CS276850B6 - Process for preparing methylenediphosphonic acid - Google Patents

Abstract

The solution falls into the field of preparation of organic compounds forming chelates with metal cations and the chelate of methylenediphosphonic acid with technetium-99m can be used as a radiodiagnostic agent for visualization of the bone skeleton. The problem of preparation of methylenediphosphonic acid by thermal decomposition of its tetraisopropyl ester to form propene, which is separated from the reaction mixture as a gas and methylenediphosphonic acid, which remains in the residue from which it is obtained by dissolving in acetic acid and subsequent crystallization is solved.

Description

The present invention relates to processes for the preparation of methylenediphosphonic acid, the complexes of which with technetium-99m are used in nuclear medicine for imaging the skeletal skeleton.

Methylenediphosphonic acid is usually prepared by acidic deesterification of its alkyl esters. Essentially two main methods of preparation are known for the preparation of alkyl esters of methylenediphosphonic acid, the other methods being considered as modifications.

The first method is based on halogenated methylphosphonic acids resp. their esters. These substances by the action of sodium dialkyl phosphite / Schwarzenbach G.akol. · - Monatsch.Chem. 81.202.1950; Richard J.J. et al .: J. Am.Chem.Soc. 83, 1722, 1961 / or trialkyl esters of phosphorous acid (Ginsburg V.A .: Ž-obšč.chim. 28,728,1958 / provide methylenediphosphonic acid alkyl ester.

The second method uses essentially the same reactions as the first method. The starting material is diiodomethane and the required iodomethylphosphonic acid is formed as an intermediate in the reaction of diiodomethane with sodium dialkylphosphate or with a trialkyl phosphorous acid ester to form the methylenediphosphonic acid alkyl ester solapoff G.M .:

acids / Cade J.A .: J.Chem.Soc.

J. Am.Chem.Soc. 75,1500,1953 /.

81,2266,1959; A substantial and very practical improvement of the second method is described in U.S. Pat. No. 3,251,907. The starting materials are dibromomethane and triisophosphoric acid ester. The reaction produces 2-bromopropane, which is separated from the reaction mixture by distillation through a heated column during the reaction. In this embodiment, methylenediphosphonic acid tetraisopropyl ester is obtained.

From the esters obtained by the above procedures, methylenediphosphonic acid is obtained by heating with concentrated hydrochloric acid for at least 8 hours. The reaction mixture must be further evaporated to dryness to remove any hydrochloric acid and the crude methylenediphosphonic acid obtained must be purified by recrystallization from acetic acid.

These disadvantages are overcome by the process of the invention which uses the previously described reaction of dibromomethane with triisophosphoric acid ester, but the resulting methylenediphosphonic acid tetraisopropyl ester is not isolated from the reaction mixture but subjected to thermal decomposition directly in the reaction mixture at 188 ° C to 195 ° C to give propene and methylenediphosphonic acid. The resulting propene is separated from the reaction mixture as a gas, and crude methylenediphosphonic acid remains in the reaction mixture according to the reaction:

/ f‘0 OC3 Hv 2 C

PO OC3 Hv 2

PO3 H2

--------> U2 C ^X ^ 803 Ha

CH3-CH = CH2

The crude methylenediphosphonic acid is purified by crystallization from acetic acid.

The advantage of this process is in particular that all operations up to crystallization are carried out in the same reaction vessel and it is not necessary to deesterify methylenediphosphonic acid tetraisopropyl ester by heating with concentrated hydrochloric acid for 8 hours and then remove the hydrochloric acid by evaporation to dryness. The process leads to an increase in the yield and purity of the substance, to a reduction in labor and a substantial shortening of the preparation time.

The following example illustrates the embodiment.

Example

720 mmol of phosphoric acid triisopropyl ester and 300 mmol of dibromomethane are added to a 500 ml two-necked reaction flask. A thermometer with a measuring range of up to 250 ° C is introduced into one mixture through one neck and the other neck of the flask is fitted with a rain column heated with water from a thermostat to 70 ° C. The flask with the reaction mixture was slowly heated in a silicone oil bath so that in 6 hours the temperature of the reaction mixture reached a value in the range of 150 ° C to 160 ° C. Isopropyl bromide is separated from the reaction mixture by distillation, and the reaction mixture is maintained under the above-mentioned conditions until the isopropyl bromide stops distilling; the usual reaction time is 4 to 6 hours. The reaction mixture is then heated slowly to 188 ° C to 195 ° C and the thermometer is closely monitored until the temperature in the reaction mixture drops (about 30 ° C) accompanied by the vivid evolution of propene. The reaction mixture is then reheated to 188 ° C to 195 ° C and left within this temperature range for 15 minutes until all of the propene has escaped from the mixture. The bath and reaction mixture were then cooled and the crude methylenediphosphonic acid was dissolved in a minimum amount of boiling acetic acid and the solution was removed from the reaction flask. A solution of methylenediphosphonic acid in acetic acid was concentrated to crystallize and allowed to crystallize overnight. The precipitated crystals were washed with ethanol and dried in vacuo.

The methylenediphosphonic acid thus prepared can be used as a radiodiagnostic means of bone skeletal visualization after neutralization to disodium technetium-99m, which can be used in nuclear medicine for silos for the preparation of the complex.

Claims (1)

PATENT CLAIMS Process for the preparation of methylenediphosphonic acid by reaction of dibromomethane and phosphoric acid triisopropyl ester to give methylenediphosphonic acid tetraisopropyl ester, characterized in that the methylenediphosphonic acid tetraisopropyl ester formed is deesterified directly in the reaction mixture by raising the temperature to 188 ° C to 195 ° C to give deesterification. propene, which escapes from the mixture as a gas, and methylene ifosonic acid, which remains in the residue from which methylene ifosonic acid is obtained by dissolving in acetic acid and subsequent crystallization. End of document