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

HRID 2172331Notes

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].[N:14]1C=CN=C[C:15]=1N.S(Cl)(Cl)(=O)=O.C1C2[C:30](=[C:31]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][C:37]=3[C:46]3[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH:47]=3)[CH:32]=[CH:33]C=2)[CH2:29][CH2:28]N1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[N:14]1[CH:15]=[CH:10][N:11]=[CH:12][C:13]=1[NH:9][S:1]([N:4]1[CH2:5][CH2:33][C:32]2[C:7](=[CH:28][CH:29]=[CH:30][C:31]=2[C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:44])([F:45])[F:43])=[CH:38][C:37]=2[C:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH:47]=2)[CH2:8]1)(=[O:2])=[O:3]

Participants

Conditions

Temperature: 80 °C

Procedure

A solution of 1H-imidazole (0.238 g, 3.49 mmol) and pyrazin-2-amine (0.083 g, 0.872 mmol) in 5 mL DCM and 1 mL DMF was cooled to −10° C. and 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 then treated with tert-butyl 4-(2-(1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (Example 46, Step 2, 0.200 g, 0.436 mmol) and triethylamine (0.608 ml, 4.36 mmol) and was heated to 80° C. for 20 minutes. After cooling to room temperature, 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 C18 150 g, 10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave tert-butyl 4-(2-(2-(N-(pyrazin-2-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.180 g, 0.292 mmol). This material was taken up in 1 mL THF, was treated with HCl 4N in dioxane (0.109 ml, 0.436 mmol) and was heated to 80° C. for one hour. LC/MS showed exclusively product so the reaction mixture was concentrated. Purification of the resulting residue by reverse phase column chromatography [RediSep Gold C18 100 g, 10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave N-(pyrazin-2-yl)-5-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.113 g, 0.219 mmol). [M+H]+=515.8 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.25 (s, 1H), 7.94 (s, 1H), 7.71-7.78 (m, 2H), 7.50 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.16 (t, J=7.80 Hz, 1H), 7.09 (d, J=7.80 Hz, 1H), 7.00 (d, J=8.22 Hz, 1H), 5.67 (br. s., 1H), 4.24-4.42 (m, 2H), 3.48 (br. s., 2H), 3.30-3.39 (m, 1H), 3.19-3.29 (m, 1H), 2.91-3.01 (m, 1H), 2.78-2.86 (m, 1H), 2.45-2.52 (m, 1H), 2.29-2.36 (m, 1H), 1.81-2.08 (m, 2H)

Workup

customthe cooling bath was removed
stirringto stir for an additional 15 minutes
temperatureAfter cooling to room temperature
washwashed with 1N citric acid solution
customPurification of the resulting residue by reverse phase column chromatography [RediSep Gold C18 150 g, 10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)]

Sources & evidence

ORD record: ord-a5ca0a4dc66d41739c13a5dd91d8e7cb
Source dataset: uspto-grants-2015_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09051311B2

Reaction notes

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