Sodium Bicarbonate → N-[9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-benzene-1,4-diamine

HRID 1948866Notes

Reaction equation

HRID 1948866 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][N:8]=[C:7]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:6]=2[CH:34]=1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=4)[N:14]=[CH:15][C:10]=3[CH2:9][N:8]=[C:7]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:6]=2[CH:34]=1

Participants

4

Reactant 2

HCID 516892Sodium BicarbonateHCID 57798211[9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-nitro-phenyl)-amine

Product 1

HCID 57797709N-[9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-benzene-1,4-diamineYield 106.3%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

A mixture of [9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-nitro-phenyl)-amine (I-212, 500 mg, 1.05 mmol), stannous chloride dihydrate (1.42 g, 6.3 mmol) and ethyl acetate (15 mL) was refluxed for 28 hours, then cooled to room temperature and allowed to sit overnight. The mustard-yellow reaction mixture was poured onto ˜50 g cracked ice with stirring, and sat. NaHCO3 solution was added to adjust the pH to 8. The mixture was extracted with ethyl acetate (3×100 mL). The extracts were combined, dried (Na2SO4), filtered and evaporated in vacuo to provide N-[9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-benzene-1,4-diamine as an orange/yellow solid (500 mg, 100%) MS m/z=448 (M+H). A solution of this product (50 mg, 0.1 mmol), 4-methylpiperazine-1-carbonylchloride (89 mg, 0.6 mmol), diisopropylethylamine (142 mg, 1.1 mmol), in dioxane (0.5 nit) was submitted to microwave irradiation (300 W) for 60 minutes at 160° C. The reaction solution was cooled to room temperature and slowly poured into a stirring saline solution (10 mL). The resulting precipitate was collected by filtration, washed with water and purified by RP-HPLC (C18, 0 to 100% CH3CN in 0.1% aqueous HCO2H) to yield I-280 as a pale yellow solid (6 mg, 10%) MS m/z=574 (M+H).

Workup

  1. temperaturewas refluxed for 28 hours
  2. additionThe mustard-yellow reaction mixture was poured onto ˜50 g
  3. extractionThe mixture was extracted with ethyl acetate (3×100 mL)
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. customevaporated in vacuo

Sources & evidence

ORD record
ord-12c6b733358e4f3f939e8b6682b78408
Source dataset
uspto-grants-2013_03
Patent number
US08399659B2

Reaction notes

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