2-Bromothiazole → cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[2-(2-thiazolylamino)ethyl]-4-piperidinyl]benzamide

HRID 654183Notes

Reaction equation

HRID 654183 reaction equation
Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][C:8]1[C:27]([Cl:28])=[CH:26][C:11]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH2:23])[CH2:17][C@H:16]2[O:24][CH3:25])=[O:13])=[C:10]([O:29][CH3:30])[CH:9]=1>N1C=CC=CC=1>[NH2:7][C:8]1[C:27]([Cl:28])=[CH:26][C:11]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH:23][C:2]3[S:3][CH:4]=[CH:5][N:6]=3)[CH2:17][C@H:16]2[O:24][CH3:25])=[O:13])=[C:10]([O:29][CH3:30])[CH:9]=1

Participants

4

Reactant 2

HCID 764302-BromothiazoleHCID 14854954cis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide

Product 1

HCID 14855029cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[2-(2-thiazolylamino)ethyl]-4-piperidinyl]benzamideYield 11%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of 2 parts of 2-bromothiazole and 4.28 parts of cis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide was stirred for one hour at 60° C. Ths mixture solidified. It was suspended in 10 parts of pyridine and stirring was continued overnight at reflux. The reaction mixture was evaporated. The residue was taken up in a saturated sodium carbonate solution. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (93:7 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and the free base was liberated in the conventional manner and extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane. The product was filtered off and dried, yielding 0.6 parts (11%) of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[2-(2-thiazolylamino)ethyl]-4-piperidinyl]benzamide; mp. 140.9° C. (compound 44).

Workup

  1. stirringstirring
  2. waitwas continued overnight
  3. temperatureat reflux
  4. customThe reaction mixture was evaporated
  5. extractionThe product was extracted with trichloromethane
  6. customThe extract was dried
  7. filtrationfiltered
  8. customevaporated
  9. customThe residue was purified by column chromatography over silica gel using
  10. additiona mixture of trichloromethane and methanol (93:7 by volume) as eluent
  11. customThe pure fractions were collected
  12. customthe eluent was evaporated
  13. filtrationThe salt was filtered off
  14. extractionextracted with trichloromethane
  15. customThe extract was dried
  16. filtrationfiltered
  17. customevaporated
  18. customThe residue was purified by column chromatography over silica gel using
  19. additiona mixture of trichloromethane and methanol
  20. customThe pure fractions were collected
  21. customthe eluent was evaporated
  22. customThe residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane
  23. filtrationThe product was filtered off
  24. customdried

Sources & evidence

ORD record
ord-d723af58e08841778400c83e897b7e5a
Source dataset
uspto-grants-1992_07
Patent number
US05130312

Reaction notes

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