Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-26
2001-06-19
Lambkin, Deborah C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C560S048000
Reexamination Certificate
active
06248903
ABSTRACT:
This application is a 371 PCT/GB99/01307 Apr. 27, 1999.
The invention concerns a novel chemical process, and more particularly, it concerns a novel chemical process for the manufacture of methyl (2S)-2-[(3R)-3-(-[tert-butyloxycarbonyl]-amino)-2-oxopyrrolidin-1 -yl]propionate of the formula I
which, for example, is useful in the manufacture of compounds disclosed in International Patent Application, Publication No. WO 97/31023 possessing pharmacologically useful properties for use in treating autoimmune diseases or medical conditions, such as rheumatoid arthritis and other MHC Class II dependent T-cell mediated diseases.
The compound of formula I has previously been prepared by the method disclosed in Example 1 of WO 97/31023. In this method the compound of formula II
which may be named as Boc-(D)-Met-(L)-Ala-OMe, is methylated using a large excess (about 10 equivalents) of methyl iodide in a mixture of N,N-dimethylformamide (DMF) and dichloromethane, followed by removal of excess methyl iodide and cyclisation of the sulfonium salt formed, using sodium hydride, to form the lactam ring. The product is purified after work-up by chromatography.
There are several disadvantages with carrying out this known process on a large scale. For example, one disadvantage is the use of a large excess of methyl iodide. This results in the production of undesired by-products and is environmentally undesirable. A further disadvantage, for example, is that the alkylation step and the cyclisation step cannot be telescoped together without prior removal of the excess methyl iodide. Unless all the methyl iodide is removed before cyclisation, under the strongly basic conditions used methylation of the amide nitrogen takes place. Further disadvantages for large scale manufacture are the use of DMF as solvent and its removal, and the use of chromatography to purify the product. Also the reaction of methyl iodide with the compound of formula I is reversible and in removing excess methyl iodide from the reaction mixture the product partially reverts to starting material, which effect is enhanced on increasing scale. Such disadvantages make the process unattractive for operation on a commercial scale.
A process has now been discovered for the manufacture of the compound of formula I from Boc-(D)-Met-(L)-Ala-OMe which overcomes one or more of the problems encountered with the known process.
According to the invention, there is provided a process for the manufacture of methyl (2S)-2-[(3R)-3-(N-[tert-butyloxycarbonyl]amino)-2-oxopyrrolidin-1-yl]propionate (Formula I) which comprises
(1) methylation of the compound of formula II using trimethyloxonium tetrafluoroborate in a suitable solvent; followed by
(2) cyclisation under basic conditions.
In Step (1), a particular solvent which may be employed includes, for example, an inert solvent such as dichloromethane, acetonitrile, tetrahydrofuran or sulpholane, or a mixture thereof. Of these, a preferred solvent is dichloromethane or acetonitrile, especially dichioromethane. Preferably 0.95 to 1.3 equivalents, more preferably 1.0 to 1.25 equivalents (such as 1.13 to 1.23 equivalents), of trimethyloxonium tetrafluoroborate per equivalent of compound of formula II are used in the reaction. Using less than 0.95 equivalents of trimethyloxonium tetrafluoroborate results in significant amounts of unreacted starting material and using a large excess of trimethyloxonium tetrafluoroborate significantly inhibits the subsequent cyclisation step when steps (1) and (2) are telescoped. Most preferably 1.17 equivalents of trimethyloxonium tetrafluoroborate is used. Preferably the addition of the trimethyloxonium tetrafluoroborate is carried out at a temperature in the range −40° C. to ambient temperature, for example 40° C. to +20° C. and conveniently 10 to +10° C., such as 5 to +5° C. The reaction mixture may then conveniently be allowed to proceed to completion at or about ambient temperature, for example, +10° C. to +30° C.
It will be appreciated that the intermediate formed in step (1) is the sulfonium salt of the formula III;
and that this compound is a further aspect of the present invention. In Step (2), a particular base which can be employed includes, for example, an alkali metal alkoxide (such as potassium tert-butoxide, lithium tert-butoxide, sodium tert-butoxide or sodium methoxide), an alkali metal hydride (such as sodium hydride), an alkali metal dialkylamide (such as lithium di-isopropylamide) or an alkyl lithium (such as n-butyl lithium). A preferred base includes, for example, potassium tert-butoxide. Conveniently, 0.8 to 1.1 equivalents (for example 0.85 to 1.05 equivalents, and more especially 0.9 to 1.0 equivalents) of such a base per equivalent of compound of formula II are used, and preferably about 0.94 equivalents (to minimise epimerisation). When such bases are used in Step (2), the reaction is preferably carried out at low temperature, for example −50° C. to 0° C., such as in the range 40° C. to −20° C., and preferably at or about −40° C., such as −50° C. to −30° C.
Surprisingly it has also been found that an alkali metal carbonate, such as sodium or potassium carbonate, especially an alkali metal carbonate in a form having a high surface area, such as powdered anhydrous potassium carbonate (for example 325 mesh size), can be used as the base in Step (2). Furthermore excess of such a carbonate base may be used and the reaction can be carried out satisfactorily at temperatures between ambient temperature and +90° C. for example 20 to 80° C. Preferably 1 to 4 equivalents of such a base per equivalent of compound of formula II are used, especially 2 to 4 equivalents, for example 3 equivalents. Advantages associated with the use of such a carbonate base include, for example, that it is more convenient to use on a large scale, low temperatures do not have to be employed to restrict epimerisation as with a strong base, and the reaction can be carried out at higher concentrations. A preferred aspect of the present invention is therefore the use of such a carbonate base in Step 2 It will be appreciated that other inorganic bases, or mixtures of such bases, having a basicity similar to that of an alkali metal carbonate may also be used in the reaction, preferably in a finely divided form.
A suitable solvent for use in Step (2) includes, for example, any of those suitable for carrying out Step (1), or a mixture thereof. A preferred solvent includes, for example, acetonitrile and dichloromethane, especially the latter. The reaction is generally carried out for 6 to 18 hours, such as about 12 hours. When anhydrous potassium carbonate in dichloromethane is used, it is preferable to carry out Step 2 at the refluxing temperature of dichloromethane. Similarly, Step 2 may be carried out, for example, in refluxing THF, acetonitrile or at 80° C. in sulpholane.
An especially preferred aspect of the present invention comprises a process which comprises (1) methylation of a compound of formula II using 0.95 to 1.05 equivalents of trimethyloxonium tetrafluoroborate per equivalent of compound of formula II, followed by (2) cyclisation under basic conditions using an alkali metal carbonate (preferably anhydrous potassium carbonate).
In a further preferred aspect of the invention, Steps (1) and (2) are telescoped, without prior isolation of the sulphonium salt formed in Step (1). This is particularly advantageous for large scale manufacture. A telescoped procedure using a carbonate base in Step (2) is especially preferred.
The reaction may be worked up by cooling, addition of water, filtration, separation of the organic phase, washing the organic phase with water and removal of volatile material by distillation. The product may be crystallised from a suitable solvent, such as a mixture of dichloromethane and isohexane, tetrahydrofuran and Essochem Solvent 30, an ester such as ethyl, propyl or butyl acetate, or preferably a mixture of n-butyl acetate and isohexane. Alternat
Brown Richard J
Harris Craig S
Leung Chiu W
Patel Ian
D'Souza Andrea M
Lambkin Deborah C.
Pillsbury & Winthrop LLP
Zeneca Limited
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