DD222030A1 - PROCESS FOR PREPARING AMINO-1-HYDROXY-ALKAN-1,1-BISPHOSPHONESAEURES - Google Patents

Abstract

The invention relates to a process for the preparation of amino-1-hydroxy-alkane-1,1-bisphosphonates having 2-8 C-atoms from corresponding aminoalkanecarboxylic acids or their salts or derivatives and phosphorus (III) oxide, P4O6, by reaction in one compared to phosphorus (III) oxide inert solvents at temperatures of about 370 K and subsequent hydrolysis of the reaction mixture. Yields of about 40-60% are achieved. Amino-1-hydroxy-alkane-1,1-bisphosphonic acids find technical application u. a. as a complexing agent for water softening and metal extraction, in the cosmetic and pharmaceutical industry as well as in clinical medicine.

Description

Field of application of the invention

The invention relates to a process for the preparation of amino-i-hydroxy-alkane-IJ-bisphosphonic acids. In general, substituted alkane-1,1-bisphosphonic acids, their salts and derivatives are good, technically desirable chelating agents and therefore they are i.a. used for water softening, in metal extraction and in detergents. Also worth mentioning is their suitability as corrosion inhibitors. Aminoalkane-1,1-bisphosphonic acids are also increasingly used in the cosmetic and pharmaceutical industries and in clinical medicine.

Characteristic of the known technical solutions

From DE-PS 2130794 and DE-OS 3016289 it is known that omega-amino-i-hydröxy-alkane-Ubisphosphonsäuren by reaction of omega-Amino'-alkanecarboxylic acids with mixtures of phosphorous acid and phosphorus trichloride, PCI _3, or Phpsphoroxychlorid, POCI ₃ , can be made. According to DE-OS 2943498, instead of the PCI ₃ phosphorus (V) chloride, PCI ₅ , can be used or generated directly in the reaction mixture of PCI ₃ and chlorine. Here, yields of omega-amino-1-hydroxy-alkane-1,1-bisphosphonic are described on average 50-70%. These processes are, despite the stated relatively high yields, economically burdened with the use of up to 7.5 moles of chlorine per mole of aminoalkanecarboxylic acid which are converted to impure dilute hydrochloric acid in the course of the process, the latter having to be dumped in an environmentally harmful manner or worked up in a complicated manner. .. -,

Object of the invention

The aim of the invention is to develop an economically favorable process for the preparation of amino-i-hydroxy-alkane-1,1-bisphosphonic acids, in which the starting material chlorine - as free chlorine or in the form of phosphorus chlorides - largely or completely by other cheap Starting materials is replaced, and with the highest possible yields pure amino-1-hydroxy-alkane-IJ-bisphosphonic acids results.

Explanation of the essence of the invention

The invention has for its object to develop a method by which amino-i-hydroxy-alkane-1,1-bisphosphonic acids can be prepared from cheap, technically accessible and largely chlorine-free starting materials.

It has been found that the phosphorus (III) oxide, P ₄ O ₆ , which is technically readily available and inexpensive to produce, is prepared with aminoalkanoic acids having 2-8 C atoms or their salts or derivatives to give amino-1-hydroxy-alkane-1,1- bisphosphonic in a molar ratio between 1: 1 and 1: 3, preferably 1: 2 can be reacted, if these starting materials in an opposite phosphorus (lll) oxide inert organic solvent, preferably dioxane, a longer time to temperatures of about 370K

to be heated. , j;

After hydrolysis with water or acids, the bisphosphonic acid can easily be separated from the reaction mixture in yields of 40-70%. Occasionally occurring small amounts of red-yellow low Phdsphorsuboxiden can either by filtration or oxidation, z. B. with hydrogen peroxide can be removed. The use of Anhinoalkancarbonsäurehydrochloriden resulting, to other methods comparatively low amounts of HCL (1 mole per mole of carboxylic acid) can be reused for re-representation of the required Aminoalkancarbonsäurehydrochloride.

Exemplary embodiments Example 1

0.1 mol of β-alanine hydrochloride are auspensiert in 50ml of 1,4-dioxane, mixed with 0.05MoI P ₄ O ₆ and stirred for about 15min. Then, the reaction mixture is slowly heated to boiling and refluxed for 3 hours. The resulting semi-solid mass is brought into solution with 15 ml of water and optionally filtered. The filtrate is refluxed for about 2-3 hours, upon cooling, 65.4% pure 3-amino-1-hydroxy-propane-1,1-bisphosphonic acid crystallize, the yield can be increased by precipitating the filtrate with methanol or acetone

Q .: 220-2 ⁰ C; ³¹ PNMR: triplet, σ = 17.4ppm

Example 2:

0.1 mol of β-alanine suspended in 40 ml of dioxane are reacted with 0.05 mol of P ₄ O ₆ , as described under 1. Yield: 36.8% pure bisphosphonic acid.

Example 3:

0.1 mol of e-amino-caproic acid hydrochloride are suspended in 50 ml of dioxane and reacted with 0.05 mol of P ₄ O ₆ as in 1. The resulting solution after hydrolysis is precipitated with twice the amount of acetone. Yield: 62.8% e-amino-i-hydroxy-hexane-ii-bisphosphonic acid

F .: 200 ^° C. "

Example 4:

0.1 mol of D, L-alanine are reacted with 0.05 mol of phosphorus (III) oxide in 30 ml of dioxane as described under 1. and hydrolyzed. The hydrolysis solution is precipitated with three times the amount of methanol or acetone. Yield: 38.7% of 2-amino-1-hydroxy-propane-1,1-bisphosphonic acid.

Claims (1)

-ι- 255 999 5 Invention claim: A process for the preparation of amirto-i-hydroxyalkane-ii-bisphosphonic acids, which comprises reacting an arninoalkanecarboxylic acid having 2-8 C atoms or salts or derivatives thereof with phosphorus (III) oxide in a molar ratio of between 1: 1 and 3 : 1, preferably 2: 1, in a solvent inert to phosphorus (III) oxide, preferably 1,4-dioxane, at a temperature between 330 and 430K, preferably 370K, and the reaction mixture is hydrolyzed with water or acid.