg), toluene (10ml) into a 50ML three-necked flask, and replace with nitrogen for 3 Once, react at 90°C for 10h, cool down, add DSV208 (500mg), sodium carbonate aqueous solution (1M, 2.7ml), PdCl 2 (dppf) (50mg), toluene (10ml), nitrogen replacement 3 times, react at 90°C for 16h. The temperature was lowered for crystallization, and column chromatography was used for separation to obtain 337 mg of off-white solid DSV103 with a yield of 80.2% and a purity of 96.5%.

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Abstract

The invention provides a method for preparing a compound shown in formula I. The method comprises the steps as follows: a compound shown in formula II is contacted with a compound shown in formula III, so that the compound shown in formula I is obtained, wherein X1 is Cl, Br, I, trifluoromethanesulfonic acid and enol phosphate; R is alkyl, hydroxyl or alkoxy. The compound shown in the formula is an intermediate DSV103 of daclatasvir. The method for preparing the intermediate DSV103 has the characteristics of being high in purity, high in yield, low in cost, simple to operate, small in toxicityand pollution and stable in process, the yield can reach 60%-80%, and the purity can reach 95% or above. Daclatasvir can be further obtained from the daclatasvir intermediate obtained with the preparation process, and the obtained daclatasvir has higher purity and yield than the prior art.

Description

technical field [0001] The present invention relates to the field of medicine, specifically, the present invention relates to a method for preparing a compound, more specifically, the present invention relates to a method for preparing a daclatasvir intermediate. Background technique [0002] Daclatasvir (DSV) is an oral inhibitor of hepatitis C target NS5A, whose structure is shown below: [0003] [0004] The drug has the potential to treat patients infected with chronic hereditary 1b hepatitis C. It is a highly selective hepatitis C virus (HCV) NS5A inhibitor and can be used to treat chronic hepatitis C combined including genotypes 1, 2, Compensatory liver disease of types 3 and 4. [0005] However, the preparation process of daclatasvir still needs to be further improved. Contents of the invention [0006] The present invention aims to solve one of the technical problems in the related art at least to a certain extent. For this reason, an object of the present in...

Claims

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Application Information

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IPC IPC(8): C07D403/14
CPCC07D403/14
Inventor 寇景平吴舒铭林碧悦
Owner SUNSHINE LAKE PHARM CO LTD
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