CS276287B6 - Process for preparing diastereisomers of 4,8-diaza-3,6,6,9-tetramethyl undecane-2,10-dione bisoxime - Google Patents

Abstract

The solution falls within the area of organic- chelating compounds with metallic compounds cations and diastereomer complexes d, l- -HM-PAO with technetium-99m can be used for brain scintigraphy in nuclear medicine. Preparation of diastereomers 4,8-diaza-3,6,6,9- -tetramethylundecane-2,10-dionbisoxime (meso-HM-PAO and d, l-HM-PAO) two-stage synthesis, and is prepared in the first step condensation of diacetone monoxime with 2,2- -dimethyl-1,3-diaminopropane in the medium benzene and under moderate acid cation exchange catalysis 4,8-diaza-3,6,6,9-tetramethyl \ t -3,8-diene-2,10-bisoxime and from it by reduction sodium borohydride in ethanol a solution of a mixture of meso-HM-PAO and d, l-HM-PAO, wherein the strongly enriched meso-HM-PAO crystallizes already when thickening the solution and strongly the enriched d, l-HM-PAO is extracted with chloroform from the filtrate after separation of the crystals, then the two enriched forms are repeatedly repeated crystallization from ethyl acetate.

Description

The invention relates to a process for the preparation of diastereomers of 4,8-diaza-3,6,6,9-tetramethylundecane-2,10-dione bisoxime.

Said compound is usually referred to by the simple abbreviation HM-PAO derived from the alternative name hexamethylene-propyleneamino oxime and exists in the two diastereomers meso-HM-PAO ad, 1-HM-PAO. The practical significance of HM-PAO is that it is able to form lipophilic chelates with a wide range of cations, for example with Ni ^ ⁺ , Co ^ ⁺ , Cu ^ ⁺ , TcO ^ ⁺ and others. The HM-PAO complex with technetium-99m is used for cerebral blood flow (CBF) scintigraphy in nuclear medicine.

The synthesis of HM-PAO has been described by R. D. Neirinckx et al., J. Nucl. Med., 28, 191-202 (1987). The first step in the synthesis is the condensation of the diacetone monooxime of formula I with 2,2-dimethyl-1,3-aminopropane of formula II to 4,8-diaza-3,6,6,9-tetramethylundecane-3,8-diene-2,10-dionbisoxime formula III, which according to the above authors takes place in an environment of acetic acid and benzene (3: 2 vol.) and in a nitrogen atmosphere according to the equation:

? ^H 3

CH, - CO + CH ₀ - C - CH „ii 2। _t 2

CH ₃ - C - NOH NH ₂ CH ₃ NH ₂

CH ₃ CH

---- *

CH ₂ ^Z 0¾

CH- - C = N. N = C - CH, ti 3

CH ₃ - C - NOH HON - C - CH ₃

III

The iminodioxime of formula III then provides, by reduction with sodium borohydride in ethanol, saturated dioxime existing in two diastereomers, meso-HM-PAO of formula IV and d, l-HM-PAO of formula V according to the equation:

NaBHe lil

CHe CHe

NH NH

CH ₃ / \ CH

^. ^c C ^

H ’’ II H

C = NN = C / ii \

CH ₃ OH PH CH ₃ ch ₃ ch c

CH _E CHe

NH. NH

CH ₃ I \ H

Η II 'CH ₃

C = NN = C / II \

CH ₃ OH OH CH ₃

IV

CS 276287 B6 2

However, under the conditions described in the above work, these substances cannot be prepared because the reaction of a compound of formula I and a compound of formula II in acetic acid and benzene produces predominantly dimethylglyoxime instead of the iminodioxime of formula III.

These deficiencies are overcome by a process for the preparation of diastereomers of 4,8-diaza-3,6,6,9-tetramethylundecane-2,10-dionbisoxime, meso-HM-PAO ad, 1-HM-PAO, by reacting diacetone monooxime with 2,2-dimethylaminopropane under formation of 4,8-diaza-3,6,6,9-tetramethylundecane-3,8-diene-2,10-dionbisoxime and reduction of the resulting product with sodium borohydride in ethanol, according to the invention. The essence of the invention is that the condensation of diacetone monooxime with 2,2-dimethyl-1,3-aminopropane takes place only in the environment of benzene in the presence of a weakly acidic cation exchange resin and it is not necessary to use nitrogen atmospheres, the resulting 4,8-diaza-3,6,6,9 -tetramethylenundecane-3,8-diene-2,10-dionbisoxime is then subjected to reduction with sodium borohydride in ethanol, after completion of the reduction and dilution of the reaction mixture with water, the ethanol is distilled on a rotary evaporator from a 40 ° C bath at a pressure of 2.5 to 3.5 kPa . During this slow concentration, a crystalline substance is precipitated when a magnetic stirrer is placed in the rotating flask, which aids in friction crystallization as the flask rotates. The concentrated residue is diluted again with water, shaken and filtered. The crystalline product obtained on the filter is strongly enriched in the form of meso-HM-PAO. The aqueous alkaline filtrate is shaken several times with chloroform, and the combined extracts are evaporated to a syrupy liquid which, after dilution with ethyl acetate, gives a portion strongly enriched in the form of d, l-HM-PAO. Both enriched forms are further purified by repeated crystallization from ethyl acetate.

The process described allows efficient and rapid separation of the mixture of diastereomers of formula IV and V.

The invention is further illustrated by specific examples.

Example 1

To a solution of 120 mmol diacetone monooxime in 100 mL benzene was added 300 mg of weakly acidic Amberlite IRC-50 cation exchange resin. The mixture was stirred and heated to reflux the benzene vividly. A solution of 50 mmol of 2,2-dimethyl-1,3-diaminopropane in 100 ml of benzene was added dropwise to this solution over four hours. A Dean-Stark attachment was attached to the apparatus to separate the azeotropically distilled water formed in the reaction. After addition of all the 2,2-dimethyl-1,3-aminopropane solution, the mixture was heated for an additional 17 hours to give a clear yellow solution of the iminodioxime of formula III. A small amount of dimethylglyoxime crystals, which also formed during the reaction, precipitated on the walls of the flask. The clear yellow solution was poured off and concentrated on a rotary evaporator. The precipitated needle crystals were filtered off and dried in vacuo. 34.5 mmol of product of formula III were obtained.

Example 2 mmol of the product obtained in Example 1 were dissolved in 60 ml of 96% ethanol at 0 ° C + 5 ° C and 27 mmol of sodium borohydride were added gradually in small portions with stirring. The reaction mixture was stirred at this temperature for a further 2 hours and after the addition of 25 ml of water for a further 1 hour at room temperature. The mixture was then concentrated on a rotary evaporator at a bath temperature of 40 DEG C. and a pressure of 3 kPa, and a magnetic stirrer was placed in the rotating flask. Crystals gradually formed in the mixture, and once the ethanol had stopped distilling off, 30 ml of water was added to the residue. The precipitated crystals were filtered off and, after three crystallizations from ethyl acetate, gave 3.7 mmol of pure meso-HM-PAO, m.p. 143-145 ° C in the form of acicular crystals.

The aqueous filtrate was shaken several times with chloroform, and the combined extracts were concentrated to give a syrupy liquid. After diluting this syrupy liquid with ethyl acetate, crystals precipitated which, after five crystallizations from ethyl acetate, gave 1.5 mmol of pure d, l-HM-PAO with m.p. 131 ° C in the form of massive prismatic crystals. Both isomers provided the corresponding elemental analysis (C, Η, N)

Claims (1)

Process for the preparation of diastereomers of 4,8-diaza-3,6,6,9-tetramethylundecane-2,10-dionbisoxime, mesoad, 1-hexamethylene-propylene-aminooxime, by reaction of diacetone monooxime with 2,2-dimethyl-1,3- aminopropane to give 4,8-diaza-3,6,6,9-tetramethylundecane-3,8-diene-2,10-dionbisoxime and reduction of the resulting product with sodium borohydride in ethanol, characterized in that the reaction of diacetone monooxime with 2, The 2-dimethyl-1,3-aminopropane is catalyzed by a weakly acidic cation exchange resin and, after reduction of 4,8-diaza-3,6,6,9-tetramethylundecane-3,8-diene-2,10-dionbisoxime, the ethanolic solution is diluted with water. and concentrated by slow distillation of ethanol at a bath temperature of 40 DEG C. and a pressure of 2.5 to 3.5 kPa on a rotary evaporator with a magnetic stirrer. recrystallization three times from ethyl acetate to give the pure mesoform, the filtrate is further extracted repeatedly with chloroform after dilution with water, and the combined extracts are concentrated to dryness. a husky liquid from which, after dilution with ethyl acetate, crystals strongly enriched in d, 1-hexamethylene-propylene-aminooxime precipitate, which are recrystallized five times from ethyl acetate to give the pure d, l-form.