Cesium carbonate → US9777003, Example 66

HRID 628312Notes

Reaction equation

HRID 628312 reaction equation
[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[N:19]=[CH:20][S:21][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]([C:32](OC(C)(C)C)=O)[NH:24]C(OC(C)(C)C)=O.[C:39]([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]3[N:12]([C:32]([CH3:39])=[N:23][N:24]=3)[C:11]=2[CH:10]=[C:9]1[C:18]1[N:19]=[CH:20][S:21][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 85431Di-tert-butyl bicarbamate2×HCID 1181597341-benzyl-5-chloro-2-(1,3-thiazol-4-yl)-1H-pyrrolo[3,2-b]pyridine

Product 1

HCID 118159421US9777003, Example 66

Reagents, catalysts & solvents 2

HCID 178439015HCID 178439015, compoundCatalyst2×HCID 1140TolueneSolvent

Conditions

Temperature
108 °C

Procedure

1-Benzyl-5-chloro-2-(1,3-thiazol-4-yl)-1H-pyrrolo[3,2-b]pyridine (32 mg, 0.098 mmol, from Step 1), di-tert-butyl hydrazine-1,2-dicarboxylate (27 mg, 0.12 mmol) and Cs2CO3 (32 mg, 0.098 mmol) were combined in toluene (3.0 mL) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (7.7 mg, 0.0098 mmol) was added. The mixture was degassed by a stream of nitrogen through the solution for 10 minutes. The reaction was heated to 108° C. overnight. Additional di-tert-butyl hydrazine-1,2-dicarboxylate (23 mg, 0.098 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (7.7 mg, 0.0098 mmol) were added. The reaction was heated to 110° C. over a second night. The mixture was partitioned between EtOAc and water, extracted three times, and the combined extracts were dried over sodium sulfate, filtered and concentrated. The intermediate di-tert-butyl 1-[1-benzyl-2-(1,3-thiazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) and the eluent was evaporated. The product was dissolved in AcOH (0.60 mL) and was heated in the microwave to a temperature of 156° C. for 5 minutes. The AcOH was removed in vacuo and the sample was reconstituted and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (1.0 mg, 2.9%).

Workup

  1. customThe mixture was degassed by a stream of nitrogen through the solution for 10 minutes
  2. temperatureThe reaction was heated to 110° C. over a second night
  3. customThe mixture was partitioned between EtOAc and water
  4. extractionextracted three times
  5. dry with materialthe combined extracts were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe intermediate di-tert-butyl 1-[1-benzyl-2-(1,3-thiazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate was purified via preparative HPLC-MS (C18
  9. washeluting with a gradient of MeCN and H2O containing 0.15% NH4OH) and the eluent
  10. customwas evaporated
  11. dissolutionThe product was dissolved in AcOH (0.60 mL)
  12. temperaturewas heated in the microwave to a temperature of 156° C. for 5 minutes
  13. customThe AcOH was removed in vacuo
  14. custompurified via preparative HPLC-MS (C18
  15. washeluting with a gradient of MeCN and H2O containing 0.15% NH4OH)

Sources & evidence

ORD record
ord-32a98109962b42cc9cfeadb2f4445ca9
Source dataset
uspto-grants-2016_04
Patent number
US09309246B2

Reaction notes

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