An improved process for the preparation of RSV intermediates
Publication Date: 2009-Mar-18
The IP.com Prior Art Database
AN IMPROVED PROCESS FOR THE PREPARATION OF RSV INTERMEDIATES
(7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino) pyrimidin-5-yl]-(3R, 5S)- dihydroxy-(E)-6-heptenoicacid) calcium ("RSV Ca", "compound of formula I") is a HMG-Co A inhibitor which belongs to a class of drugs which are therapeutically effective for reducing low-density lipoprotein (LDL)-cholesterol and triglycerides levels concentration in the blood stream of patients at risk for cardiovascular disease. RSV is one such statin which is used to treat hypercholesterolemia and to prevent cardiovascular disease.
Preparation of t-butyl-7-[ 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino) pyrimidin -5-yl]-(R)-3-(t-butyldimethylsilyloxy)-5-oxo-(E)-6-heptenoate ("compound of formula VII") can be done by condensation of 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5- pyrimidinecarbaldehyde ("compound of formula VI") with t-butyl-(R)-3-(t-butyldimethylsilyloxy)-6- dimethoxyphosphinyl-5-oxohexanoate ("compound of formula V"), preferably in the presence of a base and a solvent system containing at least two solvents.
Suitable solvent may be selected from a group consisting of C1-C2 halogenated hydrocarbon, C1-C5 alcohol, C2-C7 ether, aliphatic & aromatic hydrocarbon and mixtures thereof. C1-C2 halogenated hydrocarbon may be selected from a group consisting of: cyclic or acyclic, saturated or unsaturated, aliphatic or aromatic hydrocarbon (such as dichloromethane, chloroethane), and halogenated aromatic solvent (such as chlorobenzene, chlorotoluene, dichlorobenzene). The aliphatic hydrocarbon may be acyclic or cyclic that is substituted or unsubstituted hexane, heptane, or cyclohexane. The preferred aromatic hydrocarbon is toluene and xylene. The C2-C7 ether may be acyclic ethers that are alkyl or arylalkyl ethers, such as diethyl ether, diispropyl ether, methyl-tert butylether, methyl propyl ether, dibutyl ether. The preferred cyclic ether may be dioxane or tetrahydrofuran ("THF").The preferred ether is diethyl ether, methyl tert-butyl ether or THF. The C1-C5 alcohol may be selected from the group consisting of: methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, tert-butyl and amyl alcohol. The preferred alcohol may be methyl or ethyl alcohol. Preferably, a mixture of two solvent is used. Preferably, one of the solvents is THF. The ratio of the THF and the second solvent is 1:0.1 to 1:1.5.
The reaction is carried out in presence of a suitable base, which may be an inorganic base selected from a group consisting of: alkali and alkaline earth metal carbonate, alkali and alkaline earth metal bicarbonate, alkali and alkaline earth metal hydroxide, alkali and alkaline earth metal alkoxide, alkali and alkaline earth metal hydride and alkali and alkaline earth metal alkyl. Preferred suitable alkali or alkaline earth metal carbonate or bicarbonates may be selected from the group consistin...