Ethyl bromoacetate → HCID 66654779, compound

HRID 2036196Notes

Reaction equation

HRID 2036196 reaction equation
C(OC([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[O:28][CH2:29]C=C)=O)C1C=CC=CC=1.CN1[C:40](=O)[CH2:39][C:37](=O)N(C)C1=O.[C:43]([O-:46])([O-])=[O:44].[Cs+].[Cs+].BrC[C:51]([O:53][CH2:54][CH3:55])=[O:52].[CH3:56][CH2:57]OC(C)=O>CO.CN(C=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:54]([O:53][C:51]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[O:28][CH2:29][C:43]([OH:46])=[O:44])=[O:52])[C:55]1[CH:37]=[CH:39][CH:40]=[CH:57][CH:56]=1

Participants

10

Reactant 5

HCID 7748Ethyl bromoacetateHCID 8857Ethyl AcetateHCID 10796Cesium carbonateHCID 69860Dimethylbarbituric acidHCID 66654642HCID 66654642, compound

Product 1

HCID 66654779HCID 66654779, compound

Reagents, catalysts & solvents 4

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

A mixture under N2 of (±)-1-(2-allyloxy-4-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (200 mg, 0.48 mmol, 1.00 eq.), 1,3-dimethylbarbituric acid (150 mg, 0.96 mmol, 2.00 eq.) and tetrakis(triphenylphosphine) palladium (0) (28 mg, 0.02 mmol, 0.05 eq.) in MeOH (5 mL) was stirred at r.t. for 5 hours. The mixture was partitioned between AcOEt (25 mL) and water (25 mL). The layers were separated and the aq. phase was extracted with AcOEt (2×25 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×25 mL), dried over MgSO4, and concentrated in vacuo. To a solution of the residue and Cs2CO3 (468 mg, 1.44 mmol, 3.00 eq.) in DMF (3 mL), ethyl bromoacetate (79 μL, 0.72 mmol, 1.50 eq.) was added. The reaction mixture was stirred at 50° C. for 5 hours. The reaction mixture was diluted with water (25 mL) and AcOEt (50 mL). The layers were separated. The aq. phase was extracted with AcOEt (2×25 mL). The comb. org. phases were washed with water (1×25 mL), sat. aq. NaCl soln. (1×25 mL), dried over MgSO4, and concentrated in vacuo. To a solution of the residue in DMF (2 mL), 1M aq. NaOH (2 mL) was added. The resulting solution was stirred at 50° C. for 5 hours. The solution was neutralized with formic acid (1 mL) and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid.

Workup

  1. customThe mixture was partitioned between AcOEt (25 mL) and water (25 mL)
  2. customThe layers were separated
  3. extractionthe aq. phase was extracted with AcOEt (2×25 mL)
  4. washphases were washed with sat. aq. NaCl soln
  5. dry with material(1×25 mL), dried over MgSO4
  6. concentrationconcentrated in vacuo
  7. customThe layers were separated
  8. extractionThe aq. phase was extracted with AcOEt (2×25 mL)
  9. washphases were washed with water (1×25 mL), sat. aq. NaCl soln
  10. dry with material(1×25 mL), dried over MgSO4
  11. concentrationconcentrated in vacuo
  12. additionTo a solution of the residue in DMF (2 mL), 1M aq. NaOH (2 mL) was added
  13. stirringThe resulting solution was stirred at 50° C. for 5 hours
  14. custompurified by prep
  15. concentrationHPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo

Sources & evidence

ORD record
ord-a2464730510a47fa954319b153b843bd
Source dataset
uspto-grants-2013_11
Patent number
US08575158B2

Reaction notes

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