3-Hydroxybenzaldehyde → N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(3-hydroxyphenyl)-methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide formate

HRID 529791Notes

Reaction equation

HRID 529791 reaction equation
[BH3-]C#N.[Na+].[NH2:5][CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[C:10]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=2[O:32][CH:33]([F:35])[F:34])=[N:9]1.[OH:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O>CO>[CH:33]([OH:32])=[O:36].[Cl:31][C:29]1[CH:28]=[CH:27][C:26]([O:32][CH:33]([F:34])[F:35])=[C:25]([C:10]2[C:11]([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:12][N:8]([CH2:7][CH2:6][NH:5][CH2:40][C:39]3[CH:42]=[CH:43][CH:44]=[C:37]([OH:36])[CH:38]=3)[N:9]=2)[CH:30]=1

Participants

5

Reactant 3

HCID 1013-HydroxybenzaldehydeHCID 5003444Sodium cyanoborohydrideHCID 118522637N-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Product 1

HCID 118522584N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(3-hydroxyphenyl)-methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide formate

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

NaBH3CN (28 mg, 0.45 mmol) was added to a solution of N-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.22 mmol) in MeOH (10 mL) and 3-hydroxybenzaldehyde (55 mg, 0.45 mmol). The resulting solution was stirred for at room temperature overnight. The reaction was then quenched by the addition of 0.2 mL of water. The resulting mixture was concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 2.5% MeOH in DCM. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (32.0% up to 36.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 32.0% in 2 min); Detector, UV 254/220 nm. This resulted in 25.7 mg (19%) of the formic acid salt of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(3-hydroxyphenyl)-methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide formate as a white solid. LCMS (Method 20) [M+H]+=554.2, RT=1.58 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.37 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.68-8.67 (m, 2H), 8.37 (s, 1H), 7.61 (dd, 1H, J=2.4, 8.8 Hz), 7.60 (d, 1H, J=2.4 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz), 7.05 (t, 1H, J=73.2 Hz), 7.10-7.06 (m, 1H), 6.74-6.72 (m, 2H), 6.60 (d, 1H, J=7.2 Hz), 4.25 (t, 2H, J=6.0 Hz), 3.66 (s, 2H), 2.94 (t, 2H, J=6.0 Hz).

Workup

  1. customThe reaction was then quenched by the addition of 0.2 mL of water
  2. concentrationThe resulting mixture was concentrated under vacuum
  3. customThe crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005)
  4. waitmobile phase, water with 0.05% FA and MeCN (32.0% up to 36.0% in 10 min
  5. waitup to 95.0% in 1 min
  6. customin 1 min
  7. waitdown to 32.0% in 2 min)

Sources & evidence

ORD record
ord-ba6ccf6b45c54b81ab84d2b8726a64fe
Source dataset
uspto-grants-2016_05
Patent number
US09346815B2

Reaction notes

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