Toluene → Atorvastatin tert-butyl ester

HRID 7219

Reaction equation

HRID 7219 reaction equation
[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

Participants

5

Reactant 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

Product 1

HCID 11238911Atorvastatin tert-butyl ester

Reagents, catalysts & solvents 1

HCID 284Formic AcidSolvent

Procedure

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

Workup

  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

Sources & evidence

ORD record
ord-b1cd8102a8b040e4af724b1fac0c3aa2
Source dataset
uspto-grants-2006_08
Patent number
US07084282B2

Linked notes

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