Trifluoroacetic acid → N-Cyclopropyl-3-fluoro-5-[2-{[1-(hydroxymethyl)cyclobutyl]methyl}-1-oxo-4-(piperazin-1-ylmethyl)-1,2-dihydroisoquinolin-6-yl]-4-methylbenzamide

HRID 906429Notes

Reaction equation

HRID 906429 reaction equation
FC(F)(F)C(O)=O.[Si]([O:15][CH2:16][C:17]1([CH2:21][N:22]2[CH:31]=[C:30]([CH2:32][N:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:46]4[CH:51]=[C:50]([C:52](=[O:57])[NH:53][CH:54]5[CH2:56][CH2:55]5)[CH:49]=[C:48]([F:58])[C:47]=4[CH3:59])[CH:28]=3)[C:23]2=[O:60])[CH2:20][CH2:19][CH2:18]1)(C(C)(C)C)(C)C>C(Cl)Cl>[CH:54]1([NH:53][C:52](=[O:57])[C:50]2[CH:51]=[C:46]([C:27]3[CH:28]=[C:29]4[C:24](=[CH:25][CH:26]=3)[C:23](=[O:60])[N:22]([CH2:21][C:17]3([CH2:16][OH:15])[CH2:18][CH2:19][CH2:20]3)[CH:31]=[C:30]4[CH2:32][N:33]3[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]3)[C:47]([CH3:59])=[C:48]([F:58])[CH:49]=2)[CH2:56][CH2:55]1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 67391526Tert-butyl 4-[(2-{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]methyl}-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl]piperazine-1-carboxylate2×

Product 1

HCID 59285277N-Cyclopropyl-3-fluoro-5-[2-{[1-(hydroxymethyl)cyclobutyl]methyl}-1-oxo-4-(piperazin-1-ylmethyl)-1,2-dihydroisoquinolin-6-yl]-4-methylbenzamideYield 31.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Trifluoroacetic Acid (3 mL, 38.94 mmol) was added to a solution of tert-butyl 4-[(2-{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]methyl}-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl]piperazine-1-carboxylate (Example 27d 0.099 g) in DCM (9 mL) at room temperature. The reaction was stirred for 30 min before azeotroping with toluene (3×10 mL). The residue was passed through SCX resin, eluting with methanol to remove impurities, and then ˜0.7 N methanolic ammonia to elute product, which was then purified by preparative HPLC (Sunfire column using a 95-30% gradient of 0.3% aqueous ammonia in acetonitrile as eluent). The solvents were removed and the residue triturated with diethyl ether to leave the title compound (0.022 g) as a white solid.

Workup

  1. custombefore azeotroping with toluene (3×10 mL)
  2. washeluting with methanol
  3. customto remove impurities
  4. wash˜0.7 N methanolic ammonia to elute product, which
  5. customwas then purified by preparative HPLC (Sunfire column
  6. customThe solvents were removed
  7. customthe residue triturated with diethyl ether

Sources & evidence

ORD record
ord-a7a443d2a4a641c4b73eff4ace06667b
Source dataset
uspto-grants-2011_09
Patent number
US08012980B2

Reaction notes

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