1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 3-bicyclo[2.2.1]hept-2-yl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

HRID 19357Notes

Reaction equation

HRID 19357 reaction equation
[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][CH:9]([N:13]1[CH2:17][C:16]([O:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[CH:15][C:14]1=[O:27])[C:10]([OH:12])=O.[CH3:28]N(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[OH:50][C@@H:51]([CH2:81]O)[CH2:52][N:53]1[CH:57]=[CH:56][C:55]([NH:58]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:54]1>ClCCl>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][CH:9]([N:13]1[CH2:17][C:16]([O:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[CH:15][C:14]1=[O:27])[C:10]([NH:58][C:55]1[CH:56]=[CH:57][N:53]([CH2:52][C:51]([OH:50])([CH3:81])[CH3:28])[N:54]=1)=[O:12]

Participants

6

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 668952363-Bicyclo[2.2.1]hept-2-yl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acidHCID 66899094HMS5552 HCl

Product 1

HCID 579201873-bicyclo[2.2.1]hept-2-yl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamideYield 40.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
25 °C

Procedure

In a round bottom flask under argon was placed 3-bicyclo[2.2.1]hept-2-yl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (73 mg, 0.19 mmol) in dichloromethane (5 mL). To this mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (38 μL, 0.21 mmol) and 1-hydoxybenzotriazole (27 mg, 0.20 mmol) and was stirred at 25° C. for 2 h. After this time period, 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in US20080021032, Example 80, 36 mg, 0.23 mmol) was added and stirred for 16 h at 25° C. After this time, the mixture was diluted with dichloromethane (10 mL) and washed with a 1N aqueous hydrochloric acid solution (10 mL), water (10 mL), a saturated aqueous sodium bicarbonate solution (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix IntelliFlash flash chromatography (12 g column, 40% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) afforded 3-bicyclo[2.2.1]hept-2-yl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (40 mg, 40%) as a light orange solid as a mixture of diastereomers: HR-ES-MS m/z calculated for C27H32N4O4F2 [M+H]+ 515.2465, observed 515.2464; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (br. s., 3H), 1.06 (br. s., 3H), 1.10-2.10 (m, 11H), 2.15 (br. s., 2H), 3.89 (s, 2H), 4.28 (d, J=19.3 Hz, 1H), 4.57-4.65 (m, 1H), 4.67 (s, 1H), 472-486 (2×m, 1H), 5.04 (s, 1H), 6.41-6.49 (m, 1H), 7.29-7.51 (m, 3H), 7.54 (s, 1H), 10.81 (2×s, 1H).

Workup

  1. customIn a round bottom flask under argon was placed
  2. stirringstirred for 16 h at 25° C
  3. washwashed with a 1N aqueous hydrochloric acid solution (10 mL), water (10 mL)
  4. dry with materiala saturated aqueous sodium bicarbonate solution (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customPurification by AnaLogix IntelliFlash flash chromatography (12 g column, 40% ethyl acetate/hexanes to 80% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-e18004d9609645c199f56d82864c83ec
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

Loading…