Acetic Acid → ethyl 2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)(pyridin-3-ylmethyl)amino]acetate

HRID 529815Notes

Reaction equation

HRID 529815 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH:35]([F:37])[F:36])=[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][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:9]=2)[CH:7]=1.CC(O)=O.[N:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH:48]=O)[CH:43]=1.[BH3-]C#N.[Na+]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH:35]([F:37])[F:36])=[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]([CH2:48][C:44]3[CH:43]=[N:42][CH:47]=[CH:46][CH:45]=3)[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:9]=2)[CH:7]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 103713-PyridinecarboxaldehydeHCID 5003444Sodium cyanoborohydrideHCID 118522396Ethyl 2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)amino]acetate

Product 1

HCID 118522709ethyl 2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)(pyridin-3-ylmethyl)amino]acetateYield 5.3%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

To a solution of ethyl 2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)amino]acetate (420 mg, 0.79 mmol) in EtOH (30 mL) was added AcOH (0.1 mL, 1.75 mmol), pyridine-3-carbaldehyde (126 mg, 1.18 mmol). The mixture was stirred at room temperature for 3 h and NaBH3CN (99 mg, 1.58 mmol) was added. The resulting solution was stirred at 60° C. for 12 h. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 3% MeOH in DCM. The crude product (100 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-2): Column, C18 silica gel; mobile phase, CH3CN:H2O=5:95 increasing to CH3CN:H2O=24:40 within 12 min; Detector, UV 254 nm. 26 mg product was obtained. This resulted in 25.6 mg (5%) of ethyl 2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-ethyl)(pyridin-3-ylmethyl)amino]acetate as an off-white solid. LCMS (Method 20) [M+H]+=625.3, RT=1.68 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.73 (s, 1H), 9.35 (d, 1H, J=6.8 Hz), 8.69-8.68 (m, 2H), 8.39-8.37 (m, 3H), 7.63-7.61 (m, 2H), 7.51 (s, 1H), 7.43 (d, 1H, J=8.8 Hz), 7.31-7.25 (m, 2H), 7.04 (t, 1H, J=73.6 Hz), 4.30-4.27 (m, 2H), 4.07 (q, 2H, J=6.8 Hz), 3.82 (s, 2H), 3.44 (s, 2H), 3.15-3.11 (m, 2H), 1.17 (t, 3H, J=7.2 Hz).

Workup

  1. stirringThe resulting solution was stirred at 60° C. for 12 h
  2. filtrationThe solids were filtered out
  3. concentrationThe resulting mixture was concentrated under vacuum
  4. customThe residue was purified by flash chromatography on silica gel eluting with 3% MeOH in DCM
  5. customThe crude product (100 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-2)
  6. waitmobile phase, CH3CN:H2O=5:95 increasing to CH3CN:H2O=24:40 within 12 min

Sources & evidence

ORD record
ord-13d5769f13ba49ab93d256efa62510c8
Source dataset
uspto-grants-2016_05
Patent number
US09346815B2

Reaction notes

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