Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus esters
Patent
1995-01-04
1996-04-23
Richter, Johann
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus esters
558166, 562 16, C07F 932, C07F 930
Patent
active
055105041
DESCRIPTION:
BRIEF SUMMARY
This application is a continuation of International Application No. PCT/EP93/00838, filed Apr. 5, 1993.
.alpha.-Aminophosphonic acids and their derivatives are becoming increasingly important, often as enzyme inhibitors, in biochemistry, pharmaceutical chemistry and in the area of crop protection E. Neuzil, A. Cassaigne, Exp. Ann. Biochim. Medicale 34 (1980) 165!. There is a whole range of processes for preparing this class of compound and these are summarized in various articles Kukhar and Solodenko, Russ. Chem. Rev. 56 (1987) 859; Redmoore, Topics in Phosphorus Chemistry, vol. 11, Grayson and Griffith, Ed., Wiley, 1976, 515!.
The preparation of another class of compounds, bis(aminomethyl)phosphinic acid and its derivatives, which are also gaining in importance in pharmaceutical chemistry (EP 0435 059 A1), is far more complex and not very well documented. The synthesis of the parent compound was first described by Meier L. Meier, J. Organomet. Chem. 178 (1979) 157; DE 2805074A1, see also Kober et al., DE 3824961A1!. A possibility for preparing .alpha.- or .alpha.,.alpha.'-substituted derivatives of bis(aminomethyl)phosphinic acid is described by Tyka et al. Phosphorus, Sulfur and Silicon 62 (1991) 75!. The method is based on the addition reaction of hypophosphorous acid with Schiff's bases to form aminoalkylphosphonous acids in the first step and the reaction of the latter with arylidenebisamides to give .alpha.,.alpha.'-bis(aminoalkyl)phosphinic acids. This process, however, is restricted to reaction with arylidenebisamides and is further distinguished by modest yields. Only modest yields were observed also for the double addition reaction of hypophosphorous acid with Schiff's bases to form .alpha.,.alpha.'-bis(aminoalkyl)phosphinic acids.
The invention relates to a new process for the preparation of .alpha.- or .alpha.,.alpha.'-substituted derivatives of the bis(aminomethyl)phosphinic acid of the formula I and their acid or basic salts, ##STR2## in which R.sup.1 is R.sup.6 =alkyl, C.sub.2 -C.sub.18 alkenyl, C.sub.2 -C.sub.18 alkynyl, C.sub.6 -C.sub.12 aryl or C.sub.7 -C.sub.20 arylalkyl and aryl or arylalkyl may be mono- or polysubstituted by fluorine, chlorine, bromine, NO.sub.2, CN, OH, COOH, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C(O)--O--(C.sub.1 -C.sub.6) alkyl, C(O)--(C.sub.1 -C.sub.6) alkyl or O--C(O)--(C.sub.1 -C.sub.6) alkyl and R.sup.1 is also hydrogen or basic salt radicals of .alpha.- or .alpha.,.alpha.'-substituted derivatives of the bis(aminomethyl)phosphinic acid, especially alkali metal or alkaline earth metal salts, or else ammonium or trialkylammonium salts, R.sup.2 and R.sup.3 are identical or different and are, independently of each other, hydrogen, C.sub.1 -C.sub.18 alkyl, C.sub.2 -C.sub.18 alkenyl, C.sub.2 -C.sub.18 alkynyl, C.sub.6 -C.sub.12 aryl or C.sub.7 -C.sub.22 arylalkyl, where alkyl, alkenyl or alkynyl may each be mono-or polysubstituted by fluorine, chlorine, bromine, NO.sub.2, NH.sub.2, CN, OH, COOH, C(O)--O--(C.sub.1 -C.sub.6) alkyl, C(O)--(C.sub.1 -C.sub.6) alkyl, O--C(O)--(C.sub.1 -C.sub.6) alkyl or C.sub.1 -C.sub.6 alkoxy and aryl may be mono- or polysubstituted by fluorine, chlorine, bromine, NO.sub.2, CN, OH, COOH, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C(O)--O--(C.sub.1 -C.sub.6) alkyl, C(O)--(C.sub.1 -C.sub.6) alkyl or O--C(O)--(C.sub.1 -C.sub.6) alkyl, with the proviso that if R.sup.2 =hydrogen and R.sup.3 has the above-mentioned meaning, R.sup.3 must not also be hydrogen, and vice versa.
R.sup.1 is preferably hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, phenyl, benzyl, Li.sup.+, Na.sup.+, K.sup.+, Mg.sup.2+, NH.sub.4.sup.+, HN(C.sub.2 H.sub.5).sub.3.sup.+, especially hydrogen and C.sub.1 -C.sub.4 alkyl.
R.sup.2 and R.sup.3 are particularly preferably C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.6 -C.sub.12 aryl, C.sub.7 -C.sub.13 arylalkyl, where aryl or arylalkyl may be mono- or polysubstituted by chlorine, bromine, --CN or O--C.sub.1 -C.sub.3 alkyl.
R.sup.2 and R.sup.3 are very pa
REFERENCES:
patent: 4171969 (1979-10-01), Maier
Peyman et al., "C2-Symetric Phosphinic Acid Inhibitors of HIV Protease," Tetrahedron Letters, vol. 33, No. 32, pp. 4549-4552, 1992.
Tyka et al., "Synthese Symmetrischer Und Asymmetrischer a, a'-Bis(aminoalkyl)--Phoshinsauren Des Typs NH2CHR1 (NH2CHR2) PH (O) OH (R1=Ph; R2=Ph, Me)," Phosphorus, Sulfur, and Silicon, vol. 62, pp. 75-81, 1991.
Derwent Abstract of DE 3824961A1, 1995.
Budt Karl-Heinz
Li Jian-Qi
Peyman Anuschirwan
Spanig Jorg
Stowasser Bernd
Ambrose Michael G.
Hoechst Aktiengesellschaft
Richter Johann
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