Diisopropylethylamine → N-((6-Amino-4-(cyclohexyloxy)-2-methylpyridin-3-yl)methyl)-1-benzyl-1H-pyrazole-4-carboxamide

HRID 928390Notes

Reaction equation

HRID 928390 reaction equation
[NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]([C:6]#[N:7])=[C:4]([CH3:17])[N:3]=1.NC1N=C(C)C(CN[C:28]([C:30]2[CH:31]=[N:32][N:33]([CH2:35][C:36]3[CH:41]=[CH:40][C:39](OC)=[CH:38][CH:37]=3)[CH:34]=2)=[O:29])=C(C)C=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCO.CO.CN(C1C=CN=CC=1)C.[Ni].C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([CH3:17])[C:5]([CH2:6][NH:7][C:28]([C:30]2[CH:31]=[N:32][N:33]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:34]=2)=[O:29])=[C:8]([O:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:9]=1

Participants

10

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 56836258Plasma kallikrein-IN-3HCID 667236456-Amino-4-(cyclohexyloxy)-2-methylnicotinonitrile

Product 1

HCID 56836259N-((6-Amino-4-(cyclohexyloxy)-2-methylpyridin-3-yl)methyl)-1-benzyl-1H-pyrazole-4-carboxamide

Reagents, catalysts & solvents 5

HCID 935NickelCatalystHCID 142844-(Dimethylamino)pyridineCatalystHCID 702EthanolSolventHCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a mixture of 6-Amino-4-(cyclohexyloxy)-2-methylnicotinonitrile (30.0 mg, 0.130 mmol) in EtOH (5 ml) were added about 10 cm3 of a Raney-Ni suspension in MeOH under Ar. The flask was sealed, and the suspension was vigorously stirred at it for 3 d under an atmosphere of hydrogen. The reaction mixture was filtered over a plug of cellite and eluted with DCM-MeOH (9:1, 100 ml), DCM (50 ml), MeOH (50 ml) and NH3 in MeOH (7N, 50 ml). The combined filtrates were concentrated. Dry THF (5 ml), 1-benzyl-1H-pyrazole-4-carboxylic acid (26.3 mg, 0.130 mmol, prepared in analogy to example 13), DIPEA (0.091 ml, 0.520 mmol), DMAP (0.80 mg, 0.0065 mmol) and HATU (49.4 mg, 0.130 mmol) were added, and the reaction mixture was stirred at it for 10 h, before it was concentrated to dryness. The crude product was purified by column chromatography (CombiFlash Companion, 4 g SiO2, DCM to DCM:MeOH 9:1), followed by preparative HPLC (Waters Sunfire Prep C18 OBD 5 um, 100×19 mm, A: H2O+0.1% TFA, B: MeCN+0.1% TFA, 15-45% B in 10 min, 30 ml/min, rt) affording the title compound. 1H-NMR (DMSO-d6, 400 MHz): 1.15-1.27 (m, 1H), 1.27-1.38 (m, 2 H), 1.40-1.50 (m, 1H), 1.51-1.62 (m, 2H), 1.62-1.72 (m, 2H), 1.77-1.88 (m, 2 H), 2.44 (s, 3H), 4.24 (d, 2H), 4.47 (mc, 1H), 5.34 (s, 2H), 6.29 (s, 1H), 7.19-7.25 (m, 2H), 7.27-7.41 (m, 5H), 7.84 (s, 1H), 7.92 (t, 1H), 8.21 (s, 1H), 12.81 (s, 1H); LCMS RtK=1.11 min, [M+H]+=420.4.

Workup

  1. customThe flask was sealed
  2. filtrationThe reaction mixture was filtered over a plug of cellite
  3. washeluted with DCM-MeOH (9:1, 100 ml), DCM (50 ml), MeOH (50 ml) and NH3 in MeOH (7N, 50 ml)
  4. concentrationThe combined filtrates were concentrated
  5. stirringthe reaction mixture was stirred at it for 10 h, before it
  6. concentrationwas concentrated to dryness
  7. customThe crude product was purified by column chromatography (CombiFlash Companion, 4 g SiO2, DCM to DCM:MeOH 9:1)
  8. waitA: H2O+0.1% TFA, B: MeCN+0.1% TFA, 15-45% B in 10 min

Sources & evidence

ORD record
ord-58b4763a01ad49fc9f4a4890679b999f
Source dataset
uspto-grants-2016_03
Patent number
US09290485B2

Reaction notes

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