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Process for preparing abacavir intermediate in formula V by adopting one-pot method

A technology for abacavir and intermediates, applied in the field of preparation of abacavir formula V intermediates, can solve problems such as failure to meet industrialization requirements, easy formation of by-products, poor product quality, etc., to facilitate large-scale production and yield The effect of high efficiency and simplified preparation process

Inactive Publication Date: 2015-06-03
SHANGHAI DESANO CHEM PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this route still adopts triethyl orthoformate as the reaction solvent and concentrated hydrochloric acid to hydrolyze the amino group at the 5-position of pyrimidine, so that by-products are easily formed, resulting in poor product quality and low yield, which cannot meet the requirements of industrialization

Method used

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  • Process for preparing abacavir intermediate in formula V by adopting one-pot method
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  • Process for preparing abacavir intermediate in formula V by adopting one-pot method

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Experimental program
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Effect test

Embodiment 1

[0033] The formula II compound (53.2g, 0.36mol) was added to 700mL of absolute ethanol, then sodium bicarbonate (100g, 0.94mol) was added, and stirred at room temperature for 0.5 hours under argon protection; the formula III compound (70g, 0.34 mol) into the above reaction system, heat up to 80°C and then keep warm for reaction. When TLC (PE / EA=1 / 1, V / V) detects that the reaction is basically complete (after about 6-7 hours of reaction), cool down to room temperature, Suction filtration; triethyl orthoformate (251.5 g, 1.69 mol) was added to the filtrate, and HCl-isopropanol solution (8.5 mol / L, 60 mL) was added dropwise to the reaction system under stirring at room temperature. Stir the reaction, when TLC (CH 2 Cl 2 / MeOH=10 / 1, V / V) detect that the reaction is complete (after about 6-7 hours of reaction), cool down to 10-15°C, and continue to stir for 0.5 hours; After vacuum drying at °C, 92.4 g of a light yellow to off-white intermediate of formula V was obtained, with a m...

Embodiment 2

[0035] The formula II compound (59.6g, 0.40mol) was added in 750mL isopropanol, then potassium bicarbonate (114.0g, 1.14mol) was added, and stirred at room temperature for 0.5 hours under argon protection; the formula III compound (78.3g ,0.38mol) into the above reaction system, heat up to 80°C and then keep warm for reaction. When TLC (PE / EA=1 / 1, V / V) detects that the reaction is basically complete (after about 6-7 hours of reaction), drop to Suction filtration at room temperature; triethyl orthoformate (450.5 g, 3.04 mol) was added to the filtrate, and HCl-ethanol solution (6.0 mol / L, 80 mL) was added dropwise to the reaction system under stirring at room temperature. Stir the reaction, when TLC (CH 2 Cl 2 / MeOH=10 / 1, V / V) detect that the reaction is complete (after about 6-7 hours of reaction), cool down to 10-15°C, and continue to stir for 0.5 hours; After vacuum drying at °C, 101.0 g of a light yellow to off-white intermediate of formula V was obtained, with a molar yie...

Embodiment 3

[0037] The formula II compound (32.8g, 0.22mol) was added in 750mL isopropanol, then triethylamine (83.6mL, 0.60mol) was added, under the protection of argon, stirred at room temperature for 0.5 hours; the formula III compound (41.2g ,0.20mol) into the above reaction system, heat up to 80°C and then keep warm for reaction. When TLC (PE / EA=1 / 1, V / V) detects that the reaction is basically complete (after about 6-7 hours of reaction), drop to Suction filtration at room temperature; triethyl orthoformate (118.6 g, 0.80 mol) was added to the filtrate, and HCl-ethanol solution (12.0 mol / L, 30 mL) was added dropwise to the reaction system under stirring at room temperature. Stir the reaction, when TLC (CH 2 Cl 2 / MeOH=10 / 1, V / V) detect that the reaction is complete (after about 6-7 hours of reaction), cool down to 10-15°C, and continue to stir for 0.5 hours; After vacuum drying at °C, 52.6 g of a light yellow to off-white intermediate of formula V was obtained, with a molar yield o...

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Abstract

The invention discloses a process for preparing an abacavir intermediate in a formula V by adopting a one-pot method. The process comprises the reaction as shown in the specification, namely reacting a compound shown in the formula II with a compound shown in the formula III for 3-10 hours at 50-150 DEG C under an alkali condition, then adding triethyl orthoformate and hydrochloric acid solution, reacting for 3-20 hours at 10-80 DEG C, filtering, and drying to obtain the intermediate in a formula V. By adopting the process, the abacavir V intermediate in a formula V is prepared by adopting the one-pot method, the yield is high, and the HPLC (High Performance Liquid Chromatography) purity can be more than or equal to 90% without complicated post treatment; when abacavir is prepared from the intermediate in a formula V, the HPLC purity of the product can be more than 99% without re-crystallization, so that the preparation process of abacavir is simplified; and the preparation process is simple in operation and high in yield, provides a convenient condition for production of abacavir V, and is very favorable for large-scale production of abacavir.

Description

technical field [0001] The invention relates to a process for preparing an abacavir formula V intermediate by a one-pot method, belonging to the technical field of organic chemistry. Background technique [0002] Abacavir (ABC) is an anti-AIDS drug, a new carbocyclic 2'-deoxyguanosine nucleoside drug, with high oral bioavailability and easy penetration into the central nervous system. It was first produced by GlaxoSmithKline in the United Kingdom with the trade name Ziagen. In 1998, the U.S. FDA approved the tablets and oral liquid of abacavir sulfate to go on the market. Like other nucleoside reverse transcriptase inhibitors, it is a The inactive prodrug can play a synergistic effect in combination with lamivudine (3TC) and zidovuding (AZT). [0003] The structure of abacavir is shown in formula I: [0004] [0005] In the prior art, there are mainly the following two routes for synthesizing abacavir, which are recorded in European Patent EP0349242B1. [0006] Route 1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/32
CPCC07D473/40
Inventor 李金亮赵楠葛瑞娟
Owner SHANGHAI DESANO CHEM PHARMA
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