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Green and environment-friendly preparation method of tenofovir

An inorganic and compound technology, applied in the field of chemistry, can solve the problems of difficulty in fully utilizing raw materials and by-products, reduce the added value of products, etc., and achieve the effects of easy control of the degree of reaction, low cost and high safety.

Active Publication Date: 2020-05-29
南京道尔医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The chiral reagents involved in the reported various reactions are often in the R configuration. During the chiral resolution of the starting materials, the raw materials and by-products in the S configuration are difficult to be fully utilized, which reduces the additional cost of the product. value

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Compound I is The molar ratio of compound I to potassium carbonate is 1:5; the molar ratio of compound I to dimethyl hydroxymethylphosphonate is 1:5; the molar ratio of compound I to diethyl azodicarboxylate is 1:1.5 ; The molar ratio of compound I and triphenylphosphine is 1:1.5; the molar ratio of compound I and sodium hydroxide is 1:1.5.

[0030] Specific steps are as follows:

[0031] Step (1), the compound I (102g), S-propylene carbonate (149g), potassium carbonate (690g) aqueous solution was dissolved in the organic solvent dimethylformamide, reacted at 100 ° C for 4h, cooled to room temperature, reduced Concentrate the system under pressure to obtain intermediate II; the hydrogen spectrum of intermediate II: 1 H-NMR (600MHz, DMSO-d 6 )δ H :10.51(s,1H),8.59(s,1H),8.19(s,1H),8.05(s,1H),3.90(m,2H),3.70(d,J=8.8Hz,1H),1.16( d, J=8.8Hz, 3H).

[0032] Step (2), dissolve intermediate II, dimethyl hydroxymethylphosphonate (700g) and triphenylphosphine (393.5g) in d...

Embodiment 2

[0035] Compound I is The mol ratio of compound I and potassium bicarbonate is 1:5; The mol ratio of compound I and diethyl hydroxymethyl phosphonate is 1:5; The mol ratio of compound I and two p-chlorobenzyl azodicarboxylates is 1:1.5; the molar ratio of compound I to trimethylphosphine is 1:1.5; the molar ratio of compound I to lithium hydroxide is 1:1.5.

[0036] Specific steps are as follows:

[0037] In step (1), compound I (149g), S-propylene carbonate (102g), and potassium bicarbonate (500g) were dissolved in toluene, an organic solvent, reacted at 110°C for 5h, cooled to room temperature, and concentrated under reduced pressure to obtain Intermediate II; hydrogen spectrum data of intermediate II; 1 H-NMR (600MHz, DMSO-d 6 )δ H :10.61(s,1H),8.63(s,1H),8.03(s,1H),3.90(m,2H),3.68(d,J=8.6Hz,1H),2.14(s,3H),1.15( d, J=8.6Hz, 3H).

[0038] Step (2), dissolve intermediate II, diethyl hydroxymethylphosphonate (700g) and trimethylphosphine (114g) in toluene, stir at room t...

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PUM

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Abstract

The invention discloses a green and environment-friendly tenofovir preparation method which comprises the following steps: dissolving a compound I, S-propylene carbonate and an inorganic weak base inan organic solvent, reacting for 3-6 hours at 85-120 DEG C, cooling to room temperature, and concentrating an obtained system under reduced pressure to obtain an intermediate II; dissolving the intermediate II, hydroxymethylphosphonic acid dialkyl ester and trialkyl (aryl) phosphine in an organic solvent, stirring at room temperature, slowly adding azodicarboxylic acid diester, and reacting for 20minutes to 3 hours to obtain an intermediate III; slowly adding an inorganic strong alkali into the intermediate III, carrying out ice bath, filtering, adjusting the pH value of an obtained filtrate,standing, carrying out suction filtration, washing an obtained filter cake, and carrying out vacuum drying under reduced pressure. According to the method, S-propylene carbonate, adenine and derivatives thereof are taken as initial raw materials; PMPA is generated through configuration inversion of Mitsunobu reaction, the used organic solvents can be recycled, the generated wastewater is mainly aharmless inorganic salt solution, the cost for further treatment and up-to-standard discharge is low, the method is environmentally friendly, the reaction is easy to control, the safety is high, andthe comprehensive economic benefit is high.

Description

technical field [0001] The invention belongs to the field of chemistry, relates to the technical fields of medicinal chemistry and waste liquid recycling, and in particular relates to a green and environment-friendly preparation method of tenofovir. Background technique [0002] Tenofovir (PMPA), chemically named R-9-(2-methoxypropyl phosphate) adenine, is an important antiviral drug. In 1995, some scholars found that PMPA can completely prevent the infection of simian immunodeficiency virus (SIV) which protects rhesus monkeys. As a new open-ring nucleotide anti-HIV infection drug, PMBA was approved by the FDA in 2001 for the treatment of HIV-infected patients. It has excellent dual activities against HIV and HBV in vitro. The effect of HBV is stronger than that of lamivudine. In clinical use, it is found that it is not only applicable to HIV and HBV infected patients who have been treated with lamivudine, but also can be used to treat patients who are resistant to lamivud...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561
CPCC07B2200/07C07F9/65616
Inventor 王琦李好瑾彭晗彭菲菲徐先强
Owner 南京道尔医药科技有限公司
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