Synthesis method of Daclatasvir

A synthesis method and technology of synthesis process, applied in the direction of organic chemistry, etc., can solve the problems of unsustainable response of patients, cumbersome treatment, adverse reactions, etc., and achieve the effects of cheap raw materials, simplified operation process, and little environmental pollution.

Inactive Publication Date: 2016-07-20
安徽联创生物医药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The current standard of care for HCV infection involves interferon-alpha alone or in combination with ribavirin, which is c

Method used

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  • Synthesis method of Daclatasvir
  • Synthesis method of Daclatasvir
  • Synthesis method of Daclatasvir

Examples

Experimental program
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Example Embodiment

[0029] Example 1

[0030] This embodiment relates to a synthetic method of dacatavir, which consists of the following steps:

[0031] Step 1. Synthesis of Intermediate 1

[0032] Dissolve 4.4-diacetyl biphenyl (40g, 0.17mol) and DIPEA (53g, 0.41mol) in 1000mL dichloromethane, add TMSOTf (0.37mol) dropwise at 0°C, stir for 15 minutes after dripping, and add NBS( 0.39mol) in dichloromethane (200mL) solution, after dripping at 0℃, stirring for 2h, the reaction is complete, the system is poured into 500mL water, layered, dried with anhydrous sodium sulfate, suction filtered, concentrated to remove the dichloromethane to obtain the intermediate 1 Crude product, toluene crystallized to obtain 61g solid, yield 91%;

[0033] MP: 224-226℃, 1 HNMR(400MHz, CDCl 3 ):δ(ppm):7.96-7.84(m,4H),7.61-7.52(m,4H),4.26(s,4H), HRMS(ESI):m / z[M+H] - 394.93.

[0034] Step two, synthesis of intermediate 2

[0035] Intermediate 1 (40g, 0.101mol) and L-proline derivative (60g, 0.222mol) were dissolved in 400mL of ...

Example Embodiment

[0039] Example 2

[0040] This embodiment relates to a synthetic method of dacatavir, which consists of the following steps:

[0041] Step 1. Synthesis of Intermediate 1

[0042] Dissolve 4.4-diacetylbiphenyl (40g, 0.17mol) and DIPEA (49g, 0.38mol) in 1000mL dichloromethane, add TMSOTf (0.39mol) dropwise at 0°C, stir for 15 minutes after dripping, and add NBS( 73g, 0.41mol) in dichloromethane (200mL) solution, after dripping at 0℃, stirring for 2h, the reaction is complete, the system is poured into 500mL water, layered, dried with anhydrous sodium sulfate, filtered with suction, concentrated to remove the dichloromethane, The crude intermediate 1 was crystallized from toluene to obtain 62 g of solid with a yield of 92%;

[0043] MP: 224.5-226.5℃, 1 HNMR(400MHz, CDCl 3 ):δ(ppm):7.95-7.84(m,4H),7.62-7.52(m,4H),4.27(s,4H), HRMS(ESI):m / z[M+H] - 394.94.

[0044] Step two, synthesis of intermediate 2

[0045] Intermediate 1 (40g, 0.101mol) and L-proline derivative (60g, 0.252mol) were disso...

Example Embodiment

[0049] Example 3

[0050] This embodiment relates to a synthetic method of dacatavir, which consists of the following steps:

[0051] Step 1. Synthesis of Intermediate 1

[0052] Dissolve 4.4-diacetyl biphenyl (40g, 0.17mol) and DIPEA (0.39mol) in 1000mL dichloromethane, add TMSOTf (91g, 0.41mol) dropwise at 0°C, stir for 15 minutes after dripping, and add NBS( 66g, 0.37mol) in dichloromethane (200mL) solution, after dripping and stirring at 0°C for 2h, the reaction is complete, the system is poured into 500mL water, separated into layers, dried with anhydrous sodium sulfate, filtered with suction, concentrated to remove the dichloromethane to obtain The crude intermediate 1 was crystallized from toluene to obtain 62 g of solid with a yield of 92%;

[0053] MP:225-226℃, 1 HNMR(400MHz, CDCl 3 ):δ(ppm):7.96-7.85(m,4H),7.60-7.52(m,4H),4.27(s,4H), HRMS(ESI):m / z[M+H] - 394.93.

[0054] Step two, synthesis of intermediate 2

[0055] Intermediate 1 (40g, 0.101mol) and L-proline derivative (60...

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Abstract

The invention relates to a synthesis method of Daclatasvir. The method comprises the following steps: step 1, performing a bromination reaction on 4.4-diacetyl biphenyl which serves as a raw material so as to obtain an intermediate 1; step 2, performing a substitution reaction on the intermediate 1 so as to obtain an intermediate 2; step 3, performing a cyclization reaction on the intermediate 2 so as to finally obtain the Daclatasvir. Compared with reported synthesis routes, a synthesis route of the method has the following advantages that the route is short, and the yield is high; general means such as suction filtration, extraction and concentration are adopted for aftertreatment, and aftertreatment is simple and convenient; severe-pollution and high-toxicity reagents such as bromine are avoided, and a process of repeatedly using an acetic acid washing reaction system is avoided.

Description

technical field [0001] The invention relates to a synthesis method of hepatitis C virus NS5A inhibitor, in particular to a synthesis method of Daclatasvirdihydrocholide. Background technique [0002] Hepatitis C virus (HCV) is the main cause of chronic liver disease, and there is currently no vaccine to prevent HCV infection. The current standard of care for HCV infection involves interferon-alpha alone or in combination with ribavirin, which is cumbersome and has debilitating or other serious adverse effects, and many patients do not respond sustainably to treatment. Daclatasvir (Daclatasvirdihydrocholide), as a highly selective hepatitis C virus NS5A inhibitor, is a small molecule drug with direct antiviral effect, and it is also the first NS5A replication complex inhibitor for hepatitis C clinical use. [0003] In recent years, ShawnK.Pack (US7728027B2, published on June 01, 2010) and others have used 4.4-diacetylbiphenyl as raw material to obtain intermediate 1 through ...

Claims

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Application Information

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IPC IPC(8): C07D403/14
CPCC07D403/14
Inventor 张中涛吴其华葛德培刘涛
Owner 安徽联创生物医药股份有限公司
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