Nitrogen → HCID 90410816, compound

HRID 1527774Notes

Reaction equation

HRID 1527774 reaction equation
Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[C:31]([OH:33])=[O:32])=[CH:4][CH:3]=1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.Cl.[F:70][C:71]1([F:76])[CH2:75][CH2:74][NH:73][CH2:72]1.N#N>>[F:70][C:71]1([F:76])[CH2:75][CH2:74][N:73]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[C:13]([O:16][CH2:17][C:18]5[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=5)[CH:14]=[CH:15][C:10]=4[N:9]=[C:8]3[C@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]3[C:31]([OH:33])=[O:32])=[CH:4][CH:3]=2)[CH2:72]1

Participants

5

Reactant 4

HCID 947NitrogenHCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 249034823,3-Difluoropyrrolidine hydrochlorideHCID 86268284HCID 86268284, compound

Product 1

HCID 90410816HCID 90410816, compoundYield 40.8%

Conditions

Temperature
50 °C

Procedure

To a sealable vial was added racemic cis-2-{1-(4-bromobenzyl)-6-[(5-methylpyridin-2-yl)methoxy]-1H-benzimidazol-2-yl}cyclohexanecarboxylic acid (320 mg, 0.56 mmol) RuPhos precatalyst (45 mg, 0.060 mmol), RuPhos (28.5 mg, 0.060 mmol) and 3,3-difluoropyrrolidine hydrochloride (172 mg, 1.20 mmol) and N2 sparged THF (6.0 mL) followed by LiHMDS (3.0 mL, 1.0 M in THF). The resulting reddish mixture was heated to 50° Celsius for 2 h. The reaction mixture was cooled to RT and treated with HCl (3 mL, 0.5 N) and MeOH until homogeneous. The mixture was purified using reverse phase HPLC to afford the title compound (128 mg, 38%). MS (ESI): mass calcd. for C32H34F2N4O3, 560.26; m/z found, 561.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.32 (s, 1H), 7.64 (dd, J=8.0, 1.6, 1H), 7.54 (d, J=8.9, 1H), 7.43 (d, J=8.0, 1H), 7.03-6.92 (m, 4H), 6.54 (d, J=8.7, 2H), 5.42 (d, J=16.5, 1H), 5.33 (d, J=16.5, 1H), 5.10 (s, 2H), 3.62 (t, J=13.3, 2H), 3.58-3.52 (m, 1H), 3.47 (t, J=7.2, 2H), 2.92-2.82 (m, 1H), 2.48 (m, 2H), 2.38-2.27 (m, 4H), 2.07-1.95 (m, 1H), 1.88-1.69 (m, 4H), 1.56-1.37 (m, 2H).

Workup

  1. customsparged THF (6.0 mL)
  2. temperatureThe reaction mixture was cooled to RT
  3. additiontreated with HCl (3 mL, 0.5 N) and MeOH until homogeneous
  4. customThe mixture was purified

Sources & evidence

ORD record
ord-f235b027318d4494a4cf1df44bfbc848
Source dataset
uspto-grants-2015_07
Patent number
US09089569B2

Reaction notes

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