Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-06-27
1997-07-15
Gerstl, Robert
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D27722
Patent
active
056484984
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a novel process for the preparation of 4-methyl-5-(2-chloroalkyl)-thiazoles of the general formula ##STR1## wherein R stands for a straight chained C.sub.1-5 alkyl group substituted by a chloride atom in the 2-position, ##STR2## and acid addition salts thereof (Clomethiazole) is the therapeutically widely applied active ingredient of anticonvulsives and sedatives. The compound of the formula (Ia) was first described in 1935 [J. Am. Chem. Soc. 57, 1876 (1935)]. Its hydrochloride and ethane disulphonate salt are disclosed in GB-PS 792,158. Its phosphate salt is known from US-PS 3,639,415.
The known methods for the preparation-of the thiazole derivatives unsubstituted in position 2 can be divided into two main types. When proceeding according to methods of the first type the 2-unsubstituted thiazole is obtained in one step. According to methods of the second type thiazole derivatives containing an easily removable substituent in position 2 are prepared and this substituent is removed in a second step.
According to methods of the first type the thiazole ring is formed by reacting a halogenated ketone or aldehyde, which are halogenated in the .alpha.-position or aldehyde with thioformamide [Elderfield, R. C.: Heterocyclic Compounds, Vol. 5, page 516 (1957)] (Reaction scheme A). ##STR3## R.sup.1 and R.sup.2 =alkyl, aryl or hydrogen X=halogen
This type of methods gives a good yield only in some cases [Buchman and Richardson: J. Am. Chem. Soc. 67, 395 (1945); Erne, Ramirez and Burger: Helv. Chim. Acta 34, 143 (1951)]. A further disadvantage of this method is the difficulty of preparing pure thioformamide and the instable character of thioformamide. To eliminate this difficulty the preparation of thioformamide was carried out in the reaction mixture itself from formamide and phosphorous pentasulphide, but this method succeeded only in some cases [Ganapathi and Venkataraman: Proc. Indian Acad. Sci. 22, 362 (1945)]. This method is strongly contaminating the environment because of the use of phosphorous pentasulphide.
As the direct synthesis described above can hardly be realized on industrial scale, attention was paid to the indirect synthesis variants. One of these variants eliminates the amino group in position 2 via diazotization and the subsequent reduction of the diazonium group [Ganapathi and Venkataraman: Proc. Indian Acad. Sci 22, 366 (194S)]. The 2-amino-thiazole derivative necessary for this method is to be prepared in a separate step from a-halogen-ketone with thiourea [e.g. Tanida, Tamura and Sara: J. Pharm. Soc. Japan 74, 652 (1954); C. A. 48, 10737 (1945)] (reaction scheme B). ##STR4## By this route the target compounds can be obtained in poor yields ranging between 30 and 60%.
A further possibility is the oxidative removal of the thio group in position 2 of the thiazole [GB-PS 492,637; Buchman, Reims and Sargnet: J. Org. Chem. 6, 764 (1941)], of the desulphuration of the 2-mercapto-thiazole derivative by boiling with Raney nickel at a great excess [Cook et al: J. Chem. Soc. 1954 (1947); Hurd and Rudner: J. Am. Chem. Soc. 73, 5157 (1951)]. The required 2-mercapto-thiazole has also to be prepared in a separate step from .alpha.-halogen-ketone and ammonium-dithiocarbamate (e.g. GB-PS 492,637) (Reaction Scheme C). ##STR5##
A disadvantage of this method is that for the preparation of ammonium dithiocarbamate carbon disulphide is needed, requiring a special workshop when prepared on industrial scale because of the great danger of fire. Further, the reagent and the by-products of the synthesis are contaminating the environment to a great extent. For the desulphuration with Raney nickel a great excess of nickel is required, which significantly increases the costs of the synthesis.
A third possibility is the dehalogenation of the 2-halo-thiazole derivatives. For this purpose mostly zinc is used in an acetic acid medium [GB-PS 456,751; Gibbs and Robinson: J. Chem. Soc. 925 (1945); Andersag and Westphal: Bet. 70, 2035 (1937)].
Catalytic dehalogenation was described only in case of 2-bromo
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Ban Karoly
Bone Istvan
Buttkai Ildiko
Garaczy Sandor
Gonczi Csaba
Astra Aktiebolag
Gerstl Robert
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