Toluene → cis-4-amino-5-chloro-N-[1-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide

HRID 1110398Notes

Reaction equation

HRID 1110398 reaction equation
[C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])O1.[NH2:12][C:13]1[C:33]([Cl:34])=[CH:32][C:16]([C:17]([NH:19][C@H:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH2:29])[CH2:22][C@H:21]2[O:30][CH3:31])=[O:18])=[C:15]([O:35][CH3:36])[CH:14]=1.CC1C=CC=CC=1>O>[NH2:12][C:13]1[C:33]([Cl:34])=[CH:32][C:16]([C:17]([NH:19][C@H:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][N:29]3[C:3](=[O:10])[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:1]3=[O:11])[CH2:22][C@H:21]2[O:30][CH3:31])=[O:18])=[C:15]([O:35][CH3:36])[CH:14]=1

Participants

5

Reactant 3

HCID 1140TolueneHCID 6811Phthalic AnhydrideHCID 14854959HCID 14854959, compound

Product 1

HCID 67922873cis-4-amino-5-chloro-N-[1-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamideYield 42%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

A mixture of 1.85 parts of 1,3-isobenzofurandione, 4.4 parts of cis-4-amino-N-[1-(3-aminopropyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide and 45 parts of methylbenzene was stirred for 3 hours at reflux temperature, using a water separator. The reaction mixture was evaporated. The residue was taken up in trichloromethane. The organic phase was washed with a saturate solution of sodium carbonate and water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.5 parts (42,4%) of cis-4-amino-5-chloro-N-[1-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 208.2° C. (compound 88).

Workup

  1. temperatureat reflux temperature
  2. customThe reaction mixture was evaporated
  3. washThe organic phase was washed with a saturate solution of sodium carbonate and water
  4. customdried
  5. filtrationfiltered
  6. customevaporated
  7. customThe residue was purified by column chromatography over silica gel using
  8. additiona mixture of trichloromethane and methanol
  9. customThe pure fractions were collected
  10. customthe eluent was evaporated
  11. customThe residue was crystallized from acetonitrile
  12. filtrationThe product was filtered off
  13. customdried

Sources & evidence

ORD record
ord-79e66662825a4780a508323e93826655
Source dataset
uspto-grants-1990_12
Patent number
US04975439

Reaction notes

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