Formaldehyde → 5-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)naphthalene-2-sulfonamide 2,2,2-trifluoroacetate

HRID 1473332Notes

Reaction equation

HRID 1473332 reaction equation
[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=3[C:38]3[CH2:39][CH2:40][NH:41][CH2:42][CH:43]=3)[CH:19]=2)(=[O:17])=[O:16])=[N:10][CH:9]=1.C=O.[Na]>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:2][N:41]1[CH2:40][CH:39]=[C:38]([C:29]2[CH:30]=[C:31]([C:34]([F:35])([F:36])[F:37])[CH:32]=[CH:33][C:28]=2[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:25]=2[CH:26]=[CH:27][C:18]([S:15]([NH:14][C:11]2[CH:12]=[CH:13][N:8]=[CH:9][N:10]=2)(=[O:17])=[O:16])=[CH:19]3)[CH2:43][CH2:42]1

Participants

5

Reactant 3

HCID 712FormaldehydeHCID 5360545SodiumHCID 86687370N-(pyrimidin-4-yl)-5-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonamide 2,2,2-trifluoroacetate

Product 1

HCID 866873855-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)naphthalene-2-sulfonamide 2,2,2-trifluoroacetateYield 182.3%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a round bottom flask charged with N-(pyrimidin-4-yl)-5-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonamide (EXAMPLE 48, 167.0 mg, 0.327 mmol) was added MeOH (3271 μl), then formaldehyde (265 μl, 3.27 mmol). The solution was maintained at rt for 15 min, then sodium triacetoxyhydroborate (693 mg, 3.27 mmol) was added portionwise. After 10 min, the reaction mixture was partitioned between ice and saturated NaHCO3 and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (1×25 mL). The combined organic extracts were washed with brine (1×20 mL) and dried over Na2SO4 and concentrated under a vacuum. The residue was taken up in minimal MeOH and purified by reverse phase preparative HPLC (20 to 80% CH3CN:H2O (1% TFA modifier) over 15 min). Clean fractions were combined and concentrated to afford 5-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)naphthalene-2-sulfonamide 2,2,2-trifluoroacetate (190 mg, 0.298 mmol) as a off-white amorphous solid. 1H NMR (400 MHz, MeOH) δ ppm 1.98-2.47 (m, 2H) 2.49-2.90 (m, 4H) 3.08-3.28 (m, 1H) 3.37-3.58 (m, 1H) 3.64-3.90 (m, 1H) 5.68 (d, J=8.51 Hz, 1H) 7.16 (dd, J=6.36, 0.98 Hz, 1H) 7.54 (d, J=8.02 Hz, 1H) 7.58-7.69 (m, 2H) 7.70-7.85 (m, 3H) 7.94 (d, J=8.61 Hz, 1H) 8.18 (d, J=8.31 Hz, 1H) 8.30 (d, J=6.36 Hz, 1H) 8.60 (s, 1H) 8.72 (d, J=1.37 Hz, 1H); m/z (ESI, +ve ion) 525.2 (M+H)+.

Workup

  1. customthe reaction mixture was partitioned between ice and saturated NaHCO3 and EtOAc
  2. customThe layers were separated
  3. extractionthe aqueous layer was extracted with EtOAc (1×25 mL)
  4. washThe combined organic extracts were washed with brine (1×20 mL)
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated under a vacuum
  7. custompurified by reverse phase preparative HPLC (20 to 80% CH3CN:H2O (1% TFA modifier) over 15 min)
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-672f0209cf4440cb951dad2317cd7836
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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