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

HRID 928388Notes

Reaction equation

HRID 928388 reaction equation
[NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]([C:6]#[N:7])=[C:4]([CH3:12])[N:3]=1.CC(C[AlH]CC(C)C)C.O.NC1N=C(C)C(CN[C:33]([C:35]2[CH:36]=[N:37][N:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44](OC)=[CH:43][CH:42]=3)[CH:39]=2)=[O:34])=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>C1COCC1.CN(C1C=CN=CC=1)C.CO>[NH2:1][C:2]1[N:3]=[C:4]([CH3:12])[C:5]([CH2:6][NH:7][C:33]([C:35]2[CH:36]=[N:37][N:38]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:39]=2)=[O:34])=[C:8]([O:10][CH3:11])[CH:9]=1

Participants

10

Reactant 6

HCID 962WaterHCID 14487Diisobutylaluminum hydrideHCID 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 667237286-Amino-4-methoxy-2-methylnicotinonitrile

Product 1

HCID 56836190N-((6-Amino-4-methoxy-2-methylpyridin-3-yl)methyl)-1-benzyl-1H-pyrazole-4-carboxamide

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

A mixture of 6-amino-4-methoxy-2-methylnicotinonitrile (100 mg, 0.613 mmol) in THF (4 ml) was cooled to −78° C., and treated with DIBAL-H (1M in THF, 3.68 ml, 3.68 mmol). The mixture was slowly warmed to rt. Stirring was continued for 24 h at rt, before the reaction mixture was carefully transferred to an ice-cold mixture of MeOH (50 ml) and water (0.2 ml, 11.0 mmol). The resulting suspension was adsorbed on celite (ca. 30 cm3) and dried in vacuo. Elution with DCM-MeOH (9:1, 200 ml) and removal of all volatiles afforded a yellow oil. Dry THF (5 ml), 1-benzyl-1H-pyrazole-4-carboxylic acid (79.0 mg, 0.389 mmol, prepared in analogy to example 13), DIPEA (0.209 ml, 1.20 mmol), DMAP (1.8 mg, 0.015 mmol) and HATU (148 mg, 0.389 mmol) were added, and the reaction mixture was stirred at it for 14 h, before it was concentrated to dryness. The crude product was purified by column chromatography (CombiFlash Rf, 13 g RediSep Rf C18, MeCN:water 5:95+0.1% TFA to MeCN), followed by preparative HPLC (Waters Sunfire Prep C18 OBD 5 um, 100×30 mm, A: H2O+0.1% TFA, B: MeCN+0.1% TFA, 5-35% B in 15 min, 30 ml/min, rt) to afford the title compound. 1H-NMR (DMSO-d6, 400 MHz): 2.47 (s, 3H), 3.91 (s, 3 H), 4.22 (d, 2H), 5.33 (s, 2H), 6.26 (s, 1H), 7.22-7.27 (m, 2H), 7.28-7.38 (m, 3H), 7.53 (br, s, 2H), 7.86 (s, 1H), 8.09 (t, 1H), 8.23 (s, 1H), 12.95 (s, 1H); LCMS RtK=0.82 min, [M+H]+=352.4.

Workup

  1. temperatureThe mixture was slowly warmed to rt
  2. customdried in vacuo
  3. washElution
  4. customwith DCM-MeOH (9:1, 200 ml) and removal of all volatiles
  5. customafforded a yellow oil
  6. stirringthe reaction mixture was stirred at it for 14 h, before it
  7. concentrationwas concentrated to dryness
  8. customThe crude product was purified by column chromatography (CombiFlash Rf, 13 g RediSep Rf C18, MeCN:water 5:95+0.1% TFA to MeCN)
  9. waitA: H2O+0.1% TFA, B: MeCN+0.1% TFA, 5-35% B in 15 min

Sources & evidence

ORD record
ord-abc627b9dc0c43c79e34416fc47cde5d
Source dataset
uspto-grants-2016_03
Patent number
US09290485B2

Reaction notes

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