Formaldehyde → HCID 118522600, compound

HRID 529823Notes

Reaction equation

HRID 529823 reaction equation
N[C@@H:2]([CH3:32])[CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=23)=[O:11])[C:6]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH:29]([F:31])[F:30])=[N:5]1.[CH2:33]=O.[BH3-][C:36]#[N:37].[Na+]>CO>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH:29]([F:31])[F:30])=[C:21]([C:6]2[C:7]([NH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[N:17][C:16]=34)=[O:11])=[CH:8][N:4]([CH2:3][C@@H:2]([N:37]([CH3:36])[CH3:33])[CH3:32])[N:5]=2)[CH:26]=1

Participants

5

Reactant 3

HCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 118522674HCID 118522674, compound

Product 1

HCID 118522600HCID 118522600, compound

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a solution of N-[1-[(2S)-2-aminopropyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (170 mg, 0.37 mmol) in MeOH (15 mL) was added 37% formaldehyde solution (16.6 mg, 0.55 mmol), NaBH3CN (23.3 mg, 0.37 mmol). The resulting solution was stirred at room temperature for 12 h and concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 10% MeOH in DCM. The crude product (80 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 10 mM NH4CO3 and MeCN (20.0% MeCN up to 35.0% in 8 min); Detector, 254/220. This resulted in 29 mg (16%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-(dimethylamino)propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as an off-white solid. LCMS (Method 10) [M+H]+=490.1, RT=0.84 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.73 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.66 (m, 2H), 8.34 (s, 1H), 7.61 (dd, 1H, J=2.7, 8.7 Hz), 7.60 (d, 1H, J=2.1 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.5, 7.2 Hz), 6.99 (t, 1H, J=73.5 Hz), 4.22 (dd, 1H, J=7.2, 13.8 Hz), 4.02 (dd, 1H, J=6.9, 13.8 Hz), 3.20-3.18 (m, 1H), 2.22 (s, 6H), 0.88 (d, 3H, J=6.6 Hz).

Workup

  1. concentrationconcentrated under vacuum
  2. customThe crude product (80 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters))
  3. waitmobile phase, Water with 10 mM NH4CO3 and MeCN (20.0% MeCN up to 35.0% in 8 min)
  4. customThis resulted in 29 mg (16%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-(dimethylamino)propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as an off-white solid

Sources & evidence

ORD record
ord-d4ae44e218be4a37abf1f885da22daca
Source dataset
uspto-grants-2016_05
Patent number
US09346815B2

Reaction notes

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