Citric Acid → (-)-{[(1R)-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-1-methylpropyl]oxy}acetic acid tert.-butyl ester

HRID 1926933Notes

Reaction equation

HRID 1926933 reaction equation
C(OC(=O)COCC[C@H](O)C)(C)(C)C.[C:15]([O:19][C:20](=[O:28])[CH2:21][O:22][C@H:23]([CH3:27])[CH2:24][CH2:25][OH:26])([CH3:18])([CH3:17])[CH3:16].Cl[C:30]1[C:31]2[C:38]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[C:37]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[O:36][C:32]=2[N:33]=[CH:34][N:35]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:15]([O:19][C:20](=[O:28])[CH2:21][O:22][C@H:23]([CH3:27])[CH2:24][CH2:25][O:26][C:30]1[C:31]2[C:38]([C:39]3[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=3)=[C:37]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[O:36][C:32]=2[N:33]=[CH:34][N:35]=1)([CH3:18])([CH3:16])[CH3:17]

Participants

7

Reactant 4

HCID 311Citric AcidHCID 580168154-Chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidineHCID 58016861[(3R)-3-Hydroxybutyl]oxy-acetic acid tert.-butyl esterHCID 86637370{[(1R)-3-hydroxy-1-methylpropyl]oxy}acetic acid tert.-butyl ester

Product 1

HCID 58016969(-)-{[(1R)-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-1-methylpropyl]oxy}acetic acid tert.-butyl esterYield 9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

Put 455 mg (2.23 mmol) {[(3R)-3-hydroxybutyl]oxy}acetic acid tert.-butyl ester (which contains up to approx. 10% {[(1R)-3-hydroxy-1-methylpropyl]oxy}acetic acid tert.-butyl ester) under argon in 5 ml THF and cool to 0° C. Add 1.15 ml (2.23 mmol) of a 2 M solution of phosphazene base P2-tert.-butyl in THF and stir for a further 10 min at RT. Then cool to 0° C. again. Add 500 mg (1.49 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and stir overnight at RT. Then dilute with water, acidify with 10% aqueous citric acid solution and extract twice with ethyl acetate. Combine the ethyl acetate phases and wash once with satd. sodium chloride solution. Dry over magnesium sulphate and concentrate by evaporation. Purify the residue by chromatography on silica gel (solvent: cyclohexane/ethyl acetate 9:1). 450 mg (60.1% of theor.) of the target compound is obtained. 75 mg (9.0% of theor.) of (−)-{[(1R)-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-1-methylpropyl]oxy}acetic acid tert.-butyl ester is isolated as by-product (see Example 77).

Workup

  1. temperatureThen cool to 0° C. again
  2. stirringstir overnight at RT
  3. extractionextract twice with ethyl acetate
  4. washwash once with satd
  5. dry with materialDry over magnesium sulphate
  6. concentrationconcentrate by evaporation
  7. customPurify the residue by chromatography on silica gel (solvent: cyclohexane/ethyl acetate 9:1)
  8. custom450 mg (60.1% of theor.) of the target compound is obtained

Sources & evidence

ORD record
ord-c0b71c779bca4a71b90634025d1698ab
Source dataset
uspto-grants-2012_05
Patent number
US08183246B2

Reaction notes

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