Method of reducing impurities in synthesis process of emtricitabine intermediate MGH

A synthesis process and technology of emtricitabine, applied in chemical instruments and methods, preparation of organic compounds, preparation of sulfonates, etc., can solve the problems of long production cycle, increased amount of impurity compound III during holding time, and reduced production capacity, etc. To achieve the effect of reducing the impurity content, shortening the reaction cycle and improving the yield

Active Publication Date: 2015-12-09
JIANGXI FUSHINE PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] At present, the vast majority of documents require a long time of heat preservation (>20h) in the addition process of sodiu

Method used

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  • Method of reducing impurities in synthesis process of emtricitabine intermediate MGH
  • Method of reducing impurities in synthesis process of emtricitabine intermediate MGH
  • Method of reducing impurities in synthesis process of emtricitabine intermediate MGH

Examples

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Embodiment 1

[0039] Add 100g cyclohexane in 1000ml bottle, add 87.2g50% glyoxylic acid (0.59mol) and 5g vitriol oil, heat up and reflux, slowly add the cyclohexane solution of 220gL-menthol (L-menthol 120g (0.77mol) , cyclohexane 100g), reflux and water separation for about 5 hours. The temperature was lowered under the protection of nitrogen, and 30ml of cyclohexane and 60ml of water were added, stirred for 10 minutes, and allowed to stand to separate into layers. The organic phase was washed once with 60 g of water and 50 ml of saturated NaCl aqueous solution, and the organic phase was collected for use.

[0040] Add 150g NaHSO to a 2000ml bottle 3 Aqueous solution (NaHSO 3 0.60mol), stirring and controlling the temperature at 25-30°C, adding the organic phase of the previous step, and using saturated Na 2 CO 3 Adjust pH=4.5-5.5, keep the temperature and pH value at 60°C for 8 hours, and let stand to separate layers. The aqueous layer was washed once with 100g cyclohexane, and then ...

Embodiment 2

[0045] In 1000ml bottle, add 100g cyclohexane, add 87.2g50% glyoxylic acid (0.59mol) and 5g vitriol oil, heat up and reflux, slowly add the cyclohexane solution of 220gL-menthol (L-menthol 120g (0.77mol) , cyclohexane 100g), reflux and water separation for about 5 hours. The temperature was lowered under the protection of nitrogen, and 30ml of cyclohexane and 60ml of water were added, stirred for 10 minutes, and allowed to stand to separate into layers. The organic phase was washed once with 60 g of water and 50 ml of saturated NaCl aqueous solution, and the organic phase was collected for use.

[0046] Add 150g NaHSO to a 2000ml bottle3 Aqueous solution (NaHSO 3 0.60mol), stirring and controlling the temperature at 25-30°C, adding the organic phase of the previous step, and using saturated Na 2 CO 3 Adjust the pH=4.5-5.5, keep the temperature and pH value at 50°C for 6 hours, and let stand to separate layers. The aqueous layer was washed once with 100g cyclohexane, and th...

Embodiment 3

[0050] Add 100g cyclohexane in 1000ml bottle, add 87.2g50% glyoxylic acid (0.59mol) and 5g vitriol oil, heat up and reflux, slowly add the cyclohexane solution of 220gL-menthol (L-menthol 120g (0.77mol) , cyclohexane 100g), reflux and water separation for about 5 hours. The temperature was lowered under the protection of nitrogen, and 30ml of cyclohexane and 60ml of water were added, stirred for 10 minutes, and allowed to stand to separate into layers. The organic phase was washed once with 60 g of water and 50 ml of saturated NaCl aqueous solution, and the organic phase was collected for use.

[0051] Add 150g NaHSO to a 2000ml bottle 3 Aqueous solution (NaHSO 3 0.60mol), stirring and controlling the temperature at 25-30°C, adding the organic phase of the previous step, and using saturated Na 2 CO 3 Adjust the pH=4.5-5.5, keep the temperature and pH value at 55°C for 5 hours, and let stand to separate the layers. The aqueous layer was washed once with 100g cyclohexane, a...

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Abstract

The invention discloses a method of reducing impurities in a synthesis process of an emtricitabine intermediate MGH. The method comprises the following steps: taking L-menthol and glyoxylic acid as raw materials; carrying out an esterification reaction under acid catalysis; carrying out an addition reaction under the action of sodium hydrogen sulfite; carrying out a hydroxylation reaction under the action of formaldehyde; carrying out post-treatment to obtain L-menthyl dyhydroxy acetate, wherein in the process of the addition reaction, the pH value is 4-6, and the reaction temperature is 40-80 DEG C and the reaction time is 4-10 hours. With the adoption of the method, the reaction time is greatly shortened and a reaction period is shortened; meanwhile, in a reaction process, cyclohexane is only used as an organic solvent, so that the operation is simple and the post-treatment is convenient; by controlling process conditions and post-treatment conditions, the content of impurities is greatly reduced and the yield is improved. Meanwhile, certain helps are provided for registration and application, and production and center control of emtricitabine, and improvement of quality standards of the emtricitabine intermediate.

Description

technical field [0001] The invention relates to a method for reducing synthetic impurities of an emtricitabine intermediate MGH, which belongs to the technical field of drug synthesis. Background technique [0002] Emtricitabine, chemical name: 5-fluoro-1-(2R,5S)-[2-hydroxymethyl-1,3-oxathione-5-yl]cytosine, the structure is as follows: [0003] [0004] Compound (I). [0005] Emtricitabine (emtricitabine) is an HIV treatment drug developed by GileadSciences of the United States. It was first launched in the United States in July 2003, and the clinical trial as a hepatitis B treatment drug is about to be completed. Emtricitabine (Emtriva) is a class of nucleoside reverse transcriptase inhibitors that are phosphorylated to 5'-triphosphate by cellular enzymes, and 5'-triphosphate is passed with deoxy 5'-triphosphate substrate Competitively inhibits the activity of HIV-1 reverse transcriptase and binds to viral DNA to cause chain termination, thereby inhibiting the virus. ...

Claims

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Application Information

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IPC IPC(8): C07C67/31C07C69/675
CPCC07C67/08C07C67/31C07C303/32C07C69/716C07C69/675C07C309/17
Inventor 余翔周忠波龚杰谢永居刘霞张桂菊杨玉平储玲洁
Owner JIANGXI FUSHINE PHARMA CO LTD
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