Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-07-02
2004-08-31
Shah, Mukund L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S256000, C544S322000, C544S316000, C544S318000
Reexamination Certificate
active
06784171
ABSTRACT:
This invention concerns a novel chemical process, and more particularly it concerns a novel chemical process for the manufacture of tert-butyl (E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2dimethyl[1,3]dioxan-4-yl)acetate of formula I,
(hereinafter referred to as BEM) which is useful, for example, as a chemical intermediate in the production of a pharmaceutical useful in the treatment of, inter alia, hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. The invention further includes the novel starting material used in said process and the use of the process in the manufacture of an HMG CoA reductase inhibitor.
In European Patent Application, Publication No. (EPA) 0521471 is disclosed (E)-7-[4(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5dihydroxyhept 6-enoic acid and its sodium salt and calcium salt (illustrated below)
(hereinafter referred to collectively as “The Agent”) as inibitors of HMG CoA reductase. The Agent is obtained therein via reduction of methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl-amino)pyrimidin-5-yl-(3R)-3-hydroxy-5-oxo-(E)-heptenoate and subsequent processing. However the Agent may be obtained from BEM by treatment with acid (to cleave the acetonide protecting group) followed by base (to cleave the ester) and (as described in EPA 0521471) conversion of the initially formed salt to the free acid or the calcium salt.
We have now discovered a useful and advantageous process for preparing BEM.
According to the invention there is provided a process for preparing BEM (formula I) which comprises reaction of diphenyl [4-(4-fluoropheny)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-ylmethyl] phosphine oxide of formula III
(hereinafter referred to as DPPO) with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl}acetate of formula II
(hereinafter referred to as BFA) in the presence of a strong base.
The process is carried out in a suitable solvent, or mixture of solvents for example, ethereal or aromatic solvents or mixtures thereof. Particularly suitable solvents include, for example, tetrahydrofuran (THF), dimethoxyethane and toluene, or mixtures thereof. Particularly preferred solvents include, for example, THF and THF and toluene.
Suitable bases for use in the process include, for example, amide bases, alkyl metals and metal hydrides. Particular bases include, for example, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium bis(trimethysilyl)amide, butyllithium and sodium hydride. A particularly preferred base is, for example, sodium bis(trimethylsilyl)amide (NaHMDS).
The reaction may be carried out at a temperature in the range of, for example, −20° C. to −90° C., such as −40° C. to −90° C., for example −40° C. to −80° C. A convenient tempreture at which to carry out the reaction is, for example, that of a mixture of acetone and solid carbon dioxide (about −75° C.).
The process is advantageously carried out with 1.0 to 1.2 equivalents of base (per equivalent of DPPO), such as 1.05 to 1.2 equivalents and preferably 1.05 to 1.12 equivalents. Although BFA can be present in large excess, it is convenient to use 1.0 to 1.35 equivalents (per equivalent of DPPO), and preferably 1.05 to 1.3 equivalents, especially 1.05 to 1.15 equivalents.
The process of the invention provides significantly improved yields and quality of product by comparison to when a corresponding dialkyl phosphonate (—PO(Oalkyl)
2
) starting material is used instead of DPPO.
The starting material, DPPO, which is a further aspect of the present invention, may be obtained as described in the Examples hereinafter, starting from an alkyl 2-amino-4-(4-fluorophenyl)-6-isopropylpyrimidin-5-carboxylate, for example the methyl ester which may be obtained as described in Japanese Patent Application No. 06-256318, or the ethyl ester which may be obtained as described in EPA 0521471. BFA may be obtained as described in EPA 0319847 (Example 6).
A further aspect of the present invention is a process for the manufacture of a compound of the formula IV
in which R
1
is hydrogen or a pharmaceutically acceptable cation, which comprises;
(1) reaction of DPPO with BFA in the presence of a strong base (as described above) to give BEM;
(2) cleavage of the dihydroxy (acetonide) protecting group (for example by acid hydrolysis, such as by using HCl in THF or acetonitrile); and
(3) cleavage of the tert-butyl ester group under basic conditions to form a compound of the formula IV in which R
1
is a pharmaceutically acceptable cation (for example by using a solution of a metallic hydroxide in a polar solvent, such as using aqueous sodium hydroxide in ethanol or acetonitrile to form the sodium salt);
optionally followed by neutralisation to give a compound of the formula IV in which R
1
is hydrogen;
and/or optionally followed by conversion to another compound of the formula IV in which R
1
is a pharmaceutically acceptable cation (for example conversion of the sodium salt to the calcium salt by treatment with a water soluble calcium salt (such as calcium chloride) under aqueous conditions).
Suitable conditions for steps (2), (3) and the subsequent optional steps are analogous to, or the same as, those disclosed in EPA 0521471 and/or EPA 0319847, which are hereby incorporated herein by reference. To obtain the calcium salt of the compound of formula IV, as illustrated on page 1, preferably steps (2), (3) and conversion to the calcium salt via the methylamine salt are carried out as described in Example 7, which steps form a further aspect of the invention.
It will be appreciated that, in the processes described above, BFA may replaced by a compound of the general formula V
in which P
3
is a carboxylic acid protecting group, for example (1-8C)alkyl (such as 1-4C)alkyl), and P
1
and P
2
are alcohol protecting groups, or P
1
and P
2
taken together is a 1 , 3-diol protecting group, such as those described in EPA 0319845 and GB 2244705 which are included herein by reference. For example, in some preferred embodiments, the 1,3-dial protecting groups can be
where R
1
and R
2
are independently (1-4C)alkyl or R
1
and R
2,
taken together with the carbon atom to which they are attached, form a cyclopentyl. cyclohexyl or cycloheptyl ring. Reaction of a compound of the formula V with a compound of the formula III forms a compound of the formula VI
The compound of the formula VI may be converted to the Agent by cleavage of the alcohol or diol protecting groups and conversion of the COOP
3
to a COOH group or a pharmaceutically acceptable salt thereof. Such general processes form further features of the present invention.
The invention if further illustrated, but not limited by the following Examples.
Preparation 1
Preparation of DPPO
A stirred mixture of methyl 4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-carboxylate (12.0 g) in toluene (55 ml) was cooled to −10° C. and diisobutyl aluminium hydride (50 ml of a 1.5M solution in toluene) was added over two hours maintaining the temperature below 0° C. After addition, the mixture was stirred for 30 minutes at 0° C. Methanol (0.64 ml) was added to the mixture maintaining the temperature at 0° C. The mixture was then added over two hours to a stirred mixture of concentrated hydrochloric acid (23.3 ml), water (40.5 ml) and acetonitrile (24 ml) at 40° C., maintaining the temperature of the mixture at 40° C. After addition, the mixture was stirred at 40° C. for a further 30 minutes and then purged with nitrogen (to remove any isobutane). The mixture was cooled to 20° C. and allowed to stand for 20 minutes. The organic phase was separated and washed with a mixture of concentrated hydrochloric acid (0.7 ml) and water (30 ml). Acetonitrile (24 ml) was added to the organic phase and the mixture washed with a solution of sodium bicarb
Diorazio Loius J
Kabaki Mikio
Koike Haruo
Taylor Nigel P
AstraZeneca
Morgan & Lewis & Bockius, LLP
Patel Sudhaker B.
Shah Mukund L.
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