The subject of the present invention is a novel process for the preparation of [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-thiazolo-2-yl]-[2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-ethyl]-amine of formula (I)
and new intermediates of the preparation process.
The compound of formula (I) is a key intermediate to the preparation of [4-(2-chloro-4-methoxy-5-methylphenyl)-N-propynyl-5-methyl-thiazolo-2-yl]-[2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-ethyl]-amine of formula (VI)
The thiazolamine of formula (I) is presently prepared in several steps, utilizing the Hantzsch synthesis (WO2001/005776, Sanofi-Aventis).
The preparation process used so far (WO2001/005776, Sanofi-Aventis) starts from the compound of formula (II)
Our aim was to find a starting material for the preparation of the compound of formula (I) which is well characterized, easy to treat, which is well crystallizable, and can be prepared conveniently, in high yield. To our surprise, we found that 2-thiocyanato-1-(2-chloro-4-methoxy-5-methylphenyl)-propan-1-one of formula (III)
is a starting material which fulfills all our needs. A further advantage of applying the compound of formula (III) is that under specific conditions, i.e. in the presence of a phase transfer catalyst, it can be prepared easily in aqueous medium, from the previously used compound of general formula (II). This new process according to our invention is environment friendly, since only aqueous effluent is formed, the amount of the used organic solvents is small and the solvents can be re-used, the process can be performed in industrial scale and it results high purity product in high yield.
The preparation of the ketone derivative (III) in aqueous conditions is surprising, since the thiocyanate group is sensitive to water, it can easily transform into isothiocyanate, or it can suffer hydrolysis. Therefore, in the state of art, it is prepared either in ionic liquid (Tetrahedron Letters 46 (2005), 1489-1491) or in alcoholic medium (J. Indian Chem. Soc., 81 (2004), 786-788), but in any case in the absence of water.
A subject of the invention is a novel process for the preparation of [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-thiazolo-2-yl]-[2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-ethyl]-amine of formula (I)
wherein
where X means halogen, is reacted with an alkali metal-thiocyanate, in the presence of a phase-transfer catalyst, and
or a tautomeric form of it is reacted with the 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-ethyl-amine
of formula (IV).
To prepare the appropriate optically active isomer of the compound of formula (I) we have to start from the respective optically active amine of formula (IV).
In one embodiment of the process according to the invention, in step a.) the reaction is performed in the binary system consisting of an aprotic solvent and water.
In one alternative of the process according to the invention, the compound of the general formula (II)—where X is particularly a chloro or bromo group, more particularly a bromo group,—is dissolved in an aprotic organic solvent and reacted with the aqueous solution of an alkali metal-thiocyanate—preferably potassium-thiocyanate—in the presence of a phase transfer catalyst—preferably TBAB (tetrabutyl-ammonium bromide). The reaction mixture is worked-up by separation of the organic phase after dilution of the mixture with water. In a given case after solvent exchange, the compound of the formula (III) can be well crystallized, in high yield.
In one variant of step b.) the compound of formula (III) is added to the compound of formula (IV), to obtain the desired product with a favorable impurity profile and in high yield.
To achieve the best yield the addition period lasts for at least one hour.
In step b.) favorably an apolar aprotic solvent is applied, preferably methyl-cyclohexane or toluene. Step b.) is preferably performed at a temperature range between 25° C. and reflux temperature, most preferably at reflux temperature.
The compounds of the general formula (II) and the amine of formula (IV), as well as their preparation are known from the patent application of publication number WO2001/005776.
A further subject of the invention is the new compound of formula (III) and its tautomers, as well as their preparation.
Of the tautomers of compound (III), the 5-(2-chloro-4-methoxy-5-methylphenyl)-4-methyl-[1.3]-oxathiol-2-ylideneamine of formula (V)
is also a subject of the invention.
Further details of our process are demonstrated in the following examples without limiting the claims to the examples.
Number | Date | Country | Kind |
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0900267 | Apr 2009 | HU | national |
Number | Name | Date | Kind |
---|---|---|---|
3222248 | Lukes et al. | Dec 1965 | A |
3433803 | Ottmann et al. | Mar 1969 | A |
6586456 | Fontaine et al. | Jul 2003 | B1 |
Number | Date | Country |
---|---|---|
823251 | Nov 1959 | GB |
10036360 | Feb 1998 | JP |
WO 9309107 | May 1993 | WO |
WO 0105776 | Jan 2001 | WO |
WO 2010125414 | Nov 2010 | WO |
Number | Date | Country | |
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20120083608 A1 | Apr 2012 | US |
Number | Date | Country | |
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Parent | PCT/HU2010/000047 | Apr 2010 | US |
Child | 13282721 | US |