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PROCESS FOR THE PREPARATION OF RSV INTERMEDIATES

IP.com Disclosure Number: IPCOM000173020D
Publication Date: 2008-Jul-24
Document File: 4 page(s) / 26K

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PROCESS FOR THE PREPARATION OF RSV INTERMEDIATES

RSV calcium has the chemical name (7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino) pyrimidin-5-yl]-(3R, 5S)-dihydroxy-(E)-6-heptenoic acid calcium salt), and has the following chemical formula:

F

N

SO2CH3

RSV calcium

RSV calcium is an HMG-CoA reductase inhibitor, developed by Shionogi for the once daily oral treatment of hyperlipidaemia (Ann Rep, Shionogi, 1996; Direct communications, Shionogi, 8 Feb 1999 & 25 Feb 2000). RSV calcium is a superstatin, which can lower LDL- cholesterol and triglycerides more effectively than first generation statin drugs.

RSV calcium is marketed under the name CRESTOR for the treatment of a mammal such as a human. According to the maker of CRESTOR, it is administered in a daily dose of from about 5 mg to about 40 mg.

    The term 'alkyl' refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like. Preferably the alkyl group is a C1-C4 group. Preferably the alkyl group is a C1-C4 group,
i.e. lower alkyl. The term "alkoxy" denotes alkyl group as defined above attached via oxygen linkage to the rest of the molecule. Representative examples of those groups are - OCH3, -OC2H5 and the like. Preferably the alkoxy group is a C1-C4 group. The substituents in the "substituted alkyl" or "substituted aryl or phenyl" may be selected from the groups such as hydroxy, carboxyl, alkyl (such as C1-C4), alkoxy (such as C6-C12), aryl (such as C6-C12), arylalkyl (such as C6-C12), cycloalkyl (such as C6-C12) and amino.

   Provides is a process for the preparation of the compound of the formula (I) having the following structure:

OH

OHCO2-

Ca2 +

2

N

N

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O

R

R2O

O

R2O

O

P

1

O

XY

Formula I

wherein X is O, N, or S, Y is a C1-C4 alkyl group, aryl, or alkylaryl, R1 is a hydroxy protecting group, and R2 is C1 to C4 alkyl group.

The compound of formula (I) can be prepared from the compound of Formula A:

O

O

R

1

O

Y

X

X

Y

by reacting compound of formula (A) with dialkyl phosphonate in the presence of a base.

OOR1

P

O

O

R

1

O

O

R2O

YX

O

XY

R2O

X

Y

Formula (A)Formula (I)

wherein X is O, N, or S, Y is a C1-C4 alkyl, aryl, or alkylaryl group, R1 is a hydroxy protecting group, and R2 is C1 to C4 alkyl group.

Formula (I) may be the compound t-butyl (3R)-3-(t-butyl dimethylsilyloxy)- 6dimethoxyphosphinyl-5-oxohexanoate ("TBPO-19"). Formula (A) may be the compound Methyl t-butyl-(3R)-3-(t-butyldimethylsilyloxy)glutaric acid ("MBSG").

Specifically the process may be for the preparation of formula 19TBPO from MBSG, optionally with the use of LiCl, as shown in the following scheme:

CO2C4H9

OTBDMS

MeO

O

PCH3

    O H3CO

H3CO

PCH2_

    O H3CO

H3CO Li...