DD300742A5 - With 99m [indtc] markable kit and method for the preparation of isonitrile ethers - Google Patents

Abstract

The invention relates to a diagnosable with exp 99m Tc diagnostic set of a metal salt adduct of an isonitrile ether of the formula (II), in which R is a straight or branched C ind2-8-alkylene optionally with a halogen, phenyl or Halogenphenylsubstituenten and R 'is a straight or branched C ind1-4-alkyl group, or a mixture of such adducts and 0.03 to 1.0 parts by weight of a reducing agent, based on the mass of the adduct, contains. The diagnostic reagent kit according to the invention further contains 0.5 to 5 parts by mass, based on the mass of the adduct, of an antioxidant, at least 10 parts by mass, based on the mass of the adduct, of a saccharide

Description

CN-R-OR '(II)

in which R and R 'have the meanings given in claim 1, characterized in that

a) a nitrite of the formula HO-R "-CN, wherein R" _f _ ₇ alkylene group means a straight or branched C and optionally a halogen, phenyl or Halogenphenylsubstituenten, in the presence of a Lewis acid catalyst with an alkylating agent of the formula R'-X, in which R 'has the abovementioned meaning and X is halogen or hydroxyl, reacting the resulting compound of the formula R'OR "-CN, in which R' and R" have the meaning given above a complex metal hydride is reduced, the resulting amine of the formula RO-R-NH ₂ , in which R and R 'have the above meaning, is formylated with formic acid or with a reactive formic acid derivative, and the resulting formylated compound is dehydrated, or

b) an amine of the formula RO-R-NH ₂ , in which R and R 'have the abovementioned meaning, is reacted in the presence of alkali metal hydroxide with chloroform, or

c) a compound of the formula R "= CH ₂ in which R" has the abovementioned meaning, in the presence of mercury dD acetate with an alcohol of the formula R'-OH, in which R 'has the above meaning, is reacted, the resulting A compound of the formula R'OR-HgOAc in which R and R 'have the abovementioned meaning and Ac represents acetate, with an alkali halide of the formula AIk-Hal, in which Alk is an alkali metal atom and Hal is a halogen having an atomic mass of about 36 is reacted, the resulting compound of formula R'OR-Hg-Hal, in which R, R 'and Hai have the above meaning, with a halogen of the formula HaI ₂ , in which "shark has the above meaning, is reacted, the resulting compound of formula R'OR-Hal, in which R, R 'un _u rial have the meanings defined above, is reacted with silver cyanide, and the resulting compound of the formula R'OR-NC · Ag-Hal, in which R, R 'and Hai have the above meaning, is treated with alkali metal cyanide.

The invention relates to a ^99m Tc markable diagnostic reagent set. The invention further relates to a process for producing isonitrile ethers which are precursors of the isonitrile ether metal salt adducts used as a constituent of the diagnostic kit of the invention

 It is known that technetium salts of the isonitrile ethers of the formula (I)

[(CN-R-OrV) ₆ ⁹⁹ Tc] ⁺ A- (I)

in the

R is an unbranched or branched C ₂ e-alkylene group optionally having a halogen, phenyl or halophenyl substituent,

R 'is a straight or branched C 1-4 alkyl group and

A "is a monovalent anion or one equivalent of a polyvalent anion

are advantageously used for the purposes of isotope diagnostics, in particular in the detection of Myokarderkrankungen. Salts or complexes of hexakis (C 1 -C 4 -alkyl-isonitrile) -technetium (I) cations are particularly frequently used for this purpose (Int. J. Nucl. Med. Biol. 11 [1984] p.225, J. Nucl Med. 25 [1984] p. 1350; Eur. J. Nucl. Med. 12

(1986) p. 219; J. Nucl. Med. 27 [1986] p. 404). These labeled salts or complexes are prepared by reacting a suitable isonitrile ether of formula (II),

CN-R-OR ' _m (II)

where R and R 'are as defined above, with a technetium salt or complex ^{containing 89m} Tc with an oxidation ^value greater than one; the reaction is carried out in the presence of a reducing agent (US-PS 4452774). This patent also describes a reagent set for the preparation of compounds of formula (I); the reagent kit consists of an isonitrile of the formula (II) and a reducing agent.

A disadvantage of the reagent set described in detail in US Pat. No. 4,452,774 is that it is difficult to handle and store because most of the isonitrile ethers of formula (II) are volatile.

According to the worship described in detail in EP-PS 183155, the disadvantages arising from the volatile nature of the isonitrile ethers are eliminated by treating the isonitriles of the formula (II) with a salt of a metal with 3d orbit and the Isonitrile ether metal salt Add.kto may be used in the work set instead of the isonitrile ethers. Besides the adduct, the reagent kit also contains a reducing agent. EP-PS 183155 describes the use of Zn, Cd, Hg, Ga, In, Tl, Sn, Pb and Bi salts, while in EP-PS 233368 the use of Cu , Mo, Pd, Co, Ni, Cr and Rh salts. It is noted in both patents that the nature of the counterion in the metal salt is not critical and, in addition, metal complexes can be used in place of the metal salts.

In the preparation of a radiodiagnostic substance, the reagent set according to the above-mentioned published European patent applications is reacted with a "Tc-containing technetium salt or complex having an oxidation value greater than one." The reaction is allowed to take place in an aqueous medium elevated temperature.

By the methods described in EP-PS 188155 and 233368, the problems associated with storage and handling of the reagent sets can be avoided. A disadvantage, however, is that a radiodiagnostic substance having insufficient stability is obtained in the reaction of a reagent kit comprising a reducing agent and an isonitrile ether-metal salt adduct with a ^09m Tc ion source. This can be attributed to the fact that the isonitrilather ligands linked to the "Tc ion decompose relatively rapidly, and hence the amount of the radioactive ion-bearing ligands is no longer sufficient several hours after the radiodiagnostic substance is produced to carry out the diagnostic measurement.

The aim of the invention is to provide a diagnostic reagent set which, upon reaction with a ^Wm Tc ion source, provides a radiodiagnostic substance which is stable over a longer period of time, ie, in which the degradation of the isonitrile ether ligands is considerably delayed ,

It has been found that the above-mentioned requirements can be fully met when a diagnostic reagent kit of known composition containing an isonitrile ether-metal salt adduct and a reducing agent is replaced by a protective colloid which is a saccharide and / or an amino acid of the Formula H ₂ N- (CH ₂ I _n -COOH, where η is an integer from 1 to 4, a buffer and an antioxidant is completed.

On this basis, the invention relates to a " ^m Tc-markable diagnostic reagent set which comprises a metal salt adduct of an isonitrile ether of the formula (II) in which R and R 'have the meanings mentioned above, or a mixture of such adducts and 0.03 The diagnostic reagent kit according to the invention further contains 0.5 to 5 parts by mass, based on the mass of the adduct, of an antioxidant, at least 10 parts by mass, based on the mass of the adduct Adduct, a saccharide and / or an amino acid of the formula H ₂ N- (CH ₂ I _n -COOH, where η is an integer from 1 to 4! ^J eutet, and a buffer in the required amount to the pH on 4-6 when the diagnostic reagent set is dissolved in water.

The diagnostic reagent kit of the present invention contains, as the amino acid of the formula H ₂ N- (CH ₂ J _n -COOH, preferably glycine.) The isonitrile-ether metal salt adducts contained in the diagnostic reagent kit of the present invention may be the same as those described in the above-mentioned published European Patent Applications Of these, the Cu (I) tetrafluoroborate adducts of the isonitrile ethers of the formula (II) have proved to be particularly preferred. The term "isonitrile ether-metal salt adduct" also includes the adducts formed with metal complexes as described in the above-mentioned Sources are described -

Any of the substances generally used to reduce "Tc" ions having an oxidation value greater than one may serve as a reducing agent, of which tin (II) chloride-2-water, tin (II) -tartrate, ZinndD citrate, stannous gluconate, stannous fluoride, stannous aprotinin and stannous pyrosophosphate.

The diagnostic reagent kit according to the invention contains as buffer a substance which adjusts the pH of the aqueous reaction medium to 4-6, preferably 4.5-5.5, in the reaction with an ^M -ion source. which can be used for this purpose are sodium citrate, sodium pyrophosphate, glycine, potassium phthalate and sodium phthalate.

Of the saccharides contained in the diagnostic reagent kit according to the invention, mention may be made, by way of example, of mannitol, glucose, inositol, dextrose and maltose. These substances play a protective colloid-like role, protecting against clouding the solution to be used for the radiodiagnostic purpose; In addition, they increase the water solubility of the poorly soluble isonitrile ether metal salt adducts.

As antioxidant, the diagnostic reagent kit according to the invention may e.g. Penicillamine, cysteine, α-mercapto-propionylglycine, dithiothreitol, glutathione and / or ascorbic acid. Most antioxidants such as penicillamine, cysteine, α-mercaptopropionyl-glycine, dithiothreitol, and glutathione also show radioprotective effects. These substances are excreted by the liver and kidneys together with the radioactive substance; Thus, the radioactive load of the patient in isotope diagnostic test can be considerably reduced. If the antioxidant used has no radioprotective effect (ascorbic acid is one of these antioxidants), preferably a radioprotective agent is also added to the diagnostic reagent kit.

Due to the combined effect of Saccharic), buffers, and antioxidant, which are contained in the inventive diagnostic reagent kit, the stability of the information obtained during the reaction with the ^"m Tc-ion source radiodiagnostic substance considerably increases. Measurements according to the stability least tripled in comparison to the stability of the radiodiagnostic substance prepared from a diagnostic reagent kit of conventional composition containing only a reducing agent and an isonitrile ether-metal salt adduct.

The diagnostic reagent kit according to the invention can most easily be prepared by mixing the individual components. If necessary, the ingredients may be pulverized prior to mixing, or a mixture of ingredients may be homogenized with simultaneous comminution (e.g., grinding).

If the diagnostic reagent set at least one water-insoluble component Iz. Preferably, the reagent set is prepared as follows: The low water solubility component is dissolved in an organic solvent, the other components are added to the resulting solution either as such or as an aqueous solution, and The resulting mixture is freeze-dried. These operations are carried out under an oxygen-free atmosphere.

A labeled with ^99m Tc radiodiagnostic substance can from the diagnostic reagent set according to the invention in the above sources, for. For example, in EP-PS 183155 and 233308, described manner be prepared.

The isonitrile ethers of the formula (II), which are used as precursors in the preparation of the isonitrile ether-metal salt adducts contained in the reagent set according to the invention, can be prepared by known methods such. B. the method described in EP-PS 233308 and in the sources cited therein. However, new processes for the preparation of compounds of the formula (II) have been worked out which make it possible to prepare the compounds in question more easily with a lower number of stages, in higher yields, under milder reaction conditions and / or from readily available starting substances.

Therefore, the invention further relates to novel processes for the isoformation of isonitrile ethers of the formula (II) in which R and R 'are the same as those mentioned above. Have meaning. According to the invention, the procedure is as follows:

a) a nitrile of the formula HO-R "-CN, wherein R" _(an unbranched or branched C. ₇ alkylene group optionally with a halogen, phenyl or Halogenphenylsubstituenten, in the presence of a Lewis acid catalyst with an alkylating agent of the formula R'-X, in which R 'has the abovementioned meaning and X is halogen or hydroxy, the resulting compound of the formula R'OR "-CN, in which R' and R" have the meaning above, is assigned with reduced, a complex metal hydride, the resulting amine of the formula R ¹ OR-NH ₂ , in which R and R 'have the above meaning, is formylated with formic acid or with a reactive formic acid derivative, and the resulting formylated compound is dehydrated, or

b) an amine of the formula R ¹ OR-NH ₂ , in which R and R 'have the above bedoutung, is reacted in the presence of alkali metal hydroxide with chloroform, or

c) a compound of the formula R "-CH ₂ , in which R" has the meaning given above, is reacted in the presence of mercury (II) acetate with an alcohol of the formula R'-OH, in which R 'has the abovementioned meaning, reacted, the resulting precursor of the formula R'OR-HgOAc, in which R and R 'have the above meaning and Ac is acetate, with an alkali metal halide of the formula AIk-Hal, in which Alk is an alkali metal atom and Hal is a halogen with a Atomic mass above 36, implemented, the resulting compound of the formula R'OR-Hg-Hal, in which R, R 'and Hai have the above meaning, with a halogen of the formula HaI ₂ , in which Hai has the above meaning, reacted, the resulting compound of the formula R'OR-Hal, in which R, R 'and Hai have the above meaning, is reacted with silver cyanide, and the resulting compound of the formula R'OR-NC · Ag-Hal, in which R , R 'and Hai have the meaning above, is treated with alkali metal cyanide.

Process a) has the advantage that it provides the intermediate of the formula R ¹ OR-NH ₂ in a simpler process and in higher yield than the previously known processes, so that the overall yield of the process also increases. The main advantage of process b) is its feasibility, while process c) has the advantage that readily available reactants and mild reaction conditions are used.

In the first stage of process a) z. As zinc chloride or aluminum trichloride can be used as a Lewis acid catalyst. The complex metal hydride used as a reducing agent in the second stage may e.g. As lithium alanate or sodium borohydride. For formylating the amine of the formula RO-R-NH ₂ , a lower alkyl formate or a mixed anhydride of formic acid and a lower alkane carboxylic acid is preferably used as the reactive formic acid derivative. The last step of the reaction series is the dehydration, which is realized with a customary dehydrating agent such as diphosgene, phosphorus oxychloride, phosphorous chloride or thionyl chloride in the presence of an organic base such as pyridine, diisopropylamine or triethylamine.

In the process b), the alkali hydroxide may also be introduced as an aqueous solution into the reaction mixture, whereby a heterogeneous reaction medium is formed. Under these circumstances, a phase transfer catalyst is preferably added to the mixture to accelerate the reaction or to increase the yield. As phase transfer catalyst, e.g. quaternary ammonium or phosphonium salts are used. The invention is illustrated by the following examples, without being limited thereby. NMR-chemical shifts: δ values in ppm.

example 1 Preparation of 2-methoxy-2-ethylbutyrone tryl

145 ml of water and 46.0 g (0.94 mol) of sodium cyanide are introduced into a flask equipped with HCN absorber, stirrer, thermometer and dropping funnel. To the solution, 86 g (1.0 mol) of diethyl ketone are added, followed by dropwise addition of 252 ml of an aqueous sulfuric acid solution having a mass fraction of 40% under ice-cooling at 5-10 ° C. The mixture is stirred for a further 30 min at 5-10 ° C. For phase separation is allowed to stand, the aqueous phase is separated and washed twice with 100ml diethyl ether. The washings are combined with the organic phase, the organic solution is dried over anhydrous sodium sulfate, then the diethyl ether is evaporated and the residue is distilled under reduced pressure. Yield: 78g (69%) 2-hydroxy-2-ethyl-butyronitrile; Bp 116 ° C / 40 mm Hg. NMR (CDCl ₃ ): 1.05 (6H, 2CH ₃ ), 1.8 (4H, 2CH ₂ ), 3.45 (1H, OH).

A mixture of 56.5 g (0.5 mol) of 2-hydroxy-2-ethyl-butyronitrile, which was obtained according to the above procedure, 24 g (0.75 mol) of abs. Methanol and 68.1 g (0.5 mol) of anhydrous zinc chloride is gerühit 6 h at 60 ° C. The reaction mixture is allowed to cool to room temperature and 100 ml of water and 100 ml of diethyl ether are added. The phases are separated, the organic phase is washed four times with 30 ml of water each time. The aqueous phase is washed four times with 30 ml of diethyl ether. The organic solutions are combined and dried over sodium sulfate, then the diethyl ether is evaporated and the residue is distilled. Yield: 33g (52%) 2-methoxy-2-ethyl-butyronitrile; Kp. WC

NMP (CDCl ₃ ): 0.96 (6H, 2CH ₃ ), 1.76 (4H, 2CH ₂ ), 3.36 (3H, OCH ₃ ).

Example 2 Preparation of 2-methoxy-isobutyronitrile A mixture of 85 g (1.0 mol) acetone cyanohydrin, 48 g (1.5 mol) abs. Methanol and 136.2 g (1.0 mol) of anhydrous zinc chloride

is stirred at 60 ⁰ C for ⁴ h. The reaction mixture is cooled to room temperature, and 200ml of water and 200ml

Diethyl ether was added. The phases are separated, the organic phase is washed four times with 50 ml of water,

and the aqueous phase is washed four times with 50 ml of diethyl ether each time. .en. The ethereal phases are combined, over

Dried sodium sulfate, the solvent is evaporated, and the residue is distilled. Yield: 73g (74%)

2-methoxy-lsobutyronitril; Bp 117 ⁰ C.

NMR (CDCl ₃ ): 1.48 (6H, 2CH ₃ ), 3.33 (3H, OCH ₃ ). Example 3 Preparation of 2-methoxy-2-methylbutyrone tryl A mixture of 99 g (1.0 mol) 2-hydroxy-2-methyl-butyronitrile, 48 g (1.5 mol) abs. Methanol and 136.2 g (1.0 mol) of anhydrous Zinc chloride is stirred for 5 h at 6O ⁰ C. The reaction mixture is cooled to room temperature, and 200 ml of water and 200 ml Diethyl ether are added. The phases are separated, the organic phase is washed four times with 50 ml of water,

and the aqueous phase is washed four times with 50 ml of diethyl ether. The organic solutions are combined, over

Dried sodium sulfate, the diethyl ether is evaporated, and the residue is distilled. Yield: 61 g (54%) 2- Methoxy-2-methyl-butyronitrile; Bp. 135 ⁰ C. NMR (CDCl ₃ ): 0.99 (3H, CH ₃ ), 1.45 (3H, CH ₃ ), 1.74-1.79 (2H, CH ₂ ), 3.37 (3H, OCH ₃ ). Example 4 Preparation of 2-methoxy-isobutylamines A mixture of 20.9 g (0.55 mol) of lithium alanate and 600 ml of dry diethyl ether is added with stirring under a Nitrogen atmosphere cooled to below 20 ° C, and a mixture of 49.5g (0.5 mol) of 2-methoxy-isobutyronitrile and 100ml

dry diethyl ether is added dropwise with cooling to the solution. Then 35ml of an aqueous

Sodium hydroxide solution with a mass fraction of 10% and then 70 ml of water added dropwise with cooling to the mixture. The precipitated colorless precipitate is filtered off and washed three times with 50 ml of diethyl ether. The filtrate and the Washing liquids are combined, the resulting solution is dried over sodium sulfate, then the Solvent evaporated and the residue distilled under reduced pressure. Yield: 45.3g (88%)

2-methoxy-isobutylamine; Bp 58 ° C / 120mm Hg.

NMR (CDCl ₃ ): 1.13 (6H, 2CH ₃ ), 1.82 (2H, NH ₂ ), 2.62 (2H, CH ₂ ), 3.19 (3H, OCH ₃ ). Example 5 Preparation of 2-Mothoxy-2-methyl-butylamine A mixture of 20.9 g (0.55 mol) of lithium alanate and 600 ml of dry diethyl ether is added with stirring under a Nitrogen atmosphere cooled to below 2O ⁰ C, and a mixture of 56.5 g (0.5 mol) of 2-methyl-isobutyronitrile and 150ml abs. Diethyl ether is added dropwise to the solution while cooling. The mixture is stirred for a further 30 min, and then

35 ml of an aqueous sodium hydroxide solution with a mass fraction of 10% and then added 70 ml of water to the mixture. The precipitated colorless precipitate is filtered off and washed three times with 50 ml of diethyl ether. The filtrate and washings are combined, dried over sodium sulfate, the ether is evaporated and the residue is distilled under reduced pressure. Yield: 52.6 g (90%) of 2-methoxy-2-methyl-butylamine; Bp. 76 ° C / 100mm Hg.

NMR (CDCl ₃ ): 0.61 (3H, CH ₃ ), 0.85 (3H, CH ₃ ), 1.13 (2H, NH ₂ ), 1.29 (2H, CH ₂ ), 2.41 ( 2H, CH ₂ ), 2.92 (3H, OCH ₃ ). Example 6 Preparation of 2-methoxy-2-ethyl-butylamine A mixture of 10.5 g (0.275 mol) of lithium alanate and 300 ml of dry diethyl ether is added with stirring under a Nitrogen atmosphere cooled to below 20 ⁰ C, and a mixture of 31.75 g (0.25 mol) of 2-methoxy-2-ethyl-butyronitrile and 50ml

dry diethyl ether is added dropwise to the mixture with cooling. The mixture is then stirred at room temperature for 30 minutes and then 18 ml of a 10% by weight aqueous sodium hydroxide solution is added dropwise under cooling, after which 35 ml of water are added. The precipitated colorless precipitate is filtered off and three times with yes 25 ml

Washed diethyl ether. The filtrate and washings are combined, dried over anhydrous sodium sulfate,

the ether is evaporated, and the residue is distilled under reduced pressure. Yield: 29.5 g (90%) of 2-methoxy-2-ethyl-butylamine; Bp. 94 ° C / 100mm Hg.

NMR (CDCl ₃ ): 0.78 (6H, 2CH ₃ ), 1.04 (2H, NH ₂ ), 1.35 (4H, 2CH ₂ ), 2.31 (2H, CH ₂ ), 2.82 (3H, OCH ₃ ). Example 7 Preparation of 2-methoxy-isobutyl-formamide A mixture of 43.2 g (0.42 mol) of 2-methoxy-isobutylamine and 200 ml (184.6 g, 6 equivalents) of ethyl formate is 16h in a Autoclave cooked under a pressure of 8 atmospheres. The excess ethyl formate and the ethanol formed become

evaporated. Yield: 55 g (99%) of crude 2-methoxy-isobutyl-formamide. The substance is sufficiently pure for the others

Transformation (dehydration). NMR (CDCl ₃ ): 't, 18 (6H, 2CH ₃ ), 3,12 (2H, CH ₂ ), 3,27 (3H, OCH ₃ ), 6,56 (1H, NH), 8,18 ( 1H, HCO). Example 8 Preparation of 2-methoxy-2-methyl-lutyl-formamld

A mixture of 49.14 g (0.42 mol) of 2-methoxy-2-methyl-butylamine and 200 ml (184.6 g, β equivalents) of ethyl formate is boiled for 20 hours in an autoclave under a pressure of 8 atmospheres. The excess ethyl formate and düs formed ethanol are evaporated. Yield: 60.4 g (99%) of crude 2-methoxy-2-methyl-butyl formaldehyde. The substance is sufficiently pure for further transformation (dehydration).

Example 9 Preparation of 2-methoxy-2-ethyl-butyl formamide

A mixture of 27.5 g (0.21 mol) of 2-methoxy-2-ethyl-butylamine and 100 ml (92.3 g, 6 equivalents) of ethyl formate is boiled for 24 h in an autoclave under a pressure of 8 atmospheres. The excess ethyl formate and the ethanol formed become

evaporated. Yield: 33.1 g (99%) of crude ^ -methoxy-ethyl-butyl-formamide. The substance is sufficiently pure for further conversion (dehydration).

Example 10 Preparation of 2-methoxy-isobutyl-isonitrile

76.7 g (0.5 mol) of phosphorus oxychloride are added with stirring and cooling at 0 ° C. to a mixture of 52.4 g (0.4 mol) of 2-methoxy-isobutyl-formamide, 101.2 g (1 mol ) Diisopropylam'n and 300 ml of dichloromethane are added dropwise. Then a solution of 75 g of sodium carbonate in 300 ml of water is added. The phases are separated, the aqueous phase is washed three times with 100 ml of dichloromethane, and the organic phase is washed three times with 150 ml of water. The organic solutions are combined, dried over sodium sulfate, and the solvent is evaporated. The residue is distilled under reduced pressure. Yield: 35.2 g (78%) of 2-methoxy-isobutyl-isonitrile; Bp. 64 "C / 25mm Hg.

NMR (CDCl ₃ ): 1.24 (6H, 2CH ₃ ), 3.23 (3H, OCH ₃ ), 3.35 (2H, CH ₂ ).

Example 11 Preparation of 2-methoxy-2-methyl-butyl-enone-trll

76.6 g (0.5 mol) of phosphorus oxychloride are added with stirring and cooling at 2 ° C to a mixture of 58 g (0.4 mol) of 2-methoxy-2-methyl-butyl-formamide, 101.2 g (1 mol) diisopropylamine and 300 ml of dichloromethane are added dropwise. Subsequently, a solution of 75 g of sodium carbonate in 300 ml of water is added dropwise with cooling to the mixture. The phases are separated, the aqueous phase is washed three times with 100 ml of dichloromethari, and the organic phase is washed three times with 150 ml of water. The organic solutions are combined, dried over sodium sulfate, the solvent is evaporated and the residue is distilled under reduced pressure. Yield: 38.1 g (75%) of 2-methoxy-2-methylbutylisonitrile; Bp. 75 ° C / 25mm Hg.

NMR (CDCl ₃ ): 0.72 (3H, CH ₃ ), 0.94 (3H, CH ₃ ), 2.37 (2H, CH ₂ ), 3.12 (3H, OCH ₃ ), 3.28 ( 2H, CH ₂ ).

Example 12 Preparation of 2-methoxy-2-ethyl-butyl-isonitrile

38.35 g (0.25 mol) of phosphorus oxychloride are added with stirring and cooling at 4 ° C. to a mixture of 31.8 g (0.2 mol) of 2-methoxy-2-ethyl-butyl-formamide, 50, 6a (0.5 mol) of diisopropylamine and 150 ml of dichloromethane are added dropwise. Subsequently, a solution of 38 g of sodium carbonate in 150 ml of water is added dropwise with cooling to the mixture. The phases are separated, the aqueous phase is washed three times with 50 ml of dichloromethane, and the organic phase is washed three times with 80 ml of water. The organic solutions are combined, dried over sodium sulfate, the solvent is evaporated and the residue is distilled under reduced pressure. Yield: 20.6 g (73%) of 2-methoxy-2-ethylbutylisononitrile; Bp. 87 ° C / 25mm Hg.

NMR (CDCl ₃ ): 0.85 (6H, 2CH ₃ ), 2.14 (4H, 2CH ₂ ), 2.91 (3H, OCH ₃ ), 3.17 (2H, CH ₂ ).

Example 13

Preparation of 2-methoxy-isobutyl-isonitrile

60 ml of dichloromethane are added to a mixture of 20.6 g (0.2 mol) of 2-methoxy-isobutylamine, 24 g (0.2 mol) of chloroform and 100 mg of benzyltriethylammonium chloride catalyst, followed by 60 ml of an aqueous sodium chloride solution having a mass fraction of 50 % with stirring: at room temperature added dropwise to the mixture. The reaction mixture is refluxed for 2 h. The mixture is diluted with 150mL of dichloromethane and washed three times with 50mL each of water. The organic phase is dried over sodium sulfate, the solvent is evaporated and the residue is distilled under reduced pressure. Yield: 15.3 g (68%) of 2-methoxy-isobutyl-isonitrile; Kp.64 ° C / 25mmHg.

NMR (CDCl ₃ ): 1.24 (6H, 2CH ₃ ), 3.23 (3H, OCH ₃ ), 3.35 (2H, CH ₂ ).

Example 14

Preparation of 2-methoxy-2-methyl-butyl-isonitrile

60 ml of a 50% by weight aqueous sodium hydroxide solution are added at room temperature to a mixture of 23.4 g (0.2 mol) 2-methoxy-2-methyl-butylamine, 24.0 g (0.2 mol, 16 ml) chloroform, 100 mg catalyst Benzyltriethylammonium chloride and 60ml dichloromethane added dropwise. The reaction mixture is refluxed for 2.5 h. Then 150 ml of dichloromethane are added and the mixture is washed three times with 50 ml of water each time, the organic solution is dried over sodium sulphate, the dichloromethane is evaporated off and the residue is distilled under reduced pressure.

Yield: 16.7 g (66%) of 2-methoxy-2-methyl-butyl-isonitrile; Bp. 75 ° C / 25mm Hg.

NMR (CDCl ₃ ): 0.72 (3H, CH ₃ ), 0.94 (3H, CH ₃ ), 2.37 (2H, CH ₂ ), 3.12 (3H, OCH ₃ ), 3.28 ( 2H, CH ₂ ).

Example 15 Partitioning of 2-methoxy-2-ethyl-butyl isonitrile

60 ml of a 50% by weight aqueous sodium hydroxide solution is added at room temperature to a mixture of 26.2 g (0.2 mol) 2-methoxy-2-ethyl-butylamine, 24 g (0.2 mol, 16 ml) chloroform, 100 mg Catalyst benzyl triethylammonium chloride and 60 ml of dichloromethane was added dropwise. The reaction mixture is refluxed for 3 hours and then diluted with 150 ml of dichloromethane. The mixture is washed three times with 50 ml of water each time, dried over sodium sulfate, the dichloromethane is evaporated off and the residue is distilled under reduced pressure. Yield: 18.3 g (65%) of 2-methoxy-2-ethyl-butyl-isonitrile; Bp. 87 ° C / 25mm Hg.

NMR (CDCl ₃ ): 0.85 (6H, 2CH ₃ ), 2.14 (4H, 2CH ₂ ), 2.91 (3H, OCH ₃ ), 3.17 (2H, CH ₂ ). Example 16 Preparation of 2-methoxy-isobutyl-lsonltrll copper (I) tetrafluoroborate adduct A solution of 2.47 g (0.025 mol) of copper (I) chloride and 2.65 g (0.025 mol) of sodium tetrafluoroborate in 60 mL of 1 N aqueous Hydrochloric acid is added with cooling and stirring to 11.3 g (0.1 mol) of 2-methoxy-isobutyl-isonitrile. The mixture

is kept at 0 ° C for 2 h, then the deposited crystals are filtered off, washed with water and a little alcohol and dried. Yield: 10.5 g (70%) of a colorless, crystalline product.

NMR (CDCI _3): 1.24 (6 H, 2 CH _3), 3.23 (3 H, _OCH3), 3.35 (2 H, CH _2). Example 17 Preparation of 2-methoxy-2-methylbutyl-irononitrile-copper (I) tetrafluoroborate adduct A solution of 2.47 g (0.025 mol) of copper (I) chloride and 2.65 g (0.025 mol) of sodium tetrafluoroborate in 60 mL of 1 N aqueous Hydrochloric acid is added under cooling and stirring to 12.7 g (0.1 mol) of 2-methoxy-2-methyl-butyl-isonitrile. The Mixture is kept for 2 h at ^{0 0} C, then the deposited crystals are filtered off, with water and a little alcohol

washed and dried. Yield: 11.8 g (72%) of a pale yellow, crystalline substance.

NMR (CDCl ₃ ): 0.72 (3H, CH ₃ ), 0.94 (3H, CH ₃ ), 2.37 (2H, CH ₂ ), 3.12 (3H, OCH ₃ ), 3.28 ( 2H, CH ₂ ). Example 18 Preparation of 2-methoxy-2-ethyl-butyl-isonitrile-copper (I) -tetralluorborate adduct A solution of 2.47 g (0.025 mol) of copper (I) chloride and 2.65 g (0.025 mol) of sodium tetrafluoroborate in 60 mL of 1 N aqueous Hydrochloric acid is added with cooling and stirring to 14.1 g (0.1 mol) of 2-methoxy-2-ethyl-butyl-isonitrile. The mixture

is held for 2 h at ^{0 0} C sn, then the deposited crystals are filtered off, washed with water and a little alcohol and dried. Yield: 11.6 g (65%) of a pale yellow, crystalline substance.

NMR (CDCl ₃ ): 0.85 (6H, 2CH ₃ ), 2.14 (4H, 2CH ₂ ), 2.91 (3H, OCH ₃ ), 3.17 (2H, CH ₂ ). Example 19 Preparation of a diagnostic reagent set A diagnostic reagent kit of the following composition is prepared:

2-methoxy-isobutyl isonitrile copper (0-

tetrafluoroborate adduct 0.43 mg

Sodium pyrophosphate-10-water 1.2 mg

Glucose 12.0 mg

L-cysteine hydrochloride 0.54 mg Tin (II) chloride 2-water 0.03 mg In the preparation of the diagnostic reagent set, the adduct is dissolved in nitrogen-saturated ethanol and added to the

In ethanolic solution, an aqueous solution of the other components will g. All these operations are under

Nitrogen performed. The resulting solution is withdrawn in 1 ml portions onto ampoules, and the contents of the ampoule become

freeze-dried.

Example 20 Preparation of a diagnostic reagent set A diaynose reagent set of the following composition is prepared according to the procedure in Example 19:

2-methoxy-2-methyl-butyl isonitrile copper (l) -

tetrafluoroborate adduct 0.50 mg

Sodium pyrophosphate-10-water 1.2 mg

Glucose 12.0 mg

L-cysteine hydrochloride 0.54 mg Tin (II) chloride 2-water 0.03 mg Example 21 Preparation of a diagnostic reagent set A diagnostic reagent kit of the following composition is prepared according to the procedure in Example 19:

2-methoxy-2-ethyl-butyl-isonitrile copper (D-

tetrafluoroborate adduct 0.55 mg

Sodium pyrophosphate-10-water 1.2 mg

Glucose 12.0 mg

L-cysteine hydrochloride 0.54 mg Tin (II) chloride 2-water 0.03 mg Example 22 Production of a diagnostic pulley set A diagnostic reagent set of the following composition is prepared according to the procedure in Example 19:

2-methoxy-isobutyl-isonitr! L copper (U-

tetrafluoroborate adduct 0.45 mg

Sodium citrate-2-water 1.2 mg

Maltose 12.0 mg

L-cysteine hydrochloride 0.43 mg Tin (II) chloride 2-water 0.03 mg Example 23 Preparation of a diagnostic reagent kit A diagnostic reagent set of the following composition is prepared according to the procedure in Example 19:

2-methoxy-2-methyl-butyl isonitrile copper (0-

tetrafluoroborate adduct 0.50 mg

Sodium citrate-2-water 1.2 mg

Maltose 12.0 mg

L-cysteine hydrochloride 0.45 mg Tin (II) chloride 2-water 0.03 mg Example 24 Preparation of a diagnostic reagent set A diagnostic reagent set of the following composition is prepared according to the procedure in Example 19:

2-methoxy-2-ethyl-butyl-isonitrile copper (l) -

tetrafluoroborate adduct 0.55 mg

Sodium citrate-2-water 1.2 mg Maltose 12.0 rrg L-cysteine hydrochloride 0.45 mg Tin (II) chloride 2-water 0.03 mg Example 25 Preparation of a diagnostic reagent set A diagnostic reagent set of the following composition is prepared according to the procedure in Example 19:

2-methoxy-isobutyl isonitrile copper (l) -

tetrafluoroborate adduct 0.45 mg

Glycine 0.3 mg

Inositol 12.0 mg

a-Mercapto-propionyl-glycine 0.3 mg

Tin (II) chloride 2-water 0.03 mg Example 26 Preparation of a diagnostic reagent set A diagnostic reagent set of the following composition is prepared according to the procedure in Example 19:

2-methoxy-2-methyl-butyl isonitrile copper {l) -

tetrafluoroborate adduct 0.50 mg

Glycine 0.3 mg

Inositol 12,0 right

a-Mercapto-propionyl-glycine 0.3 mg

Tin (II) chloride 2-water 0.03 mg Example 27 Preparation of a diagnostic reagent set A diagnostic reagent set of the following composition is prepared according to the procedure in Example 19:

2-methoxy-2-ethyl-butyl isonitrile Kupter {l) -

tetrafluoroborate adduct 0.55 mg

Glycine ^ 0.3 mg

Inositol 12.0 mg

a-Mercapto-propionyl-glycine 0.3 mg

Tin (II) chloride 2-water 0.03 mg When dissolved in water, the diagnostic reagent sets according to Examples 19 to 27 give solutions with a pH of Example 28 Stability test The diagnostic reagent sets described in Examples 19 to 21 were dissolved in aqueous medium with 2.0 ml of ^99m Tc. Pf rtechnetat (activity: 370-1110MBq) implemented. The reactions were carried out in 10 minutes on a steam bath. The resulting radiodiagnostic substances were periodically sampled, and the content of lipid-soluble

^99m Tc-lsonitriletherkomplex the samples was determined by chromatography. The chromatographic tests were carried out under the following conditions:

"Α"; adsorbent: Merck Kieselgel 60DC - aluminum foil plate (2.5 x 20cm), developer: ethanol; "B": adsorbent: Merck aluminumum oxide 60dc plastic foil plate (2.6 x 20cm), developer: ethanol.

The content of lipid-soluble ^Wm Tc-lsonltriletherkomplex the individual samples was in%, based on the initial amount,

expressed. The results are summarized in Table I.

Table I

Time example lipid soluble "B" ^e9m Tc-lsonitrile ether complex,% 20 "B" example 21 "B" "A" 19 99.1 example 99.0 -A " 98.6 98.9 98.8 "A" 98.8 98.4 98.5 15 minutes 98.6 98.6 98.6 98.7 98.2 98.3 1h 98.5 98.3 98.3 98.4 98.1 98.3 2h 98.3 98.2 98.2 98.3 98.0 98.1 3h 97.8 96.0 98.0 95.4 97.2 95.7 8h 94.7 97.3 95.3 24 hours 94.4

Example 29 Preparation of 2-ethoxy-isobutyronitrile The procedure according to the procedure in Example 2, with the difference that in place of ab-. Methanol 69g (1.5mol) abs. Ethanol can be used. Yield: 94g (33%) 2-ethoxy-isobutyronitrile; Bp. 124 ° C. Example 30 Preparation of 2-n-PropoKy-isobutyronitrile The procedure is according to the procedure in Example 2, with the difference that instead of abs. Methanol 99g (1.5mol) abs.

n-Propanol be used. Yield: 102.9 g (81%) of 2-n-propoxy-isobutyronitrile; Bp. 129 ^° C.

Example 31 Preparation of 2-isopropoxy-isobutyronitrile The procedure is according to the procedure in Example 2, with the difference that instead of abs. Methanol 99g (1.5mol) abs. Isopiopanol can be used. Yield: 97.8 g (77%) of 2-isopropoxy-isobutyronitrile; Bp 127 ° C. Example 32 Preparation of 2-ethoxy-isobutyiamine The procedure according to the procedure in Example 4, with the difference that instead of 2-methoxy-isobutyronitrile 56.5 g

(0.5 mol) of 2-ethoxy-isobutyronitrile can be used. Yield: 54.4 g (93%) of 2-ethoxy-isobutylamine; Kp. 62 ° C / 120mm Hg.

Example 33 Preparation of 2-n-propoxyisobutylamines The procedure according to the procedure in Example 4, with the difference that instead of 2-methoxy-isobutyronitrile 63.5 g

(0.5 mol) of 2-n-propoxy-isobutyronitrile can be used. Yield: 58.9 g (90%) of 2-n-propoxy-isobutylamine, bp 66 ° C / 120 mmHg.

Example 34 Preparation of 2-isopropoxy-isobutylamine The procedure according to the procedure in Example 4, with the difference that in place of 2-methoxy-isobutyronitrile 63.5 g

(0.5 mol) 2-isopropoxy-isobutyronitrile vr ·. be used. Yield: 57.0 g (87%) of 2-isopropoxy-isobutylamine, b.p.65 ^e C / 120 mmHg.

Example 35

üsrsieüüMy vün2- £: üioxy-isobuiyi-formamld

The procedure according to the procedure in Example 7, with the difference that instead of 2-methoxy-isobutylamine 49.14g

(0.42moJ) 2-ethoxy-isobutylamine. Yield: 60.29 g (99%) of 2-ethoxy-isobutyl-formamide.

Example 36 Preparation of 2-n-propoxy-isobutyl-formamld The procedure according to the procedure in Example 7, with the difference that instead of 2-methoxy-isobutylamin 55.02 g

(0.42 mol) of 2-n-propoxy-isobutylamine. Yield: 66.11 g (99%) of 2-n-propoxy-isobutyl-formamide.

Example 37 Preparation of 2-isopropoxy-isobutyl-formamide The procedure according to the procedure in Example 7, with the difference that instead of 2-methoxy-isobutylamin 55.02 g

(0.42 mol) of 2-lcopropoxy-isobutylamine. Yield: 66.11 g (99%) of 2-isopropoxy-isobutyl-formamide.

Example 38 Preparation of 2-ethoxy-isobutyl-lsonltrll

The procedure is as described in Example 10 except that 2-ethoxy-isobutyl-formamide is used in place of 2-mothoxy-isobutyl-formamicl 58.0g (0.4M). Yield: 40.64 g (80%) of 2-ethoxy-isobutyl-isonitrile; Kp.67'C / 25mmHg.

Example 39 Preparation of 2-n-propoxy-isobutyl-isonetriam

The procedure is as described in Example 10 except that instead of 2-methoxy-isobutyl-formamide, 63.6 g (0.4 mol) of 2-n-propoxy-isobutyl-formamide are used. Yield: 44.0 g (78%) of 2-n-propoxy-isobutyl-isonitrile; Kp.69 ° C / 25mmHg.

Example 40 Preparation of 2-isopropoxy-isobutyl-lsonltril

The procedure is as in Example 10, except that instead of 2-methoxy-isobutyl-formamide 63.6 g (0.4 mol) of 2-isopropoxy-isobutyl-formamide are used. Yield: 43.4 g (77%) of 2-isopropoxy-isobutyl-lsonitrile; Kp.67 ° C / 25mmHg.

Example 41 Preparation of 2-ethoxy-isobutyl-lsonltrll

The procedure according to the procedure in Example 13, with the difference that instead of 2-methoxy-isobutylamin 23.4 g (0.2 mol) of 2-ethoxy-isobutylamine are used. Yield: 17.27 g (68%) of 2-ethoxy-isobutyl-isonitrile; Bp 67 ° C / 25mm Hg.

Example 42

Preparation of 2-n-propoxy-isobutyl-1-butanol. The procedure is as described in Example 13, with the difference that instead of 2-methoxy-isobutylamine, 26.2 g (0.2 mol) of 2-n-propoxy-isobutylamine be used. Yield: 18.47 g (65%) of 2-n-propoxy-isobutyl-isonitrile; Kp.69 ° C / 25mmHg.

Bolsplel 43

Preparation of 2-isopropoxy-isobutyl-isonitrile

The procedure according to the procedure in Example 13, with the difference that instead of 2-methoxy-isobutylamin 26.2 g (0.2 mol) of 2-isopropoxy-isobutylamin be used. Yield: 18.05 g (64%) of 2-isopropoxy-isobutyl-isonitrile; Kp.68 ^e C / 25mmHg.

Example 44

Preparation of α-ethoxy-isobutyl-isonitrile-copper-O-tetrafluoroborate adduct The procedure is as described in Example 16, with the difference that instead of 2-methoxy-isobutyl-isonitrile 12.7 g (0.1 mol) of 2 -Ethoxy-isobut, l-isonitrile can be used. Yield: 12.78 g (78%) of 2-ethoxy-isobutyl-isonitrile-copper (I) · tetrafluoroborate adduct.

Example 45 Preparation of n-n-propoxy-isobutyl-lsonitrile-copper (I) tetrafluoroborate adduct

The procedure according to the procedure in Example 16, with the difference that instead of 2-methoxy-isobutyl-isonitrile 14.1 g (0.1 mol) of 2-n-propoxy-isobutyl-isonitrile are used. Yield: 12.49 g (70%) of 2 n-propoxy-isobutyl-isonitrile-copper (l) -

tetrafluoroborate adduct. '

Example 46 Preparation of 2-isopropoxy-isobutyl-isonitrile-copper (I) tetrafluoroborate adduct

The procedure according to the procedure in 'Example 16, with the difference that instead of 2-Mothoxy-isobutyl-isonitrile 14.1 g (0.1 mol) of 2-isopropoxy-isobutyl-isonitrile be used. Yield: 12.85 g (72%) of 2-isopropoxy-isobutyl-isonitrile-copper (U-tetrafluoroborate adduct.

Example 47

Preparation of a Diagnostic Reagent Set A Diagrose reagent kit of the following composition is prepared according to the procedure in Example 19:

2-methoxy-isobutyl isonitrile copper (0-

tetrafluoroborate adduct 0.5 mg

Sodium pyrophosphate-10-water 5.2 mg

Glycine 16.0 mg

L-cysteine hydrochloride "2.0 mg

Tin (II) chloride-2-water 0.3 mg

Example 48 Preparation of a diagnostic reagent set A diaanose reagent kit of the following composition is prepared according to the procedure in Example 19:

2-Metlioxy-2-methyl-butyl isonitrile Kuprer (l) ·

tetrafluoroborate adduct 0.50 mg

Sodium pyrophosphate-10-water 5.2 mg

Glycine 16.0 mg

L-Cysteln-hydrochloride 2.0 mg Tin (II) chloride 2-water 0.3 mg Example 49 Production of a diagnostic residue kit A diagnostic reagent set of the following composition is prepared according to the procedure in Example 19:

2-methoxy-2-othyl-butyl isonitrile copper (I) ·

tetrafluoroborate adduct 0.5 mg

Sodium pyrophosphate-10-water 5.2 mg

Glycine 16.0 mg

L-cysteine hydrochloride 2.0 mg Tin (II) chloride-2-water 0.3 mg Example 50 Preparation of a diagnostic reagent kit A diagnostic reagent set of the following composition is prepared according to the procedure in Example 19:

2-methoxy-isobutyl isonitrile copper (l) -

tetrafluoroborate adduct 0.25 mg

2-methoxy-2-mothyl-butyl isonitrile copper (l) -

tetrafluoroborate adduct 0.25 mg

Sodium pyrophosphate-10-water 5.2 mg

Glycine 16.0 mg

L-cysteine hydrochloride 2.0 mg

Tin (II) chloride-2-water 0.3 mg

Example 51 Preparation of a diagnostic reagent set A diagnostic reagent set of the following composition is prepared according to the procedure in Example 19:

2-ethoxy-isobutyl isonitrile copper (l) -

tetrafluoroborate adduct 0.50 mg

Sodium pyrophosphate-10-water 5.2 mg

Glycine 16.0 mg

L-cysteine hydrochloride 2.0 mg Tin (II) chloride-2-water 0.3 mg Example 52 Preparation of a diagnostic reagent set A diagnostic reagent set of the following composition is prepared according to the procedure in Example 19:

2-ethoxy-isobutyl isonitrile copper (l) -

tetrafluoroborate adduct 0.25 mg

2-methoxy-isobutyl isonitrile copper (l) -

tetrafluoroborate adduct '0.25 mg

Sodium pyrophosphate-10-water 5.2 mg

Glycine 16.0 mg

L-cysteine hydrochloride 2.0 mg Tin (II) chloride-2-water 0.3 mg Example 53 Preparation of a diagnostic reagent set A diagnostic reagent set of the following composition is prepared according to the procedure in Example 19:

2-n-propoxy-isobutyl-isonitiil copper (D-

tetrafluoroborate adduct 0.5 mg

Sodium pyrophosphate-10-water 5.2 mg

Glycine 16.0 mg

L-cysteine hydrochloride 2.0 mg Tin (II) chloride-2-water 0.3 mg Example 64 Preparation of a diagnostic reagent set

A diagnostic reagent set of the following composition is prepared according to the procedure in Example 19:

2-isopropoxy-lsobutyMsonitril copper (l) ·

tetrafluoroborate adduct 0.50 mg

Sodium pyrophosphate-IO-water b, 2 mg

Glycine 16.0 mg

L-Cysteln-hydrochloride 2.0 mg

Tin (II) chloride-2-water 0.3 mg

Claims (2)

1. ^99m Tc-labeled diagnostic reagent kit comprising a metal salt adduct of an isonitrile ether of the formula (II), CN-R-OR '(II) in the R is an unbranched or branched C ₂ _e-alkylene group optionally having a halogen, phenyl or halophonyl substituent and R 'is an unbranched or branched C 1-4 alkyl group, or contains a mixture of such adducts and 0.03 to 1.0 parts by weight of a reducing agent, based on the mass of the adduct, characterized in that the diagnostic reagent set further comprises 0.5 to 5 parts by weight, based on the mass of the adduct, of an antioxidant, at least 10 parts by weight, based on the mass of the adduct, of a saccharide and / or an amino acid of the formula: H2N- (CH ₂ ) _n -COOH, where η is an integer from 1 to 4, and a buffer in the required amount to adjust the pH to 4-6 when the diagnostic reagent set is dissolved in water. 2. Process for the preparation of an isonitrile ether of the formula (II)