Lithium Hydroxide → 10-fluoro-2-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]-2-pyridyl]amino]-6-oxo-pyridazin-3-yl]-2-pyridyl]-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1-one

HRID 592941Notes

Reaction equation

HRID 592941 reaction equation
C([O:4][CH2:5][C:6]1[C:7]([N:38]2[CH2:51][CH2:50][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[C:48]([F:49])=[C:40]3[C:39]2=[O:52])=[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][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][C@@H:26]3[CH3:35])=[CH:21][N:20]=2)[C:15](=[O:36])[N:14]([CH3:37])[N:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[F:49][C:48]1[C:47]2[CH2:46][CH2:45][CH2:44][CH2:43][C:42]=2[N:41]2[CH2:50][CH2:51][N:38]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([C:12]4[CH:17]=[C:16]([NH:18][C:19]5[CH:24]=[CH:23][C:22]([N:25]6[CH2:30][CH2:29][N:28]([CH:31]7[CH2:34][O:33][CH2:32]7)[CH2:27][C@@H:26]6[CH3:35])=[CH:21][N:20]=5)[C:15](=[O:36])[N:14]([CH3:37])[N:13]=4)[CH:10]=[CH:9][N:8]=3)[C:39](=[O:52])[C:40]=12

Participants

5

Reactant 2

HCID 3939Lithium HydroxideHCID 86684435(S)-(2-(10-Fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-4-(1-methyl-5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)pyridin-3-yl)methyl Acetate

Product 1

HCID 8668443610-fluoro-2-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]-2-pyridyl]amino]-6-oxo-pyridazin-3-yl]-2-pyridyl]-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1-oneYield 59%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 22597222Tetrahydrofuran 2-propanolSolvent

Procedure

A mixture of 231d (150 mg, 0.21 mmol) and lithium hydroxide (51 mg, 2.1 mmol) in i-propanol/THF (1:1, 10 mL) and water (3 mL) was stirred at room temperature for 1 h. The mixture was evaporated under reduced pressure and the residue was extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 231 (83 mg, 59%) as a yellow solid. MS-ESI: [M+H]+ 670.3. 1H NMR (500 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.42 (s, 1H), 7.91 (s, 1H), 7.43-7.40 (m, 3H), 4.76 (bs, 1H), 4.60-4.54 (m, 3H), 4.49-4.46 (m, 1H), 4.43-4.37 (m, 2H), 4.21-4.56 (m, 2H), 4.07-4.03 (m, 1H), 3.89-3.83 (m, 2H), 3.78 (s, 3H), 3.41-3.37 (m, 1H), 3.22-3.19 (m, 1H), 3.00-2.93 (m, 1H), 2.65-2.60 (m, 2H), 2.55-2.54 (m, 1H), 2.43-2.39 (m, 3H), 2.27-2.24 (m, 1H), 2.12-2.07 (m, 1H), 1.76-1.66 (m, 4H), 0.97 (d, J=9.0 Hz, 3H).

Workup

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

Sources & evidence

ORD record
ord-d2a19bcb59a5471cbc9fe1cb868ed78a
Source dataset
uspto-grants-2016_01
Patent number
US09238655B2

Reaction notes

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