Tert-butyl 4-{5-[2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinolin-5-yl]pyridin-2-yl}piperazine-1-carboxylate → 8-chloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-[6-(piperazin-1-yl)pyridin-3-yl]-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one

HRID 577522Notes

Reaction equation

HRID 577522 reaction equation
C([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:49])[C:20]([O:45][CH:46]([CH3:48])[CH3:47])=[CH:21][C:22]=3[C:26]3[CH:27]=[CH:28][C:29]([N:32]4[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]4)=[N:30][CH:31]=3)[C:17]2=[O:50])=[C:13]([CH3:51])[CH:12]=[C:11]([CH3:52])[N:10]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:49][C:19]1[C:20]([O:45][CH:46]([CH3:48])[CH3:47])=[CH:21][C:22]([C:26]2[CH:31]=[N:30][C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)=[C:23]2[C:18]=1[C:17](=[O:50])[N:16]([CH2:15][C:14]1[C:9](=[O:8])[NH:10][C:11]([CH3:52])=[CH:12][C:13]=1[CH3:51])[CH2:25][CH2:24]2

Participants

3

Reactant 1

HCID 86723748Tert-butyl 4-{5-[2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinolin-5-yl]pyridin-2-yl}piperazine-1-carboxylate

Product 1

HCID 867237498-chloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-[6-(piperazin-1-yl)pyridin-3-yl]-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-oneYield 15%

Reagents, catalysts & solvents 1

HCID 6422Trifluoroacetic acidSolvent

Procedure

A mixture of tert-butyl 4-{5-[2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinolin-5-yl]pyridin-2-yl}piperazine-1-carboxylate (77f, 46 mg, 0.063 mmol) in TFA (2 mL) was stirred at room temperature for 3 hours. After concentrating volatiles under vacuum, the resulting residue was partitioned between ethyl acetate (30 mL) and sodium bicarbonate (30 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (1×30 mL). The combined organic phases were dried over sodium sulfate, concentrated under vacuum, and purified by prep HPLC to give the title compound (Example 77, 5.0 mg, 15% yield) as a solid. 1H NMR (400 MHz, methanol-d4) δ 8.09 (d, J=2.27 Hz, 1H), 7.56 (dd, J=8.59, 2.53 Hz, 1H), 7.09 (s, 1H), 6.88 (d, J=8.84 Hz, 1H), 6.10 (s, 1H), 4.77 (s, 2H), 4.60-4.70 (m, 1H), 3.55-3.63 (m, 4H), 3.35 (t, J=6.06 Hz, 2H), 2.92-3.02 (m, 4H), 2.75 (t, J=6.06 Hz, 2H), 2.30 (s, 3H), 2.24 (s, 3H), 1.36 (d, J=5.81 Hz, 6H); MS 536.3 [M+H].

Workup

  1. concentrationAfter concentrating volatiles under vacuum
  2. customthe resulting residue was partitioned between ethyl acetate (30 mL) and sodium bicarbonate (30 mL)
  3. customThe organic phase was separated
  4. extractionthe aqueous phase was extracted with ethyl acetate (1×30 mL)
  5. dry with materialThe combined organic phases were dried over sodium sulfate
  6. concentrationconcentrated under vacuum
  7. custompurified by prep HPLC

Sources & evidence

ORD record
ord-5e32ec04fd7243dcbbb1b720c114b01e
Source dataset
uspto-grants-2015_05
Patent number
US09040515B2

Reaction notes

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