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Emtricitabine benzoate, preparation method thereof, and method of preparing emtricitabine from emtricitabine benzoate

A technology of emtricitabine and benzoic acid, applied in the field of biochemistry, can solve the problems of poor product quality of emtricitabine, poor solid form of emtricitabine salt, and low yield

Active Publication Date: 2015-12-09
SHANDONG WEIFANG PHARMA FACTORY
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AI Technical Summary

Problems solved by technology

[0005] The disadvantage of method 1 is that the solid state of emtricitabine salt of salicylic acid or fluorobenzoic acid is poor. Experiments show that agglomeration and semi-solidification often occur, and the obtained corresponding emtricitabine salt wraps many inorganic salts and reaction by-products The shortcoming of method two is that the entire process does not carry out the complete separation of the emtricitabine product and the reduction reaction system, the yield is low, and the alcohol extract contains a large amount of reduction by-products
Simultaneously method one, the maximum defective that method two is shared is that the emtricitabine product quality that two kinds of processes obtain is poor, and wherein emtricitabine product China, the water dissolution of United States Pharmacopoeia requirement (1g emtricitabine is dissolved in less than or equal to 10ml of water, the solution should be clear) the index is difficult to meet the standard, the product aqueous solution has turbidity and white floating matter, and emtricitabine needs to be recrystallized many times to meet the requirements of the Pharmacopoeia

Method used

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  • Emtricitabine benzoate, preparation method thereof, and method of preparing emtricitabine from emtricitabine benzoate
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  • Emtricitabine benzoate, preparation method thereof, and method of preparing emtricitabine from emtricitabine benzoate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Embodiment 1: the preparation of emtricitabine benzoate

[0023] Add 160g of dipotassium hydrogen phosphate and 180g of water into the reaction flask equipped with a stirrer and a thermometer, stir until the dipotassium hydrogen phosphate is dissolved, add 120g of FCME and 1L of ethanol, and drop the mixed solution (2.4ml25% Aqueous sodium hydroxide solution, 48.6g potassium borohydride, 240ml water). After dropping, stir at 15-30°C for 2 hours. Use hydrochloric acid to adjust the pH to 4.0-4.5, and then use sodium hydroxide aqueous solution to adjust the pH to 6.8-7.2. Remove most of the ethanol under reduced pressure, and wash the remaining liquid with toluene three times. Move the water phase into a 1L reaction flask, add 36.7g of benzoic acid after heating to 40°C, keep stirring at 40-50°C for 2 hours, filter, wash with water, and dry the filter cake to obtain 95g of emtricitabine benzoate, The yield is 85%. MP: 121.2-122.6°C, 1 HNMR (DMSO) 400MHzδ8.211~8.228 (d...

Embodiment 2

[0024] Embodiment 2. Preparation of Emtricitabine Benzoate

[0025] Add 160g of dipotassium hydrogen phosphate and 180g of water into the reaction flask, stir until the dipotassium hydrogen phosphate dissolves, add 120g of FCME and 1L of ethanol, and drop the mixed solution (2.4ml of 25% sodium hydroxide aqueous solution, 34.13g of boron sodium hydride, 240ml water). After dropping, stir at 15-30°C for 5 hours. Use hydrochloric acid to adjust the pH to 4.0-4.5, and then use sodium hydroxide aqueous solution to adjust the pH to 6.8-7.2. Remove most of the ethanol under reduced pressure, and wash the remaining liquid with toluene three times. Move the water phase into a 1L reaction flask, add 36.7g of benzoic acid after heating to 40°C, keep stirring at 40-50°C for 2 hours, filter, wash with water, and dry the filter cake to obtain 85g of emtricitabine benzoate. Yield 77%.

Embodiment 3

[0026] Embodiment 3. Preparation of Emtricitabine

[0027] Add 95g of emtricitabine benzoate and 475g of isopropyl acetate into a 1L reaction flask, add 40.8g of triethylamine dropwise under stirring, after the drop is complete, keep stirring at 15-30°C for 4 hours, filter with suction, and filter the cake Wash twice with isopropyl acetate. The filter cake was dried to obtain 57.2 g of white solid emtricitabine. Yield 90%, purity greater than 99%, MP: 152.8-153.5°C.

[0028] 1 HNMR (DMSO) 400MHzδ8.18~8.20(d,J=8.0,1H),7.56,7.80(weak,2H),6.13~6.16(m,1H),5.38~5.41(weak,1H),5.18~5.20( t, J=4.0,1H), 3.82~3.71(2m,2H), 3.40~3.45(dd, J=12.0,1H), 3.11~3.15(dd,J=12.0,1H).

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Abstract

The invention discloses emtricitabine benzoate, a preparation method thereof, and a method of preparing emtricitabine from emtricitabine benzoate, and belongs to the biochemistry field. Emtricitabine benzoate is a novel compound, has not been reported before, and is not recorded in any product catalogue. The emtricitabine benzoate is prepared by combining benzoic acid and emtricitabine in a water phase or an organic phase. When benzoic acid and emtricitabine are combined in a water phase or an organic phase, emtricitabine benzoate can be easily separated from the reaction system. By adding organic base or inorganic base into the water phase / organic phase reaction system, emtricitabine benzoate can be decomposed to obtain emtricitabine. By preparing emtricitabine from emtricitabine benzoate, after the reactions, emtricitabine can be easily separated from the reaction system, the purity of the obtained emtricitabine is more than 99%, and the yield is usually more than 80%.

Description

technical field [0001] The invention relates to the field of biochemistry, in particular to emtricitabine benzoate salt, a preparation method thereof and a method for preparing emtricitabine with emtricitabine benzoate salt. Background technique [0002] Emtricitabine is a deoxyribose flucytosine drug, its chemical name is 5-fluoro-1-(2R,5S)-[2-hydroxymethyl-1,3-oxathione-5-yl] Cytosine has a good anti-HIV effect and is widely used in the treatment of HIV. [0003] The existing emtricitabine production technology is mostly chiral chemical synthesis, from FCME (2R,5S)-(5-fluoropyrimidine)-(1.3)oxathiolane-2-carboxylic acid-1-meng base ester) obtained by reduction reaction, because it is necessary to maintain the chirality of the material in the reaction process, a large amount of dipotassium hydrogen phosphate is added in the reaction system, and its reducing agent is mostly one of sodium borohydride, potassium borohydride or red aluminum, so In the reaction system, there a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D411/04C07C63/08C07C51/41
CPCC07D411/04
Inventor 王素梅冉东升邓兵李金姑
Owner SHANDONG WEIFANG PHARMA FACTORY
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