2-Aminothiazole → 1-methyl-3-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-1H-indole-6-sulfonamide 2,2,2-trifluoroacetate

HRID 1524440Notes

Reaction equation

HRID 1524440 reaction equation
[NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:17](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:19])=[O:18])[CH:15]=2)[C:10]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:33]=2[C:42]2[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH:43]=2)=[CH:9]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:65]([OH:71])([C:67]([F:70])([F:69])[F:68])=[O:66]>C1COCC1>[F:68][C:67]([F:70])([F:69])[C:65]([OH:71])=[O:66].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:17]([NH:1][C:2]3[S:3][CH:4]=[CH:5][N:6]=3)(=[O:19])=[O:18])[CH:15]=2)[C:10]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:40])([F:39])[F:41])=[CH:34][C:33]=2[C:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH:43]=2)=[CH:9]1

Participants

6

Reactant 4

HCID 21552-Aminothiazole2×HCID 6422Trifluoroacetic acidHCID 2733832Lithium Hexamethyldisilazide2×HCID 89407773tert-butyl 4-(2-(1-methyl-6-((perfluorophenoxy)sulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate2×

Product 1

HCID 894076911-methyl-3-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-1H-indole-6-sulfonamide 2,2,2-trifluoroacetate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A flask containing a mixture of 2-aminothiazole (7.93 mg, 0.079 mmol), tert-butyl 4-(2-(1-methyl-6-((perfluorophenoxy)sulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (INTERMEDIATE O) (0.053 g, 0.075 mmol), and THF (0.503 ml) was cooled to 0° C. LHMDS (1.0M in THF) (0.151 ml, 0.151 mmol) was added dropwise and the reaction was stirred for 15 minutes at 0° C. An additional equivalent of aminothiazole was added, followed by 2 equivalents of LHMDS solution. The reaction was stirred for one hour at 0° C. The reaction was quenched with saturated ammonium chloride solution, diluted with DCM, and the layers were separated. The aqueous layer was extracted with DCM, and the combined organic layers were concentrated. The material was dissolved in DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred at 50° C. overnight. The reaction was concentrated and the material was purified via column chromatography (RediSep Gold 12 g silica gel column (Teledyne Isco, Lincoln, Nebr., gradient elution 0 to 10% MeOH:DCM) to afford 1-methyl-3-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-1H-indole-6-sulfonamide 2,2,2-trifluoroacetate as a tan solid. m/z (ESI) 519.4 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.61 (br. s., 1 H), 8.70 (br. s., 2 H), 7.99 (s, 1 H), 7.81-7.67 (m, 5 H), 7.59-7.52 (m, 2 H), 7.24 (d, J=4.8 Hz, 1 H), 6.81 (d, J=4.5 Hz, 1 H), 5.89 (br. s., 1 H), 3.95 (s, 3 H), 3.71 (br. s., 2 H), 2.98 (br. s., 2 H), 2.11 (br. s., 3 H)

Workup

  1. additionA flask containing
  2. stirringThe reaction was stirred for one hour at 0° C
  3. customThe reaction was quenched with saturated ammonium chloride solution
  4. additiondiluted with DCM
  5. customthe layers were separated
  6. extractionThe aqueous layer was extracted with DCM
  7. concentrationthe combined organic layers were concentrated
  8. dissolutionThe material was dissolved in DCM
  9. stirringThe reaction was stirred at 50° C. overnight
  10. concentrationThe reaction was concentrated
  11. customthe material was purified via column chromatography (
  12. washRediSep Gold 12 g silica gel column (Teledyne Isco, Lincoln, Nebr., gradient elution 0 to 10% MeOH:DCM)

Sources & evidence

ORD record
ord-e2ec9626757e49418d18ccd491beb83a
Source dataset
uspto-grants-2015_07
Patent number
US09079902B2

Reaction notes

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