Preparation method of key intermediate TAF (tenofovir alafenamide fumarate)

A technology of tenofovir fumarate and alafenamide, which is applied in the field of drug synthesis, can solve the problems of increasing environmental protection pressure, not producing superior effects, increasing waste liquid discharge and treatment, etc., and achieving stable batch scale-up production and low cost Low, less by-product effect

Active Publication Date: 2018-11-16
CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] This route is similar to the patent US20130090473A1, except that the material 1′ with a protective group is used, the rest of the reaction conditions are the same, and the additional protective group not only increases the n

Method used

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  • Preparation method of key intermediate TAF (tenofovir alafenamide fumarate)
  • Preparation method of key intermediate TAF (tenofovir alafenamide fumarate)
  • Preparation method of key intermediate TAF (tenofovir alafenamide fumarate)

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] The preparation of embodiment 1 high diastereoisomeric purity intermediate 2

[0045]

[0046] (1) Preparation of intermediate 1‐1:

[0047] Preparation of 9‐[(R)‐2[[(S)‐[di‐(phenoxy)phosphinyl]methoxy]propyl]adenine

[0048]At room temperature, add 25L of acetonitrile to a 100L glass-lined reactor, start stirring, then add tenofovir (5kg, 17.4mol), thionyl chloride (6.2kg, 52.1mol), and replace nitrogen protection (nitrogen replacement 3 Once, the vacuum degree of the reactor is ≤-0.080MPa, stir for 3-5 minutes, backfill nitrogen to normal pressure and stir for 3-5 minutes for a nitrogen replacement). After the addition is complete, raise the temperature to 70°C, keep the temperature for 2 hours, concentrate under reduced pressure, and then add 25L of acetonitrile and phenol (6.6kg, 69.6mol) into the glass-lined reactor, start stirring, and heat up to about 80°C. React for 13 hours, concentrate under reduced pressure, add 25L of ethyl acetate to the 100L glass-lin...

Embodiment 2

[0067] The nuclear magnetic data of embodiment 2-5 is consistent with embodiment 1 result.

Embodiment 6

[0068] The preparation of embodiment 6 high diastereoisomeric purity intermediate 2

[0069]

[0070] Add intermediate 1 9‐[(R)‐2‐[[(hydroxyphenoxyphosphono)methoxy]propyl]]adenine (10.0g, 27.5mmol) and 200.0g xylene in a 250ml three-necked flask , acetonitrile 20.0g, oxalyl chloride (34.9g, 275.0mmol), magnetic stirring, nitrogen replacement protection, heating up to 60°C, heat preservation reaction for 30h, cooling down to room temperature, concentrating under reduced pressure to remove oxalyl chloride, filtering, and vacuum drying to obtain off-white The solid is 9.9g, that is, intermediate 2, and the yield is 94%. Diastereomeric purity 91.59%. The NMR data is consistent with the result of Example 1.

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Abstract

The invention belongs to the field of pharmaceutical synthesis, relates to a preparation method of a drug intermediate and particularly relates to a preparation method of a key intermediate TAF (tenofovir alafenamide fumarate). The invention provides a method for preparing a key intermediate TAF 2 with high diastereoisomer purity; the method has the characteristics of being short in reaction time,less in by-products, simple in operation, good in product quality and high in reaction recovery, being suitable for industrial production and the like.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, and relates to a preparation method of a medicine intermediate, in particular to a preparation method of a key intermediate of tenofovir alafenamide fumarate. Background technique [0002] The chemical name of tenofovir (PMPA, TFV) is (R)-9-(2-phosphomethoxypropyl)-adenine, which has antiviral and anti-hepatitis B activities, and its toxicity is much lower than that of adefovir. Tenofovir has strong acidity and high polarity, it is difficult to penetrate the cell membrane, and its bioavailability is poor. Its strong acidity has certain toxicity to bone. Tenofovir can increase the osmotic burden of glomeruli, especially in patients with impaired renal function. [0003] Tenofovir disoproxil fumarate (TDF), its chemical name is: 9‐[(R)‐2‐[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methanol Oxygen]‐propyl]adenine fumarate (1:1), is a new type of nucleotide reverse transcriptase inhibitors (...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
CPCC07F9/65616
Inventor 王颖林松张涛
Owner CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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