2-Aminothiazole → tert-butyl 4-(2-(2-(N-(thiazol-2-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

HRID 2172315Notes

Reaction equation

HRID 2172315 reaction equation
[S:1]([N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1)([N:4]1[CH:8]=[CH:7]N=[CH:5]1)(=[O:3])=[O:2].[S:14]1C=CN=C1N.S(Cl)(Cl)(=O)=O.C1C2[C:29](=[C:30]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:36]=3[C:45]3[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH:46]=3)[CH:31]=[CH:32]C=2)[CH2:28][CH2:27]N1.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[S:14]1[CH:13]=[CH:12][N:11]=[C:10]1[NH:9][S:1]([N:4]1[CH2:5][CH2:32][C:31]2[C:7](=[CH:27][CH:28]=[CH:29][C:30]=2[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:42])([F:44])[F:43])=[CH:37][C:36]=2[C:45]2[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:55])([CH3:57])[CH3:56])=[O:52])[CH2:47][CH:46]=2)[CH2:8]1)(=[O:2])=[O:3]

Participants

8

Reactant 5

HCID 21552-AminothiazoleHCID 8471TriethylamineHCID 24648Sulfuryl chlorideHCID 816091,1'-sulphonylbis-1H-imidazoleHCID 89815601tert-butyl 4-(2-(1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

Product 1

HCID 89815491tert-butyl 4-(2-(2-(N-(thiazol-2-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylateYield 49.1%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

A solution of 1H-imidazole (0.238 g, 3.49 mmol) and thiazol-2-amine (TCI America, Portland, Oreg., 0.087 g, 0.872 mmol) in 6 mL DCM was cooled to −10° C. and was treated with sulfuryl chloride (0.071 ml, 0.872 mmol). After stirring for 15 minutes, the cooling bath was removed, and the reaction mixture was allowed to stir for an additional 15 minutes. The reaction mixture was treated with tert-butyl 4-(2-(1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.200 g, 0.436 mmol) and triethylamine (0.608 ml, 4.36 mmol) and was heated to 80° C. for 20 minutes. The reaction mixture was diluted with EtOAc, washed with 1N citric acid solution and the organics concentrated. Purification of the resulting residue by reverse phase column chromatography [RediSep Gold C-18 100 g, 10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave tert-butyl 4-(2-(2-(N-(thiazol-2-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.133 g, 0.214 mmol). This material was taken up in 1 mL THF, was treated with HCl 4N in dioxane (1.090 ml, 4.36 mmol) and was heated to 80° C. for one hour. Concentration and purification of the resulting residue by reverse phase column chromatography [RediSep Gold C-18 50 g 10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 5-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.053 g, 0.102 mmol). [M+H]+=520.8 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.75 (d, J=8.1 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.43 (s, 1H), 7.12 (t, J=7.9 Hz, 1H), 6.90-7.04 (m, 3H), 6.54 (d, J=4.1 Hz, 1H), 5.75 (br. s., 1H), 4.11-4.40 (m, 2H), 3.52 (br. s., 2H), 3.33-3.48 (m, 1H), 3.00-3.13 (m, 2H), 2.73-2.86 (m, 1H), 2.60-2.73 (m, 1H), 2.08-2.23 (m, 1H), 1.77-2.03 (m, 2H)

Workup

  1. customthe cooling bath was removed
  2. stirringto stir for an additional 15 minutes
  3. washwashed with 1N citric acid solution
  4. customPurification of the resulting residue by reverse phase column chromatography [RediSep Gold C-18 100 g, 10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)]

Sources & evidence

ORD record
ord-3fa16a73b7e64c269b7955f162963fcb
Source dataset
uspto-grants-2015_06
Patent number
US09051311B2

Reaction notes

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