Formaldehyde → (+/-)-5-chloro-7-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-1H-indole-3-carbonitrile

HRID 914048Notes

Reaction equation

HRID 914048 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:20][CH2:19][N:18]([C:21](OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:35]#[N:36].C(O)(C(F)(F)F)=O.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:35]#[N:36]

Participants

6

Reactant 4

HCID 712FormaldehydeHCID 6422Trifluoroacetic acidHCID 5049666Sodium triacetoxyborohydrideHCID 57545997(+/-)-tert-butyl 4-((1-(5-chloro-3-cyano-1H-indol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate

Product 1

HCID 25159528(+/-)-5-chloro-7-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-1H-indole-3-carbonitrileYield 94.2%

Reagents, catalysts & solvents 1

HCID 8471TriethylamineSolvent

Procedure

(±)-tert-butyl 4-((1-(5-chloro-3-cyano-1H-indol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (70 mg, 0.137 mmol) was stirred in TFA (2 mL, 26.0 mmol) at 0° C. for 20 minutes. The solvent was evaporated at a bath temperature of 23° C. The residue was taken up in Ethanol (5 mL), then triethylamine (1 mL), formaldehyde (0.102 mL, 1.367 mmol) and sodium triacetoxyborohydride (87 mg, 0.410 mmol) were added. The reaction was stirred 1 hour, then solvent was evaporated. The residue was taken up in aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (4×10 mL). The organic phase was dried with MgSO4 and evaporated. The residue was purified by chromatography on SiO2 with 3%-5%% 2M ammonia in methanol/dichloromethane to give (±)-5-chloro-7-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-1H-indole-3-carbonitrile (55 mg, 0.129 mmol, 94% yield) as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 8.27 (bs, 1H), 7.56 (d, J=1.8 Hz, 1H), 7.27 (m, 2H), 7.14 (d, J=2.8 Hz, 1H), 7.08 (t, J=8.5 Hz, 2H), 6.93 (d, J=1.8 Hz, 1H), 4.55 (q, J=6.5 Hz, 1H), 4.55 (m, 1H), 3.19 (d, J=8.6 Hz, 1H), 2.62 (m, 1H), 2.52 (m, 2H), 2.35 (m, 1H), 1.95-2.20 (m, 2H), 1.86 (m, 1H), 1.48 (m, 1H), 1.41 (d, J=6.5 Hz, 3H). LC/MS (HPLC method 4): tR=2.84 min, 426.14(MH)+.

Workup

  1. customThe solvent was evaporated at a bath temperature of 23° C
  2. customsolvent was evaporated
  3. extractionextracted with ethyl acetate (4×10 mL)
  4. dry with materialThe organic phase was dried with MgSO4
  5. customevaporated
  6. customThe residue was purified by chromatography on SiO2 with 3%-5%% 2M ammonia in methanol/dichloromethane

Sources & evidence

ORD record
ord-ada85f864add4f9cbf07d7a70af0f65d
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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