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Preparation method of fosamprenavir derivative and related intermediate thereof

A technology of fosamprenavir and derivatives, which is applied in the field of preparation of fosamprenavir derivatives and fosamprenavir derivatives, can solve the problems of high cost and low yield, and achieves improved yield, cost saving, Suitable for large-scale promotion and application

Active Publication Date: 2012-05-16
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The applicant prepared according to the method provided by it, the yield was 77-79%, the cost was high, and the yield was low

Method used

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  • Preparation method of fosamprenavir derivative and related intermediate thereof
  • Preparation method of fosamprenavir derivative and related intermediate thereof
  • Preparation method of fosamprenavir derivative and related intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] 15g (3S) Tetrahydro-3-furyl (1S, 2R)-3-[[(4-aminophenyl)-sulfonyl](isobutyl)amino-1-benzyl-2-(phosphono Oxy)propyl-carbamate was dissolved in 45ml of methanol and heated to 55°C, and a mixture of 4.2g of calcium acetate monohydrate and 150ml of water was added dropwise. After the addition was completed, it was kept at 55°C for half an hour. Cool to 20°C, filter and dry.

[0026] The dry product was dissolved in 200 ml of methanol, 0.3 g of 10% Pd / C was added, and the mixture was stirred under hydrogen for 20 hours. The catalyst was filtered off.

[0027] After the filtrate was concentrated under reduced pressure to the remaining 100ml, it was dropped into 150ml of water at room temperature to crystallize. After the drop was completed, it was stirred at room temperature for half an hour, filtered, and dried in vacuo to obtain 13.2g of calcium (3S) tetrahydro-3-furyl (1S, 2R)-3 -[[(4-Aminophenyl)-sulfonyl](isobutyl)amino-1-benzyl-2-(phosphonooxy)propyl-carbamate. Yield...

Embodiment 2

[0029] In a clean and dry 250ml four-necked flask, put 10g (3S) tetrahydro-3-furyl (1S, 2R)-3-[[(4-aminophenyl)-sulfonyl](isobutyl)amino- 1-Benzyl-2-(phosphonooxy)propyl-carbamate, add 30ml of absolute ethanol to dissolve, and heat to 50°C, add dropwise a mixture of 2.8g sodium acetate and 100ml water, drop After the addition, keep the temperature at 50°C for half an hour. After the heat preservation is completed, evaporate the solvent to dryness under reduced pressure in a water bath at 60°C, add 100ml of methyl tert-butyl ether for beating and crystallization, filter and dry.

[0030] In a clean and dry autoclave, put the dried material, 120ml methanol and 0.2g10% Pd / C, close the autoclave, first replace with nitrogen three times, then replace with hydrogen three times, increase the hydrogen pressure to 1.0Mpa, and pass hydrogen at room temperature 24 hours, until the reaction of compound 2 is complete, vent, take out the material, filter, and concentrate the filtrate to dry...

Embodiment 3

[0032] 10.5g (3S) Tetrahydro-3-furyl (1S, 2R)-3-[[(4-nitrophenyl)-sulfonyl] (isobutyl) amino-1-benzyl-2-( Diethylamine salt (II) of phosphonooxy)propyl-carbamate, dissolved in 30ml of absolute ethanol, and heated to 50°C, added dropwise a mixture of 2.8g of calcium acetate monohydrate and 100ml of water , after the dropwise addition, keep warm at 50°C for half an hour, then cool to room temperature, filter and dry.

[0033] Dissolve the dry product in 120ml of propanol and 0.2g of 10% Pd / C, close the autoclave, first replace it with nitrogen three times, then replace it with hydrogen three times, raise the pressure of hydrogen to 1.0Mpa, and pass hydrogen at room temperature for 24 hours until the reaction is complete, then vent it, The material was taken out, filtered, and after the filtrate was concentrated under reduced pressure to the remaining 60ml, it was dropped into 100ml of water for crystallization at room temperature. , 2R)-3-[[(4-aminophenyl)-sulfonyl](isobutyl)am...

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Abstract

The invention relates to s preparation method of a fosamprenavir derivative, which comprises the following steps: reacting a compound disclosed as Formula II or ammonium salt thereof with a metallic ion source in a solvent to obtain a compound disclosed as Formula III, separating or purifying, and carrying out catalytic reduction on the compound disclosed as Formula III to obtain a compound disclosed as Formula I, wherein X is a metallic ion, the metallic ion source is preferably a calcium ion source, sodium ion source or potassium ion source, and X is preferably a calcium ion, sodium ion or potassium ion; the solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol or sec-butanol; the catalytic reduction is carried out by using palladium-on-carbon as a catalyst and hydrogen as a reducer; and the ammonium salt is a monomethyl amine salt, dimethyl amine salt, monoethyl amine salt, diethylamine salt, isopropylamine salt, di-n-butylamine salt, dipropyl amine salt, tert-butylamine salt or dicyclohexyl amine salt. The invention also provides a related intermediate of the preparation method of the fosamprenavir derivative. The preparation method of the fosamprenavir derivative saves the cost, enhances the yield, and is suitable for large-scale popularization.

Description

technical field [0001] The present invention relates to the technical field of fosamprenavir derivatives, in particular to the technical field of preparation of fosamprenavir derivatives, in particular to a preparation method of fosamprenavir derivatives and related intermediates. Background technique [0002] Fosamprenavir calcium, trade name: LEXIVA, chemical name: [(3S)-oxolane-3-yl]N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl- (2-Methylpropyl) amino]-1-phenyl-3-phosphoryloxy-butane-2-yl] carbamate calcium salt, its structural formula is shown in the following formula I, wherein X is a calcium ion : [0003] [0004] Fosamprenavir calcium is the prodrug of the HIV protease inhibitor Amprenavir (Amprenavir, APV, Agenerase), which was jointly developed by GlaxoSmithKline (GSK) and Vertex Pharmaceuticals to phosphorylate APV and then make calcium Salt, its solubility in water at 25°C is increased from 0.04mg / ml to 100mg / ml, which is convenient for gastrointestinal absorption a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/655
CPCC07F9/65515
Inventor 徐建康叶美其陈斌徐巧巧
Owner ZHEJIANG JIUZHOU PHARM CO LTD
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