Carbon Dioxide → 5-({[(2S)-1-Methyl-2-pyrrolidinyl]methyl}oxy)-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide

HRID 1623788Notes

Reaction equation

HRID 1623788 reaction equation
[C:1]1([CH2:7][O:8][C:9]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[CH:20][C:10]=2[C:11]([NH:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:33](=O)=O.C([O-])(O)=O.[Na+]>C(O)=O>[CH3:33][N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:10]([CH:20]=1)[C:11]([NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:12]

Participants

6

Reactant 4

HCID 280Carbon DioxideHCID 712FormaldehydeHCID 516892Sodium BicarbonateHCID 671078412-[(Phenylmethyl)oxy]-N-3-pyridinyl-5-{[(2S)-2-pyrrolidinylmethyl]oxy}benzamide

Product 1

HCID 681087035-({[(2S)-1-Methyl-2-pyrrolidinyl]methyl}oxy)-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide

Reagents, catalysts & solvents 1

HCID 284Formic AcidSolvent

Procedure

2-[(Phenylmethyl)oxy]-N-3-pyridinyl-5-{[(2S)-2-pyrrolidinylmethyl]oxy}benzamide (may be prepared as described in Example 46; 80 mg, 0.20 mmol) was added to formic acid (4 ml) at 5° C., followed by aqueous formaldehyde (40%, 2.0 ml). When the initial evolution of carbon dioxide had subsided, the mixture was refluxed for 2 h. After the solution was cooled, the pH of the solution was adjusted to 7-8 by adding aqueous NaHCO3 solution. The mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by prep-HPLC (Gilson GX-281, waters X-Bridge 5 μm, 100*19 mm; A: 0.04% NH3.H2O/water, B: CH3CN; 0-7.2 min, 40%-50%; 7.2-7.5 min, 50%-95%; 7.5-11.5 min, 95%, RT=4.0 min) to yield the title compound as a white solid. 68 mg.

Workup

  1. temperaturethe mixture was refluxed for 2 h
  2. temperatureAfter the solution was cooled
  3. extractionThe mixture was extracted with dichloromethane
  4. dry with materialThe organic layer was dried over Na2SO4
  5. concentrationconcentrated
  6. customto obtain a crude product
  7. customThe crude product was purified by prep-HPLC (Gilson GX-281, waters X-Bridge 5 μm, 100*19 mm
  8. custom0-7.2 min, 40%-50%
  9. custom7.2-7.5 min, 50%-95%

Sources & evidence

ORD record
ord-627bc10e41ca4adca1b259db1231eaad
Source dataset
uspto-grants-2014_07
Patent number
US08778939B2

Reaction notes

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