Lithium Hydroxide → 2-[3-[5-[[5-[(2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl]-2-pyridyl]amino]-1-methyl-6-oxo-3-pyridyl]-5-fluoro-2-(hydroxymethyl)phenyl]-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-1-one

HRID 519386Notes

Reaction equation

HRID 519386 reaction equation
C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][C:22]3[N:21]4[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]4)=[CH:15][C:14]=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][C@@H:44]([CH3:46])[N:43]([CH:47]4[CH2:50][O:49][CH2:48]4)[CH2:42][C@@H:41]3[CH3:51])=[CH:36][N:35]=2)[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[CH3:51][C@H:41]1[CH2:42][N:43]([CH:47]2[CH2:50][O:49][CH2:48]2)[C@H:44]([CH3:46])[CH2:45][N:40]1[C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]2[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=[C:27]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([N:12]4[CH2:24][CH2:23][C:22]5[N:21]6[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]6)=[CH:15][C:14]=5[C:13]4=[O:25])[CH:10]=[C:9]([F:26])[CH:8]=3)[CH:32]=2)=[N:35][CH:36]=1

Participants

5

Reactant 2

HCID 3939Lithium HydroxideHCID 866837672-(5-(5-((2S,5R)-2,5-Dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)benzyl Acetate

Product 1

HCID 715254282-[3-[5-[[5-[(2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl]-2-pyridyl]amino]-1-methyl-6-oxo-3-pyridyl]-5-fluoro-2-(hydroxymethyl)phenyl]-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-1-oneYield 33%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 22597222Tetrahydrofuran 2-propanolSolvent

Conditions

Temperature
30 °C

Procedure

A mixture of 126a (150 mg, 0.20 mmol) and lithium hydroxide (72 mg, 3.0 mmol) in i-propanol/THF (5:3, 8.0 mL) and water (2.0 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure and the residue was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by prep-HPLC to afford 126 (45 mg, 33%) as a white solid. MS: [M+H]+ 682.9. 1H NMR (500 MHz, CHCl3) δ 8.60 (dd, J=2, 5 Hz, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.54 (s, 1H), 7.37-7.35 (m, 1H), 7.14-7.12 (m, 1H), 6.96-6.94 (m, 1H), 6.82-6.80 (m, 1H), 6.31 (s, 1H), 4.77-4.71 (m, 2H), 4.67-4.62 (m, 2H), 4.58-4.55 (m, 1H), 4.41-4.40 (m, 1H), 4.29-4.25 (m, 1H), 4.13-4.09 (m, 1H), 3.91-3.80 (m, 3H), 3.77-3.74 (m, 1H), 3.70 (s, 3H), 3.18 (d, J=5.0 Hz, 1H), 3.06-3.01 (m, 1H), 2.98-2.90 (m, 2H), 2.83 (m, 2H), 2.77-2.70 (m, 2H), 2.47 (m, 1H), 2.06-2.01 (m, 2H), 1.97-1.93 (m, 1H), 1.88-1.87 (m, 2H), 0.91-0.89 (m, 6H).

Workup

  1. customThe mixture was evaporated under reduced pressure
  2. extractionthe residue was extracted with ethyl acetate (2×20 mL)
  3. extractionThe combined ethyl acetate extract
  4. concentrationwas concentrated under reduced pressure
  5. customthe residue was purified by prep-HPLC

Sources & evidence

ORD record
ord-7f00b959dab0438c924d1ba4398914a3
Source dataset
uspto-grants-2015_08
Patent number
US09115152B2

Reaction notes

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