CZ323791A3 - Process for preparing isonitrile ethers - Google Patents

Abstract

Diagnosis-reagent compsn. labellable with 99m-Tc, comprises: (a) a metal salt adduct of an isonitrile ether of formula CN-R-0R (II) opt. in combination with 0.03-1.0 pts.wt. of a reducing agent; (b) 0.5-5 pts.wt. of an antioxidant; (c) at least 10 pts.wt. of a saccharide and/or an amine acid of formula H2N-(CH2)n-C00H (III); and (d) enough buffer to set the pH to 4-6 when the compsn. is dissolved in water. R = 2-8C alkylene, opt. substd. by halo, phenyl or halophenyl; R1 = 1-4C alkyl; n = 1-4; All pt.wt. values are based on wt. of adduct.

Description

Technical field

The invention relates to a process for the preparation of isonitrile ethers of the general formula I

CN-R-OR * (I) wherein R is a straight or branched alkylene group having 2 to 8 carbon atoms, and

R ^# is a straight or branched chain alkyl group having 1 to 4 carbon atoms.

BACKGROUND OF THE INVENTION

The above compounds of formula (I) are used in radiodiagnoetic methods to prepare complexes containing ^99m Tc. These complex compounds have the general formula II / (CN-R-ORI ^99m Tc_7 ⁺ A "(II) wherein R * is as defined above and R has the same meaning and this substituent may also be substituted, and A" represents a monovalent anion or These complex compounds are widely used in methods for the detection of myocardial disorders, see, for example, Int. J. Nucl., Med. Biol.

Copper. 25, 1350 (1984) and 27, 404 (1986) J and Eur. J. Nucl.

Copper. 12, 219 (1986).

As described in U.S. Patent 4,452,774 and European Patent No. 233,368, the above compounds of Formula I are prepared by formylation of an amine of Formula III

R'O-R-NHg (III)

In which R and R 'have the same meaning as previously described, with the presence of formic acid or with the aid of a reactive formic acid derivative, the formyl derivative thus obtained being subjected to dehydration. The disadvantage of this process is that formylation requires considerably long time intervals (ranging from 20 to 30 hours) and the reaction mixture must be heated to boiling under pressure above atmospheric values (for example from 0.5 to 1 MPa). ). Therefore, performing this step requires considerable energy.

SUMMARY OF THE INVENTION

The object of the process according to the invention is to be carried out in a fast manner with a low energy consumption, the resulting product of formula (I) being obtained in a suitable yield.

The process according to the invention is characterized in that the abovementioned compounds of the general formula I are used

CN - K - OR * (I) wherein R is an alkylene group having 2 to 8 carbon atoms and R * is an alkyl group having 1 to 4 carbon atoms, both of which may be straight or branched chain, prepared by reaction of an amine of formula III

R 0 - R - _NH2 (III) wherein R ^# and R are as defined above, with chloroform in the presence of alkali metal hydroxide.

An advantage of the process according to the invention is that the above reaction takes place within a few hours. Further, the reaction can be preferably accelerated or completed by heating the reaction mixture. The alkali metal hydroxide may also be added to the reaction mixture in the form of an aqueous solution to form heterogeneous

- 3 (biphasic) reaction medium. In these cases, it is preferred to add a phase transfer catalyst to the reaction medium to accelerate the reaction and to increase the yield. As the above-mentioned phase transfer catalyst, for example, a quaternary ammonium salt or a phosphonium salt can be added to the reaction medium.

DETAILED DESCRIPTION OF THE INVENTION

The process for the preparation of the isonitrile ether compounds of formula (I) will be illustrated by the following practical examples which illustrate the process without limiting it.

Example 1

The addition of 2-methoxycarbonyl may be used.

60 ml of dichloromethane were added to the mixture containing

20.6 grams (0.2 mol) of 2-methoxyisobutylamine, grams (0.2 mol) of chloroform (16 ml) and 100 milligrams of benzyltriethylammonium chloride were added dropwise to 60 ml of aqueous hydroxide solution. Sodium 50% by weight at room temperature with stirring. The reaction mixture was then heated at reflux and at the reflux temperature of the solvent for 2 hours. The reaction mixture was diluted with 150 ml of dichloromethane and extracted three times with 50 ml of water to form the phases. The organic phases were dried over sodium sulphate, filtered off and the solvent was evaporated to give a residue which was distilled under reduced pressure. Prepared as described in this example

15.3 g of 2-methoxy-isobutylisobitrile (68% yield). Boiling point: 64 ° C (3 kPa),

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

Example 2

Preparation of 2-methoxy-2-methylbutylisonitrile.

60 ml of 50% strength aqueous sodium hydroxide solution was added dropwise at room temperature to a stirred mixture of 23.4 g (0.2 mol) of 2-methoxy-2-methylbutylamine, 24.0 grams (corresponding to 0.2 mol or 16 milliliters) of chloroform, 100 milligrams of benzyltriethylammonium chloride as a phase transfer catalyst and 60 milliliters of dichloromethane. The reaction mixture was heated at reflux for 2.5 hours, diluted with 150 ml of dichloromethane and washed three times with 50 ml of water.

The phases were separated, the organic phase was dried over sodium sulfate, filtered and the solvent was evaporated to give a residue which was distilled under reduced pressure. 16.7 g were obtained

Of 2-methoxy-2-methylbutylisonitrile (yield 66%).

Boiling point: 75 ° C (3 kPa).

NMR (CDCl ₃ )? 0.72 (3H, CH ₃ ), 0.94 (3H, CH ₃ ), 2.37 (2H, CH ₂ ),

3.12 (3H, 0CH _3), 3.28 (2H, _CH2) ppm.

Example 3

Preparation of 2-methoxy-2-ethylbutylisonitrile.

Milliliters of a 1% w / w aqueous sodium hydroxide solution was added dropwise at room temperature to a stirred reaction solution containing 26.2 grams (corresponding to 0.2 mole) of 2-methoxy-2-ethylbutylamine. ,

24 grams (corresponding to 0.2 mol) of chloroform (16 milliliters), 100 milligrams of benzyltriethylammonium chloride as a phase transfer catalyst, and 60 milliliters of dichloromethane.

The reaction mixture was heated at reflux temperature for one hour, diluted with 150 ml of dichloromethane and washed three times with water, each time with 50 ml. The phases were separated, the organic phase was dried over sodium sulfate, filtered, and the solvent was evaporated. The residue was distilled under reduced pressure. Prepared as described in this example

18.3 g of 2-methoxy-2-ethylbutylisonitrile (yield 65%). Boiling point: 87 ° C (3 kPa).

3.17 (2H, _CH2) ppm.

Example 4

Preparation of 2-ethoxy-isobutylisonitrile.

The procedure of Example 1 was followed except that 23.4 g (0.2 mol) of 2-ethoxy-isobutylamine was used in place of 2-methoxyisobutylamine. 17.27 grams of 2-ethoxyxsobutylisonitrile (68% yield) was prepared.

Boiling point: 67 ° C (3 kPa).

Example 5

Preparation of 2-n-propoxybenzylitrile.

The procedure of Example 1 was followed except that 26.2 g (0.2 mol) of 2-n-propoxyisobutylamine was used in place of 2-methoxy-isobutylamine. 18.47 g of 2-n-propoxyisobutylisonitrile (65% yield) were prepared. Boiling point: 69 ° C (3 kPa).

- 6 Example 6

Preparation of 2-i-propoxyisobutylisonitrile.

The procedure of this example was carried out in the same manner as in Example 1 except that 26.2 g (0.2 mol) of 2-i-propoxyisobutylamine was used instead of 2-methoxyisobutylamine. 18.05 g of 2-i-propoxyisobutylisonitrile were obtained (yield 64%).

Boiling point: 68 ° C (3 kPa).

Claims (2)

Claims PATENTOVÉ A process for the preparation of isonitrile ethers of formula I CN-R-OR * (I) wherein R is a straight or branched alkylene group having 2 to 8 carbon atoms, and R * is a straight or branched chain alkyl group having 1 to 4 carbon atoms, characterized in that an amine compound of formula III is reacted R 0 - R - NH ₂ (UL) in which R and R * are as defined above, with chloroform in the presence of alkali metal hydroxide. The process according to claim 1, wherein the alkali metal hydroxide is added to the reaction mixture in the form of an aqueous solution and the reaction is carried out in the presence of a phase transfer catalyst.