Preparation method of 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo (3.2.1)octane

A -4H-1, azabicycle technology, applied in organic chemistry and other directions, can solve the problems of low product yield and purity, interfere with recrystallization, etc., and achieve the effects of good product purity, complete reaction, and high yield

Inactive Publication Date: 2012-11-07
WENZHOU MEDICAL UNIV
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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 of 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo (3.2.1)octane

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] PCl 5 (1.46g, 7.0mmol) plus CH 2 Cl 2 (22.6mL, 30.0g), cooled in an ice-salt bath, added N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutyramide (2.0g, 7.0mmol), After stirring for half an hour, remove ice water, rise to room temperature and stir for 1.5 h, cool with ice water, add ethanol (1.97 mL, 35.0 mmol) and Et 3 N (1.95mL, 14.0 mmol) mixed solution, after dripping, remove ice water, raise room temperature and stir overnight, then cool in ice water, add NaOH aqueous solution dropwise to pH>9, separate organic layer, and wash water layer with CH 2 Cl 2 (50mlx2) extraction, combined organic phases, and evaporated to dryness under reduced pressure to obtain ethyl N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylimidate (2.02g , yield 91.7%).

[0016] Dissolve ethyl N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylimidate (1.57g, 5.0mmol) obtained in the previous step in isoamyl alcohol ( 34.9mL, 28.26g), add acetylhydrazide (0.56g, 7.5mmol), heat to reflux for 3h, ...

Embodiment 2

[0018] SOCl 2 (1.66g, 14.0mmol) plus CHCl 3 (27.0mL, 40.0g), cooled in an ice-salt bath, added N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutyramide (2.0g, 7.0mmol), After stirring for half an hour, remove ice water, rise to room temperature and stir for 1 h, cool with ice water, add isopropanol (5.4 mL, 70.0 mmol) and Et 3 N (3.4mL, 24.5mmol) mixed solution, after dripping, remove ice water, raise room temperature and stir overnight, then cool with ice water, add KOH aqueous solution dropwise to pH>9, separate organic layer, and wash water layer with CH 2 Cl 2 (50mlx2) extraction, combined organic phases, and evaporated to dryness under reduced pressure to obtain isopropyl N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylimidate (2.12 g, yield 92.2%).

[0019] Dissolve N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylimidate (1.64g, 5.0mmol) in ethanol (41.5 mL, 32.8g), add acetylhydrazide (0.74g, 10mmol), heat to reflux for 2h, evaporate the solvent under reduced pressure...

Embodiment 3

[0021] Add oxalyl chloride (2.7g, 21.0mmol) to 1,2-dichloroethane (39.8mL, 50g), cool in an ice-salt bath, add N-(8-benzyl-8-azabicyclo[3.2.1 ]oct-3-yl)isobutyramide (2.0g, 7.0mmol), stirred for half an hour, removed ice water, raised to room temperature and stirred for 2h, cooled with ice water, added dropwise benzyl alcohol (10.9mL, 105.0mmol) and Et 3 N (4.9 mL, 35.0 mmol) mixed solution, drop off, remove ice water, raise room temperature and stir overnight, then cool in ice water, add NaOH aqueous solution dropwise to pH>9, separate organic layer, and wash the water layer with CH 2 Cl 2 (50mlx2) extraction, combined organic phases, and evaporated to dryness under reduced pressure to obtain benzyl N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylimidate (2.42g , yield 92.0%).

[0022] Dissolve the benzyl N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylimidate (1.88g, 5.0mmol) obtained in the previous step in isobutanol ( 51.1mL, 41.36g), add acetylhydrazide (0.93g, 12.5mm...

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Abstract

The invention provides a preparation method of 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo(3.2.1)octane, which comprises the following steps successively: taking N-(8-benzyl-8-azabicyclo(3.2.1)oct-3-yl)-isobutyramide as a raw material and heating to reflux with a chlorinating agent in an aprotic solvent, then reacting with alcohol under the action of triethylamine to obtain isobutyl-N-(8-benzyl-8-azabicyclo(3.2.1)oct-3-yl)imidate, and heating to reflux with acetohydrazide in alcohol of C2-C5 to obtain 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo [3.2.1] octane crude, and finally purifying by n-heptane and ethyl acetate to obtain the target product with high purity. The 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo [3.2.1] octane prepared by the method provided by the invention has the advantages of less byproducts, high yield and high product purity.

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] 8-Benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane is a novel The key intermediate of the anti-AIDS drug Maraviroc (Maraviroc), the common point of the current synthesis route of this intermediate is that N-(8-benzyl-8-azabicyclo[3.2.1]octyl-3- Base) isobutyramide is chlorinated into N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutyrimidic acid chloride, and then converted to N- (8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutyric acid hydrazide, and then obtained 8-benzyl-3-(3-isopropyl- 5-Methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane (WO2008063600; WO2010040272; Organic Process Research & Development 2008,12,1094– 1103), the methods of different documents are only slightly different in the specific implementation of the route. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/08
Inventor 王学东
Owner WENZHOU MEDICAL UNIV
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