Methyl chloroformate → N-[2-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2-oxo-2H-1-benzopyran-3-carboxamide (E)-2-butenedioate

HRID 280348Notes

Reaction equation

HRID 280348 reaction equation
[O:1]=[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[O:3]1.C(N(CC)CC)C.[C:22](Cl)(=[O:25])[O:23]C.[NH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:37]2[N:41]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)[C:40]3[CH:50]=[CH:51][CH:52]=[CH:53][C:39]=3[N:38]=2)[CH2:32][CH2:31]1>ClC(Cl)Cl>[C:2]([OH:3])(=[O:1])/[CH:7]=[CH:6]/[C:22]([OH:23])=[O:25].[F:49][C:46]1[CH:47]=[CH:48][C:43]([CH2:42][N:41]2[C:40]3[CH:50]=[CH:51][CH:52]=[CH:53][C:39]=3[N:38]=[C:37]2[NH:36][CH:33]2[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][NH:27][C:8]([C:7]3[C:2](=[O:1])[O:3][C:4]4[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=4[CH:6]=3)=[O:10])[CH2:31][CH2:32]2)=[CH:44][CH:45]=1

Participants

6

Reactant 4

HCID 6586Methyl chloroformateHCID 8471TriethylamineHCID 10752Coumarin-3-Carboxylic AcidHCID 12891741N-[1-(2-aminoethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine

Product 1

HCID 131714676N-[2-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2-oxo-2H-1-benzopyran-3-carboxamide (E)-2-butenedioateYield 47.5%

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent3×

Procedure

To a stirred and cooled (below 10° C.) mixture of 3.8 parts of 2-oxo-2H-1-benzopyran-3-carboxylic acid, 2.2 parts of N,N-diethylethanamine and 225 parts of trichloromethane was added dropwise a solution of 1.9 parts of methyl carbonochloridate in 75 parts of trichloromethane. Upon completion, stirring was continued for 30 minutes at room temperature. This solution was added dropwise to a stirred and cooled solution of 6.6 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine in 75 parts of trichloromethane at 5° C. The whole was stirred for 1 hour while the mixture was allowed to reach room temperature. The reaction mixture was washed successively with water, a sodium hydroxide solution 10% and again with water. The organic phase was 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 converted into the (E)-2-butenedioate salt in methanol. The salt was filtered off and dried, yielding 6.6 parts (47.5%) of N-[2-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2-oxo-2H-1-benzopyran-3-carboxamide (E)-2-butenedioate(1:2); mp. 216.8° C. (compound 44).

Workup

  1. temperaturecooled
  2. stirringUpon completion, stirring
  3. additionThis solution was added dropwise to
  4. stirringa stirred
  5. stirringThe whole was stirred for 1 hour while the mixture
  6. customto reach room temperature
  7. washThe reaction mixture was washed successively with water
  8. customThe organic phase was dried
  9. filtrationfiltered
  10. customevaporated
  11. customThe residue was purified by column chromatography over silica gel using
  12. additiona mixture of trichloromethane and methanol (95:5 by volume) as eluent
  13. customThe pure fractions were collected
  14. customthe eluent was evaporated
  15. filtrationThe salt was filtered off
  16. customdried

Sources & evidence

ORD record
ord-4b1f34903d6149c0b25d8b69c5830f9c
Source dataset
uspto-grants-1986_05
Patent number
US04588722

Reaction notes

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