Preparation of phosphonic acid derivatives

Details Preparation of phosphonic acid derivatives Preparation of phosphonic acid derivatives

2000-09-05

2001-04-10

Ambrose, Michael G. (Department: 1626)

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

Organic compounds

Phosphorus esters

C558S087000, C558S217000, C562S008000, C562S022000

Reexamination Certificate

active

06215013

ABSTRACT:

The present invention provides a novel method for the preparation of phosphonic acid derivatives, especially alkene diphosphonic acids e.g. vinylidene diphosphonic acid (VDPA) and salts thereof. Said phosphonic acids and salts are produced in a purer form than has hitherto been achieved and in a high yield.
VDPA exhibits greater chelancy than VPA. VDPA is known for use as a chelant for metals and for use in pharmaceutical applications. VDPA and VPA may be used in combination with each other according to the required properties of the mixture, depending upon the application in question. Because of its ability to polymerise, VDPA may be used as a copolymer with other polymerisable compounds.
VDPA is conventionally prepared from either methylene bis phosphonates, or from diphosphonic acid derivatives.
U.S. Pat. No. 3,686,290 describes the preparation of VDPA salts from the tetrasodium salt of 1-hydroxy, 1-ethylidene diphosphonic acid, at a pyrolysis temperature of from 300° C. to 500° C., preferably 350° C. to 425° C. However the product is typically obtained in low yields.
EP-0-252-244 describes the preparation of VDPA salts from the sodium salt of 1-(O-acyl)ethane-1,1-diphosphonic acid, at a temperature of between 200° C. to 250° C. However the product is typically obtained in a maximum yield of 75%.
The preparation of VDPA from bis phosphonates, using a two step procedure involving the base catalysed reaction of an ethylene bis(phosphonate)ester with paraformaldehyde followed by acid catalysed elimination of methanol and conversion to the free acid by reaction with bromotrimethylsilane is described in J. Org. Chem 1986, 51,3488-3490.
It has been found that alkene diphosphonic acids and their derivatives produced by this method typically exhibit a purity of less than 80 mol %, and were produced in low yield.
The multistage production of VDPA and its derivatives from methylene diphosphonate and bis(diethylamino)methane using temperatures of 170-180° C. is described by Prishchenko et al in
Zhurnal Obshchei Khimii
. Vol 61. No.4.p.1018. It has been found that this method produces low yields (58%), and products of low purity.
There are several disadvantages associated with the known methods of preparation of alkene diphosphonic acids, although not all disadvantages may be associated with each known method. Some require high dehydration temperatures, typically above 400° C., to produce the alkene diphosphonic acids. This is above the decomposition temperature of approximately 285° C. of tetra-sodium VDPA and hence products are obtained in a low yield and are of low purity due to the presence of high amounts of esters of the aforementioned acids. The methods of preparation of the prior art typically provide products of, for example, 50 mol % to 80 mol % purity. This may be unacceptably low for some uses, for example pharmaceutical applications. Furthermore due to the impure products typically obtained by said known methods of preparation longwinded and cumbersome purification methods are frequently required.
There is therefore a requirement to provide a method of preparation of alkene phosphonic acids, such as VDPA which produces the reaction product in a stable, purer form than has hitherto been possible, whilst being obtained in a high yield. Furthermore the method of preparation should preferably require the products to undergo minimal purification.
We have now discovered that alkene phosphonic acids e.g. VDPA may be prepared from the salts of &agr;-hydroxy-alkane diphosphonic acid dimers or the corresponding acids thereof, by the dehydration of the reactant followed by the low temperature pyrolysis thereof. The dehydration and pyrolysis may be carried out in the presence of a heat transfer agent.
The alkene phosphonic acids prepared by the method of the invention are obtained in high yield and in a substantially pure form.
According to one embodiment, the present invention provides a method of preparation of alkene phosphonic acids or salts thereof of general formula (I):
wherein each R
2
is independently H, an alkyl group, an alkali metal, an alkaline earth metal, or a nitrogen-containing group;
R
3
and R
4
are independently H, or an alkyl group; and R
5
is H, an alkyl group or
wherein said method comprises the steps:
(a) the azeotropic removal of water from the reactant of general formula (II)
wherein R
1
is CHR
3
R
4
;
R
2
, R
3
, R
4
and R
5
are as hereinabove defined; and
X is a number between 0 and 20,
(b) the pyrolysis of the dehydrated reactant (II) at a temperature of from 170° C. to 300° C., and
(c) optionally, conversion of any anhydrides formed during stage (b) to the corresponding acid or salt having the general formula (I).
According to a second embodiment, the present invention provides a method for the preparation of alkene phosphonic acids or salts thereof of general formula (I) as hereinabove defined, wherein
(a) said azeotropic removal of water from said reactant (II) is carried out by dehydrating a reactant of general formula (II) in the presence of at least one inert liquid heat transfer agent which exhibits effective azeotropic properties with water and which is liquid at the reaction temperature; and
(b) said pyrolysis of dehydrated reactant (II) is carried out by adding at least one inert heat transfer agent which is liquid at the reaction temperature to the reaction mixture from (a), and the reaction mixture is maintained at 170° C. to 300° C. until pyrolysis of the dehydrated reactant (II) is complete
According to a third embodiment, the present invention provides a method of preparation of the alkene phosphonic acids or salts thereof of general formula (I) as defined hereinabove, wherein pyrolysis of the dehydrated reactant (II) at a temperature of from 170° C. to 300° C. is in the presence of at least one base, and optionally at least one inert heat transfer agent.
Reactants and Products
The alkene phosphonic acids are produced from a cyclic reactant of general formula (II) as given hereinabove, which may be present either as a salt or as the acid. Suitable salts of the acid include amongst others the alkali metal, alkaline earth metal, or nitrogen-containing salts. The alkyl groups R
2
, R
3
and R
5
are preferably each C
1
-C
6
alkyl groups. The or each nitrogen-containing group R
2
is preferably an amine salt. Particularly preferred as a reactant is the hexa-sodium salt of ADPA dimer [Formula (II) wherein R
1
is CH
3
,
and R
2
is Na]
Said reactant (II) may be produced in situ without being isolated and said reactant may be subsequently converted to a compound having the general formula (I) i.e. by means of a multistage preparation incorporating the process of the present invention. An example of such a multistage reaction is the conversion of phosphorous acid and acetic anhydride to the sodium salt of ADPA dimer, followed by the conversion of said dimer to VDPA by the process of the present invention. Alternatively the process of the present invention may be used to convert the isolated cyclic reactant e.g. ADPA dimer or the sodium salt thereof, to the alkene phosphonic acid (I).
The reactant may be added to the reaction vessel as a solid or as a solution e.g. an aqueous solution.
The present invention provides a particularly advantageous method for the preparation of alkene diphosphonic acids of general formula (I).
Reaction Conditions
Any one or more of steps (a), (b) and (c) of the method of the invention may be carried out under reduced pressure. Alternatively any one or more of steps (a), (b) and (c) of the method may, if required, be carried out at pressures greater than atmospheric pressure.
According to the present invention, stage (a) and/or stage (b) may be carried out in the absence of heat transfer agents, for example by heating the reactant (II) under vacuum to dehydrate and/or pyrolyse said reactant (II).
Heat Transfer Agents
Preferably, both of stages (a) and (b) of the reaction are carried out in the presence of heat transfer agents. However stage (a) and/or stage (b) may be carried out in the absence of s

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