Hydrochloric Acid → [(3-{[5-(4-Ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}cyclohexyl)oxy]acetic acid tert-butyl ester

HRID 2189122Notes

Reaction equation

HRID 2189122 reaction equation
[OH-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:18]([O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH:23]([OH:27])[CH2:22]4)=[N:17][CH:16]=[N:15][C:14]=3[O:13][C:12]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])=[CH:7][CH:6]=1)[CH3:4].[C:35]([O:39][C:40](=[O:43])[CH2:41]Br)([CH3:38])([CH3:37])[CH3:36].Cl>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:35]([O:39][C:40](=[O:43])[CH2:41][O:27][CH:23]1[CH2:24][CH2:25][CH2:26][CH:21]([O:20][C:18]2[C:19]3[C:11]([C:8]4[CH:9]=[CH:10][C:5]([CH2:3][CH3:4])=[CH:6][CH:7]=4)=[C:12]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[F:34])[O:13][C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:22]1)([CH3:38])([CH3:37])[CH3:36]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 79177tert-Butyl bromoacetate2×HCID 582801733-{[5-(4-Ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}cyclohexanol

Product 1

HCID 58280111[(3-{[5-(4-Ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}cyclohexyl)oxy]acetic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 94433Tetrabutylammonium hydrogen sulfateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
70 °C

Procedure

1.4 ml of an 11.25N sodium hydroxide solution is added at 70° C. to a solution of 700 mg (1.62 mmol) of 3-{[5-(4-ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}cyclohexanol in 15 ml of toluene. After adding 55 mg (0.16 mmol) of tetra-n-butylammonium hydrogensulphate and 631 mg (3.24 mmol) of bromoacetic acid tert-butyl ester, stir the reaction mixture at 70° C. for 30 hours. Then add a further 330 mg (1.69 mmol) of bromoacetic acid tert-butyl ester to the reaction mixture and stir at 70° C. for another 14 hours. After cooling to room temperature, adjust to pH 7 with conc. hydrochloric acid. Extract with dichloromethane. Wash the organic phase with satd. sodium chloride solution, dry over sodium sulphate, filter and concentrate under reduced pressure. Purify the residue by means of preparative RP-HPLC (eluent:water/acetonitrile gradient). 632 mg (69% of theory) of the desired product are obtained as a racemic diastereomer mixture.

Workup

  1. stirringstir at 70° C. for another 14 hours
  2. temperatureAfter cooling to room temperature
  3. extractionExtract with dichloromethane
  4. washWash the organic phase with satd
  5. dry with materialsodium chloride solution, dry over sodium sulphate
  6. filtrationfilter
  7. concentrationconcentrate under reduced pressure
  8. customPurify the residue by means of preparative RP-HPLC (eluent:water/acetonitrile gradient)

Sources & evidence

ORD record
ord-85b1116064e648c4856014c90516b83f
Source dataset
uspto-grants-2012_12
Patent number
US08324222B2

Reaction notes

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