Hydrochloric Acid → (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone

HRID 920656Notes

Reaction equation

HRID 920656 reaction equation
Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]4[C@:20]([C:22]([C:24]5[N:25]=[CH:26][S:27][CH:28]=5)=[O:23])([CH2:21][C:12]=3[CH:11]=[N:10]2)[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]4)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[Cl:45][C:46]1[CH:47]=[C:48]([S:53](Cl)(=[O:55])=[O:54])[CH:49]=[CH:50][C:51]=1[Cl:52]>CCOCC.ClCCl>[Cl:45][C:46]1[CH:47]=[C:48]([S:53]([N:18]2[CH2:17][CH2:16][C:15]3[C@:20]([C:22]([C:24]4[N:25]=[CH:26][S:27][CH:28]=4)=[O:23])([CH2:21][C:12]4[CH:11]=[N:10][N:9]([C:6]5[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=5)[C:13]=4[CH:14]=3)[CH2:19]2)(=[O:54])=[O:55])[CH:49]=[CH:50][C:51]=1[Cl:52]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 7383Benzenesulfonyl chloride, 3,4-dichloro-HCID 81531DiisopropylethylamineHCID 86709999(R)-tert-butyl 1-(4-fluorophenyl)-4a-(thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

Product 1

HCID 86710005(R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanoneYield 67%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolvent2×HCID 6344DichloromethaneSolvent

Procedure

To HCl 2M in ether (2809 μl, 5.62 mmol) was added (R)-tert-butyl 1-(4-fluorophenyl)-4a-(thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (135 mg, 0.281 mmol) as a solution in ether (1 mL). The resulting suspension was stirred at room temperature for 1 h. The solvent was removed to give a white solid. This was dissolved in dichloromethane (1.4 mL) and Hunig's base (245 μl, 1.405 mmol), and 3,4-dichlorobenzene-1-sulfonyl chloride (76 mg, 0.309 mmol) was added to the solution. The resulting solution was stirred at room temperature for 18 h. The crude product was purified by chromatography on silica gel (gradient: 5-95% ethyl acetate in isohexane to afford (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone (111 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.76 min, m+H=588.8; 1H NMR (400 MHz, CDCl3): δ 8.85 (1H, d, J=2.2 Hz), 8.22 (1H, d, J=2.2 Hz), 7.77 (1H, t, J=1.2 Hz), 7.52 (2H, d, J=1.2 Hz), 7.45-7.40 (2H, m), 7.28 (1H, s), 7.20-7.13 (2H, m), 6.52 (1H, d, J=2.2 Hz), 5.44 (1H, dd, J=12.6, 2.2 Hz), 4.13 (1H, d, J=16.8 Hz), 3.90-3.87 (1H, m), 2.92-2.81 (2H, m), 2.78 (1H, d, J=12.6 Hz), 2.62-2.50 (2H, m).

Workup

  1. customThe solvent was removed
  2. customto give a white solid
  3. stirringThe resulting solution was stirred at room temperature for 18 h
  4. customThe crude product was purified by chromatography on silica gel (gradient

Sources & evidence

ORD record
ord-ac633345ec9342aeadd1f24bcf1705e4
Source dataset
uspto-grants-2016_03
Patent number
US09273047B2

Reaction notes

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