Hydrochloric Acid → 5-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-ylthio)-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine trihydrochloride

HRID 911830Notes

Reaction equation

HRID 911830 reaction equation
[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[N:13]=[CH:12][C:11]([S:14]CCC(OC)=O)=[CH:10][C:9]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:5][CH:6]=1.[Cl:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[CH2:35][N:36](C(OCC)=O)[CH2:37][C:30]=12.CC([O-])(C)C.[K+].[NH4+].[Cl-:50].[OH-].[K+].Cl>CO.O.CS(C)=O>[ClH:28].[ClH:50].[ClH:28].[N:32]1[CH:33]=[CH:34][C:29]([S:14][C:11]2[CH:10]=[C:9]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:8]([NH:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)=[N:13][CH:12]=2)=[C:30]2[CH2:37][NH:36][CH2:35][C:31]=12

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 14797Potassium HydroxideHCID 25517Ammonium Chloride2×HCID 23665647Potassium tert-butoxideHCID 24765636Methyl 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoateHCID 66995010953045-41-5

Product 1

HCID 866314995-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-ylthio)-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine trihydrochlorideYield 33%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 887MethanolSolventHCID 962WaterSolvent

Procedure

A 10 mL round-bottomed flask was charged with methyl 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate (65 mg, 0.16 mmol), ethyl 4-chloro-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate (55 mg, 0.24 mmol), and DMSO (2 mL). The reaction was bubbled through with nitrogen and potassium 2-methylpropan-2-olate (54 mg, 0.49 mmol) was added and stirred at ambient temperature for 30 minutes. The reaction was poured into saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (50% EtOAc in hexanes) to afford a residue that was dissolved in methanol, KOH (xs) and water (0.5 mL) added and heated to 60° C. over the weekend. The reaction was poured into saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (100% EtOAc to 20% methanol in CH2Cl2 with 0.2% ammonia) to afford the title compound (29 mg, 33% yield) as a yellow solid after HCl salt formation. 1H NMR (d6-DMSO) δ 10.12 (bs, 2H), 8.34 (d, 1H), 8.31 (d, 1H), 7.42 (m, 2H), 7.36 (d, 1H), 7.17 (m, 3H), 6.84 (d, 1H), 6.76 (s, 1H), 4.47 (m, 4H), 2.28 (s, 3H). Mass spectrum (apci) m/z=434.2 (M+H-3HCl).

Workup

  1. additionwas added
  2. extractionextracted with EtOAc
  3. dry with materialThe organic layer was dried with sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was purified on silica gel (50% EtOAc in hexanes)
  7. customto afford a residue that
  8. temperatureheated to 60° C. over the weekend
  9. extractionextracted with EtOAc
  10. dry with materialThe organic layer was dried with sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customThe residue was purified on silica gel (100% EtOAc to 20% methanol in CH2Cl2 with 0.2% ammonia)

Sources & evidence

ORD record
ord-ecdd2b8de7224d88ba8f7f28ae866de1
Source dataset
uspto-grants-2011_09
Patent number
US08022223B2

Reaction notes

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