Triethylamine → (-) 2-(7-chloro-6-fluoro-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-fluorophenyl]ethyl}acetamide

HRID 419997Notes

Reaction equation

HRID 419997 reaction equation
[Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:14])=O)[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:15].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([F:30])[CH:20]=1)[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N.[OH-].[Na+]>[Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[C:21]([F:30])[CH:20]=3)[CH3:18])=[O:14])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:15]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 58298447(7-chloro-6-fluoro-1H-benzimidazol-1-yl)acetic acidHCID 582984652-[4-(1-Aminoethyl)-2-fluorophenyl]-2-methylpropanenitrile

Product 1

HCID 24850172(-) 2-(7-chloro-6-fluoro-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-fluorophenyl]ethyl}acetamide

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 14798Sodium HydroxideSolvent

Procedure

A mixture of (7-chloro-6-fluoro-1H-benzimidazol-1-yl)acetic acid (210 mg, 0.921 mmol) prepared according to scheme 12, 2-{4-[1-aminoethyl]-2-fluorophenyl}-2-methylpropanenitrile (190 mg 0.921 mmol)) prepared according to scheme 7 and Et3N (280 mg, 2.76 mmol, 0.39 mL) is stirred in MeCN (10.0 mL). HATU (350 mg, 0.921 mmol) is added, and after 2 hours of stirring, the mixture is diluted with 1N NaOH (40.0 mL) and then extracted 4 times with EtOAc (4×40.0 mL). The organic phases are combined and dried over MgSO4. The mixture is filtered and concentrated. The product is purified by a Gilson prep pump, flow rate: 30 ml/min, column: Synergi Polar (4u) 21.2×50 mm, mobile phase: A=water (0.1% TFA), B=MeCN (206 mg, 54%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.38 (d, J=6.84 Hz, 3H) 1.71 (s, 6H) 4.85-5.00 (m, J=7.13, 7.13 Hz, 1H) 5.21 (s, 2H) 7.15-7.31 (m, 3H) 7.42 (t, J=8.30 Hz, 1H) 7.63 (dd, J=8.89, 4.39 Hz, 1H) 8.21 (s, 1H) 8.84 (d, J=7.81 Hz, 1H). The enantiomers are separated on a chiral AD column, eluting with 30% EtOH (0.1% DIEA) and hexanes 70% (0.1% DIEA), MS [M+H], calcd: 417.1. found: 417.3 [α]D=+154 (c=13, MeOH) and [α]D=−155 (c=15, MeOH).

Workup

  1. customprepared
  2. customprepared
  3. extractionextracted 4 times with EtOAc (4×40.0 mL)
  4. dry with materialdried over MgSO4
  5. filtrationThe mixture is filtered
  6. concentrationconcentrated
  7. customThe product is purified by a Gilson prep pump, flow rate: 30 ml/min, column
  8. customThe enantiomers are separated on a chiral AD column
  9. washeluting with 30% EtOH (0.1% DIEA) and hexanes 70% (0.1% DIEA), MS [M+H], calcd

Sources & evidence

ORD record
ord-4a72d01434ab4f39ba77092171dd7a25
Source dataset
uspto-grants-2012_01
Patent number
US08093402B2

Reaction notes

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