Formaldehyde → HCID 118522515, compound

HRID 529774Notes

Reaction equation

HRID 529774 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[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][C:26]([N:28]3[CH2:31][C:30]4([CH2:35][CH2:34][NH:33][CH2:32]4)[CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.[CH2:40]=O.[BH4-].[Na+]>FC(F)(F)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[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][C:26]([N:28]3[CH2:31][C:30]4([CH2:35][CH2:34][N:33]([CH3:40])[CH2:32]4)[CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1

Participants

5

Reactant 3

HCID 712FormaldehydeHCID 4311764Sodium borohydrideHCID 118523277HCID 118523277, compound

Product 1

HCID 118522515HCID 118522515, compound

Reagents, catalysts & solvents 1

HCID 64092,2,2-TrifluoroethanolSolvent

Conditions

Temperature
90 °C

Procedure

Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-(2,6-diaza-spiro[3.4]oct-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide (70 mg, 0.13 mmol) and paraformaldehyde (19 mg, 0.63 mmol) were stirred in 2,2,2-trifluoroethanol for 15 minutes. Sodium borohydride (14 mg, 0.38 mmol) was added and the reaction mixture was heated at 90° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and was quenched with MeOH. The mixture was loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. Evaporation gave a crude product which was purified by HPLC (Method 1). The pure fractions were loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. Evaporation gave the free base which was crystallised from MeOH/Et2O. The title compound was obtained as a white solid (28 mg, 39%). LCMS (Method 5) [M+H]+=570.9, RT=2.86 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.5, 7.0 Hz), 8.69-8.66 (m, 2H), 8.34 (s, 1H), 8.15 (s, 1H), 7.64 (dd, 1H, J=2.7, 8.9 Hz), 7.57 (d, 1H, J=2.7 Hz), 7.47 (d, 1H, J=8.8 Hz), 7.29 (dd, 2H, J=4.3, 7.1 Hz), 7.25 (t, 1H, J=73.5 Hz), 4.94 (s, 2H), 4.04 (q, 2H, J=8.8 Hz), 3.90-3.81 (m, 2H), 2.69 (s, 2H), 2.27 (s, 3H), 2.03 (dd, 2H, J=6.8, 6.8 Hz).

Workup

  1. temperatureto cool to room temperature
  2. customwas quenched with MeOH
  3. customAfter flushing with MeOH
  4. washthe product was eluted with 2M ammonia in MeOH
  5. customEvaporation
  6. customgave a crude product which
  7. customwas purified by HPLC (Method 1)
  8. customAfter flushing with MeOH
  9. washthe product was eluted with 2M ammonia in MeOH
  10. customEvaporation
  11. customgave the free base which
  12. customwas crystallised from MeOH/Et2O

Sources & evidence

ORD record
ord-937a94f280e845f28076120ba04b1934
Source dataset
uspto-grants-2016_05
Patent number
US09346815B2

Reaction notes

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