Hydrochloric Acid → HCID 67344666, compound

HRID 1951166Notes

Reaction equation

HRID 1951166 reaction equation
[CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[N:11][N:10]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1.[ClH:36]>C(Cl)Cl>[ClH:36].[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:6]2[CH2:7][C@@H:2]([CH3:1])[N:3]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)=[N:11][N:10]=3)[CH2:4][C@@H:5]2[CH3:8])=[O:35])=[CH:29][CH:28]=1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 709554-Fluorophenyl isocyanateHCID 58379010HCID 58379010, compound

Product 1

HCID 67344666HCID 67344666, compoundYield 43%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Treat a solution of 1-(trans-2,5-dimethylpiperazin-1-yl)-4-(4-fluorophenyl)phthalazine (0.3 g, 0.89 mmol) in CH2Cl2 (5 mL) with 1-fluoro-4-isocyanatobenzene (0.17 g, 1.25 mmol). Stir the reaction at ambient temperature for 1 h. Purify the reaction mixture by flash silica gel chromatography (0-50% EtOAc in hexanes). Pool and concentrate the appropriate fractions. Dissolve the mixture of N-(4-fluorophenyl)-4-(4-(4-fluorophenyl) phthalazin-1-yl)-trans-2,5-dimethylpiperazine-1-carboxamide isomers (0.3 g, 0.59 mmol) in MeOH (2 mL). Separate the mixture of trans-isomers by chiral chromatography (Chiralcel OJ-H, flow rate 30 mL/min, detection 225 nm, 6:4 MeOH: acetonitrile). Collect first eluting peak as Isomer 1 and the second eluting peak as Isomer 2. Pool and concentrate appropriate fractions. Dissolve the separated isomers in MeOH (1 mL) and treat each solution with 1 equivalent of 1 N aqueous HCl. Concentrate to give the hydrochloride salts of Isomer 1 (0.131 g, 44%) and Isomer 2 (0.129 g, 43%). Isomer 1: ES/MS m/z 474.2 (M+1), 99% ee. Isomer 2: ES/MS m/z 474.2 (M+1), 99% ee.

Workup

  1. customthe reaction at ambient temperature for 1 h
  2. customPurify the reaction mixture by flash silica gel chromatography (0-50% EtOAc in hexanes)
  3. concentrationPool and concentrate the appropriate fractions
  4. dissolutionDissolve
  5. additionthe mixture of N-(4-fluorophenyl)-4-(4-(4-fluorophenyl) phthalazin-1-yl)-trans-2,5-dimethylpiperazine-1-carboxamide isomers (0.3 g, 0.59 mmol) in MeOH (2 mL)
  6. customSeparate
  7. additionthe mixture of trans-isomers by chiral chromatography (Chiralcel OJ-H, flow rate 30 mL/min, detection 225 nm, 6:4 MeOH: acetonitrile)
  8. customCollect first eluting peak as Isomer 1
  9. concentrationPool and concentrate appropriate fractions
  10. dissolutionDissolve the separated isomers in MeOH (1 mL)
  11. concentrationConcentrate

Sources & evidence

ORD record
ord-876c9bf5a5b74aa7965761076d7ff54e
Source dataset
uspto-grants-2013_03
Patent number
US08404687B2

Reaction notes

Loading…