Diisopropylethylamine → (R)-methyl 1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

HRID 920623Notes

Reaction equation

HRID 920623 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([O:23][CH3:24])=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1.C(N(C(C)C)CC)(C)C>FC(F)(F)C(O)=O.ClCCl.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([O:23][CH3:24])=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:40]([C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:32])([F:44])[F:45])[CH:35]=2)(=[O:42])=[O:41])[CH2:16][CH2:15]4)=[CH:6][CH:7]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 27332503-(Trifluoromethyl)benzenesulfonyl chlorideHCID 583333606-O-tert-butyl 4a-O-methyl 1-(4-fluorophenyl)-4,5,7,8-tetrahydropyrazolo(3,4-g)isoquinoline-4a,6-dicarboxylate

Product 1

HCID 86709985(R)-methyl 1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylateYield 37.1%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 21863450Trifluoroacetic acid methylene chlorideSolvent

Procedure

A solution of (R)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (2.0 g, 4.68 mmol) in 20% trifluoroacetic acid/dichloromethane (50 mL) was stirred at room temperature for 1 hour. The solvent was removed in vacuo, azeotroping three times with toluene (˜20 mL), to give a dark orange oil. The oil was dissolved in dichloromethane (50 mL) and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.900 ml, 5.61 mmol) was added followed by diisopropylethylamine (4.09 ml, 23.39 mmol). The reaction mixture was stirred at room temperature for 20 minutes, and then solvent removed in vacuo to give a dark orange oil. The crude product was purified by chromatography on silica gel (gradient: 0-45% ethyl acetate in isohexane) to afford (R)-methyl 1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (931 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.62 min, m+H=536.2.

Workup

  1. customThe solvent was removed in vacuo
  2. customazeotroping three times with toluene (˜20 mL)
  3. customto give a dark orange oil
  4. customsolvent removed in vacuo
  5. customto give a dark orange oil
  6. customThe crude product was purified by chromatography on silica gel (gradient: 0-45% ethyl acetate in isohexane)

Sources & evidence

ORD record
ord-bf9a129d93f844f69b007d9c056e360d
Source dataset
uspto-grants-2016_03
Patent number
US09273047B2

Reaction notes

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