Citric Acid → 5-(2-(1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

HRID 2172310Notes

Reaction equation

HRID 2172310 reaction equation
[S:1]1[C:5]([NH2:6])=[N:4][CH:3]=[N:2]1.[CH2:7]([N:9](CC)CC)[CH3:8].[S:14](Cl)(Cl)(=[O:16])=[O:15].[N:19]1([C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=2[C:34]2[CH:35]=[CH:36][CH:37]=[C:38]3[C:43]=2CNC[CH2:39]3)[CH:23]=[CH:22][N:21]=[CH:20]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[N:19]1([C:24]2[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[CH:26][C:25]=2[C:34]2[CH:35]=[CH:36][CH:37]=[C:38]3[C:43]=2[CH2:8][CH2:7][N:9]([S:14]([NH:6][C:5]2[S:1][N:2]=[CH:3][N:4]=2)(=[O:16])=[O:15])[CH2:39]3)[CH:23]=[CH:22][N:21]=[CH:20]1

Participants

7

Reactant 5

HCID 311Citric AcidHCID 8471TriethylamineHCID 24648Sulfuryl chlorideHCID 2902745-Amino-1,2,4-thiadiazoleHCID 898151228-(2-(1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline2×

Product 1

HCID 717365885-(2-(1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A solution of 1,2,4-thiadiazol-5-amine (0.265 g, 2.62 mmol) and triethylamine (1.096 ml, 7.86 mmol) in 5 mL DCM was cooled to −78° C. and was treated with sulfuryl chloride (0.213 ml, 2.62 mmol). The cooling bath was removed, and the reaction mixture was allowed to stir for 20 minutes before 8-(2-(1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (Intermediate R, 0.450 g, 1.311 mmol) was added as a solution in 5 mL DCM. The reaction mixture was allowed to stir for one hour before being poured into 1N citric acid and extracted with EtOAc. The organic layers were concentrated and purified by reverse phase column chromatography [RediSep Gold C-18 150 g, 10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 5-(2-(1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide. [M+H]+=507.0 1H NMR (400 MHz, Acetone-d6) δ ppm: 8.16 (s, 1H), 7.99 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.55 (s, 1H), 7.48 (t, J=1.3 Hz, 1H), 7.03-7.15 (m, 3H), 6.92-6.97 (m, 1H), 4.25-4.45 (m, 2H), 3.75-3.86 (m, 1H), 3.28-3.35 (m, 1H), 2.46-2.63 (m, 2H)

Workup

  1. customThe cooling bath was removed
  2. extractionextracted with EtOAc
  3. concentrationThe organic layers were concentrated
  4. custompurified by reverse phase column chromatography [RediSep Gold C-18 150 g, 10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)]

Sources & evidence

ORD record
ord-ab4f5d1d1fb643efad47224fb28a7d3a
Source dataset
uspto-grants-2015_06
Patent number
US09051311B2

Reaction notes

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