Hydrochloric Acid → HCID 178469169, compound

HRID 1912635Notes

Reaction equation

HRID 1912635 reaction equation
[NH2:1][C:2]1[N:3]([CH:15]2[CH2:17][CH2:16]2)[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([O:13]C)=O.C(O[C:21]([CH3:28])=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])C.CC1C=CC(S(O)(=O)=O)=CC=1.[O-]CC.[Na+].Cl>C1(C)C=CC=CC=1.O>[CH:15]1([N:3]2[C:4]3[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=3[C:10]3[C:11]([OH:13])=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:21]([CH3:28])=[N:1][C:2]2=3)[CH2:17][CH2:16]1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 6101p-Toluenesulfonic acidHCID 791372-Butenoic acid, 3-ethoxy-, ethyl esterHCID 2723922Sodium ethoxideHCID 71209039HCID 71209039, compound

Product 1

HCID 178469169HCID 178469169, compoundYield 43.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
135 °C

Procedure

A suspension of methyl 2-amino-1-cyclopropyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylate (2.29 g, 9.77 mmol) in Toluene (46 mL) was treated with ethyl 3-ethoxybut-2-enoate (3.09 g, 19.55 mmol) and pTsOH (0.093 g, 0.489 mmol), and then heated to reflux (135° C.) for 2.5 hours using Dean-Stark. The mixture was cooled to rt, slowly treated with sodium ethoxide (21 wt % in EtOH) (4.38 mL, 11.73 mmol), and refluxed at 135° C. with Dean-Stark for 4 hours. The reaction was cooled to rt and concentrated. The brown residue was diluted with water and 1N HCl until neutral (pH ˜6), extracted with EtOAc, washed with brine, dried with Na2SO4, filtered, and concentrated to give 2.9568 g crude product. Water layer still contained some product. It was acidified with 1N HCl. extracted with EtOAc, washed with brine, dried with Na2SO4, filtered, and concentrated to give 203 mg crude product. Both products were combined and purified with column chromatography (0-50% EtOAc/Hexane) to give ethyl 9-cyclopropyl-4-hydroxy-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-3-carboxylate (1.3474 g, 4.29 mmol, 43.8% yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 12.48 (s, 1 H), 4.43 (q, J=7.1 Hz, 2 H), 3.06 (quin, J=5.4 Hz, 1 H), 2.94-2.85 (m, 2 H), 2.85-2.70 (m, 5 H), 1.96-1.75 (m, 4 H), 1.45 (t, J=7.1 Hz, 3 H), 1.11 (d, 4 H); LCMS (m/z) ES+=315 (M+1).

Workup

  1. temperatureheated
  2. temperatureThe mixture was cooled to rt
  3. temperaturerefluxed at 135° C. with Dean-Stark for 4 hours
  4. temperatureThe reaction was cooled to rt
  5. concentrationconcentrated
  6. additionThe brown residue was diluted with water and 1N HCl until neutral (pH ˜6)
  7. extractionextracted with EtOAc
  8. washwashed with brine
  9. dry with materialdried with Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customto give 2.9568 g crude product
  13. extractionextracted with EtOAc
  14. washwashed with brine
  15. dry with materialdried with Na2SO4
  16. filtrationfiltered
  17. concentrationconcentrated
  18. customto give 203 mg crude product
  19. custompurified with column chromatography (0-50% EtOAc/Hexane)

Sources & evidence

ORD record
ord-5d7e0a87202e46938b78093402fac204
Source dataset
uspto-grants-2013_12
Patent number
US08609653B2

Reaction notes

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