Formaldehyde → HCID 118522649, compound

HRID 529839Notes

Reaction equation

HRID 529839 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:38])[F:37])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][NH:27][CH2:28][CH:29]3[CH2:33][CH2:32][C:31](=[O:34])[O:30]3)[N:9]=2)[CH:7]=1.C=O.[BH3-][C:42]#N.[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:38])[F:37])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][N:27]([CH3:42])[CH2:28][CH:29]3[CH2:33][CH2:32][C:31](=[O:34])[O:30]3)[N:9]=2)[CH:7]=1

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 118522521HCID 118522521, compound

Product 1

HCID 118522649HCID 118522649, compound

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Procedure

To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(5-oxooxolan-2-yl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (140 mg, 0.26 mmol) in MeOH (20 mL) was added 37% formaldehyde in water (23 mg), followed by NaBH3CN (24.6 mg, 0.39 mmol). The resulting solution was stirred at room temperature for 3 h. The resulting mixture was concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 8% MeOH in DCM. The crude product (60 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 0.05% FA and MeCN (18.0% MeCN up to 36.0% in 8 min); Detector, 254/220. This resulted in 22.4 mg of the formic acid salt of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[methyl[(5-oxooxolan-2-yl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 28) [M+H]+=560.2, RT=0.94 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.67 (m, 2H), 8.38 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.60 (d, 1H, J=2.4 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.0, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 4.59-4.55 (m, 1H), 4.30-4.27 (m, 2H), 2.94-2.88 (m, 2H), 2.62 (d, 2H, J=5.6 Hz), 2.44-2.41 (m, 2H), 2.32 (s, 3H), 2.14-2.11 (m, 1H), 1.83-1.77 (m, 1H).

Workup

  1. concentrationThe resulting mixture was concentrated under vacuum
  2. customThe crude product (60 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters))
  3. waitmobile phase, Water with 0.05% FA and MeCN (18.0% MeCN up to 36.0% in 8 min)

Sources & evidence

ORD record
ord-852e2125b76c46aa8ee4a995123fbc2c
Source dataset
uspto-grants-2016_05
Patent number
US09346815B2

Reaction notes

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