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A kind of preparation method of key intermediate of tenofovir alafenamide fumarate
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A technology of tenofovir fumarate and alafenamide, which is applied in the field of drug synthesis, can solve the problems of no advantageous effect, increased waste liquid discharge treatment, increased environmental protection pressure, etc., and achieves stable mass scale-up production, secondary The effect of less product and lower cost
Active Publication Date: 2020-08-11
CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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[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 number of reaction steps obtained from the raw material, increases the cost, but also increases the waste liquid Discharge treatment, increased the pressure of environmental protection, and did not produce any substantial advantages
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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 present 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. The present invention provides a new method for preparing tenofovir alafenamide fumarate key intermediate 2 with high diastereomer purity. The method has the advantages of short reaction time, few by-products, simple operation and high product quality Good quality, high reaction yield, more suitable for industrial production and other characteristics.
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 (...
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