Potassium Carbonate → 6-Methoxy-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-3,4-dihydroisoquinolin-1(2H)-one

HRID 579338Notes

Reaction equation

HRID 579338 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.Br[C:15]1[S:19][C:18]([N:20]([CH3:31])[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)=[N:17][N:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.[Cu]I>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:15]1[S:19][C:18]([N:20]([CH3:31])[CH:21]3[CH2:26][C:25]([CH3:27])([CH3:28])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]3)=[N:17][N:16]=1)[CH2:7][CH2:6]2

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 106073926-methoxy-3,4-dihydroisoquinolin-1(2H)-oneHCID 867271295-Bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine3×

Product 1

HCID 867271606-Methoxy-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-3,4-dihydroisoquinolin-1(2H)-one

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst2×HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
150 °C

Procedure

To a stirred suspension of 6-methoxy-3,4-dihydroisoquinolin-1(2H)-one (50 mg, 0.282 mmol) and 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (Intermediate 4) (132 mg, 0.395 mmol) in DMF (0.7 mL) under nitrogen was added K2CO3 (78 mg, 0.564 mmol) followed by CuI (32 mg, 0.169 mmol). The reaction mixture was heated at 150° C. for ˜18 hours. A further 1.4 eq of 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (132 mg, 0.395 mmol) and 0.6 eq of CuI (32 mg, 0.169 mmol) were added and stirring was continued at 150° C. for an additional 48 hours. The reaction mixture was diluted with EtOAc (10 mL) and filtered through celite. The filtrate was concentrated in vacuo to afford the crude product as a dark brown oil. The crude material was purified by UV directed preparative HPLC under acidic conditions (formic acid modified) collecting at 312 nm. The product containing fractions were combined and loaded onto a 2 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (˜20 mL) then flushed with 10% DCM in [7M NH3 in MeOH] (12 mL). The DCM/MeOH/NH3 was removed in vacuo to afford the title compound as a pale yellow/brown glass-like solid (28 mg, 23% yield). LC-MS: Rt 0.91 min; MS m/z 430.5 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.88-7.97 (m, 1H), 6.96-7.03 (m, 2H), 4.35 (t, J=6.57 Hz, 2H), 4.16 (tt, J=12.19, 3.22 Hz, 1H), 3.85 (s, 3H), 3.14 (t, J=6.57 Hz, 2H), 2.91 (s, 3H), 1.58 (dd, J=12.13, 3.03 Hz, 2H), 1.42 (t, J=11.87 Hz, 2H), 1.20 (s, 6H), 1.09 (s, 6H).

Workup

  1. filtrationfiltered through celite
  2. concentrationThe filtrate was concentrated in vacuo
  3. customto afford the crude product as a dark brown oil
  4. customThe crude material was purified by UV
  5. customcollecting at 312 nm
  6. additionThe product containing fractions
  7. washThe cartridge was washed with MeOH (˜20 mL)
  8. customthen flushed with 10% DCM in [7M NH3 in MeOH] (12 mL)
  9. customThe DCM/MeOH/NH3 was removed in vacuo

Sources & evidence

ORD record
ord-c0f1bbb997b548fe9fb25b5bc5bc4d2f
Source dataset
uspto-grants-2015_05
Patent number
US09040712B2

Reaction notes

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