Lithium Hydroxide → 2-(3-{5-[5-((S)-2-Ethyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-5-fluoro-2-hydroxymethyl-phenyl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one

HRID 519340Notes

Reaction equation

HRID 519340 reaction equation
C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]5[CH2:34][O:33][CH2:32]5)[CH2:27][C@@H:26]4[CH2:35][CH3:36])=[CH:21][N:20]=3)[C:15](=[O:37])[N:14]([CH3:38])[CH:13]=2)=[CH:10][C:9]([F:39])=[CH:8][C:7]=1[N:40]1[CH2:51][CH2:50][N:49]2[C:42](=[CH:43][C:44]3[CH2:45][C:46]([CH3:53])([CH3:52])[CH2:47][C:48]=32)[C:41]1=[O:54])(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[CH2:35]([C@H:26]1[CH2:27][N:28]([CH:31]2[CH2:32][O:33][CH2:34]2)[CH2:29][CH2:30][N:25]1[C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[C:15](=[O:37])[N:14]([CH3:38])[CH:13]=[C:12]([C:11]3[C:6]([CH2:5][OH:4])=[C:7]([N:40]4[CH2:51][CH2:50][N:49]5[C:48]6[CH2:47][C:46]([CH3:53])([CH3:52])[CH2:45][C:44]=6[CH:43]=[C:42]5[C:41]4=[O:54])[CH:8]=[C:9]([F:39])[CH:10]=3)[CH:17]=2)=[N:20][CH:21]=1)[CH3:36]

Participants

5

Reactant 2

HCID 3939Lithium HydroxideHCID 86683742(2-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-6-[5-({5-[(2S)-2-ethyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]-4-fluorophenyl)methyl Acetate

Product 1

HCID 778446472-(3-{5-[5-((S)-2-Ethyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-5-fluoro-2-hydroxymethyl-phenyl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-oneYield 40.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 22597222Tetrahydrofuran 2-propanolSolvent

Conditions

Temperature
30 °C

Procedure

A mixture of 114g (115 mg, 0.16 mmol) and lithium hydroxide (38 mg, 1.6 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure and the residue was extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 114 (45 mg, 40%) as a white solid. MS: [M+H]+ 696.4. 1H NMR (500 MHz, CDCl3) δ 8.55-8.54 (m, 1H), 7.91 (s, 1H), 7.80 (d, J=1.5 Hz, 1H), 7.47 (s, 1H), 7.26 (d, J=3.0 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H), 6.95 (dd, J=2.5, 8.5 Hz, 1H), 6.83-6.81 (m, 2H), 4.71 (t, J=6.5 Hz, 2H), 4.67 (t, J=6.0 Hz, 1H), 4.62 (t, J=6.0 Hz, 1H), 4.57-4.55 (m, 1H), 4.41-4.38 (m, 1H), 4.32-4.30 (m, 1H), 4.24-4.14 (m, 3H), 3.92-3.87 (m, 1H), 3.71 (s, 3H), 3.56-3.50 (m, 1H), 3.33-3.29 (m, 1H), 3.13-3.11 (m, 2H), 2.58-2.56 (m, 3H), 2.52 (s, 2H), 2.44-2.43 (m, 2H), 2.38-2.32 (m, 1H), 1.66-1.64 (m, 1H), 1.42-1.37 (m, 1H), 1.28 (s, 6H), 0.82 (t, J=7.0 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 by reverse-phase prep-HPLC

Sources & evidence

ORD record
ord-8aa5286ddafa4d14b9eba7273d73383c
Source dataset
uspto-grants-2015_08
Patent number
US09115152B2

Reaction notes

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