Pyridine → tert-butyl 3-((R)-3-(5-cyanopyridin-2-ylamino)pyrrolidine-1-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate

HRID 72143Notes

Reaction equation

HRID 72143 reaction equation
[NH2:1][CH:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[C:17]([O-:20])(O)=O.[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.Cl.Cl.[NH:36]1[CH2:40][CH2:39][C@@H:38]([NH:41][C:42]2[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44]C=2)[CH2:37]1.[N:50]1C=CC=CC=1>C(Cl)Cl.[Cl-].[Na+].O.CCOC(C)=O>[C:46]([C:45]1[CH:48]=[CH:49][C:42]([NH:41][C@@H:38]2[CH2:39][CH2:40][N:36]([C:17]([NH:1][CH:2]3[CH2:3][CH:4]4[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]([CH2:6][CH2:5]4)[CH2:8]3)=[O:20])[CH2:37]2)=[N:50][CH:44]=1)#[N:47]

Participants

9

Reactant 5

HCID 1049PyridineHCID 94429TriphosgeneHCID 516892Sodium BicarbonateHCID 22570519tert-Butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylateHCID 66883622(R)-4-(pyrrolidin-3-ylamino)benzonitrile dihydrochloride

Product 1

HCID 66882921tert-butyl 3-((R)-3-(5-cyanopyridin-2-ylamino)pyrrolidine-1-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylateYield 18%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolvent3×HCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

To a stirred, ice-cold mixture of tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (149 mg, 0.66 mmol), CH2Cl2 (4 mL) and satd aq NaHCO3 (2 mL) was added solid triphosgene (65 mg, 0.22 mmol). The mixture was stirred in the ice bath for 30 min and diluted with CH2Cl2 (6 mL) and brine (8 mL). The organic layer was separated and added to a stirred solution of (R)-4-(pyrrolidin-3-ylamino)benzonitrile dihydrochloride (165 mg, 0.66 mmol) in CH2Cl2 (2 mL) and dry pyridine (0.5 mL). The mixture was stirred overnight at rt, diluted with EtOAc (90 mL), washed with 5% aq HCl (20 mL), satd aq NaHCO3 (20 mL) and brine (20 mL), and dried over Na2SO4. Removal of the solvent left an oil (246 mg) which was purified by prep HPLC to afford tert-butyl 3-((R)-3-(5-cyanopyridin-2-ylamino)pyrrolidine-1-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate (49 mg, 18%). LC-MS Method 1 tR=1.52 min, m/z=441, 385.

Workup

  1. customThe organic layer was separated
  2. washwashed with 5% aq HCl (20 mL)
  3. dry with materialdried over Na2SO4
  4. customRemoval of the solvent
  5. waitleft an oil (246 mg) which
  6. customwas purified by prep HPLC

Sources & evidence

ORD record
ord-813cadfc25914d14a5d7b7922bea7bf7
Source dataset
uspto-grants-2014_09
Patent number
US08828985B2

Reaction notes

Loading…