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Preparation method of 10,11-dihydro-5H-benzo[d]naphtha[2,3-b]pyranone derivative

A 3-b, derivative technology, applied in the direction of organic chemistry, etc., can solve the problem of low reaction yield and so on

Active Publication Date: 2017-07-04
苏州楚凯药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At the same time, the yields of the two-step reactions are not high, and are not suitable for scale-up industrial production.

Method used

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  • Preparation method of 10,11-dihydro-5H-benzo[d]naphtha[2,3-b]pyranone derivative
  • Preparation method of 10,11-dihydro-5H-benzo[d]naphtha[2,3-b]pyranone derivative
  • Preparation method of 10,11-dihydro-5H-benzo[d]naphtha[2,3-b]pyranone derivative

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Experimental program
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Embodiment

[0023] (1) Dissolve 91.4mg of 7-((2-bromo-5-chlorophenyl)oxo)-3,4-dihydronaphthol-1(2H)-one in 4mL of benzene, and add ligands in sequence 21 mg of new copper reagent and 70 mg of potassium tert-butoxide were reacted at 100°C with the tube sealed. The reaction was monitored by TLC until the reaction was complete. After cooling to room temperature, the intermediate I was purified.

[0024] 1 H NMR (CDCl 3 )δ7.63(m,2H),7.54(s,1H),7.35(m,1H),7.16(m,1H),5.05(s,2H),2.96(t,2H),2.65(t,2H ),2.15(m,2H);

[0025] (2), 3.36g of intermediate I obtained in step (1) and 2.1g of sodium cyanide were dissolved in 15mL of N-methylpyrrolidone, and heated to reflux for 14 hours to obtain a black reaction solution, which was cooled to 85°C , add 2.5mL of hydrochloric acid, 7.5mL of ferric chloride solution (0.53g / mL), keep the temperature at 75-80°C and stir for 1.5 hours, then cool to room temperature, extract with toluene, wash the organic phase with 5M hydrochloric acid, dry and purify Inte...

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Abstract

The invention discloses a preparation method of an anti-hepatitis C medicine Velpatasvir intermediate 10,11-dihydro-5H-benzo[d]naphtha[2,3-b]pyranone derivative which is 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-benzo[d]naphtho[2,3-b]pyran-8(9H)-one (V). The preparation method concretely comprises the following steps: carrying out coupling cyclization on a raw material 7-((2-bromo-5-chlorophenyl)oxo)-3,4-dihydronaphthalen-1(2H)-one under the action of a ligand and an alkali to synthesize 3-chloro-10,11-dihydro-5H-benzo[d]naphtho[2,3-b]pyran-8(9H)-one, substituting chlorine by using sodium cyanide to form cyanide, prearing an organic acid from the cyanide under the action of an alkali, processing the organic acid by a lithium methide reagent to obtain 3-acetyl-10,11-dihydro-5H-benzo[d]naphtho[2,3-b] ]pyran-8(9H)-one, and carrying out a two-step bromination reaction to obtain the anti-hepatitis C medicine Velpatasvir intermediate. The method provides a brand new synthesis route of the anti-hepatitis C medicine Velpatasvir intermediate, and has the advantages of easily controlled reaction steps, and realization of stable industrial production preparation.

Description

technical field [0001] The present invention relates to the field of synthesis of anti-hepatitis C drugs, specifically an anti-hepatitis C drug velpatasvir intermediate 10,11-dihydro-5H-benzo[d]naphtho[2,3-b]pyrone derivative 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-benzo[d]naphtho[2,3-b]pyran-8(9H)-one ( V) Preparation method. Background technique [0002] Gilead announced the clinical phase III results of its new anti-hepatitis C drug velpatasvir (GS5816) combined with sofosbuvir in the treatment of HCV infection in patients with decompensated liver cirrhosis. Studies have shown that the combination of Sofosbuvir-Velpatasvir can achieve a high effect on the treatment of viruses. Some experts commented: "The antiviral drug Sofosbuvir-Velpatasvir for hepatitis C has opened the door for the treatment of hepatitis C. New Era". [0003] [0004] 9-Bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-benzo[d]naphtho[2,3-b]pyran-8(9H)-one is a synthetic The key intermediate of Tasvi...

Claims

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Application Information

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IPC IPC(8): C07D311/78
CPCC07D311/78
Inventor 刘现军戴益思张中剑余飞飞黄文飞
Owner 苏州楚凯药业有限公司
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