Sodium borohydride → (S)-6-tert-Butyl-8-fluoro-2-(5-fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)phthalazin-1(2H)-one

HRID 407618Notes

Reaction equation

HRID 407618 reaction equation
[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([C:26]3[CH:31]=[C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([N:39]5[CH2:44][CH2:43][N:42]([CH:45]6[CH2:48][O:47][CH2:46]6)[CH2:41][C@@H:40]5[CH3:49])=[CH:35][N:34]=4)[C:29](=[O:50])[N:28]([CH3:51])[CH:27]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([C:26]3[CH:31]=[C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([N:39]5[CH2:44][CH2:43][N:42]([CH:45]6[CH2:46][O:47][CH2:48]6)[CH2:41][C@@H:40]5[CH3:49])=[CH:35][N:34]=4)[C:29](=[O:50])[N:28]([CH3:51])[CH:27]=3)[C:18]=1[CH2:19][OH:20])[N:9]=[CH:8]2)([CH3:2])([CH3:3])[CH3:4]

Participants

4

Reactant 2

HCID 4311764Sodium borohydrideHCID 86683917(S)-2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluoro-6-(1-methyl-5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)benzaldehyde

Product 1

HCID 86683918(S)-6-tert-Butyl-8-fluoro-2-(5-fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)phthalazin-1(2H)-oneYield 55%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
25 °C

Procedure

A mixture of (S)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluoro-6-(1-methyl-5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)benzaldehyde 104a (80 mg, 0.12 mmol), NaBH4 (14 mg, 0.36), and methanol (20 mL) was stirred at 25° C. for 1 h. Then the reaction mixture was quenched with water (10 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (2×30 mL) and the combined dichloromethane extract was concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 104 (46 mg, 55%) as a yellow solid. MS: [M+H]+ 698.3. 1H NMR (500 MHz, DMSO-d6) δ 8.54 (d, J=2.0 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.42 (s, 1H), 7.88 (s, 1H), 7.86 (d, J=3.0 Hz, 1H), 7.77-7.74 (m, 1H), 7.40-7.34 (m, 3H), 7.30 (dd, J=2.5, 9.5 Hz, 1H), 7.23 (d, J=9.0 Hz, 1H), 4.57-4.54 (m, 2H), 4.49-4.45 (m, 1H), 4.43-4.40 (m, 1H), 4.34-4.29 (m, 2H), 3.70-3.65 (m, 1H), 3.58 (s, 3H), 3.40-3.38 (m, 2H), 3.12-3.06 (m, 1H), 2.97-2.91 (m, 1H), 2.36-2.29 (m, 3H), 2.19-2.15 (m, 1H), 1.38 (s, 9H), 0.93 (d, J=6.5 Hz, 3H),

Workup

  1. customThen the reaction mixture was quenched with water (10 mL)
  2. concentrationconcentrated under reduced pressure
  3. extractionThe residue was extracted with dichloromethane (2×30 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-d93c0b2633c34f8bab0b3bee9bc2cf60
Source dataset
uspto-grants-2014_06
Patent number
US08754077B2

Reaction notes

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