Lithium Hydroxide → N-{2-[(6-{[5-(2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-3-(hydroxymethyl)pyridin-4-yl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}pyridin-2-yl)oxy]ethyl}prop-2-enamide

HRID 1774624Notes

Reaction equation

HRID 1774624 reaction equation
C([O:4][CH2:5][C:6]1[C:7]([N:35]2[CH2:46][CH2:45][N:44]3[C:37](=[CH:38][C:39]4[CH2:40][C:41]([CH3:48])([CH3:47])[CH2:42][C:43]=43)[C:36]2=[O:49])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][NH:28][C:29](=[O:32])[CH:30]=[CH2:31])[N:20]=2)[C:15](=[O:33])[N:14]([CH3:34])[CH:13]=1)(=O)C.[Li+].[OH-]>C1COCC1.CC(O)C.O.O>[CH3:47][C:41]1([CH3:48])[CH2:40][C:39]2[CH:38]=[C:37]3[N:44]([CH2:45][CH2:46][N:35]([C:7]4[C:6]([CH2:5][OH:4])=[C:11]([C:12]5[CH:17]=[C:16]([NH:18][C:19]6[N:20]=[C:21]([O:25][CH2:26][CH2:27][NH:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH:22]=[CH:23][CH:24]=6)[C:15](=[O:33])[N:14]([CH3:34])[CH:13]=5)[CH:10]=[CH:9][N:8]=4)[C:36]3=[O:49])[C:43]=2[CH2:42]1

Participants

5

Reactant 2

HCID 3939Lithium HydroxideHCID 118116637(2-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-[1-methyl-6-oxo-5-({6-[2-(prop-2-enamido)ethoxy]pyridin-2-yl}amino)-1,6-dihydropyridin-3-yl]pyridin-3-yl)methyl acetate

Product 1

HCID 118116437N-{2-[(6-{[5-(2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-3-(hydroxymethyl)pyridin-4-yl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}pyridin-2-yl)oxy]ethyl}prop-2-enamideYield 39.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 22722550Tetrahydrofuran water isopropanolSolvent

Procedure

—Step 6: To a solution of 101f (257 mg, 0.387 mmol) in THF/i-PrOH/H2O (5.0/3.0/2.0 mL) was added LiOH (46 mg, 1.95 mmol) at room temperature. The reaction was stirred for 1 h. The mixture was diluted with water (15 mL) and extracted with DCM (15 mL×3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue solid was purified by reverse-phase prep-HPLC to afford 101 (95 mg, 39% two steps) as a white solid. MS-ESI: [M+H]+ 624.2. 1H NMR (500 MHz, CDCl3) δ 8.74 (d, J=2.0 Hz, 1H), 8.53 (d, J=5.0 Hz, 1H), 9.70 (s, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.50-7.48 (m, 1H), 7.29-7.27 (m, 1H), 6.85 (s, 1H), 6.46-6.44 (m, 2H), 6.27-6.23 (m, 2H), 6.05-6.00 (m, 1H), 5.61-5.59 (m, 1H), 4.98-4.96 (m, 1H), 4.72-4.70 (m, 1H), 4.55-4.53 (m, 1H), 4.39-4.29 (m, 3H), 4.19-4.16 (m, 2H), 3.96-3.94 (m, 1H), 375-3.73 (m, 4H, overlap), 3.64-3.60 (m, 1H), 2.61-2.59 (m, 2H), 2.53-2.51 (m, 2H), 1.30 (s, 6H).

Workup

  1. extractionextracted with DCM (15 mL×3)
  2. washThe combined organic layer was washed with brine (10 mL)
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue solid was purified by reverse-phase prep-HPLC

Sources & evidence

ORD record
ord-e0a61f5195fe43a883d81936a5dfaf73
Source dataset
uspto-grants-2016_02
Patent number
US09260415B2

Reaction notes

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