Dimethylformamide → (R)-(1-{4-[(adamantan-1-ylmethyl)carbamoyl]pyrazolo[1,5-a]-pyridine-2-carbonyl}pyrrolidin-3-yl)carbamic acid tert-butyl ester

HRID 2039777Notes

Reaction equation

HRID 2039777 reaction equation
F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]12([CH2:38][NH:39][C:40]([C:42]3[C:43]4[N:44]([N:48]=[C:49]([C:51](O)=[O:52])[CH:50]=4)[CH:45]=[CH:46][CH:47]=3)=[O:41])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2.[NH:54]1[CH2:58][CH2:57][C@@H:56]([NH:59][C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63])[CH2:55]1.CN(C=O)C>CCOC(C)=O>[C:62]([O:61][C:60](=[O:66])[NH:59][C@@H:56]1[CH2:57][CH2:58][N:54]([C:51]([C:49]2[CH:50]=[C:43]3[C:42]([C:40](=[O:41])[NH:39][CH2:38][C:28]45[CH2:37][CH:32]6[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]6)[CH2:29]4)[CH2:35]5)=[CH:47][CH:46]=[CH:45][N:44]3[N:48]=2)=[O:52])[CH2:55]1)([CH3:65])([CH3:63])[CH3:64]

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 1514397(3R)-(+)-3-(tert-Butoxycarbonylamino)pyrrolidineHCID 59539009HCID 59539009, compound

Product 1

HCID 68650022(R)-(1-{4-[(adamantan-1-ylmethyl)carbamoyl]pyrazolo[1,5-a]-pyridine-2-carbonyl}pyrrolidin-3-yl)carbamic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

BOP (680 mg, 1.5 mmol) is added to a mixture of 4-[(adamantan-1-ylmethyl)carbamoyl]-pyrazolo[1,5-a]pyridine-2-carboxylic acid (417 mg, 1.18 mmol), tert-butyl (R)-pyrrolidin-3-ylcarbamate (242 mg, 1.30 mmol), iPr2Net (620 μL, 3.6 mmol) and DMF (12 mL) under N2. The reaction vessel is sealed and the solution is left to stir for 20 h. EtOAc (50 mL) is added. The solution is washed with H2O (2×50 mL) and brine (50 mL). The organics are dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography (2% MeOH in CH2Cl2) affords (R)-(1-{4-[(adamantan-1-ylmethyl)carbamoyl]pyrazolo[1,5-a]-pyridine-2-carbonyl}pyrrolidin-3-yl)carbamic acid tert-butyl ester as a tan solid. MeOH (6.8 mL) and 4 M HCl in dioxane (1.7 mL) are added. After 20 h, the volatiles are removed under reduced pressure to afford a light tan solid. 15% Aqueous K2CO3 (50 mL) is added. The solution is extracted with EtOAc (5×50 mL). The combined organics are dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography (1% NH4OH in 9:1 CH2Cl2:MeOH) affords the title compound as a tan foam. 1H NMR (300 MHz, CDCl3) δ: 8.48 (ddd, 1H), 7.62 (dd, 1H), 7.22 (dd, 1H), 6.87 (t, 1H), 6.50 (bt, 1H), 3.42-4.20 (m, 5H), 3.20 (d, 2H), 2.14 (septet, 1H), 1.96-2.04 (m, 3H), 1.55-1.88 (m, 12H). LC-MS m/z (M+H+): 422.3; RT=1.2 min.

Workup

  1. customThe reaction vessel is sealed
  2. waitthe solution is left
  3. washThe solution is washed with H2O (2×50 mL) and brine (50 mL)
  4. dry with materialThe organics are dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customPurification by flash column chromatography (2% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-62fc4b0f2ca14e5d8655cc56aef5a632
Source dataset
uspto-grants-2013_11
Patent number
US08580812B2

Reaction notes

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