Morpholine → 1-((3R,4R)-3-hydroxy-4-(6-methyl-4-morpholin-4-ylpyridin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone

HRID 1666613Notes

Reaction equation

HRID 1666613 reaction equation
NN1CCCC1.Cl[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][C@H:16]2[C@H:20]([OH:21])[CH2:19][N:18]([C:22](=[O:35])[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)[CH2:17]2)[CH:9]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[OH:21][C@H:20]1[C@H:16]([NH:15][C:10]2[CH:9]=[C:8]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:13]=[C:12]([CH3:14])[N:11]=2)[CH2:17][N:18]([C:22](=[O:35])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=2)[CH2:19]1

Participants

9

Reactant 5

HCID 8083MorpholineHCID 279461-PyrrolidinamineHCID 27342152-(Di-tert-butylphosphino)biphenylHCID 23676156Sodium t-butoxideHCID 579701641-((3R,4R)-3-(4-chloro-6-methylpyridin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone

Product 1

HCID 579701451-((3R,4R)-3-hydroxy-4-(6-methyl-4-morpholin-4-ylpyridin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolventHCID 6212ChloroformSolvent

Conditions

Temperature
100 °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. temperatureThe mixture was cooled to room temperature
  2. customwere removed by Celite filtration
  3. concentrationthe filtrate was concentrated under reduced pressure
  4. customThe residue was purified by preparative TLC (NH silica gel, ethyl acetate, and silica gel, hexane/acetone=1:1)

Sources & evidence

ORD record
ord-9f4d7ea3dfaf4720b4d8222912b1343d
Source dataset
uspto-grants-2011_10
Patent number
US08044068B2

Reaction notes

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