Formaldehyde → N-((1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-N-methyl-3'-(methylsulfonyl)biphenyl-4-amine

HRID 1673005Notes

Reaction equation

HRID 1673005 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=3)=[CH:17][CH:16]=2)=[CH:11][C:10]([C:31]([F:34])([F:33])[F:32])=[N:9]1.CO.C=O.[C:39]([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][N:14]([CH3:39])[C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:22]=3)=[CH:19][CH:20]=2)=[CH:11][C:10]([C:31]([F:34])([F:32])[F:33])=[N:9]1

Participants

6

Reactant 4

HCID 712FormaldehydeHCID 887MethanolHCID 5003444Sodium cyanoborohydrideHCID 59240161N-((1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3'-(methylsulfonyl)biphenyl-4-amine

Product 1

HCID 59240176N-((1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-N-methyl-3'-(methylsulfonyl)biphenyl-4-amine

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Procedure

Into an 8 mL vial was weighed 215 mg of N-((1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3′-(methylsulfonyl)biphenyl-4-amine (0.42 mmol). Addition of 2 mL of methanol followed by 0.5 mL of acetic acid, and 150 μL of 37% aqueous formaldehyde solution afforded a solution that was treated with 40 mg of sodium cyanoborohydride (0.64 mmol). After 30 min. at room temperature the reaction was quenched by the addition of 6N HCl (aq.). After gas evolution had subsided, the reaction mixture was diluted with EtOAc and the aqueous was made basic by the addition of saturated aqueous NaHCO3. The basic aqueous was extracted with EtOAc (3×) and the combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford a colorless film. The crude product was purified by silica gel flash chromatography on a 12 g column using gradient elution from 0% to 100% EtOAc/hexane. Appropriate fractions were combined and concentrated in vacuo to afford N-((1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-N-methyl-3′-(methylsulfonyl)biphenyl-4-amine as a colorless film. This material was impure by NMR analysis and was further purified by preparative reverse phase HPLC eluting with a gradient from 30% to 100% MeCN in H2O (each with 0.05% trifluoroacetic acid). The appropriate fractions were made basic by addition of saturated aqueous NaHCO3 solution and concentrated in vacuo to remove most of the acetonitrile. The resulting basic aqueous was extracted with CH2Cl2 (4×). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford N-((1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-N-methyl-3′-(methylsulfonyl)biphenyl-4-amine as a brittle foam that was broken up into a white powder, yield 126 mg (57% yield): 1H NMR (400 MHz, CDCl3): δ 8.11-8.08 (m, 1H, 7.84-7.79 (m, 2H, 7.62-7.56 (m, 2H, 7.52-7.40 (m, 5H), 6.72-6.67 (m, 2H), 6.52 (s, 1H), 4.43 (br s, 1H), 3.09 (s, 3H), 2.94 (S, 3H); MS (ESI) m/z 520.3 [M+H]+.

Workup

  1. customafforded a solution that
  2. customAfter 30 min. at room temperature the reaction was quenched by the addition of 6N HCl (aq.)
  3. additionthe reaction mixture was diluted with EtOAc
  4. additionthe aqueous was made basic by the addition of saturated aqueous NaHCO3
  5. extractionThe basic aqueous was extracted with EtOAc (3×)
  6. washthe combined organic extracts were washed with brine
  7. dry with materialdried (Na2SO4)
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customto afford a colorless film
  11. customThe crude product was purified by silica gel flash chromatography on a 12 g column
  12. washelution from 0% to 100% EtOAc/hexane
  13. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-7f95e241217e4420b3f99228deb04941
Source dataset
uspto-grants-2011_08
Patent number
US07998995B2

Reaction notes

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