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

HRID 529809Notes

Reaction equation

HRID 529809 reaction equation
[NH2:1][CH2:2][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.[CH3:32][S:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1.[BH3-]C#N.[Na+]>CO>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH:29]([F:30])[F:31])=[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][CH2:2][NH:1][CH2:38][C:37]3[CH:40]=[CH:41][C:34]([S:33][CH3:32])=[CH:35][CH:36]=3)[N:5]=2)[CH:26]=1

Participants

5

Reactant 3

HCID 769854-(Methylthio)benzaldehydeHCID 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 118522478N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-([[4-(methylsulfanyl)phenyl]methyl]amino)-ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

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 (130 mg, 0.29 mmol) in methanol (5 mL) was added 4-(methylsulfanyl)benzaldehyde (66.3 mg, 0.44 mmol). The mixture was stirred for 2 hr, then NaBH3CN (27.5 mg, 0.44 mmol) was added. The resulting solution was stirred at room temperature overnight and quenched with water (1 mL). The resulting mixture was concentrated under vacuum. 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 (30.0% up to 37.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 30.0% in 2 min); Detector, UV 254/220 nm. This resulted in 39.6 mg (23%) of the formic acid salt of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-([[4-(methylsulfanyl)phenyl]methyl]amino)-ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 20) [M+H]+=584.2, RT=2.23 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.67 (m, 2H), 8.37 (s, 1H), 7.61 (dd, 1H, J=2.8, 8.8 Hz), 7.59 (d, 1H, J=2.8 Hz), 7.44 (d, 1H, J=8.8 Hz), 7.31-7.27 (m, 3H), 7.18 (d, 2H, J=8.0 Hz), 7.07 (t, 1H, J=73.6 Hz), 4.25 (t, 2H, J=5.2 Hz), 3.70 (s, 2H), 2.95-2.92 (m, 2H), 2.50 (s, 3H).

Workup

  1. stirringThe resulting solution was stirred at room temperature overnight
  2. customquenched with water (1 mL)
  3. concentrationThe resulting mixture was concentrated under vacuum
  4. customThe crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005)
  5. waitmobile phase, water with 0.05% FA and MeCN (30.0% up to 37.0% in 10 min
  6. waitup to 95.0% in 1 min
  7. customin 1 min
  8. waitdown to 30.0% in 2 min)

Sources & evidence

ORD record
ord-e81327ca60c24c3dbdf84acd722b2b15
Source dataset
uspto-grants-2016_05
Patent number
US09346815B2

Reaction notes

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