Sodium Diacetate → 7-chloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one

HRID 577589

Reaction equation

HRID 577589 reaction equation
Cl[C:2]1[C:12]2[C:11](=[O:13])[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=CC=1OC.[Cl:16][C:17]1[C:18]([O:29][CH3:30])=[CH:19][C:20]2[C:26](=[O:27])[NH:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:28]=1.C(OC1C(CCl)=C(C)C=C(C)N=1)C1C=CC=CC=1.CC([O-])=O.[Na+].CC(O)=O>CN(C=O)C>[Cl:16][C:17]1[C:18]([O:29][CH3:30])=[CH:19][C:20]2[C:26](=[O:27])[N:25]([CH2:2][C:12]3[C:11](=[O:13])[NH:10][C:9]([CH3:8])=[CH:7][C:6]=3[CH3:5])[CH2:24][CH2:23][CH2:22][C:21]=2[CH:28]=1

Participants

6

Reactant 4

HCID 23662384Sodium DiacetateHCID 612578682-(Benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridineHCID 867238179-chloro-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-oneHCID 867238187-chloro-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one

Product 1

HCID 867238167-chloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-oneYield 36%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

To a mixture of 9-chloro-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (132a) and 7-chloro-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (132b) (35.0 mg, 0.150 mmol) in DMF (5 mL) was added 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 47.1 mg, 0.180 mmol). The reaction mixture was heated at 80° C. for 24 hours. The reaction mixture was poured into a NaOAc-HOAc buffer (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The resulting brown oil was dissolved in MeOH (1 mL) and HCl (3 M in n-butanol, 0.05 mL) was added. The reaction mixture was heated at 70° C. for 24 hours. The solvent was removed in vacuum and the residue was purified by preparative HPLC to give the title compounds (Example 132-A, first eluting product, 20 mg, 36%); 1H NMR (400 MHz, methanol-d4) δ 7.09-7.14 (m, 1H), 7.05-7.10 (m, 1H), 6.13 (s, 1H), 4.89 (s, 1H), 4.71-4.79 (m, 1H), 3.88 (s, 3H), 3.38 (dd, J=5.93, 14.86 Hz, 1H), 2.92-3.01 (m, 1H), 2.57-2.73 (m, 2H), 2.35 (s, 3H), 2.25 (s, 3H), 2.06-2.14 (m, 1H), 1.53-1.64 (m, 1H); MS 361.1 [M+1]; and (Example 132-B, second eluting product, 4 mg, 7%); 1H NMR (400 MHz, methanol-d4) δ 7.26 (s, 1H), 7.22 (s, 1H), 6.13 (s, 1H), 4.78 (s, 2H), 3.91 (s, 3H), 3.26-3.29 (m, 2H), 2.63 (t, J=7.09 Hz, 2H), 2.34 (s, 3H), 2.26 (s, 3H), 1.78 (t, J=6.66 Hz, 2H); MS 361.1 [M+1]; as a white solids.

Workup

  1. extractionextracted with EtOAc (2×10 mL)
  2. dry with materialThe combined organic layers were dried over sodium sulfate
  3. concentrationconcentrated under vacuum
  4. dissolutionThe resulting brown oil was dissolved in MeOH (1 mL)
  5. additionHCl (3 M in n-butanol, 0.05 mL) was added
  6. temperatureThe reaction mixture was heated at 70° C. for 24 hours
  7. customThe solvent was removed in vacuum
  8. customthe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-aa2b0cb5009d49bfad1b13b9fde98265
Source dataset
uspto-grants-2015_05
Patent number
US09040515B2

Linked notes

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