Method for synthesis of PMPA by combining biological technique and chemical technique

A chemical method, biological method, applied in the directions of biochemical equipment and methods, microorganism-based methods, chemical instruments and methods, etc., can solve the problems of unreachable and high production costs, and achieve simple post-processing and mild reaction conditions. , significant economic and social benefits

Active Publication Date: 2013-01-30
黄石福尔泰医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] This route is shorter and the yield is higher, but the optical purity of the final product is only 90-94%, which cannot m

Method used

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  • Method for synthesis of PMPA by combining biological technique and chemical technique
  • Method for synthesis of PMPA by combining biological technique and chemical technique
  • Method for synthesis of PMPA by combining biological technique and chemical technique

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] (1) Preparation of R-chloropropanol (I)

[0030] Add 10g Angel dry yeast to 150ml pH=5.91 buffer solution, place the reaction flask in a shaker at T=35℃, activate for 0.5 hours, add 0.9g chloroacetone, and sample with a centrifuge tube every 0.5h , 3mL each time; after sampling, centrifuge with a centrifuge, the speed of the centrifuge is: r=4000rpm, time t=20min; after centrifugation, take the supernatant liquid, evaporate it with a rotary evaporator, and add methanol to dissolve and let it stand still ; Do temperament analysis. When the reaction is complete, centrifuge and concentrate, add 50ml methanol to dissolve, filter and concentrate to obtain 0.65g of chloropropanol (I).

[0031] (2) Preparation of (R)-2-[bis-(isopropyl)-phosphonomethoxy]-propyl chloride (II)

[0032] Put 9.4g (100mmol) of compound (I) in a 200ML three-necked flask, add 100ML of anhydrous THF, under ice bath, add 2.88g (120mmol), 60% NaH in batches, stir for 0.5 hour, then slowly add 38.2 dropwise ...

Embodiment 2

[0038] (1) Preparation of R-chloropropanol (I)

[0039] Add 10g Angel dry yeast to 150ml pH=6.98 buffer solution, place the reaction flask in a shaker at T=35℃, activate for 0.5 hours, add 0.9g chloroacetone, and sample with a centrifuge tube every 0.5h , 3mL each time; after sampling, centrifuge with a centrifuge, the speed of the centrifuge is: r=4000rpm, time t=20min; after centrifugation, take the supernatant liquid, evaporate it with a rotary evaporator, and add methanol to dissolve and let it stand still ; Do temperament analysis. When the reaction is complete, centrifuge and concentrate, add 50ml methanol to dissolve, filter and concentrate to obtain 0.80g of chloropropanol (I).

[0040] (2) Preparation of (R)-2-[bis-(isopropyl)-phosphonomethoxy]-propyl chloride (II)

[0041] Put 9.4g (100mmol) of compound (I) in a 200ML three-necked flask, add 100ML of anhydrous THF, add 6.0g (150mmol) NaOH in batches under ice bath, stir for 0.5 hour, and then slowly drop 38.2g (120mmol)...

Embodiment 3

[0047] (1) Preparation of R-chloropropanol (I)

[0048] Add 10g Angel dry yeast to 150ml pH=8.04 buffer solution, place the reaction flask in a shaker at T=35℃, activate for 0.5 hours, add 0.9g chloroacetone, and sample with a centrifuge tube every 0.5h , 3mL each time; after sampling, centrifuge with a centrifuge, the speed of the centrifuge is: r=4000rpm, time t=20min; after centrifugation, take the supernatant liquid, evaporate it with a rotary evaporator, and add methanol to dissolve and let it stand still ; Do temperament analysis. After the reaction is complete, centrifugal concentration, add 50ml methanol to dissolve, filter and concentrate to obtain 0.89g of chloropropanol (I).

[0049] (2) Preparation of (R)-2-[bis-(isopropyl)-phosphonomethoxy]-propyl chloride (II)

[0050] Put 9.4g (100mmol) of compound (I) in a 200ML three-necked flask, add 100ML of anhydrous THF, add 6.0g (150mmol) NaOH in batches under ice bath, stir for 0.5 hour, and then slowly drop 38.2g (120mmol)...

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Abstract

Belonging to the technical field of medicine synthesis, the invention relates to a method for synthesis of PMPA by combining a biological technique and a chemical technique. The method comprises: taking chlorinated acetone as a starting raw material, conducting yeast fermentation reduction so as to obtain chiral chloropropanol (I), then subjecting the chiral chloropropanol (I) and diethyl p-toluenesulfonyloxyphosphonate to a condensation reaction under the action of alkali so as to obtain a reaction intermediate (II); preparing R-9-(2-hydroxypropyl)adenine (III) from adenine and the reaction intermediate (II); and hydrolyzing the obtained R-9[2-(diethylphosphonomethoxy)propyl]purine, thus obtaining the PMPA (IV). The method combines the biological technique and the chemical technique and obtains a key chiral alcohol by means of a biological means, i.e. fermentation. The method has the characteristics of short reaction process, short reaction time, high mass yield, and can produce products with good quality, thus being suitable for industrialized production.

Description

technical field [0001] The invention relates to a synthesis process for preparing tenofovir, an anti-AIDS and anti-hepatitis B drug, and belongs to the technical field of drug synthesis. Background technique [0002] Tenofovir disoproxil fumarate (tenofovir disoproxil fumarate), chemical name (R)-[[2-(6-amino-9H-purine-9- base)-1-methylethoxy]methyl]phosphonic acid bis(isopropionyloxymethyl) fumarate, whose structure is shown in structure 1, is a first-line treatment against hepatitis B The drug is quickly transformed into tenofovir (PMPA) after being absorbed by the human body to produce antiviral effects. PMPA has been confirmed to have broad-spectrum antiviral activity against human immunodeficiency virus HIV and HBV, and has been approved by the US FDA in 2001 as a drug for clinical treatment of AIDS. [0003] [0004] Structural formula 1 tenofovir disoproxil [0005] Tenofovir is the key intermediate of tenofovir dipivoxil, and there are mainly two kinds of synth...

Claims

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Application Information

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IPC IPC(8): C12P17/18C07F9/6561C07F9/40C12R1/865
Inventor 李剑刘莉
Owner 黄石福尔泰医药科技有限公司
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