Hydrochloric Acid → HCID 136200335, compound

HRID 2361192Notes

Reaction equation

HRID 2361192 reaction equation
C(O[C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][C:17]([N+:24]([O-])=O)=[C:18]([NH2:23])[CH:19]=3)[C:14]2=[O:27])[CH2:9]1)=O)(C)(C)C.[ClH:28].[CH2:29]=[O:30].[BH-](O[C:41]([CH3:43])=O)(OC(C)=O)OC(C)=O.[Na+]>O1CCOCC1.O.[Pd].CO.C1COCC1.CC(O)=O.CO.CC(O)C>[Cl:28][C:11]1[CH:10]=[CH:9][NH:8][C:29](=[O:30])[C:41]=1[C:43]1[NH:24][C:17]2[C:18]([N:23]=1)=[CH:19][C:20]1[C:21](=[O:22])[N:13]([CH2:12][CH:10]3[CH2:11][N:8]([CH3:6])[CH2:9]3)[C:14](=[O:27])[C:15]=1[CH:16]=2

Participants

12

Reactant 4

HCID 313Hydrochloric AcidHCID 712FormaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 66793557HCID 66793557, compound

Product 1

HCID 136200335HCID 136200335, compoundYield 38%

Reagents, catalysts & solvents 7

HCID 23938PalladiumCatalystHCID 176Acetic AcidSolvent2×HCID 887MethanolSolventHCID 962WaterSolventHCID 3776IsopropanolSolventHCID 312751,4-DioxaneSolventHCID 21899815MeOH tetrahydrofuranSolvent

Conditions

Temperature
70 °C

Procedure

To a mixture of 3-(5-amino-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-azetidine-1-carboxylic acid tert-butyl ester (830 mg, 2.2 mmol) and 10% Pd/C (85 mg) was added 2-propanol (10 mL), and then MeOH (90 mL). After it was stirred under atmospheric hydrogen for 4 h, the reaction mixture was filtered over Celite. The filtrate was mixed with 4-iodo-2-methoxynicotinic aldehyde (580 g, 2.2 mmol) and HOAc (5.0 mL), stirred at the room temperature for 18 h, and evaporated under reduced pressure to afford an oil crude which was mixed with HCl in dioxane (4 M, 30 mL) and H2O (2.5 mL), heated at 70° C. for 2.5 h and evaporated at 95° C. (the bath temperature) to dryness. The residue was diluted with a mixed solvent of DCM/MeOH (30 mL/70 mL), basified with 28% aqueous NH4OH and concentrated. Chromatography of the crude with CH2Cl2/MeOH/28% aqueous NH4OH (25:10:1) afforded a crude product which was mixed with HOAc (2.1 mL) and HCHO (37% in H2O, 2.1 mL) in a mixed solvent of MeOH/THF (24 mL/24 mL). The resulting reaction mixture was stirred at the room temperature for 10 min and followed by addition of Na(OAc)3BH (2.54 g, 12.0 mmol). The reaction mixture was stirred at the room temperature for 63 h and then evaporated. Chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (90:10:1) afforded the title compound (330 mg, 38%). ESI-MS m/z 398.3 (MH+).

Workup

  1. filtrationthe reaction mixture was filtered over Celite
  2. stirringstirred at the room temperature for 18 h
  3. customevaporated under reduced pressure
  4. customto afford an oil crude which
  5. customevaporated at 95° C. (the bath temperature) to dryness
  6. additionThe residue was diluted with a mixed solvent of DCM/MeOH (30 mL/70 mL)
  7. concentrationconcentrated
  8. customChromatography of the crude with CH2Cl2/MeOH/28% aqueous NH4OH (25:10:1) afforded a crude product which
  9. customThe resulting reaction mixture
  10. stirringwas stirred at the room temperature for 10 min
  11. stirringThe reaction mixture was stirred at the room temperature for 63 h
  12. customevaporated

Sources & evidence

ORD record
ord-a9caf810a89f46db8a45ff11c7e68bf9
Source dataset
uspto-grants-2014_04
Patent number
US08686005B2

Reaction notes

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