Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-04-23
1998-04-14
Dentz, Bernard
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
570127, C07D30754, C07C 2513
Patent
active
057393613
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP95/04153 filed Oct. 23, 1995 published as WO96/12714 May 2, 1996.
FIELD OF THE INVENTION
The present invention relates to a new and effective process for the preparation of 4-chloro-N-(2-furylmethyl)-5-sulfamoyl anthranilic acid, or furosemide, an active ingredient which has been known since long as a diuretic and antihypertensive in human therapy and as a diuretic for the treatment of animals.
PRIOR ART DISCLOSURE
Furosemide, one of the main members of the class of diuretic sulfonamides, acts simultaneously as an inhibitor of urine dilution and concentration. One of the advantages offered by said diuretic consists in its short times of action, which allow an easy control of diuresis by properly adjusting doses and administration frequency.
According to U.S. Pat. No. 3,058,882, furosemide is prepared from 2,4-dichlorobenzoic acid, which is chlorosulfonated with sulfuric chlorohydrin and then ammonolyzed. Treatment of the resulting sulfonamide with furfurylamine yields furosemide in low yields (35 to 50%). Other methods envisaging the condensation of furfurylamine with some 5-sulfamoyl-benzoic acid derivatives, such as esters, amides (DE 1 220 436; Derwent abstract) and nitriles (DE 1 806 581; Derwent abstract), are also described. However, these methods require a final hydrolysis of the carboxylic acid derivative.
All the above synthetic routes include a scarcely effective condensation step with furfurylamine yielding several by-products; as a consequence the yield is low and the purification of the final product is difficult. As disclosed in FR patent 1,396,621, practically quantitative yields may be obtained through the condensation of 4-chloro-2-fluoro-5-sulfamoyl-benzoic acid with furfurylamine. Nevertheless, the above mentioned fluoro-derivative is synthetized by chlorosulfonylation of 4-chloro-2-fluoro-benzoic acid and subsequent ammonolysis of the obtained product, showing only poor total yields (Chem Abstr. Vol. 64, 8112-8116, 1966) and rendering the process economically unprofitable.
The European patent application EPA 0 093 976 describes the photochlorination of 2-chloro-4-fluoro-toluene to give 2-chloro-4-fluoro-1-benzotrichloride.
SUMMARY OF THE INVENTION
The claimed invention relates to a process for the preparation of furosemide having the following structural formula (I): ##STR1## Said process comprises the following reaction steps:
A) 4-chloro-2-fluoro-toluene (II) is photochlorinated to give 4-chloro-2-fluoro-benzotrichloride (lII), unknown in the state of the art and essential for the following steps;
B) 4-chloro-2-fluoro-benzotrichloride (III) obtained in step A) is chlorosulfonylated by treatment with sulfuric chlorohydrin in the presence of sulfuric acid and the resulting product is ammonolyzed by tratment with ammonium hydroxyde to give 4-chloro-2-fluoro-5-sulfamoylbenzoic acid (IV):
C) finally, 4-chloro-2-fluoro-5-sulfamoylbenzoic acid (IV) obtained in step B) is condensed with furfurylamine to give furosemide (I).
The reaction scheme is as follows: ##STR2##
DETAILED DESCRIPTION OF THE INVENTION
The characteristics and advantages of the process for the preparation of furosemide (I) according to the present invention will be better illustrated in the following detailed description.
Step A:
in an apparatus properly equipped for photochemical chlorination, 4-chloro-2-fluoro-toluene (II) is treated with gaseous chlorine which is bubbled at a flow rate of 12 g/h to 16 g/h per mole of (II), preferably 14 g/h, at a temperature of 85.degree. C. to 95.degree. C., preferably 90.degree. C., for a period of 11 to 12 hrs, to give 4-chloro-2-fluoro-benzotrichloride (III), a product unknown in the state of the art.
Such a new product, easily obtainable industrially with high purity and high yields by means of the above photochlorination, plays a key role in the economy of the total process. It is to be stressed the fact that this intermediate consents to obtain very high process yields in the following reaction steps; this is mainly due to the presence
REFERENCES:
patent: 3058882 (1962-10-01), Sturm et al.
Chemische Berichte, vol. 99, No. 1, 1966, Weinheim, Germany, pp. 328-344, K. Sturm, et al, "Synthesen von 5-Sulfanyl-anthranilsaure-Derivaten".
Chemical Abstracts, vol. 64, 1966, "Heterocyclic Compounds," pp. 8113-8116.
Guerrato Alfredo
Signor Angelo
Signor Giovanni
Dentz Bernard
Proteos S.r.L.
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