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Industrialized continuous production method of hemifumarate tenofovir alafenamide

A technology for tenofovir alafenamide and production method, which is applied in the field of industrialized continuous production of tenofovir alafenamide hemi-fumarate, can solve the problems of low yield and high equipment requirements, and can reduce production time , the effect of improving production efficiency

Inactive Publication Date: 2017-12-29
SHENZHEN KEXING PHARM CO LTD
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  • Abstract
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Problems solved by technology

High requirements on equipment and low yield

Method used

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  • Industrialized continuous production method of hemifumarate tenofovir alafenamide
  • Industrialized continuous production method of hemifumarate tenofovir alafenamide
  • Industrialized continuous production method of hemifumarate tenofovir alafenamide

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Embodiment 1

[0069] Embodiment 1, industrialized continuous production tenofovir alafenamide hemifumarate

[0070] Step 1 (reaction flow chart sees Figure 5 ):

[0071] 120kg of acetonitrile was pumped into the 500L reactor, 20kg (69.6mol) of tenofovir was added, 32kg (103mol) of triphenyl phosphite, 8kg (65.5mol) of DMAP, 14kg (138mol) of triethylamine, and the temperature was slowly refluxed for 72 Hour. Cool down to 50°C and concentrate acetonitrile to dryness under reduced pressure, add 100 kg of purified water, extract three times with ethyl acetate, each time 60 kg, and keep the water layer. Acidify with hydrochloric acid to a pH value of 2.0-3.0, filter with a plate centrifuge, rinse the solid with 0.1M hydrochloric acid, rinse the solid with dichloromethane, filter until dry, and feed the solid with TAF-I M for later use.

[0072] Step 2 (reaction flow chart sees Figure 6 ):

[0073] Into the 500L reactor I, suck 250kg of toluene, add the above-mentioned TAF-I M steam to rai...

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Abstract

The invention discloses an industrialized continuous production method of tenofovir alafenamide and hemifumarate. The method comprises the following steps: firstly, in the presence of an acid-binding agent, reacting tenofovir with triphenyl phosphate to obtain a TAF-I M shown as a formula II; secondly, continuously preparing a TAF-II M by using the TAF-I M; thirdly, carrying out a salt forming reaction on the TAF-II M to obtain the hemifumarate tenofovir alafenamide. According to the industrialized continuous production method disclosed by the invention, a key compound tenofovir alafenamide is obtained by continuous production; the hemifumarate tenofovir alafenamide is obtained by accurately feeding fumaric acid and the tenofovir alafenamide; and in addition, a diastereoisomer of the tenofovir alafenamide is inhibited by using high catalytic enantioselectivity of a proline catalyst, and industrial production of optically-pure tenofovir alafenamide of which the purity is greater than 99.9 percent is realized by primary crystallization. The industrial production method disclosed by the invention has the advantages of simplicity, safety and low production cost; and besides, a high-purity product is obtained.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to an industrial continuous production method of tenofovir alafenamide hemifumarate. Background technique [0002] Tenofovir alafenamide (TAF for short), chemical name 9-[(R)-2-[[[[(S)-1-(isopropoxycarbonyl)ethyl]amino]benzene Oxyphosphinyl]methoxy]propyl]adenine is a new type of nucleoside reverse transcriptase inhibitor (NRTI), developed by Gilead, and another antiviral drug of Gilead. Compared with norfovir dipivoxil (TDF), only one-tenth of the dose of the latter can achieve excellent antiviral effect. In March 2016, the US FDA approved its new compound human immunodeficiency virus (HIV) drug F / TAF (emtricitabine / tenofoviralafenamide, emtricitabine / tenofovir alafenamide), providing HIV patients with more drugs s Choice. [0003] The structural formula of tenofovir alafenamide hemifumarate is as follows: [0004] [0005] Tenofovir alafenamide is the free base...

Claims

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Application Information

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IPC IPC(8): C07F9/6561C07C51/41C07C57/15
CPCC07F9/65616
Inventor 吴聪泉马鸿杰彭武将许月娇
Owner SHENZHEN KEXING PHARM CO LTD
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