Toluene → Atorvastatin tert-butyl ester

HRID 7219

Reaktionsgleichung

Reaktionsgleichung von HRID 7219
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C:33](=[O:45])[CH2:34][C:35](=[O:44])[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C>C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C@@H:33]([OH:45])[CH2:34][C@@H:35]([OH:44])[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1

Komponenten

5

Edukt 3

HCID 1140TolueneHCID 8471TriethylamineHCID 228947727-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoic acid, t-butyl ester

Produkt 1

HCID 11238911Atorvastatin tert-butyl ester

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 284Formic AcidLösungsmittel

Versuchsvorschrift

An argon inerted reactor was charged with 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoic acid, t-butyl ester (V-A, 100.0 mmol, prepared as indicated in U.S. Pat. No. 6,476,235) and toluene (245 ml). To the reaction mixture was added triethyl amine (55 ml), followed by slow addition of formic acid (7.5 ml). The vessel and its contents was degassed via three vacuum/argon purges. Under a steady flow of argon, the complex of Ruthenium, [N-[(1R,2R)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1,3,5-trimethylbenzene]-(1.25 g) was added, and the vessel and its contents were degassed via one vacuum/argon purge. The reaction mixture was stirred for 24 hours and condensed to a foamy solid. The crude (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid, t-butyl ester may be carried on through subsequent steps without purification, or optionally, can be isolated via flash column chromatography on silica gel, eluting with ethyl acetate-heptane mixtures. HPLC analysis (YMC ODS AQ S5; 1 ml/min; 30° C.; 254 nm: CH3CN/H2O w/0.1% formic acid, 60:40 (0–5 min) to 100:0 (15–22 min) to 60:40 (25 min) indicated a syn:anti ratio of 6:1 tr(syn)=13.9 min tr(anti)=13.5 min

Aufarbeitung

  1. customprepared
  2. customThe vessel and its contents was degassed via three vacuum/argon
  3. additionUnder a steady flow of argon, the complex of Ruthenium, [N-[(1R,2R)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1,3,5-trimethylbenzene]-(1.25 g) was added
  4. customthe vessel and its contents were degassed via one vacuum/argon
  5. custompurge
  6. customcondensed to a foamy solid
  7. customThe crude (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid, t-butyl ester may be carried on through subsequent steps without purification
  8. customoptionally, can be isolated via flash column chromatography on silica gel
  9. washeluting with ethyl acetate-heptane mixtures
  10. custom30° C.
  11. custom0.1% formic acid, 60:40 (0–5 min)
  12. customto 100:0 (15–22 min)
  13. customto 60:40 (25 min)
  14. customanti ratio of 6:1 tr(syn)=13.9 min
  15. customtr(anti)=13.5 min

Quellen und Nachweise

ORD-Eintrag
ord-b1cd8102a8b040e4af724b1fac0c3aa2
Quelldatensatz
uspto-grants-2006_08
Patentnummer
US07084282B2

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