Process for the preparation of diphosphonate derivatives

Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus esters

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558161, C07F 940

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060489952

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BRIEF SUMMARY
The present invention relates to a novel process for the preparation of diphosphonate derivatives. These compounds are disclosed in U.S. Pat. No. 5,128,331 as medicaments useful for lowering plasma lipid levels or blood pressure. A preferred compound has the following formula: ##STR4## Processes for the preparation of diphosphonate compounds are also disclosed in U.S. Pat. No. 5,128,331. However, these processes suffer from a number of disadvantages, for example moderate yield, requires the use of reagents such as titanium tetrachloride which are not ideal for large scale applications, generates excess waste for disposal, etc.
Therefore there is a need for further processes for the preparation of this type of compound which are suitable for large scale use, and give the product in high yield and purity. It has now been found that diphosphonate compounds of the above structure can be prepared in a `one-pot` procedure via reactive quinone methide intermediates which are unsubstituted at the 7-position.
In a first aspect the present invention provides a process for the preparation of a compound of formula (I): ##STR5## in which R.sup.1 and R.sup.2 are independently C.sub.1-6 alkyl groups; comprises reaction of ##STR6## in which R.sup.1, R.sup.2, and R.sup.3 are as defined in formula (I) and X is a leaving group, with a compound of formula (III): ##STR7## in which R.sup.4 and R.sup.5 are as defined in formula (I) in the presence of a base; arid optionally thereafter forming a salt.
Preferably X is a leaving group such as halo (e.g. Chloro), hydroxy, C.sub.1-6 alkoxy, phosphate, thiol and dialkylamino groups, for example dimethylamino: or monoalkyl/monoaralkyl amino groups such as monoalkyl monobenzyl amino groups; or diaralkyl amino groups such as dibenzyl amino and substituted dibenzyl amino groups; or a quaternary ammonium group such as trimethyl ammonium, or cyclic amino such as morpholino, piperidino or anilino.
Preferably the reaction is carried out in the presence of a suitable base. Examples include metal hydrides such as sodium and lithium hydride and metal hydroxides, particularly alkali metal hydroxides such as sodium hydroxide and metal alkoxides such as sodium t-butoxide. Other suitable bases are organometallic bases, for example grignard reagents such as methylmagnesium halides and organolithium bases such as alkyl and aryl lithium compounds, e.g. methyhlithium, buyllithium and phenyllithium.
Preferably the reaction is carried out in a suitable organic solvent. The organic solvent is generally a non-protic solvent, which may be polar or non polar. Examples of suitable solvents includes alkanes such as hexane or heptane, cyclic and acylic mono- and di-ethers such as dimethoxy ethane (DME) and tetrahydrofuran (THF); dimethylformamide (DMF) and aromatic hydrocarbons such as toluene and xylene. The reaction can be carried out at reduced, ambient or elevated temperature.
The solvent is preferably substantially free from water.
Optimum reaction conditions are dependent on the nature of the leaving group X, the reaction temperature and the solvent. When X is halo or a quaternary ammonium group, preferred solvents include n-hexane. Preferably the coupling reaction is carried out at reduced or ambient temperature, for example, from about -40.degree. C. to about 25.degree. C.
When X is hydroxy or dialkylamino preferred solvents include 1,2-dimethoxyethane and heptane. Preferably the coupling reaction is carried out at elevated temperature, most preferably at the reflux temperature of the mixture.
Most preferably X is dialkylamino, in particular dimethylamino and the reaction is carried out at a temperature of about 100.degree. C. Most preferably the reaction is carried out in heptane under reflux in the presence of sodium t-butoxide.
In compounds of formula (I) to (II) C.sub.1-6 alkyl groups can be straight chain or branched.
Suitably R.sup.1 and R.sup.2 are C.sub.1-6 alkyl groups and can be the same or different. Preferably R.sup.1 and R.sup.2 are identical. Most preferably R.sup.1 and R.sup.2 are both t-b

REFERENCES:
patent: 5043330 (1991-08-01), Nguyen et al.
patent: 5128331 (1992-07-01), Nguyen et al.
patent: 5153183 (1992-10-01), Kawabe et al.
Chem. Abstracts, vol. 120 (1994), p. 1213, abstract 164485, Sugioka, T., "Preparation of diazomethylenebisphosphonic acids as agrochemicals or pharmacuticals," JP 5,247,071 (Mar. 6, 1992).

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