Trifluoroacetic acid → N-Cyclopropyl-3-fluoro-5-(2-(3-hydroxy-2,2-dimethylpropyl)-1-oxo-4-(piperazin-1-ylmethyl)-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamide

HRID 906403Notes

Reaction equation

HRID 906403 reaction equation
[CH:1]1([NH:4][C:5](=[O:33])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[N:17]([CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH:16]=[C:15]4[CH:29]=O)[C:9]([CH3:31])=[C:8]([F:32])[CH:7]=2)[CH2:3][CH2:2]1.C([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(C(F)(F)F)=O>ClCCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:1]1([NH:4][C:5](=[O:33])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[N:17]([CH2:23][C:24]([CH3:27])([CH3:28])[CH2:25][OH:26])[CH:16]=[C:15]4[CH2:29][N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[C:9]([CH3:31])=[C:8]([F:32])[CH:7]=2)[CH2:2][CH2:3]1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 143452tert-Butyl piperazine-1-carboxylateHCID 5049666Sodium triacetoxyborohydrideHCID 86640963N-Cyclopropyl-3-fluoro-5-(4-formyl-2-(3-hydroxy-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamide

Product 1

HCID 59285288N-Cyclopropyl-3-fluoro-5-(2-(3-hydroxy-2,2-dimethylpropyl)-1-oxo-4-(piperazin-1-ylmethyl)-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamideYield 37.5%

Reagents, catalysts & solvents 2

HCID 11026Titanium isopropoxideCatalystHCID 111,2-DichloroethaneSolvent

Conditions

Temperature
20 °C

Procedure

A solution of N-cyclopropyl-3-fluoro-5-(4-formyl-2-(3-hydroxy-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamide (Example 1f, 0.15 g) in DCE (5 mL) was treated with 1-Boc-piperazine (0.19 g) and titanium(IV) isopropoxide (0.30 mL) under nitrogen. The resulting mixture was stirred at 20° C. for 16 h before adding sodium triacetoxyborohydride (0.28 g). The mixture was stirred at room temperature for 2 h before adding TFA (5 mL). The mixture stirred at room temperature for 2 h and evaporated to dryness. The mixture was quenched with 10% aq ammonia (5 mL) and extracted with ethyl acetate. The organic was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent) to afford the title compound (0.065 g) as a white solid.

Workup

  1. stirringThe mixture was stirred at room temperature for 2 h
  2. stirringThe mixture stirred at room temperature for 2 h
  3. customevaporated to dryness
  4. customThe mixture was quenched with 10% aq ammonia (5 mL)
  5. extractionextracted with ethyl acetate
  6. dry with materialThe organic was dried (MgSO4)
  7. filtrationfiltered
  8. customevaporated
  9. customto afford crude product
  10. customThe crude product was purified by preparative HPLC (Phenomenex Gemini column

Sources & evidence

ORD record
ord-3272be2fdeb94b31b5db9312d06595ec
Source dataset
uspto-grants-2011_09
Patent number
US08012980B2

Reaction notes

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