Formaldehyde → HCID 118522331, compound

HRID 529849Notes

Reaction equation

HRID 529849 reaction equation
C=O.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:35][CH:36]([F:38])[F:37])=[C:8]([C:10]2[C:14]([NH:15][C:16]([C:18]3[CH:19]=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[N:23][C:22]=34)=[O:17])=[CH:13][N:12]([CH2:27][CH:28]=[C:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:11]=2)[CH:9]=1.[BH3-][C:40]#N.[Na+].C(#N)C>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:35][CH:36]([F:37])[F:38])=[C:8]([C:10]2[C:14]([NH:15][C:16]([C:18]3[CH:19]=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[N:23][C:22]=34)=[O:17])=[CH:13][N:12]([CH2:27][CH:28]=[C:29]3[CH2:34][CH2:33][N:32]([CH3:40])[CH2:31][CH2:30]3)[N:11]=2)[CH:9]=1

Participants

6

Reactant 4

HCID 712FormaldehydeHCID 6342Acetonitrile2×HCID 5003444Sodium cyanoborohydrideHCID 118522597HCID 118522597, compound

Product 1

HCID 118522331HCID 118522331, compoundYield 1.2%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

An aqueous solution of 40% formaldehyde (210 mg) was added to solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(piperidin-4-ylidene)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (360.00 mg, 0.700 mmol) in methanol (30 mL). The resulting solution was stirred at ambient temperature for 2.5 h and NaBH3CN (44.02 mg, 0.700 mmol) was added. The resulting solution was stirred at this temperature for 3 h and concentrated under vacuum. The residue was applied onto a short pad of silica gel eluting with dichloromethane/MeOH (10/1). The crude product (60 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, ACN/10 mmol NH4HCO3=40% increasing to ACN/10 mmol NH4HCO3=75% within 6 min; Detector, UV 254 nm to obtain 4.3 mg (1%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(1-methylpiperidin-4-ylidene)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 32): [M+H]+=528.1, RT=2.21 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.73 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.68-8.66 (m, 2H), 8.32 (s, 1H), 7.67-7.61 (m, 2H), 7.45 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.0, 6.8 Hz), 7.06 (t, 1H, J=73.2 Hz), 5.44 (t, 1H, J=6.8 Hz), 4.27 (d, 2H, J=6.8 Hz), 2.81-2.68 (m, 2H), 2.52-2.50 (m, 2H), 2.50-2.42 (m, 2H), 2.19 (s, 3H), 2.12-2.04 (m, 2H).

Workup

  1. stirringThe resulting solution was stirred at this temperature for 3 h
  2. concentrationconcentrated under vacuum
  3. customThe crude product (60 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1)

Sources & evidence

ORD record
ord-cc27a7bc03c147008ef8b6a7b6df8ba2
Source dataset
uspto-grants-2016_05
Patent number
US09346815B2

Reaction notes

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