Hydrochloric Acid → HCID 71115178, compound

HRID 1502295Notes

Reaction equation

HRID 1502295 reaction equation
[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2[CH:18]=[C:19]([NH:24][C:25]([C:27]4[CH:32]=[CH:31][C:30]([CH:33]5[CH2:37][CH2:36][N:35]([C:38](OC(C)(C)C)=O)[CH2:34]5)=[CH:29][CH:28]=4)=[O:26])[CH:20]=[CH:21][C:22]=2[CH3:23])[CH:11]=3)=[O:5])[CH2:3][CH2:2]1.C(Cl)Cl.Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>O1CCOCC1.C(OCC)(=O)C>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2[CH:18]=[C:19]([NH:24][C:25](=[O:26])[C:27]4[CH:28]=[CH:29][C:30]([CH:33]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34]5)=[CH:31][CH:32]=4)[CH:20]=[CH:21][C:22]=2[CH3:23])[CH:11]=3)=[O:5])[CH2:3][CH2:2]1

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 6228DimethylformamideHCID 6328Methyl iodide2×HCID 6344DichloromethaneHCID 11430Potassium Carbonate2×HCID 71115083HCID 71115083, compound

Product 1

HCID 71115178HCID 71115178, compoundYield 9%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

To a solution of tert-butyl 3-(4-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenylcarbamoyl)phenyl)pyrrolidine -1-carboxylate (prepared following the procedures described for Example 15) (0.135 mmol) in methylene chloride (3.0 mL, 47 mmol) was added 4.0 M of hydrogen chloride in 1,4-dioxane (0.50 mL). The reaction mixture was stirred at room temperature for three hours, and then evaporated in vacuo. To this crude product was added potassium carbonate (53.6 mg, 0.388 mmol), N,N-dimethylformamide (3.0 mL, 39 mmol), and methyl iodide (9.0 uL, 0.14 mmol). The reaction mixture was stirred at room temperature for 18 hours, and then potassium carbonate (33.1 mg, 0.239 mmol) and methyl iodide (7.0 uL, 0.11 mmol) were added. The reaction mixture was stirred at room temperature for 24 hours, and then poured into ethyl acetate, washed with 2M aqueous Na2CO3, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 5-20% 1M NH3/MeOH in dichloromethane) to yield 6.0 mg (9%) of N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)-4-(1-methylpyrrolidin-3-yl)benzamide. LCMS (ESI): RT (Min)=4.104, M+H=505.2, method=E; 1H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 10.18 (s, 1H), 9.19 (s, 1H), 8.50 (s, 1H), 8.02 (s, 1H), 7.92 (t, J=9.3 Hz, 3H), 7.81-7.67 (m, 3H), 7.44 (d, J=8.1 Hz, 2H), 7.32 (d, J=8.4 Hz, 1H), 3.52-3.40 (m, 2H), 3.01 (unresolved, 1H), 2.82 (unresolved, 2H), 2.44 (s, 3H), 2.26 (s, 3H), 2.08 (m, 1H), 1.84 (m, 2H), 0.85 (m, 4H).

Workup

  1. customevaporated in vacuo
  2. stirringThe reaction mixture was stirred at room temperature for 18 hours
  3. stirringThe reaction mixture was stirred at room temperature for 24 hours
  4. washwashed with 2M aqueous Na2CO3
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. customevaporated in vacuo
  8. customThe crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 5-20% 1M NH3/MeOH in dichloromethane)

Sources & evidence

ORD record
ord-df81d172edaa416499788b5f31ccc23b
Source dataset
uspto-grants-2015_12
Patent number
US09206175B2

Reaction notes

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