Tetrahydrofuran → Atorvastatin lactone

HRID 6462

Reaction equation

HRID 6462 reaction equation
[NH2:1][CH2:2][CH2:3][C@H:4]1OC(C)(C)[O:7][C@@H:6]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH2:5]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=O)[CH:28]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:29]([C:39](=O)[CH:40]([CH3:42])[CH3:41])[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:31])=[CH:23][CH:22]=1.O1CCCC1.[Cl-].[NH4+]>CCCCCCC.C1(C)C=CC=CC=1.O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:1]([CH2:2][CH2:3][C@@H:4]3[CH2:5][C@@H:6]([OH:7])[CH2:12][C:13](=[O:14])[O:15]3)[C:39]([CH:40]([CH3:42])[CH3:41])=[C:29]([C:30]([NH:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:31])[C:28]=2[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[CH:25][CH:26]=1

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 25517Ammonium ChlorideHCID 2734288(4R,6R)-tert-Butyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetateHCID 99098724-(4-Fluorophenyl)-2-(2-methyl-1-oxopropyl)-4-oxo-3,N-diphenylbutanamide

Product 1

HCID 6483036Atorvastatin lactone

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 22263336Toluene heptaneSolvent

Procedure

A solution of (4R-cis)-1,1-dimethylethyl 6-(2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate, (Example 2) 2.56 g (9.36 mmol), and (±)-4-fluoroα-[2-methyl-1-oxopropyl]-γ-oxo-N,β-diphenylbenzenebutaneamide mixture of [R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*)], and [S (R*,S*)] isomers (Example 3), 3.00 g (7.20 mmol), in 60 mL of heptane:toluene (9:1) is heated at reflux for 24 hours. The solution is cooled and poured into 300 mL of tetrahydrofuran and 150 mL of saturated ammonium chloride in water. The layers are separated and the organic layer is added to 15 mL of 10% hydrochloric acid solution and the solution is stirred for 15 hours. To this solution is added sodium hydroxide (3.6 g) and the mixture is stirred for 30 hours. The reaction is stopped by adding 150 mL of water, 90 mL of hexane, and separating the layers. The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for 3 hours and extracted with 150 mL of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and the solution is allowed to stand 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 50 mL of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred 2 hours, concentrated in vacuo, and dissolved in 3.0 mL of toluene. (2R trans)-5 (4-fluorophenyl)-2 (1-methylethyl) -N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide (2.92 g) is isolated in two crops.

Workup

  1. temperatureat reflux for 24 hours
  2. temperatureThe solution is cooled
  3. customThe layers are separated
  4. additionthe organic layer is added to 15 mL of 10% hydrochloric acid solution
  5. additionTo this solution is added sodium hydroxide (3.6 g)
  6. stirringthe mixture is stirred for 30 hours
  7. additionby adding 150 mL of water, 90 mL of hexane
  8. customseparating the layers
  9. stirringstirred for 3 hours
  10. extractionextracted with 150 mL of ethyl acetate
  11. additionA drop of concentrated hydrochloric acid is added to the ethyl acetate solution
  12. waitto stand 18 hours
  13. concentrationThe solution is concentrated in vacuo
  14. dissolutionthe concentrate is redissolved in 50 mL of ethyl acetate
  15. additiontreated with one drop of concentrated hydrochloric acid
  16. stirringThe solution is stirred 2 hours
  17. concentrationconcentrated in vacuo
  18. dissolutiondissolved in 3.0 mL of toluene

Sources & evidence

ORD record
ord-abee60ee9b184c41888df66883fa9eae
Source dataset
uspto-grants-1993_09
Patent number
US05248793

Linked notes

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