Fumaric Acid → 3-[1-(2-Methyl-7,8-Dihydro-1,6,9-Trioxa-3-Aza-Cyclopenta[a]Naphthalen-8-Ylmethyl)-1,2,3,6-Tetrahydro-Pyridin-4-Yl]-1H-Indole-5-Carbonitrile

HRID 1060762Notes

Reaction equation

HRID 1060762 reaction equation
CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH:31]=[C:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([C:42]#[N:43])[CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1.C(O)(=O)/C=C/C(O)=O>CS(C)=O.C(O)C>[CH3:24][C:21]1[O:22][C:23]2=[C:15]3[C:16](=[CH:17][CH:18]=[C:19]2[N:20]=1)[O:25][CH2:26][CH:13]([CH2:12][N:27]1[CH2:28][CH:29]=[C:30]([C:33]2[C:41]4[C:36](=[CH:37][CH:38]=[C:39]([C:42]#[N:43])[CH:40]=4)[NH:35][CH:34]=2)[CH2:31][CH2:32]1)[O:14]3

Participants

6

Reactant 3

HCID 444972Fumaric AcidHCID 11245807(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl 4-methylbenzenesulfonateHCID 113335543-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carbonitrile

Product 1

HCID 98453653-[1-(2-Methyl-7,8-Dihydro-1,6,9-Trioxa-3-Aza-Cyclopenta[a]Naphthalen-8-Ylmethyl)-1,2,3,6-Tetrahydro-Pyridin-4-Yl]-1H-Indole-5-Carbonitrile

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 702EthanolSolvent2×

Conditions

Temperature
77.5 °C

Procedure

[(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl 4-methylbenzenesulfonate (0.60 g, 1.6 mmole) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole-5-carbonitrile (0.85 g, 3.8 mmole) were combined in 70 mL of DMSO under nitrogen. This solution was heated to 75-80° C. under nitrogen. After completion, the reaction was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The crude residue was column chromatographed on silica gel using 30% hexane/ethyl acetate to remove impurities. Ethyl acetate eluted the product, which was a yellow oil (0.24 g, 42%). The oil was crystallized from ethanol with the addition of a solution of fumaric acid (0.12 g, 1.02 mmole) in hot ethanol to give 0.20 g of the (S)-enantiomer of the title compound as a yellow solid difumarate.0.50 hydrate, m.p. 119° C. MS (ESI) m/z 427 (M+H)+.

Workup

  1. temperatureAfter completion, the reaction was cooled to room temperature
  2. custompartitioned between ethyl acetate and saturated aqueous sodium bicarbonate
  3. washThe organic phase was washed with brine
  4. dry with materialdried over magnesium sulfate
  5. concentrationconcentrated in vacuum
  6. customchromatographed on silica gel using 30% hexane/ethyl acetate
  7. customto remove impurities
  8. washEthyl acetate eluted the product, which

Sources & evidence

ORD record
ord-49bef598aa89428687efa9337db8faa3
Source dataset
uspto-grants-2003_02
Patent number
US06525075B2

Reaction notes

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