Triethylamine → N-Cyclopropyl-3-fluoro-5-[2-(3-hydroxy-2,2-dimethylpropyl)-4-{[(2R)-2-methylpiperazin-1-yl]methyl}-1-oxo-1,2-dihydroisoquinolin-6-yl]-4-methylbenzamide

HRID 906425Notes

Reaction equation

HRID 906425 reaction equation
CS(Cl)(=O)=O.[Si]([O:13][CH2:14][C:15]([CH3:45])([CH3:44])[CH2:16][N:17]1[CH:26]=[C:25]([CH2:27]O)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:29]3[CH:30]=[C:31]([CH:38]=[C:39]([F:42])[C:40]=3[CH3:41])[C:32]([NH:34][CH:35]3[CH2:37][CH2:36]3)=[O:33])[CH:23]=2)[C:18]1=[O:43])(C(C)(C)C)(C)C.C(N(CC)CC)C.[CH3:53][C@H:54]1[NH:59][CH2:58][CH2:57][N:56](C(OC(C)(C)C)=O)[CH2:55]1>C(Cl)Cl>[CH:35]1([NH:34][C:32](=[O:33])[C:31]2[CH:30]=[C:29]([C:22]3[CH:23]=[C:24]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:43])[N:17]([CH2:16][C:15]([CH3:44])([CH3:45])[CH2:14][OH:13])[CH:26]=[C:25]4[CH2:27][N:59]3[CH2:58][CH2:57][NH:56][CH2:55][C@H:54]3[CH3:53])[C:40]([CH3:41])=[C:39]([F:42])[CH:38]=2)[CH2:37][CH2:36]1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 2756811(R)-1-Boc-3-methylpiperazineHCID 673911003-[2-(3-{[tert-Butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-4-(hydroxymethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide

Product 1

HCID 45109830N-Cyclopropyl-3-fluoro-5-[2-(3-hydroxy-2,2-dimethylpropyl)-4-{[(2R)-2-methylpiperazin-1-yl]methyl}-1-oxo-1,2-dihydroisoquinolin-6-yl]-4-methylbenzamideYield 22.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Methanesulfonyl chloride (0.55 mL) was added to a solution of 3-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-4-(hydroxymethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide (Example 26 g, 3.65 g) and triethylamine (1.79 mL) in DCM (10 mL) at −20° C. After 30 min the solution was warmed to 0° C. and tert-butyl (3R)-3-methylpiperazine-1-carboxylate (2.58 g) was added. The reaction was stirred for 18 h at room temperature, evaporated and the residue purified (SiO2 chromatography, elution with 20 to 80% ethyl acetate in isohexane). Fractions containing product were evaporated, dissolved in THF (100 mL) and treated with 4 M HCl in dioxane (5 mL), stirred at room temperature for 60 h, evaporated to dryness and the residue purified (SiO2 chromatography, elution with 5 to 10% 7N NH3/methanol in DCM) to give the title compound (1.53 g) as a solid.

Workup

  1. customevaporated
  2. customthe residue purified
  3. wash(SiO2 chromatography, elution with 20 to 80% ethyl acetate in isohexane)
  4. additionFractions containing product
  5. customwere evaporated
  6. dissolutiondissolved in THF (100 mL)
  7. additiontreated with 4 M HCl in dioxane (5 mL)
  8. stirringstirred at room temperature for 60 h
  9. customevaporated to dryness
  10. customthe residue purified
  11. wash(SiO2 chromatography, elution with 5 to 10% 7N NH3/methanol in DCM)

Sources & evidence

ORD record
ord-c3648858314f4b9c8fb22c0efcf03fc8
Source dataset
uspto-grants-2011_09
Patent number
US08012980B2

Reaction notes

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