Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus esters
Patent
1996-07-02
1999-03-23
Nazario-Gonzalez, Porfirio
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus esters
560 21, 560 22, 560 23, C07F 940, C07F 938
Patent
active
058862064
DESCRIPTION:
BRIEF SUMMARY
This application is 371 of PCT/JP95/01683 filed Aug. 24 1995, now WO96/06100.
TECHNICAL FIELD
The present invention relates to a process for production of methanediphosphonic acid compound useful as metal chelating agent, or pharmaceuticals such as anti-inflammatory agent, anti-rheumatic agent, bone-metabolic disease-treating agent and the like.
BACKGROUND ART
A conventional process for synthesis of 1-alkylthio- or 1-arylthiomethanediphosphonic acid is described, for example, in Japanese Examined Patent Publication (Kokoku) No. 4-29676. In the process shown therein, tetraalkyl methanediphosphoniate is converted to a corresponding metal derivative by sodium hydride and the like, and then various disulfides are allowed to react with the derivative to synthesize the objective tetraalkyl 1-alkylthio- or 1-arylthiomethanediphosphonate. Since this synthetic process gives the product in a low yield, a large amount of the recovered disulfide and tetraalkyl methanediphosphonate as well as a byproduct of the reaction, thiol, exist with the objective compound in a crude product, and an industrially expensive purification process, such as silica gel column chromatography, is needed for removing these impurities. Considering the fact that the objective methanediphosphonic acid compounds are highly useful in pharmaceutical fields, the above-mentioned process is not satisfactory to provide a large amount of the compound, and therefore a simple, economical process is required.
The greatest problem in the synthetic process described in Japanese Examined Patent Publication (kokoku) No. 4-29676 is that a large amount of starting material, tetraalkyl methanediphosphonate, was recovered unchanged, resulting in significant labor-consumption for the separation and purification of the objective product from the starting material. If the remaining methanediphosphonate in the reaction mixture can be reduced, this process will be an excellent process for producing 1-alkylthio- or 1-arylthiomethanediphosphonic acid. As the result of detailed investigation of the condensation of tetraalkyl methanediphosphonate with disulfide, the present inventors found that the objective product, tetraalkyl 1-alkylthiomethanediphosphonate or tetraalkyl 1-arylthiomethanediphosphonate, can be obtained in an extremely high yield, by removing the byproduct, alkylthiolate or arylthiolate which is formed in amounts equimolar with the objective product. In addition, it is found that the addition of a metal oxide including magnesium oxide to the synthetic process also provides the objective tetraalkyl 1-alkylthiomethanediphosphonate or tetraalkyl 1-arylthiomethanediphosphonate in a high yield.
Accordingly, it is an object of the present invention to provide a novel process for production of a 1-alkylthiomehanediphosphonic acid compound or 1-arylthiomehanediphosphonic acid compound, which is extremely useful as pharmaceuticals.
DISCLOSURE OF THE INVENTION
The present invention provides a process for production of a methanediphosphonic acid compound represented by the following general formula (1): ##STR2## wherein R.sub.1 is a pharmaceutically allowable cation, hydrogen atom, or linear or branched alkyl group having 1 to 6 carbon atoms, and may be the same or different, R.sub.2 is an alkyl group having 1 to 20 carbon atoms or aryl group having 3 to 20 carbon atoms, and R4 is a hydrogen atom, or linear or branched alkyl group having 1 to 6 carbon atoms; character-zed by reacting a tetraalkyl methanediphosphonate represented by the following formula: ##STR3## wherein R'.sub.1 is a linear or branched alkyl group having 1 to 6, carbon atoms, each R'.sub.1 may be the same or different, R.sub.3 is a hydrogen, sodium, potassium, or lithium atom, and R.sub.4 is the same as above, with a dialkyldisulfide or diaryldisulfide represented by the following formula : arylthiolate as an insoluble material or an insoluble salt.
BEST MODE FOR CARRYING OUT THE INVENTION
The process for production of a 1-alkylthiomethanediphosphonic acid compound or 1-arylthiomethane
REFERENCES:
patent: 5043330 (1991-08-01), Nguyen
patent: 5128331 (1992-07-01), Nguyen
patent: 5153183 (1992-10-01), Kawabe
CA 123:112405 Process for Producing Methane Diphosphate Compounds Takanishi, K. et al WO 9419359 Abstract 1994.
Haruta Ryuichi
Kawabe Norio
Takanishi Keijiro
Tsuruta Kouichi
Uchiro Hiromi
Nazario-Gonzalez Porfirio
Toray Industries Inc.
Vollano Jean F.
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