HCID 12504008, compound → 1-((3R,4R)-3-(4-chloro-6-methylpyridin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone

HRID 1666612Notes

Reaction equation

HRID 1666612 reaction equation
Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N+:3]=1[O-].[NH2:11][C@H:12]1[C@H:16]([OH:17])[CH2:15][N:14]([C:18](=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[CH2:13]1>C(O)CCC>[Cl:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:11][C@H:12]2[C@H:16]([OH:17])[CH2:15][N:14]([C:18](=[O:31])[CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:24][CH:25]=3)[CH2:13]2)[CH:7]=1

Participants

4

Reactant 2

HCID 12504008HCID 12504008, compoundHCID 579701111-((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone

Product 1

HCID 579701641-((3R,4R)-3-(4-chloro-6-methylpyridin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanoneYield 15.6%

Reagents, catalysts & solvents 1

HCID 2631-ButanolSolvent

Conditions

Temperature
130 °C

Procedure

A mixture of 2,4-dichloro-6-methylpyridine 1-oxide (200 mg), 1-((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (340 mg), and n-butanol (0.6 mL) was stirred at 130° C. for 10 h. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate−ethyl acetate/methanol=20:1), and then the resulting solids were washed with hexane and diethyl ether to obtain 1-((3R,4R)-3-(4-chloro-6-methylpyridin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (75 mg). (2) A mixture of 1-((3R,4R)-3-(4-chloro-6-methylpyridin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (68 mg), morpholine (0.02 mL), sodium t-butoxide (42 mg), Pd(OAc)2 (1 mg), 2-(di-t-butylphosphino)biphenyl (3 mg), and toluene (1 mL) was heated at 100° C. for 10 h. The mixture was cooled to room temperature, then the reaction mixture was diluted with chloroform, insoluble matters were removed by Celite filtration, and then the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (NH silica gel, ethyl acetate, and silica gel, hexane/acetone=1:1) to obtain the title compound (8 mg).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. customthe residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate−ethyl acetate/methanol=20:1)
  3. washthe resulting solids were washed with hexane and diethyl ether

Sources & evidence

ORD record
ord-7e560da297d447df9e603b55b32b3df0
Source dataset
uspto-grants-2011_10
Patent number
US08044068B2

Reaction notes

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