Re: ORGLIST: Atorvastatin Intermediates

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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--diphenyl-benzene =
buteneamide
 =
(4R-Cis)-1,1-dimethylethyl-6-cyanomethyl-2,2dimethyl-1,3-dioxane-4-acetat=
e
 =
(4R-Cis)-1,1-dimethylethyl-6-(2-aminoethyl)-2,2dimethyl-1,3-dioxane-4-ace=
tate

 =
(4R-cis)-1,1-dimethylethyl-6-[2[2-(4-flourophenyl)-5-(1-methylethyl)-3-ph=
enyl-4-phenylamino)carbonyl]-1H-pyrrol-1-ylethyl]-2,2-dimethyl-1,3- =
dioxane-4-acetate

 =
[R-(R*,R*)]-2-(4-fluorophenyl)-,d-dihydroxy-5-[(1-methylethyl)-3-pheny=
l-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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