CZ189394A3 - Process for preparing 1,2-diaminoethane-n-n-n°n°-tetrakis(methylenephosphoni) acid monohydrate - Google Patents

Abstract

Monohydrate of 1,2-diaminoethane-N,N,N',N'-tetrakis-(methylenephosphonic acid) of structural formula I is prepared so that first of all 1,2-diaminoethane dihydrochloride is prepared by the precipitation of 1-2-diaminoethane with dry hydrogen chloride in diisopropylether dried before the use by the metal sodium, the precipitate is drained, washed with diethyl ether and dried for 60 minutes in an evacuated desiccator above sulphuric acid, and then 1 mole of freshly precipitated 1,2-diaminoethane dyhydrochloride is mixed with 2 moles of azeotropic hydrochloric acid and 4.25 moles of orthophosphorous acid, the mixture is heated to 100 to 110 degrees C until dissolution of the precipitate, and then 4.5 moles of formaldehyde in the form of 34 to 36% solution is added drop by drop at the above-mentioned temperature, and after adding all the formaldehyde the mixture is stirred at the above-mentioned temperature for 60 minutes, then the reaction mixture is cooled down to 50 degrees C and is purified by repeated extraction with penthanol, and after purification the product is separated by the precipitation of the reaction mixture in isopropanol, and after the separation of the precipitate and washing it with methanol the precipitate is dried above sulphuric acid at a pressure of 3 kPa for 3 to 5 days.<IMAGE>

Description

Process for the preparation of 1,2-diaminoethane monohydrate-N, N, N ', N' -tetrakis (methylenephosphonic acid)

Technical field

The present invention relates to 1,2-diaminoethane (methylenephosphonic acid) monohydrate (EDTMP.H _and O).

iTFs f = | O Ζ »Q j <*).

? l> 4 [<-) c □ pos ^ hp

O tr *.

C <

preparation

-UljíjíLn- - tetrakis

BACKGROUND OF THE INVENTION

Complexes of diphosphonic acids with technetium-99m have a high affinity for both hydroxyapatite and amorphous calcium phosphate, which are the main constituents of the bone structure. tissue and monitoring of regional changes of bone mineral image during tumor, metabolic and degenerative processes. The complexes can not be used for radiotherapy as none of the fourteen technetium radioisotopes allowed suitable for this purpose vlastnosti.Nejbližší homologue technetium radioisotope of rhenium has suitable characteristics for radiotherapy / 186 and rhenium ^[Re-lee 90.64 H, 1.07 Mev, β '(77% ), 0.934 MeV fl (23%), 137 keV gamma (9.2%)] However, in vivo, rhenium is released from the complex by oxidation to rhenistan, resulting in rapid elimination of the radioactive element from the bones and increased excretion from the body. More suitable radionuclides for therapy have elements from the third subgroup of the periodic system, including rare earth metals. It has particularly advantageous properties and ease of preparation [ ^X33 Sm-46.27 h, 0.805 MeV fl '(20%), MeV fl' (30%), 103 keV gamma (29.8%)].

Unfortunately, the metals of the subgroups form so weak complexes as diphosphonic acid M ³ * · cations that under in vivo conditions the M ³ * cation binds from the diphosphone complex and binds to complexing blood components, particularly plasma transferrin. The radionuclide is not accumulated in the bone skeleton but is excreted predominantly by the hepatobiliary system. This disadvantage is overcome by aminopolyphosphonic acid ligands, forming sufficiently strong complexes with trivalent cations that resist transferrin activity in vivo. These ligands need to be prepared in high purity to achieve the samarium radionuclide 153 0.710 MeV fl '(49%), 0.640 highest cumulation of the radionuclide complex in the bone skeleton, and at the same time rapid blood clearance. S. Jurrison, D. Berning, Wei Jia, and Dangshe Ma: Coordination Compounds in Nuclear Medicine, Chem. Rev. 93,148, (1993).

The simplest known procedure for the preparation of this compound is direct synthesis using the Mannich type reaction. The reaction is carried out _r β · in a strongly acidic aqueous medium according to the scheme:

110 [deg.] C., 60 min.

H N-CH-CH -NH + 4 CH = O + 4 H PO --------------> EDTMP

2 2 2 2 3 4

- 4 H _and O

Moedritzer K., Irani R.:”The direct synthesis of alpha-aminomethylphosphonic acid. Mannich-type reaction with orthophosphorous acid. ”J.org.Chem.31, 1603, (1966) .1 _{= III} ,

According to this reaction, technological processes have been described which use up to 100% excess of formaldehyde and orthophosphoric acid, yet in the reaction mixture, besides polymeric products, 1,2-diaminoethane-N-methyl- N, N ·, N'-tris (methylenephosphonic), which cannot be separated from EDTMP by conventional techniques, e.g. crystallization, and whose complexes have other pharmacological properties.

SUMMARY OF THE INVENTION

It eliminates the disadvantages of the technological processes used so far

way preparation of the monohydrate of acid 1,2 - diaminoethane- Ν, Ν, Ν ', N- '- tetrakis (methylenephosphonic) [EDTMP. H 0] structural 3 ^J of formula I HO P - CH CH - PO H 2 3 2 AND 2 3 2 AND 1 N - CH - CH , 1 - N .HO (I) 2 AND 2 and '' l P 0 P - CH 2 3 2 CH - PO H 2. 3 2

in a purity for radiopharmacy, consisting in the reaction of a mixture of a diaminoalkane derivative, phosphorous acid and hydrochloric acid with formaldehyde, the principle of which is to first prepare a fresh precipitate of 1,2-diaminoethane dihydrochloride by precipitating 1,2-diaminoethane with dry hydrogen chloride in diisopropyl ether; was dried with sodium metal before use, the precipitate was filtered off with suction, washed with diethyl ether and dried for 60 min in an evacuated desiccator over lactic acid, and then 2 moles of azeotropic hydrochloric acid and 4.25 moles were added to 1 mole of freshly precipitated 1,2-diaminoethane dihydrochloride. orthophosphoric acid, the mixture is heated to 100-110 ° C until the precipitate is dissolved and 4.5 moles of formaldehyde in the form of a 34-36% solution are added dropwise at this temperature, and the mixture is further stirred at this temperature for 60 min. then the reaction mixture is cooled to 50 ° C and After purification by repeated extraction with pentanol, after purification, the product is isolated by precipitation of the reaction mixture in isopropanol and, after separation of the precipitate and washing with methanol, the precipitate is dried over sulfuric acid at a pressure of 3 kPa for 3-5 days.

The process according to the invention uses a precisely graded excess of orthophosphoric acid and formaldehyde to 1,2-diaminoethane dihydrochloride freshly precipitated in diisopropyl ether. The molar ratio of the reactants is maintained as follows: 1,2-diaminoethane dihydrochloride / hydrochloric acid / orthophosphoric acid / formaldehyde = 1/2 / 4.25 / 4.5. The impurities that are formed in the reaction mixture despite these measures are finally removed by extraction with n-pentanol at elevated temperature. The purified reaction mixture is then precipitated in isopropyl alcohol to isolate the monohydrate - EDTMP.O, which is stable even under vacuum drying over sulfuric acid.

The complexes of EDTMP.H2O thus prepared with the radionuclides samarium 153, technetium 99m and indium 111 rapidly accumulate in the bone skeleton of rats. A. Laznickova, M. Laznicek, F. Budsky, J. Prokop, K. Kopicka: Biodistribution of EDTMP Complexes with Tc-99m, In-III and Sm-153 ”, Plzen.born.Sborn., Suppl.68,1993 : 155-158.

Full pharmacological testing and preclinical testing was performed with the Samaria 153 complex, which has the most advantageous properties for use in radiotherapy. The results obtained were submitted in October 1993 to the Commission for New Radiopharmaceuticals, which in 1994 authorized the first phase of the clinical trial. Based on results

Phase 1 of the Clinical Trial was then approved by the Commission in May 1994 to conduct Phase 2 of the Clinical Trial.

Overview of the drawings

The attached drawing shows the time dependence of the accumulation of EDTMP.H 0 complexes with radionuclides in the bone skeleton of rats.

in 600 ml solution was stopped

DETAILED DESCRIPTION OF THE INVENTION

Example 1.

mole of 1,2-diaminoethane was dissolved in sodium metal-dried diisopropyl ether and bubbled with dry hydrogen chloride until a precipitate formed. The resulting bulky white precipitate was aspirated and washed with dry diethyl ether. The 1,2-diaminoethane dihydrochloride precipitate was then dried for 60 min in a vacuum desiccator over sulfuric acid.

To a 500 ml three-necked flask (equipped with a stirrer, reflux condenser, thermometer and divider) was added 200 mmol of 1,2-diaminoethane dihydrochloride and 400 mmol of azeotropic hydrochloric acid prepared by distillation in a quartz apparatus. Further, 850 mmol of solid acid was added to the mixture. orthophosphorite, the content of which was determined by alkalimetric titration. The mixture was slowly warmed to 110 ° C with stirring until it dissolved. Thereafter, 900 mmol of formaldehyde as a 34-36% solution was added dropwise over 30 minutes at this temperature, the exact concentration of formaldehyde solution being determined by iodometric titration. After addition of all formaldehyde, the mixture was stirred under the above conditions for a further 60 min.

The reaction mixture was then cooled to 50 ^e C and to the mixture was added 80 ml of n-pentanol was stirred for 20 min. After 20 min, the mixture was transferred to a separator without cooling and the phases were separated. This operation was then repeated. The reaction mixture thus purified is poured into 500 ml of anhydrous isopropanol heated to 60 [deg.] C. while stirring under a thin stream or dropwise. A white precipitate formed which was aspirated and washed with methanol. The product was dried for 72 hours in a vacuum desiccator at 3 kPa pressure over 95% sulfuric acid. The resulting product is EDTMP.H ₂ O monohydrate,

Example 2

Dependence cumulation complexes EDTMP.H ₂ O radionuclides at the time of the bony skeleton rats is shown in the accompanying drawings, in which X-axis is time in hours, the Y axis is the percent accumulation of radioactivity based on the total radioactivity administered. Curve 1 shows the accumulation of Samaria 153 complex (Sm-EDTMP), Curve 2 of the indium 111 complex (In-EDTMP), and Curve 3 of the technetium complex 99m (Tc-EDTMP).

i f

Elementary

Content of element

Calculated

Found analysis:

% C

15.86

15.92

H

4.88 5.10

N P

6.17 27.30

6.16 27.02

Infrared spectra (KBr tablet):

2616.2297 cm ^"1 n (PO-H), 1685 cm ^<-1 σ (ΡΟ-Η), 1437.1459 cm ^-1 H- (CH _3), 1207 cm ^-x N (CN), 1119 ^αη- χ ή (PO), 1015,957 cm -1 (CPO).

¹ H-NMR spectra (sodium salt D ₌ O):

3.776 bs, 4H (CH ₂ N), 3.488 bd, 8H (J = 12.0 Ηζ, Ρ-CH 2 -N)

EDTMP.H ₂ O was titrated as hexahydric acid with two points of inflection at pH = 4.0 (3 equivalents) and pH = 8.8 _(t 6 equivalents). Two protons are coordinated to nitrogen atoms (zwitterion structure) *

Industrial applicability

1,2-Diaminoethane monohydrate - Ν, Ν, Ν ', Ν' - tetrakis (methylenephosphonic acid) [EDTMP.H ₂ O] prepared by the process of the invention is useful for the preparation of complexes with suitable radionuclides and these complexes for palliative analgesic treatment of malignant tumor dissemination into the bone skeleton.

lίσσ σα OH, OHlAfOS Μ 9'dd

Claims (2)

PATENT CLAIMS 9 6, J J 0 GISOO Process for the preparation of 1,2-diaminoethane monohydrate-N, N, N - (1 '- ^X) tetrakis (methylenephosphonic acid) [EDTMP.H 0] HO P - CH 2 3 2 CH, - PO H 2 3 2 N - CH - CH - N 2 2 • H _and O (X) P 0 P - CH 2 3 2 CH - PO H In a purity for radiopharmacy, consisting in the reaction of a mixture of a diaminoalkane derivative, phosphoric acid and hydrochloric acid with formaldehyde, characterized in that a fresh precipitate of 1,2-diaminoethane dihydrochloride is first precipitated by precipitation of a diaminoalkane derivative; 2-diaminoethane with dry hydrogen chloride in diisopropyl ether, which was dried with sodium metal before use, the precipitate is filtered off with suction, washed with diethyl ether and dried in an evacuated desiccator over sulfuric acid for 60 min. 2 moles of azeotropic hydrochloric acid and 4.25 moles of orthophosphoric acid, the mixture is heated to 100-110 ° C until the precipitate is dissolved, and 4.5 moles of formaldehyde in the form of a 34-36% solution are added dropwise at this temperature. the mixture was further stirred at this temperature for 60 min after the addition of all formaldehyde, after which the reaction mixture was cooled The product was isolated by precipitation of the reaction mixture in isopropanol and after separation of the precipitate and washing with methanol, the precipitate was dried over sulfuric acid at 3 kPa for 3-5 days.