Heptane → Tak-272

HRID 1509626Notes

Reaction equation

HRID 1509626 reaction equation
[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:33][CH:34]([CH3:36])[CH3:35])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][NH:21][CH2:20]1)=[O:17].C(OCC)(=O)C.[ClH:43].CCCCCCC>C(OCC)(=O)C>[ClH:43].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:33][CH:34]([CH3:36])[CH3:35])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][NH:21][CH2:20]1)=[O:17]

Participants

5

Reactant 3

HCID 8900Heptane2×HCID 21866389Hydrogen chloride-ethyl acetateHCID 44554894Imarikiren

Product 1

HCID 56591871Tak-272

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

1-(4-Methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide (24.4 g) was dissolved in ethyl acetate (225 ml), and the mixture was heated to 45-55° C. 4M Hydrogen chloride-ethyl acetate (12.8 ml) was added dropwise, and the precipitate was dissolved at the same temperature. After confirmation of dissolution, heptane (75 ml) was added dropwise, and the mixture was cooled to 25-35° C. The seed crystal (45 mg) was added and the mixture was stirred for 30 min. The mixture was heated to 50-55° C., and heptane (150 ml) was added dropwise. The mixture was stirred at the same temperature for 1 hr, gradually cooled to 0-5° C., and stirred at the same temperature for 1 hr. The precipitated crystals were collected by filtration, washed with ethyl acetate-heptane (90 ml), and dried under reduced pressure at 40-50° C. to give the object product (15.3 g).

Workup

  1. dissolutionthe precipitate was dissolved at the same temperature
  2. additionwas added dropwise
  3. temperaturethe mixture was cooled to 25-35° C
  4. temperatureThe mixture was heated to 50-55° C.
  5. stirringThe mixture was stirred at the same temperature for 1 hr
  6. temperaturegradually cooled to 0-5° C.
  7. stirringstirred at the same temperature for 1 hr
  8. filtrationThe precipitated crystals were collected by filtration
  9. washwashed with ethyl acetate-heptane (90 ml)
  10. customdried under reduced pressure at 40-50° C.

Sources & evidence

ORD record
ord-94867be7859140f1abf43937bd96d620
Source dataset
uspto-grants-2015_12
Patent number
US09221836B2

Reaction notes

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