Diisopropylethylamine → 3-{[4-(3,3-difluoro-1-pyrrolidinyl)-1-piperidinyl]methyl}-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide

HRID 245250Notes

Reaction equation

HRID 245250 reaction equation
[F:1][C:2]1([F:41])[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[C:15]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=4)=[N:16][C:17]4[C:22]([C:23]=3[C:24](O)=[O:25])=[CH:21][C:20]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=4)[CH2:9][CH2:8]2)[CH2:3]1.[F:42][C:43]([F:53])([F:52])[C@H:44]([NH2:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(N(CC)C(C)C)(C)C.CCCP(=O)=O>C(OCC)(=O)C.ClCCl.O>[F:41][C:2]1([F:1])[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[C:15]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=4)=[N:16][C:17]4[C:22]([C:23]=3[C:24]([NH:51][C@H:44]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:43]([F:42])([F:52])[F:53])=[O:25])=[CH:21][C:20]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:19][CH:18]=4)[CH2:9][CH2:8]2)[CH2:3]1

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 11789718(alphaR)-alpha-(Trifluoromethyl)benzenemethanamineHCID 16167369Propylphosphoric anhydrideHCID 673832513-{[4-(3,3-Difluoro-1-pyrrolidinyl)-1-piperidinyl]methyl}-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid

Product 1

HCID 534761163-{[4-(3,3-difluoro-1-pyrrolidinyl)-1-piperidinyl]methyl}-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamideYield 87.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A suspension of 3-{[4-(3,3-difluoro-1-pyrrolidinyl)-1-piperidinyl]methyl}-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.100 g, 0.167 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.046 g, 0.218 mmol), N,N-diisopropylethylamine (0.088 mL, 0.502 mmol), and propylphosphonic anhydride (0.128 mL of a 50% solution in ethyl acetate, 0.218 mmol) in dichloromethane (2.57 mL) was stirred at room temperature for 30 min. Water (2 mL) was added, and the mixture was poured into a hydrophobic frit to separate the layers. The organic phase was concentrated in vacuo, and the residue was loaded onto florisil and purified via column chromatography (ISCO, 4 g silica, 0-10% methanol/methylene chloride) to afford 3-{[4-(3,3-difluoro-1-pyrrolidinyl)-1-piperidinyl]methyl}-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.110 g, 83% yield). MS (m/z) 755.2 (M+H+).

Workup

  1. additionthe mixture was poured into a hydrophobic frit
  2. customto separate the layers
  3. concentrationThe organic phase was concentrated in vacuo
  4. custompurified via column chromatography (ISCO, 4 g silica, 0-10% methanol/methylene chloride)

Sources & evidence

ORD record
ord-2422dcc362fd4f1d860bfe9699ff704a
Source dataset
uspto-grants-2014_02
Patent number
US08658636B2

Reaction notes

Loading…