Methanol → 3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine

HRID 571369Notes

Reaction equation

HRID 571369 reaction equation
C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.Cl[C:27]1[N:32]=[CH:31][C:30]2[C:33]([C:55]3[CH:60]=[CH:59][N:58]=[C:57]([CH3:61])[CH:56]=3)=[N:34][N:35]([C:36]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:29]=2[CH:28]=1.[Li+].C[Si]([N-:67][Si](C)(C)C)(C)C.CO>C1COCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CCOC(C)=O>[CH3:61][C:57]1[CH:56]=[C:55]([C:33]2[C:30]3[CH:31]=[N:32][C:27]([NH2:67])=[CH:28][C:29]=3[N:35]([C:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[N:34]=2)[CH:60]=[CH:59][N:58]=1

Participants

10

Reactant 4

HCID 887MethanolHCID 2733832Lithium Hexamethyldisilazide2×HCID 27342162-(Dicyclohexylphosphino)biphenylHCID 895263966-chloro-3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine

Product 1

HCID 895258183-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amineYield 99.8%

Reagents, catalysts & solvents 5

HCID 27342162-(Dicyclohexylphosphino)biphenylCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
65 °C

Procedure

Pd2(dba)3 (0.192 g, 0.209 mmol), biphenyl-2-yl(dicyclohexyl)phosphane (0.073 g, 0.209 mmol), and 6-chloro-3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.02 g, 2.094 mmol) were placed in a microwave vial under nitrogen and dissolved in THF (11 mL) The reaction mixture was degassed for 5 min, LiHMDS (2.51 mL, 2.51 mmol, 1M in THF) was added via syringe and then heated to 65° C. overnight. The mixture was cooled to RT and Pd2(dba)3 (0.096 g, 0.1 mmol), biphenyl-2-yl(dicyclohexyl)phosphane (0.036 g, 0.1 mmol) and LiHMDS (1.25 mL, 1.25 mmol, 1M in THF) were added again. The mixture was degassed for 5 min and heated to 80° C. for 3 h, cooled to RT and quenched with 1N HCl. The mixture was then concentrated and partitioned between DCM and 1N NaOH. The organic layer was extracted with DCM (3×) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel over a gradient of 0-100% EtOAc in hexanes and then over a gradient of 0-30% (1:2=MeOH:EtOAc) in DCM to yield 3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine (549 mg, 2.09 mmol, 56%) as a solid. MS ESI calc'd. for C31H26N5 [M+1]+468, found 468.

Workup

  1. customwas degassed for 5 min
  2. temperatureThe mixture was cooled to RT
  3. customThe mixture was degassed for 5 min
  4. temperatureheated to 80° C. for 3 h
  5. temperaturecooled to RT
  6. customquenched with 1N HCl
  7. concentrationThe mixture was then concentrated
  8. custompartitioned between DCM and 1N NaOH
  9. extractionThe organic layer was extracted with DCM (3×)
  10. dry with materialthe combined organic layers were dried (Na2SO4)
  11. concentrationconcentrated in vacuo
  12. customThe residue was purified by chromatography on silica gel over a gradient of 0-100% EtOAc in hexanes

Sources & evidence

ORD record
ord-e9c31ea9062540dd8788cd41836c8805
Source dataset
uspto-grants-2015_05
Patent number
US09023865B2

Reaction notes

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