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Preparation method and application for high-purity tenofovir alafenamide fumarate intermediate

A technology of tenofovir and tenofovir alafenamide, which is applied in the preparation and application of high-purity tenofovir fosprovir intermediates, can solve complex operations, high production costs, and cumbersome post-treatment processes and other problems, to achieve the effect of simple and safe operation, high product purity and low production cost

Active Publication Date: 2017-03-08
SHANGHAI BOCIMED PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The technical problem to be solved by the present invention is to overcome the complex operation of the preparation method of fosprotenofovir intermediate tenofovir alafenamide II in the prior art, complicated post-treatment process, high production cost, and the resulting product Due to defects such as poor optical purity and being unsuitable for industrialized production, a preparation method and application of a high-purity fosprotenofovir intermediate are provided

Method used

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  • Preparation method and application for high-purity tenofovir alafenamide fumarate intermediate
  • Preparation method and application for high-purity tenofovir alafenamide fumarate intermediate
  • Preparation method and application for high-purity tenofovir alafenamide fumarate intermediate

Examples

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Effect test

Embodiment 1

[0041] Example 1: The preparation method of tenofovir alafenamide intermediate III (reference US7803788 Example 2)

[0042]

[0043] Add 3.0Kg of tenofovir and 1.98Kg of phenol into 9L of N-methylpyrrolidone, heat to 60℃~70℃, add 1.68Kg of N,N-diisopropylethylamine and 3.53Kg of dicyclohexylcarbodiimide , heated to 90°C-100°C and stirred for 16 hours, cooled to 10-20°C, added dropwise 7.5L of water and stirred for 2 hours, filtered, and washed with 3L of water. The filtrate is adjusted to pH 11~12 with 20% sodium hydroxide aqueous solution (the described mass percentage refers to the percentage of the quality of sodium hydroxide in the total mass of sodium hydroxide aqueous solution) with a mass percentage of 20%, and is extracted with 7.5 L of ethyl acetate Twice, after separating the water phase, adjust the pH to 2.5-3.5 with concentrated hydrochloric acid, cool to 10-20°C and stir for 2 hours, filter, and dry in vacuum (-0.08--1.0MPa) at 40-50°C for 8-12 hours 2.67Kg of...

Embodiment 2

[0044] Example 2: Preparation method of tenofovir alafenamide II crude product (reference US7803788 Example 2)

[0045]

[0046] Add 2.40Kg of tenofovir alafenamide intermediate III (HPLC purity 95.85%) into 12L of acetonitrile, add 1.20Kg of thionyl chloride, heat to 75°C to 85°C and stir for 2 hours, then distill under reduced pressure after cooling most solvents. Dissolve the residue in 9L of dichloromethane, stir and cool to -25~-15℃, then add 1.97Kg of L-alanine isopropyl ester and 8.4L of dichloromethane, then add 1.1Kg of triethylamine, Stir at -15°C for 3 hours, then rise to room temperature (10°C to 35°C), and use 10% sodium dihydrogen phosphate aqueous solution (the mass percentage refers to the mass percentage of sodium dihydrogen phosphate to sodium dihydrogen phosphate The percentage of total mass of aqueous solution) 10L washes 4 times, is 10% sodium chloride aqueous solution 9L washes 1 time with mass percentage (the described mass percentage refers to the q...

Embodiment 3

[0047] Embodiment 3: the preparation method of tenofovir alafenamide II

[0048] Tenofovir alafenamide II crude product 900g (HPLC purity 98.66%, chiral-HPLC purity 95.29%, wherein diastereoisomer 4.71%, enantiomer was not detected) was added acetonitrile 1.8L and In 7.2L of toluene, heat to 70℃~80℃ and stir at 120 rpm for 0.5 hours, slowly cool to 0~10℃ and stir at 60 rpm for 2 hours, filter, vacuum at 40~50℃ (-0.08~ -1.0 MPa) drying for 8-12 hours to obtain 760 g of tenofovir alafenamide II, with a yield of 84.4%. The HPLC purity is 99.87%, the largest single impurity is 0.04%, the chiral-HPLC purity is 99.98%, and the diastereoisomer is 0.02%, and the enantiomer is not detected.

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Abstract

The invention discloses a preparation method and an application for a high-purity tenofovir alafenamide fumarate intermediate. The preparation method for the tenofovir alafenamide fumarate intermediate namely tenofovir alafenamide II provided by the invention comprises the following steps: subjecting crude tenofovir alafenamide fumarate intermediate namely tenofovir alafenamide II to recrystallization in a mixed solvent of a nitrile solvent and water or a mixed solvent of the nitrile solvent and an aromatic hydrocarbon solvent so as to obtain the high-purity tenofovir alafenamide fumarate intermediate namely tenofovir alafenamide II. The high-purity tenofovir alafenamide II has an optical purity larger than 99.50% and a chemical purity larger than 99.60%; and the crude tenofovir alafenamide fumarate intermediate namely tenofovir alafenamide II has the optical purity in a range of 60.00% to 99.00% and the chemical purity in a range of 60.00% to 99.00%. The preparation method provided by the invention has the advantages of simple and safe operation, high yield, high product purity, low production cost, and applicability to industrial production.

Description

technical field [0001] The invention relates to a preparation method and application of a high-purity fosprotenofovir intermediate. Background technique [0002] Tenofovir alafenamide I (tenofovir alafenamide fumarate, TAF) is a new type of nucleoside reverse transcriptase inhibitor. When the dose is lower than one-tenth of Gilead's marketed drug Tenofovir Disoproxil Fumarate Tablets, it has a very high antiviral effect and can improve renal function and bone parameters. Tenofovir alafenamide fumarate was safe and well tolerated. "Compared with tenofovir disoproxil fumarate, there were no discontinuations due to renal adverse events; significantly less proteinuria and tubular proteinuria side effects; effects on spine and hip bone mineral density Significantly less impact. [0003] [0004] The preparation method of fosprotenofovir I is generally obtained in the following manner: after tenofovir activation, successively add phenol and L-alanine isopropyl ester to obtai...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561
CPCC07B2200/07C07F9/65616
Inventor 应述欢皮红军公绪栋王亮陈健
Owner SHANGHAI BOCIMED PHARMA CO LTD
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