Tenofovir synthesizing method

A technology of tenofovir and its synthesis method, which is applied in the field of medicine and chemical industry, can solve the problems of high cost, strong corrosion, and three wastes, and achieve the effects of high risk, high selectivity, and reduced occurrence of by-products

Active Publication Date: 2018-12-21
LEPING SAFELY PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] In order to overcome the shortcomings of high cost, serious waste and strong corrosion in the tenofovir synthesis technology, the invention provides a tenofovir synthesis method

Method used

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  • Tenofovir synthesizing method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Synthesis of Tenofovir

[0037] 57.9 g (0.30 mol) (R)-9-(2-hydroxypropyl) adenine was dissolved in 500 mL of DMF, and 165.6 g (alkali content 35%, 0.42 mol) freshly prepared solid base catalyst was added under good stirring K 2 CO 3 / Al 2 o 3 112.7 g (0.35 mol) diethyl p-toluenesulfonyloxymethylphosphonate was added dropwise below 40°C, the temperature was raised to 133-138°C after the drop, and the reaction was stirred for 12 hours. The solid base catalyst was recovered by filtration, and the DMF was recovered by distillation under reduced pressure. After cooling slightly, 600 ml of pure water and a strongly acidic cation exchange resin catalyst equivalent to 0.05 mole of acid were added. Stir and react at 105-110°C for 20 hours, filter and recover the strong acidic cation exchange resin catalyst, cool, filter, wash, and dry to obtain 78.3 g of crude tenofovir, with a yield of 90.9% and a content of 96.9%. The HPLC retention time and tenofovir The standa...

Embodiment 2

[0038] Example 2 Synthesis of Tenofovir

[0039] 57.9 g (0.30 mol) of (R)-9-(2-hydroxypropyl) adenine was dissolved in 330 mL of NMP, and 116.7 g (base content 18%, 0.375 mol) of freshly prepared solid base catalyst was added under good stirring KOH / Al 2 o 3 , Add 125.6 g (0.39 mol) diethyl p-toluenesulfonyloxymethylphosphonate dropwise below 40°C, raise the temperature to 110-115°C after dropping, and stir for 20 hours. The solid base catalyst is recovered by filtration, the NMP is recovered by distillation under reduced pressure, slightly cooled, and 400 milliliters of pure water and a strongly acidic cation exchange resin catalyst equivalent to 0.10 moles of acid are added. Stir and react at 102-107°C for 16 hours, filter and recover the strong acidic cation exchange resin catalyst, cool, filter, wash, and dry to obtain 77.7 g of crude tenofovir, with a yield of 90.2% and a content of 96.5%. The HPLC retention time and tenofovir The standard matches.

Embodiment 3

[0040] Example 3 Synthesis of Tenofovir

[0041] 57.9 g (0.30 mol) of (R)-9-(2-hydroxypropyl)adenine was dissolved in 380 mL of DMAc, and 62.6 g (base content 50%, 0.54 mol) of freshly prepared solid base catalyst was added under good stirring KF / Al 2 o 3 , Add 108.2 g (0.336 mol) diethyl p-toluenesulfonyloxymethylphosphonate dropwise below 40°C, raise the temperature to 98-103°C after dropping, and stir for 24 hours. The solid base catalyst was recovered by filtration, the DMAc was recovered by distillation under reduced pressure, cooled slightly, and 350 ml of pure water and a strongly acidic cation exchange resin catalyst equivalent to 0.03 moles of acid were added. Stir and react at 93-98°C for 28 hours, filter and recover the strong acidic cation exchange resin catalyst, cool, filter, wash, and dry to obtain 78.6 g of crude tenofovir, with a yield of 91.3% and a content of 97.3%. The standard matches.

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Abstract

The invention discloses a tenofovir synthesizing method. According to the method, diethyl p-toluenesulfonyloxymethylphosphonate (TSDEP), (R)-9-(2-hydroxyl propyl)adenine (HPA) and a solid base catalyst like KOH/Al2O3, strong acid cation exchange resin and the like are utilized as raw materials; a product is prepared by aftertreatment operation of condensing, hydrolysis two-step reaction, filtration, reduced pressure distillation, cooling and the like. The method disclosed by the invention has the characteristics of sufficient raw material sources, low cost, high synthesizing technology safety,high product yield, small three-waste pollution and higher industrial value; furthermore, the solid alkali catalyst and the strong acid cation exchange resin are easy to recycle and suitable for setuse after regeneration.

Description

technical field [0001] The invention relates to a method for synthesizing tenofovir, which belongs to the field of medicine and chemical industry. Background technique [0002] Tenofovir, chemical name (R)-{[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}phosphonic acid, or (R)-9 -(2-phosphonomethoxypropyl) adenine, its structural formula is: [0003] [0004] Tenofovir disoproxil fumarate is a first-line antiviral drug for treating HIV and HBV, and tenofovir is a key intermediate for preparing tenofovir disoproxil fumarate. [0005] The literature discloses a variety of synthetic routes for tenofovir, such as Chinese patent CN 102899367, which discloses a method using monochloroacetone as a raw material, which is condensed with diethyl p-toluenesulfonyloxymethylphosphonate through yeast catalytic reduction, and then A four-step reaction method of condensation with adenine and hydrolysis. For example, Chinese patent CN 101906119 discloses a method using (R)-1,2-propan...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561
CPCC07F9/65616Y02P20/584
Inventor 潘劲松陈盛邱永勇曾纪森王一键陶安妮毛春飞郑土才
Owner LEPING SAFELY PHARMA
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