4-Methylmorpholine → 6-bromo-N-((4-cyclohexyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-indazole-4-carboxamide

HRID 1476420Notes

Reaction equation

HRID 1476420 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.OC(C(F)(F)F)=O.[NH2:24][CH2:25][C:26]1[C:27](=[O:39])[NH:28][C:29]([CH3:38])=[CH:30][C:31]=1[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.N1C=CC=CC1=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O.C(Cl)CCl>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:24][CH2:25][C:26]2[C:27](=[O:39])[NH:28][C:29]([CH3:38])=[CH:30][C:31]=2[CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1

Participants

10

Reactant 6

HCID 79724-Methylmorpholine2×HCID 88712-PyridoneHCID 11430Potassium CarbonateHCID 181649HOAt2×HCID 671244353-(aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone TFAHCID 674654436-Bromo-1-isopropyl-1H-indazole-4-carboxylic acid

Product 1

HCID 682102576-bromo-N-((4-cyclohexyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-indazole-4-carboxamide

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolvent2×HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent

Procedure

6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylic acid (237 mg, 0.84 mmol), 3-(aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone TFA (378 mg, 1.13 mmol) and 1-hydroxy-7-azabenzotriazole (171 mg, 1.26 mmol) were stirred in 10 mL of DMSO for 10 min under nitrogen. N-methylmorpholine (0.37 ml, 3.35 mmol) was added along with EDC (241 mg, 1.26 mmol) and the mixture was stirred at rt overnight. An additional 0.2 eq of pyridinone, HOAt, NMM and EDC were added and the contents were stirred at rt overnight. The reaction mixture was then poured onto ice-water. A solution of 10% K2CO3 in water was added to afford a pH ˜8-9 solution. The reaction mixture was stirred at rt for 30 min and then allowed to stand at rt for 30 min. Precipitated solids were filtered and air-dried. The collected solid was treated with EtOAc (not soluble) and hexanes, and then concentrated in vacuo. To the isolated solid was then added DMF followed by heating and sonication. Water was added and beige solids crashed out. The precipitated solids were filtered, washed with water, air-dried, and dried in vacuum oven for 2 hours. The title compound was collected as a solid (308 mg, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (s, 1H) 8.63 (t, J=4.80 Hz, 1H) 8.37 (s, 1H) 8.20 (s, 1H) 7.68 (d, J=1.26 Hz, 1H) 6.01 (s, 1H) 5.05 (dt, J=13.14, 6.57 Hz, 1H) 4.43 (d, J=4.80 Hz, 2H) 2.84 (t, J=11.24 Hz, 1H) 2.15 (s, 3H) 1.70 (d, J=13.39 Hz, 2H) 1.60 (d, J=12.13 Hz, 3H) 1.47 (s, 3H) 1.45 (s, 3H) 1.42 (br. s., 1H) 1.17-1.39 (m, 4H); LCMS: 485.2/487.2 (Br pattern).

Workup

  1. stirringthe contents were stirred at rt overnight
  2. additionThe reaction mixture was then poured onto ice-water

Sources & evidence

ORD record
ord-05b5f870d8474f48b516b987fc5ea5b2
Source dataset
uspto-grants-2015_04
Patent number
US09018382B2

Reaction notes

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