Acetic Acid → (+/-)-5-Cyclopropyl-7-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-1H-indazole

HRID 914013Notes

Reaction equation

HRID 914013 reaction equation
[CH:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[C:11]([CH:13]([O:15][CH2:16][C:17]4([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH3:14])[CH:12]=2)[NH:9][N:8]=[CH:7]3)[CH2:3][CH2:2]1.[C:30]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[CH:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[C:11]([CH:13]([O:15][CH2:16][C:17]4([C:23]5[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=5)[CH2:22][CH2:21][N:20]([CH3:30])[CH2:19][CH2:18]4)[CH3:14])[CH:12]=2)[NH:9][N:8]=[CH:7]3)[CH2:3][CH2:2]1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 57546036HCID 57546036, compound

Product 1

HCID 25160321(+/-)-5-Cyclopropyl-7-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-1H-indazole

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 6342AcetonitrileSolvent

Procedure

To a suspension of (±)-5-cyclopropyl-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-1H-indazole (13.5 mg, 0.036 mmol) and sodium cyanoborohydride (11.2 mg, 0.178 mmol) in acetonitrile (1 mL) at 0° C. was added formalin (0.027 mL). The reaction was treated with 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added and the ice bath was removed, stirring continued for another hour. The reaction was diluted with diethyl ether and washed with 1 M sodium hydroxide. The ethereal was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated. It was then purified by column chromatography (10% 2 M ammonia in MeOH/CH2Cl2) to give 10.5 mg (46.5%) as clear oil. 1H-NMR (CDCl3, 500 MHz) δ 9.63 (bs, 1H), 7.86 (s, 1H), 7.23-7.27 (m, 3H), 7.03-7.07 (m, 2H), 6.78 (s, 1H), 4.47 (q, J=5.0 Hz, 1H), 3.35 (d, J=10 Hz, 1H), 3.24 (d, J=5 Hz, 1H), 2.55-2.70 (m, 2H), 1.91-2.30 (m, 9H), 1.40 (d, J=10.0 Hz, 3H), 0.9-0.94 (m, 2H), 0.62-0.68 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 161.5 (d, J=978 Hz), 136.2, 135.9, 133.9, 128.8, 125.9, 124.3, 123.3, 115.8, 115.6, 115.4, 78.9, 51.9, 51.7, 46.1, 40.3, 32.4, 32.3, 22.4, 15.4, 8.7; Mass spec.: 408.09 (MH)+.

Workup

  1. customthe ice bath was removed
  2. waitcontinued for another hour
  3. additionThe reaction was diluted with diethyl ether
  4. washwashed with 1 M sodium hydroxide
  5. concentrationThe ethereal was concentrated
  6. customThe cartridge was flushed with several volumes of methanol which
  7. washThe product was eluted with 2 M ammonia in methanol
  8. concentrationconcentrated
  9. customIt was then purified by column chromatography (10% 2 M ammonia in MeOH/CH2Cl2)
  10. customto give 10.5 mg (46.5%) as clear oil

Sources & evidence

ORD record
ord-79e7a3bc81594f6d91d5f954281d87d6
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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