Acetyl chloride → HCID 15096950, compound

HRID 1088403Notes

Reaction equation

HRID 1088403 reaction equation
[NH2:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:11][C@H:10]2[OH:26])=[O:7])=[C:4]([O:30][CH3:31])[CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40]>O1CCCC1>[C:39]([O:26][C@H:10]1[C@@H:9]([NH:8][C:6](=[O:7])[C:5]2[CH:27]=[C:28]([Cl:29])[C:2]([NH2:1])=[CH:3][C:4]=2[O:30][CH3:31])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:11]1)(=[O:41])[CH3:40]

Participants

5

Reactant 3

HCID 6367Acetyl chlorideHCID 8471TriethylamineHCID 13677777HCID 13677777, compound

Product 1

HCID 15096950HCID 15096950, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a stirred solution of 7.5 parts of cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-hydroxy-4-piperidinyl]-2-methoxybenzamide in 68 parts of tetrahydrofuran were added dropwise 2.02 parts of N,N-diethylethanamine. After cooling to 0° C., there was added dropwise a solution of 1.4 parts of acetyl chloride in 9 parts of tetrahydrofuran at a temperature below 0° C. Upon completion, stirring was continued for a while while cooling in an ice-bath. The reaction mixture was allowed to reach slowly room temperature and stirring was continued overnight at room temperature. The reaction mixture was evaporated and the residue was taken up in a sodium carbonate solution in water. The product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further separated by HPLC using a mixture of trichloromethane, hexane and methanol (48:48:4 by volume) as eluent. The second fraction (B-isomer) was collected and the eluent was evaporated. The residue was suspended in petroleum ether. The product was filtered off and dried, yielding 1.7 parts of cis-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-[3-(4-fluorophenoxy)propyl]-3-piperidinol acetate (ester); mp. 58.8° C. (compound 232).

Workup

  1. temperaturewhile cooling in an ice-bath
  2. customto reach slowly room temperature
  3. stirringstirring
  4. customThe reaction mixture was evaporated
  5. extractionThe product was extracted with methylbenzene
  6. washThe extract was washed with water
  7. customdried
  8. filtrationfiltered
  9. customevaporated The residue
  10. customwas purified by column-chromatography over silica gel using
  11. additiona mixture of trichloromethane and methanol (95:5 by volume) as eluent
  12. customThe pure fractions were collected
  13. customthe eluent was evaporated
  14. customThe residue was further separated by HPLC
  15. additiona mixture of trichloromethane, hexane and methanol (48:48:4 by volume) as eluent
  16. customThe second fraction (B-isomer) was collected
  17. customthe eluent was evaporated
  18. filtrationThe product was filtered off
  19. customdried

Sources & evidence

ORD record
ord-2a835604f7544b54a78167233386e710
Source dataset
uspto-grants-1990_10
Patent number
US04962115

Reaction notes

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