Preparation method of antiviral drug tenofovir disoproxil fumarate intermediate chloromethyl isopropyl carbonate

A kind of technology of chloromethyl isopropyl carbonate and tenofovir disoproxil, applied in the field of preparation of intermediates, can solve the complex steps, high cost, rarely reported chloromethyl chloroformate or chloromethyl isopropyl Carbonate synthesis and other problems, to achieve the effects of high reactivity, improved yield and low cost

Inactive Publication Date: 2012-04-04
扬州三友合成化工有限公司
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Problems solved by technology

Its methyl chloroformate is still prepared by the reaction of phosgene and methanol, the steps are cumbersome and the cost is high
[0010

Method used

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  • Preparation method of antiviral drug tenofovir disoproxil fumarate intermediate chloromethyl isopropyl carbonate
  • Preparation method of antiviral drug tenofovir disoproxil fumarate intermediate chloromethyl isopropyl carbonate
  • Preparation method of antiviral drug tenofovir disoproxil fumarate intermediate chloromethyl isopropyl carbonate

Examples

Experimental program
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Example Embodiment

[0039] 1. Example 1:

[0040] 1. Synthesis of a mixture of methyl chloroformate and methyl chloroformate:

[0041] Under the protection of nitrogen, with magnetic stirring, add 500 g methyl formate and 4 g AIBN to a 1000 mL four-necked flask, connect with condensed water, heat directly to reflux, and pass Cl 2 , Its tail gas adopts 20% NaOH solution to absorb the discharged HCl gas. It takes about 8-10h to complete the first step of chlorination of methyl formate. It is completely converted into methyl chloroformate and methyl chloroformate on gas chromatography (GC), and the ratio is close to 1:1. The mixed product is reserved for future use.

[0042] 2. Synthesis of chloromethyl chloroformate:

[0043] Add all the mixture of methyl chloroformate and chloromethyl formate obtained above, add 4g AIBN again, and pass in chlorine again under reflux state (60~80℃), when the main peak of chloromethyl chloroformate reaches 75-80% content At this time, the dichloromethyl chloroformat...

Example Embodiment

[0046] 2. Embodiment 2:

[0047] 1. Synthesis of a mixture of methyl chloroformate and methyl chloroformate:

[0048] Under the protection of nitrogen, with magnetic stirring, add 500 g of methyl formate and 4 g of BPO to a 1000 mL four-necked flask, connect to the condensed water, heat directly to reflux, and pass Cl 2 , Its tail gas adopts 20% NaOH solution to absorb the discharged HCl gas. It takes about 8-10h to complete the first step of chlorination of methyl formate. It is completely converted into methyl chloroformate and methyl chloroformate on GC, and the ratio is close to 1:1. The mixed product is reserved for future use.

[0049] 2. Synthesis of chloromethyl chloroformate:

[0050] Add 4g of BPO to the entire mixture of methyl chloroformate and chloromethyl formate obtained above, and add chlorine gas again under reflux (60~80℃). When the main peak of chloromethyl chloroformate reaches 75-80% content At this time, the dichloromethyl chloroformate has reached abou...

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Abstract

The invention discloses a preparation method of antiviral drug tenofovir disoproxil fumarate intermediate chloromethyl isopropyl carbonate, and belongs to the field of antiviral chemical drugs. The preparation method is characterized in that methyl formate as a raw material is synthesized into chloromethyl chloroformate by an one-kettle method and the chloromethyl chloroformate undergoes an esterification reaction to form chloromethyl isopropyl carbonate. The preparation method is easy for operation, has a low cost and a high yield, realizes high purity of products, and is very suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of antiviral chemical drugs, and in particular relates to a preparation method of an intermediate of tenofovir disoproxil, an anti-hepatitis B and HIV virus drug. Background technique [0002] Tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, chemical name (R)-[[2-(6-amino-9H-purine-9- Base]-l-methylethoxy]methyl]phosphonic acid bis(isopropionyloxymethyl)fumarate is a nucleotide reverse transcriptase inhibitor developed by Gilead Sciences in the United States. The prodrug of the oral open ring nucleotide monophosphonate has the following structural formula: [0003] [0004] Tenofovir disoproxil is rapidly converted to tenofovir (R)-9-[2-(phosphonomethoxy)propyl]adenine (PMPA) after oral absorption. PMPA has been confirmed to have broad-spectrum antiviral activity against human immunodeficiency virus HIV and other retroviruses, and has been approved by the US FDA in 2001 as a drug for clinical treatme...

Claims

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Application Information

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IPC IPC(8): C07C69/96C07C68/00
Inventor 魏开举李明成张扬张众笑李辉宁张才山
Owner 扬州三友合成化工有限公司
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