Sodium borohydride → 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-3-pyridyl]-2-pyridyl]-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-1-one

HRID 592954Notes

Reaction equation

HRID 592954 reaction equation
[F:1][C:2]1[C:3]2[C:14](=[O:15])[N:13]([C:16]3[C:21]([CH:22]=[O:23])=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][C:34]([N:37]6[CH2:42][CH2:41][N:40]([CH:43]7[CH2:46][O:45][CH2:44]7)[CH2:39][C@@H:38]6[CH3:47])=[CH:33][N:32]=5)[C:27](=[O:48])[N:26]([CH3:49])[CH:25]=4)[CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11][C:4]=2[N:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[BH4-].[Na+]>CO>[F:1][C:2]1[C:3]2[C:14](=[O:15])[N:13]([C:16]3[C:21]([CH2:22][OH:23])=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][C:34]([N:37]6[CH2:42][CH2:41][N:40]([CH:43]7[CH2:44][O:45][CH2:46]7)[CH2:39][C@@H:38]6[CH3:47])=[CH:33][N:32]=5)[C:27](=[O:48])[N:26]([CH3:49])[CH:25]=4)[CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11][C:4]=2[N:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2

Participants

4

Reactant 2

HCID 4311764Sodium borohydrideHCID 866844452-{10-Fluoro-1-oxo-1H,2H,3H,4H,6H,7H,8H,9H-pyrido[3,4-b]indolizin-2-yl}-4-[1-methyl-5-({5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]pyridine-3-carbaldehyde

Product 1

HCID 8668444710-fluoro-2-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]-2-pyridyl]amino]-6-oxo-3-pyridyl]-2-pyridyl]-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-1-oneYield 28%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
12.5 °C

Procedure

To a solution of 237a (131 mg, 0.197 mmol) in methanol (7 mL) was added sodium borohydride (59.8 mg, 1.57 mmol) at 0° C. The reaction was stirred at 0-25° C. for 1.5 h. It was then quenched with water (1.5 mL). The mixture was evaporated under reduced pressure and the residue was extracted with dichloromethane (3×30 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 237 (36 mg, 28%) as a white solid. MS-ESI: [M+H]+ 669.3. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=1.5 Hz, 1H), 8.51 (d, J=5.0 Hz, 1H), 7.99 (s, 1H), 7.85 (s, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.36-7.32 (m, 2H), 6.84 (d, J=9.0 Hz, 1H), 4.90-4.86 (m, 1H), 4.73-4.65 (m, 5H), 4.39-4.30 (m, 2H), 3.90-3.77 (m, 3H), 3.72 (s, 3H), 3.56-3.48 (m, 2H), 3.10-3.09 (m, 2H), 2.98-2.92 (m, 2H), 2.79-2.75 (m, 2H), 2.59-2.57 (m, 1H), 2.50-2.49 (m, 2H), 2.22-2.21 (s, 1H), 2.04-1.99 (m, 2H), 1.88-1.84 (m, 2H), 1.01 (d, J=6.0 Hz, 3H).

Workup

  1. customIt was then quenched with water (1.5 mL)
  2. customThe mixture was evaporated under reduced pressure
  3. extractionthe residue was extracted with dichloromethane (3×30 mL)
  4. extractionThe combined dichloromethane extract
  5. concentrationwas concentrated under reduced pressure
  6. customthe residue was purified by reverse-phase prep-HPLC

Sources & evidence

ORD record
ord-4f9e292e8a524a948ed669882f710474
Source dataset
uspto-grants-2016_01
Patent number
US09238655B2

Reaction notes

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