Methyl 6-aminonicotinate → HCID 178511630, compound

HRID 1943475Notes

Reaction equation

HRID 1943475 reaction equation
Br[C:2]1[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=[C:6](Cl)[CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][N:24]=1.CC(C)([O-])C.[K+].[C@H:39]1([NH2:46])[CH2:44][CH2:43][C@H:42]([NH2:45])[CH2:41][CH2:40]1>C1COCC1.CN(C=O)C>[NH2:45][C@H:42]1[CH2:43][CH2:44][C@H:39]([NH:46][C:6]2[CH:7]=[C:2]([NH:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=3)[C:3]3[N:4]([C:9]([C:12](=[O:13])[NH:14][C:15]4[CH:20]=[CH:19][N:18]=[CH:17][C:16]=4[F:21])=[CH:10][N:11]=3)[N:5]=2)[CH2:40][CH2:41]1

Participants

7

Reactant 4

HCID 737487Methyl 6-aminonicotinateHCID 23665647Potassium tert-butoxideHCID 596244958-Bromo-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamideHCID 178511674HCID 178511674, compound

Product 1

HCID 178511630HCID 178511630, compoundYield 5.41%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a suspension of 5A (0.050 g, 0.153 mmol) and methyl 6-aminonicotinate (0.028 g, 0.184 mmol) in THF (0.767 mL) at room temperature was added potassium tert-butoxide (0.337 mL, 0.337 mmol). The resulting suspension was stirred 2 h at room temperature. The solvent was then removed via a stream of nitrogen. The solid was taken up in NMP (0.767 mL), (trans)-cyclohexane-1,4-diamine (0.210 g, 1.840 mmol) was added, and the mixture was heated to 110° C. in a CEM Discover 300 W microwave for 20 min. The mixture was diluted with DMF and purified via preparatory HPLC using a YMC ODS C-18 column (30×250 mm), 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 60 min, flow rate 25 mL/min. Rt=48.545 min. The appropriate fractions were concentrated and lyophilized overnight, and 6-(6-((trans)-4-aminocyclohexylamino)-3-(3-fluoropyridin-4-ylcarbamoyl)imidazo[1,2-b]pyridazin-8-ylamino)nicotinic acid (7.4 mg, 8.29 μmol, 5.41% yield) was obtained as a white lyophile. HPLC: Rt=3.466 min. YMC S5 ODS-A column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% 1 min, flow rate 4 mL/min. MS: [M+H]=506.1. 1H NMR (400 MHz, DMSO-D6) δ ppm 11.20 (1H, s), 10.31 (1H, s), 8.85 (1H, d, J=2.27 Hz), 8.70 (1H, d, J=1.26 Hz), 8.45-8.51 (1H, m), 8.43 (1H, s), 8.12-8.19 (1H, m), 8.07 (1H, s), 7.93 (2H, s), 7.58 (1H, d, J=8.56 Hz), 7.24 (1H, s), 7.11 (1H, s), 6.99 (1H, s), 3.79-3.93 (1H, m), 3.00-3.13 (1H, m), 2.05-2.18 (2H, m), 1.97 (2H, s), 1.47 (2H, s), 1.33 (2H, s).

Workup

  1. customThe solvent was then removed via a stream of nitrogen
  2. temperaturethe mixture was heated to 110° C. in a CEM Discover 300 W microwave for 20 min
  3. custompurified via preparatory HPLC
  4. customB=100, gradient time 60 min, flow rate 25 mL/min
  5. concentrationThe appropriate fractions were concentrated
  6. waitlyophilized overnight

Sources & evidence

ORD record
ord-91876c60b2ee488987843b3a5f9b3eb7
Source dataset
uspto-grants-2013_03
Patent number
US08389527B2

Reaction notes

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