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Hydrochloric Acid → US9777003, Example 206

HRID 628432
Notes
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Reaction equation

HRID 628432 reaction equation
[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](Cl)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1.CC([O-])(C)C.[Na+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Cl.O1CCOCC1>C1(C)C=CC=CC=1.CCOC(C)=O.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]>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 12682914-Amino-1-Boc-piperidineHCID 23676156Sodium t-butoxideHCID 1181596216-benzyl-4-chloro-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine

Product 1

HCID 118159668US9777003, Example 206

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A degassed mixture of 6-benzyl-4-chloro-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (80. mg, 0.26 mmol, from Example 228, Step 7), tert-butyl 4-aminopiperidine-1-carboxylate (210 mg, 1.0 mmol, Combi-Blocks), NaOtBu (49 mg, 0.51 mmol, Aldrich), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (30. mg, 0.051 mmol, Aldrich) and tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.026 mmol, Aldrich) in toluene (4.0 mL) was heated at 100° C. overnight. After cooling, the reaction mixture was diluted with EtOAc and washed sequentially with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in DCM (5.0 mL) and was treated with 4.0 M HCl in dioxane (2.0 mL, 8.0 mmol) for 1 hour. The reaction mixture was concentrated in vacuo. The product was purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (40 mg, 38%).

Workup

  1. temperatureAfter cooling
  2. washwashed sequentially with water and brine
  3. dry with materialThe organic layer was dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. dissolutionThe crude product was dissolved in DCM (5.0 mL)
  7. concentrationThe reaction mixture was concentrated in vacuo
  8. customThe product was purified via preparative HPLC-MS (Waters XBridge C18
  9. washeluting with a gradient of MeCN/H2O containing 0.15% NH4OH)

Sources & evidence

ORD record
ord-fc525d26e0d64cb4ac49699e87c3eafc
Source dataset
uspto-grants-2016_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09309246B2

Reaction notes

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