Diisopropylethylamine → Relacorilant

HRID 537283Notes

Reaction equation

HRID 537283 reaction equation
Cl.O1CCOCC1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3[CH:20]=[C:21]4[C@:26]([C:28](=[O:39])[C:29]5[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=5)([CH2:27][C:18]=3[CH:17]=[N:16]2)[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C.[CH3:56][N:57]1[CH:61]=[C:60]([S:62](Cl)(=[O:64])=[O:63])[CH:59]=[N:58]1>ClCCl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3[CH:20]=[C:21]4[C@:26]([C:28]([C:29]5[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=5)=[O:39])([CH2:27][C:18]=3[CH:17]=[N:16]2)[CH2:25][N:24]([S:62]([C:60]2[CH:59]=[N:58][N:57]([CH3:56])[CH:61]=2)(=[O:64])=[O:63])[CH2:23][CH2:22]4)=[CH:11][CH:10]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 170247301-methyl-1H-pyrazole-4-sulfonyl chlorideHCID 204431481,4-Dioxane hydrochlorideHCID 86709996(R)-tert-butyl 1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

Product 1

HCID 73051463RelacorilantYield 63.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

HCl/Dioxane (4M) (25.3 ml, 101 mmol) was added to (R)-tert-butyl 1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (2.75 g, 5.07 mmol) and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo to give an orange gum. This was dissolved in dichloromethane (75 mL) and Hunig's base (4.43 ml, 25.3 mmol) was added followed by 1-methyl-1H-pyrazole-4-sulfonyl chloride (1.099 g, 6.08 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo to give an orange oil. The crude product was purified twice by chromatography on silica gel (gradient: 0-70% ethyl acetate in isohexane, followed by 0-60% ethyl acetate in dichloromethane), to give (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (1.89 g) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.39 min, m+H=587.2; 1H NMR (400 MHz, CDCl3): δ 8.87 (1H, d, J=5.0 Hz), 8.16-8.15 (1H, m), 7.72-7.70 (1H, m), 7.69-7.66 (2H, m), 7.47-7.42 (2H, m), 7.30 (1H, s), 7.21-7.14 (2H, m), 6.51 (1H, d, J=2.1 Hz), 5.44 (1H, dd, J=12.0, 2.1 Hz), 4.21 (1H, d, J=16.9 Hz), 3.93 (3H, s), 3.80-3.76 (1H, m), 2.94 (1H, J=16.9 Hz), 2.88-2.79 (1H, m), 2.66 (1H, d, J=12.1 Hz), 2.53-2.48 (1H, m), 2.43 (1H, ddd, J=12.6, 10.5, 3.5 Hz).

Workup

  1. customThe solvent was removed in vacuo
  2. customto give an orange gum
  3. stirringThe reaction mixture was stirred at room temperature for 1 h
  4. customThe solvent was removed in vacuo
  5. customto give an orange oil
  6. customThe crude product was purified twice by chromatography on silica gel (gradient: 0-70% ethyl acetate in isohexane, followed by 0-60% ethyl acetate in dichloromethane)

Sources & evidence

ORD record
ord-8e7f088ab1e9436783b489b978631c60
Source dataset
uspto-grants-2014_10
Patent number
US08859774B2

Reaction notes

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