4-Methylmorpholine → (R)-3-(4-Cyano-phenyl)-N-(3,5-dichloro-4-fluoro-phenyl)-2-[3-(2,2-dimethoxy-ethyl)-ureido]-2-methyl-propionamide

HRID 1040517Notes

Reaction equation

HRID 1040517 reaction equation
C1(C)C=CC(S([O-])(=O)=O)=CC=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C@@:21]([NH3+:35])([C:23](=[O:34])[NH:24][C:25]2[CH:30]=[C:29]([Cl:31])[C:28]([F:32])=[C:27]([Cl:33])[CH:26]=2)[CH3:22])=[CH:16][CH:15]=1)#[N:13].C1([O:42][C:43](=O)[NH:44][CH2:45][CH:46]([O:49][CH3:50])[O:47][CH3:48])C=CC=CC=1.CN1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O.CCOC(C)=O>[C:12]([C:14]1[CH:15]=[CH:16][C:17]([CH2:20][C@:21]([NH:35][C:43]([NH:44][CH2:45][CH:46]([O:49][CH3:50])[O:47][CH3:48])=[O:42])([CH3:22])[C:23]([NH:24][C:25]2[CH:30]=[C:29]([Cl:31])[C:28]([F:32])=[C:27]([Cl:33])[CH:26]=2)=[O:34])=[CH:18][CH:19]=1)#[N:13]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 10340Sodium CarbonateHCID 20246943phenyl N-(2,2-dimethoxyethyl)carbamateHCID 86657592(R)-2-(4-cyano-phenyl)-1-(3,5-dichloro-4-fluoro-phenylcarbamoyl)-1-methyl-ethyl-ammonium toluene-4-sulfonate

Product 1

HCID 67389254(R)-3-(4-Cyano-phenyl)-N-(3,5-dichloro-4-fluoro-phenyl)-2-[3-(2,2-dimethoxy-ethyl)-ureido]-2-methyl-propionamideYield 76%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
65 °C

Procedure

To a solution of (R)-2-(4-cyano-phenyl)-1-(3,5-dichloro-4-fluoro-phenylcarbamoyl)-1-methyl-ethyl-ammonium toluene-4-sulfonate (87.7 g, 162.9 mmol) and (2,2-dimethoxy-ethyl)-carbamic acid phenyl ester (40.4 g, 179 mmol) in DMSO (162 mL) was added Na3PO4 (29.4 g, 179 mmol) and N-methylmorpholine (3.04 mL, 27.7 mmol). The solution was heated to 65° C. and stirred for 6 h. The solution was cooled to 20° C. and transferred to a separatory funnel with aqueous Na2CO3 (3 wt %, 500 mL) and EtOAc (500 mL), forming a triphasic system after shaking. The bottom two layers were removed. The top organic layer was washed with 3% NaCl (500 mL), dried with Na2SO4 and concentrated in vacuo keeping internal temperature lower than 40° C. A mixture of heptane and EtOAc (10:1 heptane:EtOAc, 20 mL) was added and the resulting slurry was stirred at 22° C. for 16 h. The slurry was filtered and the solids were washed with a 10:1 mixture of heptane/EtOAc (2×100 mL) to give 61.6 g of the title compound as a white solid, m/z 497.7 [M+H]+.

Workup

  1. temperatureThe solution was cooled to 20° C.
  2. customforming a triphasic system
  3. stirringafter shaking
  4. customThe bottom two layers were removed
  5. washThe top organic layer was washed with 3% NaCl (500 mL)
  6. dry with materialdried with Na2SO4
  7. concentrationconcentrated in vacuo
  8. customlower than 40° C
  9. additionA mixture of heptane and EtOAc (10:1 heptane:EtOAc, 20 mL)
  10. additionwas added
  11. stirringthe resulting slurry was stirred at 22° C. for 16 h
  12. filtrationThe slurry was filtered
  13. washthe solids were washed with a 10:1 mixture of heptane/EtOAc (2×100 mL)

Sources & evidence

ORD record
ord-cc0a2dced5904eb69ddb9e6d526df260
Source dataset
uspto-grants-2013_10
Patent number
US08552205B2

Reaction notes

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