Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2002-04-26
2003-04-15
Davis, Brian (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S162000
Reexamination Certificate
active
06548702
ABSTRACT:
This application is a 371 of PCT HU00/00080 filed Jul. 13, 2000.
2-methoxy-4-(N-t-butylaminocarbonyl)benzenesulfonyl chloride is an important building block to the angiotensine antagonistic compound SR 121463. Its preparation is described in patent application WO 9715556. Because of the applied materials and reactions, the process described in the above patent application is appropriate to prepare the material only in laboratory scale, in low yield, and by involving several purification steps. The process is the following: it starts from 3-methoxy-4-nitrobenzoic acid, this is transformed via the acid chloride into the acylamide, the nitro group is then reduced and the amine group is exchanged in a Sandmeyer-type reaction, performed in acetic acidic medium using great excess of sulfur dioxide. The weakest part of the synthesis is the exchange of the amino group for chlorosulfonyl group. The reaction is difficult to control, the main reaction is accompanied by a series of side-reactions, thus a severely contaminated product is obtained in only about 50% yield.
Preparation of 2-methoxy-(4-aminocarbonyl)benzenesulfonamide and of 4-chlorosulfonyl-3-methoxybenzoyl chloride is known from the literature from the work of SHAH (J. Chem. Soc. 1930. 1293).
Our new process uses the basic elements of the above scientific work of 1930, but modifies it into a process, which can be technically realized and which widely satisfies the environmental, economical and technological requirements of the late 20th century.
Our process contains the following findings, compared to the method of SHAH: Sulfonation of the m-hydroxybenzoic acid is performed—instead of oleum, which is dangerous and difficult to treat—with 96% sulfuric acid, which also serves as he solvent of the reaction. After pouring the reaction mixture onto ice, the product is obtained as a precipitate which can be filtered off, which is pure, free of isomers. The yield of the reaction is around 90%. The sulfonic acid is isolated in the form of its potassium salt.
In the method described in the literature the methylation step was carried out using 18-fold excess of dimethyl sulfate, which was added in small portions subsequently with high amount of 25% potassium hydroxide. We have, however, found that even a small excess of dimethyl sulfate is sufficient if higher temperature is applied, the pH is maintained above 11.5 and a phase transfer catalyst (PTC) is used in aqueous medium or in a two-phase mixture. After isolating the product in the form of its salt, without further purification, a product of analytical purity (96-99%) can be obtained, in a yield as much as 90%.
Reacting the 3-methoxy-4-sulfobenzoic acid mono-potassium salt with an inorganic acid halogenide the 4-chlorosulfonyl-3-methoxybenzoyl chloride is obtained. To our surprise we have found that at lower temperature, in an appropriate solvent the t-butylamine reacts selectively with the aromatic acid chloride. Thus, the desired 2-methoxy-4-(N-t-butylaminocarbonyl)benzenesulfonyl chloride is obtained in 92% yield, with a purity of 96%, so it can be used without further purification for the synthesis of drug substances.
REFERENCES:
patent: 3953507 (1976-04-01), Baker et al.
patent: 5994350 (1999-11-01), Foulon et al.
patent: WO 97 15556 (1997-05-01), None
patent: WO 98/25901 (1998-06-01), None
M.S. Shah; “4-Sulpho-3-hydroxybenzoic Acid”; Journal of the Chemical Society; 1930, pp 1293-1301.
S. Ramaswamy et al; “Phase-Transfer-Catalyzed Methylation of Hydroaromatic Acids, Hydroxyaromatic Aldehydes, and Aromatic Polycarboxylic Acids”; Environmental Science Technology, vol. 19, No. 6, 1985, pp 507-512.
Database Chemabs—Online; Chemical Abstracts Service, Columbus, Ohio, No. XP002153150 (1980) (Abstract).
Csikós Éva
Csutor Andrea Sántáné
Esek Ágota Smelkóné
Gönczi Csaba
Hajdú Félix
Alexander Michael D.
Davis Brian
Dupont Paul E.
Sanofi-Synthelabo
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