Bis(aminomethyl)phosphinic acid derivatives and process for the

Details Bis(aminomethyl)phosphinic acid derivatives and process for the Bis(aminomethyl)phosphinic acid derivatives and process for the

1995-09-28

1997-03-04

Richter, Johann

Organic compounds -- part of the class 532-570 series

Organic compounds

Phosphorus esters

558155, 558158, 558159, C07F 930, C07F 932, C07F 938, C07F 940

Patent

active

056080980

DESCRIPTION:

BRIEF SUMMARY
This application was filed under 35 U.S.C. .sctn.371 and was based upon PCT International Application No. PCT/EP94/00950, filed Mar. 24, 1994.


BACKGROUND OF THE INVENTION

1. Description of the Related Art
.alpha.-Aminophosphonic acids and their derivatives are gaining greater and greater importance, e.g. as enzyme inhibitors, in biochemistry, pharmaceutical chemistry and in the field of plant protection [P. Kafarski, B. Lejczak, Phosph., Sulfur, and Silicon, 63 (1991)193]. There is a whole range of processes for the synthesis of this class of compound, which have been summarized in various reports [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 compound, bis(aminomethyl)phosphinic acid and its derivatives, which are likewise of increasing importance in pharmaceutical chemistry (EP 0435059 A1), is far more complicated and only documented to a small extent. The synthesis of the parent compound was described for the first time by Meier [L. Meier, J. Organomet. Chem. 178 (1979) 157, DE 2805074A1, see also Kober et al., DE 3824961A1]. One possibility for the preparation of .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 of hypophosphorous acid to Schiff bases with formation of aminoalkylphosphonous acids in the first step, which are then reacted in the following step with arylidene bisamides to give .alpha.,.alpha.-bis(aminoalkyl)phosphinic acids. This process, however, is limited to the reaction with arylidene bisamides and is furthermore characterized by moderate yields. Only moderate yields were also observed for the double addition of hypophosphorous acid to Schiff bases with the formation of .alpha.,.alpha.'-bis(aminoalkyl)phosphinic acids. A further process [A. Peyman et al., Tetrahedron Lett. 33 (1992) 4549] is based on the alkylation of bis(aminomethyl)phosphinic acid, but in this way only radicals can be introduced which are accessible to nucleophilic substitution. Surprisingly, it has been found that many compounds can be prepared advantageously by alkylations of reverse polarity.
2. Summary of the Invention
The invention accordingly relates to a process for the preparation of compounds of the formula VI ##STR4## in which R.sup.2 and R.sup.3, independently of one another, are hydrogen, (C.sub.1 -C.sub.18)-alkyl, (C.sub.2 -C.sub.18)-alkenyl, (C.sub.2 -C.sub.18)-alkynyl, where alkyl, alkenyl and alkynyl can in each case be substituted one or more times by fluorine, chlorine, bromine, COOH, oxo, NO.sub.2, NH.sub.2, NHC(O)--(C.sub.1 -C.sub.6)-alkyl, NHC(O)--(C.sub.6 -C.sub.12)-aryl, CN, OH, CHO, CH--[(C.sub.1 -C.sub.6)-alkoxy].sub.2, COOH, SO.sub.3 H, C(O)--O--(C.sub.1 -C.sub.6)-alkyl, C(O)--O--(C.sub.6 -C.sub.12)-aryl, C(O)--(C.sub.1 -C.sub.6)-alkyl, C(O)--(C.sub.6 -C.sub.12)-aryl, O--C(O)--(C.sub.1 -C.sub.6)-alkyl, O--C(O)--(C.sub.6 -C.sub.12)-aryl, (C.sub.1 -C.sub.6)-alkoxy, are (C.sub.6 -C.sub.12)-aryl, (C.sub.7 -C.sub.22)-arylalkyl, where aryl can be substituted one or more times by fluorine, chlorine, bromine, NO.sub.2, NH.sub.2, NHC(O)--(C.sub.1 -C.sub.6)-alkyl, NHC(O)--(C.sub.6 -C.sub.12)-aryl, 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)--O--(C.sub.6 -C.sub.12)-aryl, C(O)--(C.sub.1 -C.sub.6)-alkyl, C(O)--(C.sub.6 -C.sub.12)-aryl, O--C--(O)--(C.sub.1 -C.sub.6)-alkyl, O--C(O)--(C.sub.6 -C.sub.12)-aryl, or are P(O)[OH].sub.2, P(O)(OR.sup.23).sub.2, where R.sup.23 independently of one another is (C.sub.1 -C.sub.6)-alkyl, (C.sub.6 -C.sub.12)-aryl or (C.sub.7 -C.sub.13)-arylalkyl and where aryl can be substituted one or more times 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)--O--(C.sub.6 -C.sub.12)-aryl, C(O)--(C.sub.1 -C.sub.6)-alkyl, C(O)--(C.sub.6

REFERENCES:
patent: 5099063 (1992-03-01), Parsons et al.
Schrader, T. et al. "Synthese von 1-Aminophosphon aure -Derivaten uber Acyliminophosphons aure-Ester" Synthesis 1986, (5), 372-375.
Schrader, T. et al. "Phosphoranaloge von Aminos auren IV. Synthesen ungew ohnlicher 1-Aminophosphons auren uber Diels-Alder Reaktionen von (N-Acyliminomethyl)phosphons aurediethylestern" Synthesis 1990, (12), 1153-1156.

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