Hydrochloric Acid → Methyl 1-[4-[[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)-methyl]phenoxy]methyl]benzoyl]azetidine-3-carboxylate

HRID 520336Notes

Reaction equation

HRID 520336 reaction equation
[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([N:12]([CH2:19][C:20]1[CH:21]=[C:22]([CH:35]=[CH:36][CH:37]=1)[O:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29](OC)=[O:30])=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[CH2:2]2.[OH-].[Li+].Cl.Cl.[NH:42]1[CH2:45][CH:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:43]1.Cl.CN(C)CCCN=C=NCC>C1COCC1.CO.CN(C)C1C=CN=CC=1>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([O:9][C:10]([N:12]([CH2:19][C:20]1[CH:21]=[C:22]([CH:35]=[CH:36][CH:37]=1)[O:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([N:42]3[CH2:45][CH:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:43]3)=[O:30])=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[CH2:2]2

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 21100040Methyl azetidine-3-carboxylate hydrochlorideHCID 118558468Methyl 4-[[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]-phenoxy]methyl]benzoate

Product 1

HCID 118558450Methyl 1-[4-[[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)-methyl]phenoxy]methyl]benzoyl]azetidine-3-carboxylateYield 52%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

A stirred solution of methyl 4-[[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenoxy]methyl]benzoate (419 mg, 0.84 mmol) in THF (2 mL) and methanol (2 mL) was added with an aqueous solution of 1 N lithium hydroxide (1.7 mL, 1.68 mmol). The reaction was stirred at room temperature for 18 hours. The mixture was cooled to 0° C. and acidified by addition of 2N hydrochloric acid dropwise to pH≈2-3. The mixture was allowed to warm to room temperature and the solvent removed in vacuo and azeotroped with toluene to dryness. This crude material was dissolved in dimethylformamide (5 mL) and ⅔ of the solution was used in the next step. Methyl azetidine-3-carboxylate hydrochloride (104 mg, 0.69 mmol), 4-(dimethylamino)pyridine (38 mg, 0.32 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (182 mg, 0.95 mmol) were then added and the reaction mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was partitioned between EtOAc (50 mL) and water. The organic phase was dried over Na2SO4, filtered and the solvent was removed in vacuo to yield the title compound as an oil that solidifies on standing (190 mg, 52% yield over two steps).

Workup

  1. temperatureThe mixture was cooled to 0° C.
  2. temperatureto warm to room temperature
  3. customthe solvent removed in vacuo
  4. customazeotroped with toluene to dryness
  5. dissolutionThis crude material was dissolved in dimethylformamide (5 mL)
  6. additionwere then added
  7. stirringthe reaction mixture was stirred at room temperature for 18 hours
  8. customThe solvent was removed in vacuo
  9. customthe residue was partitioned between EtOAc (50 mL) and water
  10. dry with materialThe organic phase was dried over Na2SO4
  11. filtrationfiltered
  12. customthe solvent was removed in vacuo

Sources & evidence

ORD record
ord-6f701962c47d42a8adcde3d2af42fe6b
Source dataset
uspto-grants-2016_05
Patent number
US09326976B2

Reaction notes

Loading…