Sodium Carbonate → (R)-2-{4-[3-(3-cyano-phenyl)-ureido]-3-fluoro-phenyl}-morpholine-4-carboxylic acid tert-butyl ester

HRID 571813Notes

Reaction equation

HRID 571813 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(O[C:26](=[O:32])OC(Cl)(Cl)Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].[NH2:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[C:44]#[N:45]>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:26]([NH:40][C:41]3[CH:48]=[CH:47][CH:46]=[C:43]([C:44]#[N:45])[CH:42]=3)=[O:32])=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 167023-AminobenzonitrileHCID 94429TriphosgeneHCID 68325709(+)-(R)-2-(4-amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester

Product 1

HCID 71087021(R)-2-{4-[3-(3-cyano-phenyl)-ureido]-3-fluoro-phenyl}-morpholine-4-carboxylic acid tert-butyl esterYield 290.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Procedure

To a stirred solution of (+)-(R)-2-(4-amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (60 mg, example 1 h) in dichloromethane (2 ml) was added triphosgene (22 mg). A solution of sodium carbonate (43 mg) in water (2 ml) was then added. The reaction mixture was stirred at room temperature for 2.5 hours. TLC showed all the starting material had reacted. 3-Aminobenzonitrile (48 mg, CAS 2237-30-1) was then added and the reaction mixture was stirred at room temperature for a further 2 hours. TLC showed the reaction was complete. The reaction mixture was poured into dichloromethane and extracted with water. The organic phase was separated, dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: 0% to 80% EtOAc in hexanes) to give (R)-2-{4-[3-(3-cyano-phenyl)-ureido]-3-fluoro-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (95 mg, quant.) as a white solid. MS (ISP): 439.2 ([M−H]−).

Workup

  1. customhad reacted
  2. stirringthe reaction mixture was stirred at room temperature for a further 2 hours
  3. extractionextracted with water
  4. customThe organic phase was separated
  5. dry with materialdried over sodium sulphate
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by column chromatography (SiO2; gradient: 0% to 80% EtOAc in hexanes)

Sources & evidence

ORD record
ord-1f6e36a21e6d4eeaab297275247ef22a
Source dataset
uspto-grants-2015_05
Patent number
US09029370B2

Reaction notes

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