Diisopropylethylamine → HCID 68988707, compound

HRID 748627Notes

Reaction equation

HRID 748627 reaction equation
Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[N:18][CH:19]=1.C(N(C(C)C)CC)(C)C.[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][C@@H:39]([O:42][C:43]2[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([NH2:50])[CH:44]=2)[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH:39]([O:42][C:43]2[CH:44]=[C:45]([NH:50][C:2]([NH:13][C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[O:4])[CH:46]=[C:47]([F:49])[CH:48]=2)[CH2:38]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 94429Triphosgene2×HCID 2433135-Amino-2-methylpyridineHCID 58732854HCID 58732854, compound

Product 1

HCID 68988707HCID 68988707, compoundYield 79%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
0 °C

Procedure

A round bottom flask was charged with triphosgene (3 g, 10 mmol, 1 eq) and THF (33 mL) and chilled to 0° C. A solution of 5-amino-2-methyl pyridine (3.3 g, 10 mmol, 3 eq), diisopropylethylamine (10.3 mL, 60 mmol, 6 eq) and THF (33 mL) was added dropwise to the triphosgene solution. The mixture was allowed to warm to room temperature and stirred for 30 minutes. A solution of (R)-tert-butyl-3-(3-amino-5-fluorophenoxy)-pyrrolidine-1-carboxylate (3.0 g, 10 mmol, 1 eq) in THF (33 mL) was added dropwise. The resultant reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with a saturated sodium bicarbonate solution and the THF was removed in vacuo. The mixture was extracted with dichloromethane. The dichloromethane solution was washed with saturated sodium bicarbonate and brine. The organic layers were dried with sodium sulfate, filtered and concentrated. The residue was purified by silica column chromatography with 500 mL of ethyl acetate, 500 mL of 2.5% methanol in ethyl acetate, 500 mL of 5% methanol in ethyl acetate, 500 mL 7.5% methanol in ethyl acetate, and 10% methanol in ethyl acetate as the gradient elute to yield 3.4 g of 3-{3-fluoro-5-[3-(6-methyl-pyridin-3-yl)-ureido]-phenoxy}-pyrrolidine-1-carboxylic acid tert-butyl ester as a light yellow solid.

Workup

  1. temperatureto warm to room temperature
  2. customThe resultant reaction mixture
  3. stirringwas stirred overnight at room temperature
  4. customThe reaction mixture was quenched with a saturated sodium bicarbonate solution
  5. customthe THF was removed in vacuo
  6. extractionThe mixture was extracted with dichloromethane
  7. washThe dichloromethane solution was washed with saturated sodium bicarbonate and brine
  8. dry with materialThe organic layers were dried with sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe residue was purified by silica column chromatography with 500 mL of ethyl acetate, 500 mL of 2.5% methanol in ethyl acetate, 500 mL of 5% methanol in ethyl acetate
  12. wash500 mL 7.5% methanol in ethyl acetate, and 10% methanol in ethyl acetate as the gradient elute

Sources & evidence

ORD record
ord-ca2db6a75598486cbd2f597c42c98af3
Source dataset
uspto-grants-2008_07
Patent number
US07399866B2

Reaction notes

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