Formaldehyde → 4-(1-Cyclopropyl-7-(((1-methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-1H-indazol-5-yl)benzonitrile

HRID 914024Notes

Reaction equation

HRID 914024 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([CH2:18][O:19][CH2:20][C:21]4([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH:17]=2)[N:14]([CH:40]2[CH2:42][CH2:41]2)[N:13]=[CH:12]3)=[CH:5][CH:4]=1)#[N:2].C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[CH:40]1([N:14]2[C:15]3[C:11](=[CH:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[CH:17][C:16]=3[CH2:18][O:19][CH2:20][C:21]3([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:12]=[N:13]2)[CH2:41][CH2:42]1

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 57546084HCID 57546084, compound

Product 1

HCID 251605854-(1-Cyclopropyl-7-(((1-methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-1H-indazol-5-yl)benzonitrile

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 6422Trifluoroacetic acidSolvent

Procedure

tert-Butyl 4-(((5-(4-cyanophenyl)-1-cyclopropyl-1H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (23 mg, 0.04 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 2 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (2 mL), cooled to 0° C., and treated with sodium cyanoborohydride (12.8 mg, 0.2 mmol) and formalin (152 μL). After 5 min, the reaction was treated with a few drops of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by flash chromatography on silica gel (10% methanolic ammonia/methylene chloride) to afford 23 mg (95%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.91 (s, 1H), 7.81 (d, J=1.5 Hz, 1H), 7.71-7.73 (m, 2H), 7.65-7.67 (m, 2H), 7.40 (m, 1H), 7.24-7.30 (m, 4H), 7.16-7.19 (m, 1H), 4.93 (s, 2H), 3.49-3.52 (m, 1H), 3.46 (s, 2H), 2.51-253 (m, 2H), 2.16 (s, 3H), 2.12-2.22 (m, 4H), 1.91-1.96 (m, 2H), 1.21-1.24 (m, 2H), 0.88-0.92 (m, 2H), 13C-NMR (CDCl3, 126 MHz) δ 171.1, 161.7 (d, J=246.6 Hz), 145.8 139.1, 133.0, 132.7, 131.9, 128.3, 127.8, 127.3, 127.1, 126.5, 126.1, 122.3, 119.6, 119.1, 110.6, 70.9, 52.0, 50.8, 46.3, 40.8, 32.7, 32.1, 8.2. Mass spec.: 477.41 (MH)+.

Workup

  1. concentrationThe reaction was concentrated
  2. customflushed with several volumes of methanol which
  3. washThe crude secondary amine was eluted in 2 M ammonia in methanol
  4. concentrationconcentrated
  5. dissolutionThe resulting residue was dissolved in acetonitrile (2 mL)
  6. temperaturecooled to 0° C.
  7. waitAfter 5 min
  8. customThe ice bath was removed
  9. stirringstirring
  10. waitcontinued for 1 h
  11. concentrationThe reaction was concentrated
  12. custompurified by flash chromatography on silica gel (10% methanolic ammonia/methylene chloride)
  13. customto afford 23 mg (95%) as a clear oil

Sources & evidence

ORD record
ord-4d606ace81904d9bbc4d00e8bb36faee
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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