Benzylamine → 2-((Benzylamino)methyl)-2,3-dihydro-7H-[1,4]dioxino[2,3-e]indol-8(9H)-one

HRID 1737412Notes

Reaction equation

HRID 1737412 reaction equation
C1(C)C=CC(S(O[CH2:11][C@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.S(C1C=CC(C)=CC=1)(OC[C@@H]1OC1)(=O)=O.[CH2:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CS(C)=O>[CH2:42]([NH:49][CH2:11][CH:12]1[O:25][C:16]2=[C:17]3[C:21](=[CH:22][CH:23]=[C:15]2[O:14][CH2:13]1)[NH:20][C:19](=[O:24])[CH2:18]3)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1

Participants

5

Reactant 3

HCID 7504BenzylamineHCID 154187Glycidyl tosylate, (R)-HCID 86754567(S)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one

Product 1

HCID 99103252-((Benzylamino)methyl)-2,3-dihydro-7H-[1,4]dioxino[2,3-e]indol-8(9H)-one

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
77.5 °C

Procedure

(S)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (2.0 g, 5.3 mmole), prepared in the same manner as the (R) enantiomer described above with substitution of (S)- for (R)-glycidyl tosylate, and benzylamine (2.9 ml, 26.7 mmole) were placed in 20 ml of fresh DMSO under nitrogen. The mixture was then heated to 75-80° C. with stirring for 3 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and brine. The DMSO layer was extracted with ethyl acetate and the combined ethyl acetate extracts were washed with water to remove trace DMSO, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant to yield the free base (1.4 g, 4.5 mmole, 83%) of the expected product as a solidified oil under reduced pressure. The free base was dissolved in 20 ml of ethanol, treated with 0.25 M ethanolic fumaric acid (10 ml) and precipitated with diethyl ether to give the title compound as a pale yellow solid fumarate salt, predominantly in the (R)-configuration, m.p. 195-196° C. This sample, from which the pharmacological results reported in this application were obtained, was determined by chiral HPLC to contain 9% of the (S)-enantiomer.

Workup

  1. temperatureAfter cooling to room temperature
  2. customthe reaction mixture was partitioned between ethyl acetate and brine
  3. extractionThe DMSO layer was extracted with ethyl acetate
  4. washthe combined ethyl acetate extracts were washed with water
  5. customto remove trace DMSO
  6. dry with materialdried over anhydrous sodium sulfate
  7. concentrationconcentrated in vacuum
  8. customThe residue was chromatographed on a silica gel column

Sources & evidence

ORD record
ord-7fb6a49e1639458cb49455d1c17a33b2
Source dataset
uspto-grants-1999_10
Patent number
US05962465

Reaction notes

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