p-Toluenesulfonic acid monohydrate → HCID 71209202, compound

HRID 1912596Notes

Reaction equation

HRID 1912596 reaction equation
[NH2:1][C:2]1[N:3]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=2)[CH:4]=[CH:5][C:6]=1[C:7]#[N:8].C(O/[C:21](/[CH3:28])=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])C.O.CC1C=CC(S(O)(=O)=O)=CC=1.[O-]CC.[Na+].Cl.O>O.C1(C)C=CC=CC=1>[NH2:8][C:7]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([CH3:28])[N:1]=[C:2]2[N:3]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=3)[CH:4]=[CH:5][C:6]=12

Participants

8

Reactant 5

HCID 521998p-Toluenesulfonic acid monohydrateHCID 2723922Sodium ethoxideHCID 5354173Ethyl (2E)-3-ethoxy-2-butenoateHCID 21885828Hydrate;hydrochlorideHCID 71209216HCID 71209216, compound

Product 1

HCID 71209202HCID 71209202, compoundYield 78%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent2×

Conditions

Temperature
155 °C

Procedure

A mixture of 2-amino-1-(3,4-difluorobenzyl)-1H-pyrrole-3-carbonitrile (20 g, 86 mmol) and toluene (700 mL) was heated to reflux eliminating 30 mL of toluene using a Dean-Stark trap then (E)-ethyl 3-ethoxybut-2-enoate (14.9 g, 94 mmol) and 4-methylbenzenesulfonic acid hydrate (1.6 g, 8.56 mmol) and were added. The mixture was heated to 155° C. for 1 h using a Dean-Stark trap to eliminate 350 mL of solvent. The mixture was cooled to 0° C. and sodium ethoxide (41.6 mL, 111 mmol, 21% wt/EtOH) was added dropwise and the mixture was heated to reflux (145° C.) for 1 h using a Dean-Stark trap to eliminate 100 mL of solvent. Water was added followed by 1M HCl/water adjusting the pH-9. The mixture was extracted with EtOAc. The organic phase was dried (Na2SO4), concentrated, and purified by column chromatography provide ethyl 4-amino-1-(3,4-difluorobenzyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (23.1 g, 66.8 mmol, 78% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (t, J=7 Hz, 3 H), 2.78 (s, 3 H), 4.40 (q, J=7 Hz, 2 H), 5.36 (s, 2 H), 6.3 (br s, 2 H), 6.5 (m, 2 H), 6.6-7.2 (m, 4 H); LCMS (m/z) ES+=346 (M+1).

Workup

  1. temperaturewas heated
  2. temperatureto reflux
  3. temperatureThe mixture was cooled to 0° C.
  4. temperaturethe mixture was heated
  5. temperatureto reflux (145° C.) for 1 h
  6. extractionThe mixture was extracted with EtOAc
  7. dry with materialThe organic phase was dried (Na2SO4)
  8. concentrationconcentrated
  9. custompurified by column chromatography

Sources & evidence

ORD record
ord-eaaec39b7ca843488bfb939098231354
Source dataset
uspto-grants-2013_12
Patent number
US08609653B2

Reaction notes

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