From: CSS Support (support$##$cussyn.com)
Date: Fri Apr 22 2005 - 14:36:47 EDT
Kamal,
I have had quite a bit of experience with the synthesis of Atorvastatin. The majority of my synthetic work has focused on the synthesis of stable isotope (2H, 13C, 15N) labeled atorvastatin and its metabolites. Here are a few references that outline several methods for preparing the required intermediates and the general synthetic approach. Most of these articles detail the labeled syntheses, however, the chemistry and basic intermediates are fundamentally the same. There are many other references contained within.
Some of the required intermediates are commercially available. A little bit of searching may save you many steps. Varda sells several Atorvastatin intermediates that you may find useful (www.vardabiotech.com)
1. (4R,6R)-t-Butyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate (CAS# 125995-13-3) is available from Acros (~97.00 USD/g)
the intermediates below are also commercially available:
4-Methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide
4-Fluoro-a-2-methyl-1-oxopropyl-?-oxo-N-ß-diphenyl-benzene buteneamide
(4R-Cis)-1,1-dimethylethyl-6-cyanomethyl-2,2dimethyl-1,3-dioxane-4-acetate
(4R-Cis)-1,1-dimethylethyl-6-(2-aminoethyl)-2,2dimethyl-1,3-dioxane-4-acetate
(4R-cis)-1,1-dimethylethyl-6-[2[2-(4-flourophenyl)-5-(1-methylethyl)-3-phenyl-4-phenylamino)carbonyl]-1H-pyrrol-1-ylethyl]-2,2-dimethyl-1,3- dioxane-4-acetate
[R-(R*,R*)]-2-(4-fluorophenyl)-ß,d-dihydroxy-5-[(1-methylethyl)-3-phenyl-4-[(pehnylamino)carbonyl]-1H-pyrrol-1-heptanoic acid ter.butyl ester
Journal Refs
Journal of Labelled Compounds and Radiopharmaceuticals 42, 121-127 (1999)
Journal of Labelled Compounds and Radiopharmaceuticals 42, 129-133 (1999)
Journal of Labelled Compounds and Radiopharmaceuticals 42, 135-145 (1999)
Journal of Labelled Compounds and Radiopharmaceuticals 43, 261-270 (2000)
There are also many patents that provide the chemistry in detail.
Patents
WO 2003004457 (WO03004457)
PCT Int. Appl., 2002043667
PCT Int. Appl., 9703959
These refs should be a good staring point for you.
I hope this helps!
Brad J. Droessler
Chief Scientist-Chemist
Custom Synthesis Services
support$##$cussyn.com
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