Ethanol → HCID 67505580, compound

HRID 1948862Notes

Reaction equation

HRID 1948862 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.Cl.[NH2:27][C:28]([NH2:30])=[NH:29].C(=O)([O-])[O-].[K+].[K+].C(O)C>C(OCC)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:29]=[C:28]([NH2:30])[N:27]=[CH:13][C:10]=3[CH2:9][N:8]=[C:7]([C:17]3[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=3[F:23])[C:6]=2[CH:25]=1

Participants

7

Reactant 4

HCID 702EthanolHCID 5742Guanidine HydrochlorideHCID 11430Potassium CarbonateHCID 67505050HCID 67505050, compound

Product 1

HCID 67505580HCID 67505580, compoundYield 89%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 3283Diethyl EtherSolvent

Procedure

8-Chloro-4-dimethylaminomethylene-1-(2,6-difluorophenyl)-3,4-dihydrobenzo[c]azepin-5-one (5aa) (3.6 g, 10 mmol), guanidine hydrochloride (1.06 g, 11 mmol), potassium carbonate (4.6 g, 33 mmol), and ethanol (100 mL) were combined in a 100-mL round-bottomed flask and stirred at reflux for 3 hours. The reaction mixture was poured into 500 mL water with stirring. The mixture was extracted with ethyl acetate (4×200 mL). The organic extracts were combined, washed with saline, dried (Na2SO4), filtered, and evaporated to leave a brown solid. The solid was stirred with diethyl ether, filtered, washed with ether, then dried in vacuo to provide 9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl amine (3.16 g, 89%) as a light brown solid MS m/z=357 (M+H). The amine (2.0 g, 5.6 mmol), diiodomethane (7.7 g, 28.6 mmol), copper (I) iodide (1.1 g, 5.6 mmol), dry tetrahydrofuran (40 mL), and isoamyl nitrite (2.0 g, 16.8 mmol) were combined in a round-bottomed flask and stirred at reflux for 1 hour. The dark purple solution was cooled to room temperature and then transferred to a separatory funnel containing 1N HCl (250 mL) and ethyl acetate (150 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The organic extracts were combined, washed with ammonium hydroxide (3%), saturated ammonium chloride, and saturated saline, and then dried (Na2SO4), filtered, and concentrated to leave a dark oil. Purification by column chromatography (silica gel, CH2Cl2 to 10% ethyl acetate in CH2Cl2) afforded 9-Chloro-7-(2,6-difluorophenyl)-2-iodo-5H-benzo[c]pyrimido[4,5-e]azepine as a pale yellow solid (1.3 g, 50%) MS m/z=468 (M+H).

Workup

  1. temperatureat reflux for 3 hours
  2. stirringwith stirring
  3. extractionThe mixture was extracted with ethyl acetate (4×200 mL)
  4. washwashed with saline
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. customevaporated
  8. customto leave a brown solid
  9. filtrationfiltered
  10. washwashed with ether
  11. customdried in vacuo

Sources & evidence

ORD record
ord-a656cfc3efb442df980f5514803de8b7
Source dataset
uspto-grants-2013_03
Patent number
US08399659B2

Reaction notes

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