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Preparation method for 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazole-4-base)-8-azabicyclo[3.2.1]octane

A technology of -4H-1 and azabicyclo, applied in the direction of organic chemistry, can solve the problems of interference recrystallization, low product yield and purity, etc., and achieve the effect of good product purity, simple operation and high yield

Inactive Publication Date: 2012-07-18
ZHEJIANG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The presence of N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutyramide chloride seriously interferes with the recrystallization of the product, resulting in low product yield and purity

Method used

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  • Preparation method for 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazole-4-base)-8-azabicyclo[3.2.1]octane

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutyramide (2g, 7mmol) and P 2 S 5 (0.47g, 2.1mmol) were mixed, acetonitrile (12.6mL) was added, heated to reflux for 6h, evaporated to dryness under reduced pressure, and the obtained solid was washed with CH 2 Cl 2 (20mL) was dissolved in NaOH aqueous solution, the pH was controlled to be greater than 9, the organic layer was separated, and the aqueous layer was washed with CH 2 Cl 2 (10mLx2) extraction, combined organic layers, evaporated to dryness under reduced pressure to obtain N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylsulfamide (1.99g, yield 94.0%).

[0018] Dissolve Na (0.15g, 6.6mmol) in methanol (20mL), add N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylsulfamide (2g, 6.6mmol), after complete dissolution, add methyl sulfate (0.83g, 6.6mmol), stir at room temperature, react for 8h and distill under reduced pressure, dissolve the obtained yellow oil in CH 2 Cl 2 (50mL) and H 2 O (50mL), the organic layer...

Embodiment 2

[0021]N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutyramide (2g, 7mmol) and Lawesson's reagent (1.27g, 3.2mmol) were mixed, tetrahydrofuran (16.8 mL), heated to reflux for 4h, evaporated to dryness under reduced pressure, and the resulting solid was washed with CH 2 Cl 2 (20mL) was dissolved in KOH aqueous solution, the pH was controlled to be greater than 9, the organic layer was separated, and the aqueous layer was washed with CH 2 Cl 2 (10mLx2) extraction, combined organic layers, and evaporated to dryness under reduced pressure to obtain N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylsulfamide (2.04g, yield 96.3%).

[0022] Dissolve Na (0.18g, 7.6mmol) in ethanol (20mL), add N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylsulfamide (2g, 6.6mmol), after complete dissolution, add benzyl chloride (0.92g, 7.3mmol), stir at room temperature, react for 6h and distill under reduced pressure, dissolve the obtained yellow oil in CH 2 Cl 2 (50mL) and H 2 O (50mL), the organi...

Embodiment 3

[0025] N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutyramide (2g, 7mmol) and P 2 S 5 (0.93g, 4.2mmol) were mixed, added toluene (23mL), heated to reflux for 2h, evaporated to dryness under reduced pressure, and the obtained solid was distilled with CH 2 Cl 2 (20mL) was dissolved in KOH aqueous solution, the pH was controlled to be greater than 9, the organic layer was separated, and the aqueous layer was washed with CH 2 C 2 (10mLx2) extraction, combined organic layers, and evaporated to dryness under reduced pressure to obtain N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylsulfamide (2.02g, yield 95.6%).

[0026] Dissolve Na (0.2g, 8.6mmol) in methanol (20mL), add N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylsulfamide (2g, 6.6mmol), after complete dissolution, add iodomethane (1.22g, 8.6mmol), stir at room temperature, react for 5h and distill under reduced pressure, dissolve the obtained yellow oil in CH 2 Cl 2 (50mL) and H 2 O (50mL), the organic layer was separ...

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Abstract

The invention discloses a preparation method for 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazole-4-base)-8-azabicyclo[3.2.1]octane. The preparation method comprises the following steps of: heating and refluxing N-(8-benzyl-8-azabicyclo[3.2.1]octyl-3-base)isobutyramide serving as a raw material and a vulcanization reagent in a non-proton solvent to obtain N-(8-benzyl-8-aza-bicyclo[3.2.1]octyl-3-base)isobutyl sulfamide; making sodium alcoholate react with halogenated hydrocarbon or sulfate to obtain N-(8-benzyl-8-aza-bicyclo[3.2.1]octyl-3-base)isobutyl imine acid thioester; heating and refluxing an alcohol with 2-5 carbon atoms and acethydrazide to obtain crude 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazole-4-base)-8-aza-bicyclo[3.2.1]octane; and refining normal heptane and ethyl acetate to obtain a high-purify target product. Due to the adoption of the method for preparing the 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazole-4-base)-8-azabicyclo[3.2.1]octane, water is prevented from interfering an intermediate reaction process, the yield is high, and the product purity is high.

Description

technical field [0001] The invention relates to the key intermediate 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazole-4- The preparation method of -8-azabicyclo [3.2.1] octane. Background technique [0002] Maraviroc was approved by the US FDA and the European Commission in August and September 2007, respectively, for the treatment of patients with CCR5-tropic HIV-1 infection in combination with other antiretroviral drugs. A CCR5 antagonist and first oral entry inhibitor with significant first-to-market advantage. 8-Benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane is a new anti- The key intermediate of the AIDS drug Maraviroc, the current route to synthesize this intermediate has in common that N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl ) isobutyramide is converted into N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl) isobutyric acid chloride by chlorination, and then converted into N-( 8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutyrimidic acid hydraz...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D451/02
Inventor 戴立言袁更洋王晓钟陈英奇宋晓晓张玲玲
Owner ZHEJIANG UNIV
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