Lithium Hydroxide → (S)-2-(3-(5-(5-(2-Ethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one

HRID 519286Notes

Reaction equation

HRID 519286 reaction equation
C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[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][CH2:44][N:43]([CH:46]4[CH2:49][O:48][CH2:47]4)[CH2:42][C@@H:41]3[CH2:50][CH3:51])=[CH:36][N:35]=2)[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=1)(=O)C.[Li+].[OH-]>CC(O)C.C1COCC1.O>[CH2:50]([C@H:41]1[CH2:42][N:43]([CH:46]2[CH2:47][O:48][CH2:49]2)[CH2:44][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][N:15]5[C:16]6[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=6[CH:22]=[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)[CH3:51]

Participants

5

Reactant 2

HCID 3939Lithium HydroxideHCID 86683707(S)-2-(5-(5-(2-Ethyl-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-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl acetate

Product 1

HCID 71526521(S)-2-(3-(5-(5-(2-Ethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-oneYield 26.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 22597222Tetrahydrofuran 2-propanolSolvent

Conditions

Temperature
30 °C

Procedure

A mixture of 105a (220 mg, 0.30 mmol) and LiOH (72 mg, 3.0 mmol) in iPrOH/THF (1:1, 4 mL) and H2O (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo and the residue was extracted with EtOAc (10 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 105 (54 mg, 25%) as a white solid. LCMS: [M+H]+ 682. 1H NMR (500 MHz, CDCl3) δ 8.54 (t, J=2.5, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.47 (d, J=1.5, 1H), 7.26-7.24 (m, 1H), 7.18-7.15 (m, 1H), 6.95 (dd, J=2.5, 9.0, 1H), 6.87 (s, 1H), 6.81 (d, J=7.5, 1H), 4.72-4.61 (m, 4H), 4.54 (d, J=11.5, 1H), 4.33-4.30 (m, 2H), 4.20-4.14 (m, 3H), 3.92-3.90 (m, 1H), 3.71 (s, 3H), 3.53 (t, J=5.5, 1H), 3.31 (s, 1H), 3.12 (s, 2H), 2.61-2.56 (m, 5H), 2.44 (s, 2H), 2.35 (s, 1H), 1.91-1.89 (m, 2H), 1.80-1.79 (m, 2H), 1.67 (s, 1H), 1.43-1.37 (m, 1H), 0.82 (t, J=5.5, 3H)

Workup

  1. customThe mixture was evaporated in vacuo
  2. extractionthe residue was extracted with EtOAc (10 mL×2)
  3. extractionThe combined EtOAc extract
  4. concentrationwas concentrated under reduced pressure
  5. customthe residue was purified by reverse-phase prep-HPLC

Sources & evidence

ORD record
ord-4d49cb650f464a77af7966863df8c410
Source dataset
uspto-grants-2015_08
Patent number
US09115152B2

Reaction notes

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