Preparation method of acyclic nucleoside antiviral drug phosphoric acid monoester compound

A technology for antiviral drugs and cyclic nucleosides, applied in the field of medicine, can solve problems such as being difficult to industrialize production, and achieve the effects of easy industrial production, low price and low cost

Active Publication Date: 2012-04-18
CINKATE PHARMA INTERMEDIATES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In this patent, when synthesizing tenofovir monoester, the side chain synthesis requires two-step reactions, and the reaction for synthesizing tenofovir monoester requires stirring at 80°C for 6 hours, and the post-treatment requires column chromatography separation, which is not easy for industrialization Production

Method used

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  • Preparation method of acyclic nucleoside antiviral drug phosphoric acid monoester compound
  • Preparation method of acyclic nucleoside antiviral drug phosphoric acid monoester compound
  • Preparation method of acyclic nucleoside antiviral drug phosphoric acid monoester compound

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Example 1: Synthesis of 2-octadecyloxy-1-ethanol

[0031] Bromooctadecane (214.8g, 0.64mol) and ethylene glycol (120g, 1.93mol) were dissolved in 400ml DMSO and 400ml tetrahydrofuran (THF), KOH (144g, 2.56mol) was added, and mechanically stirred at room temperature for 16h. Pour 400 ml of deionized water into the reaction solution, and neutralize it with 18% HCl (about 250 ml). extracted with ethyl acetate, washed with saturated brine, and washed with anhydrous MgSO 4 dry. After filtration, the filtrate was spin-dried to obtain a pale yellow waxy solid. The compound was recrystallized from petroleum ether to obtain 90 g of the compound as a white solid (yield 43%). Mp: 49-51°C. 1 H-NMR (CDCl 3 )δ(ppm): 0.88(t, J=6.4Hz, 3H), 1.25(m, 30H), 1.58(m, 2H), 3.47(t, J=6.8Hz, 2H), 3.53(t, J= 4.8Hz, 2H), 3.72(t, J = 4.4Hz, 2H).

Embodiment 2

[0032] Embodiment 2: the synthesis of 3-hexadecyloxy-1-propanol

[0033] Using hexadecane bromide and 1,3-propanediol as raw materials, and using sodium hydroxide as a base, 3-hexadecyloxy-1-propanol was synthesized in a similar manner to Example 1. Yield 82%, mp: 37-40°C. 1 HNMR (CDCl 3 )δ (ppm): 0.880 (t, 3H), 1.256 (broad singlet, 24H), 1.427 (s, 1H), 1.566 (p, 2H), 1.818 (p, 4H), 3.409-3.795 (3 groups 3 heavy peak, 6H).

Embodiment 3

[0034] Embodiment 3: the synthesis of 3-tetradecyloxy-1-propanol

[0035] Using tetradecane bromide and 1,3-propanediol as raw materials and sodium carbonate as base, 3-tetradecyloxy-1-propanol was synthesized in a similar manner to Example 1. Yield 85%, mp: 32-34°C; 1 HNMR (CDCl 3 )δ (ppm): 0.873 (t, 3H), 1.309 (broad singlet, 22H), 1.558 (p, 2H), 1.823 (p, 2H), 2.503 (s, 1H), 3.401-3.783 (3 groups 3 heavy peak, 6H).

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Abstract

The invention provides a preparation method of an acyclic nucleoside antiviral drug phosphoric acid monoester compound. Acyclic nucleoside antiviral drugs like Adefovir or Viread are used as raw materials to react with liposoluble long-chain alkyloxy-ethanol / propyl alcohol to obtain the object compound. The invention overcomes insufficiencies of a prior art, can increase quality of Adefovir or Viread as well as reduce production cost, and is convenient for operation and easy for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a preparation method of a phosphate monoester compound of an acyclic nucleoside antiviral drug, in particular to a preparation method of adefovir or tenofovir monoester compound. Background technique [0002] In the treatment of viral infectious diseases, the problem of viral drug resistance has become increasingly prominent. Compared with cyclic nucleoside reverse transcriptase inhibitors, adefovir and tenofovir, acyclic nucleoside compounds, have obvious advantages in preventing viral drug resistance. The virus strain is effective, the incidence of drug resistance itself is low, and the toxicity is relatively small, so it can be used to treat patients who are co-infected with HIV-1 and HBV. However, due to the negative charge of the phosphate group, the polarity is too strong, and the biofilm permeability is poor, resulting in very low bioavailability, so that it cannot be us...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
CPCC07F9/65616
Inventor 李卓荣刘宗英易红李艳萍
Owner CINKATE PHARMA INTERMEDIATES
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