CZ286794B6 - 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 'in which R is a straight or branched alkylene group containing 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 radiodiagnostic methods to prepare complexes containing ^99m Tc. These complex compounds have the general formula Π [(CN-R-OR) ' ₆ ^99m Tc] ⁺ A' (Π) where R 'is as defined above and R has the same meaning, this substituent may also be substituted, and A' represents a monovalent anion or one equivalent of a multivalent anion. These complex substances are widespread in methods for detecting myocardial disorders. For example. Int. J. Nucl. Copper. Biol. 11,225 (1984); J. Nucl. Copper. 25, 1350 (1984) and 27,404 (1986); and Eur. J. Nucl. Copper. 12, 219 (1986).

In accordance with the procedure described in U.S. Pat. No. 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.

RO-R-NH ₂ (m) in which R and R 'have the same meaning as previously described, with formic acid or with a reactive formic acid derivative, the formyl derivative thus obtained is then dehydrated. 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 of the present invention is to be able to be carried out in a fast manner with 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-R-OR '

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 have a straight or branched chain, prepared by reaction of an amine of the formula ΙΠ

RO-R-NH ₂ (III) wherein R 'and R are as defined above, with chloroform in the presence of an 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 may preferably be accelerated or completed by heating the reaction mixture. Said alkali metal hydroxide to form a heterogeneous (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, quaternary ammonium salt or phosphonium salt can be added to the reaction medium.

DETAILED DESCRIPTION OF THE INVENTION

The process for preparing the isonitrile ether compounds of formula (I) will now be illustrated by the following practical examples, which are intended to illustrate but not limit the invention.

Example 1

Preparation of 2-methoxyisobutylisonitrile.

60 ml of dichloromethane was added to a mixture containing 20.6 g (0.2 mol) of 2-methoxyisobutylamine, 24 g (0.2 mol) of chloroform (16 ml) and 100 mg of benzytriethylammonium chloride and 60 ml of 50% strength aqueous sodium hydroxide solution was added dropwise to the reaction mixture 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 phase was dried over sodium sulfate, filtered off and the solvent was evaporated to give a residue which was distilled under reduced pressure. 15.3 g of 2-methoxy-isobutyl-isonitrile were obtained (yield 68%).

Boiling point: 64 ° C (3 kPa),

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 to the stirred solution at room temperature.

A mixture containing 23.4 grams (corresponding to 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 of a phase transfer catalyst and 60 ml 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 of 2-methoxy-2-methylbutylisonitrile were obtained (yield 66%).

Boiling point: 75 ° C (3 kPa).

NMR (CDCl ₃ ): δ 0.72 (3H, CH ₃ ), 0.94 (3H, CH ₃ ), 2.37 (2H, CH ₂ ), 3.12 (3H, OCH ₃ ), 3.28 (2H, _CH2) ppm.

Example 3

Preparation of 2-methoxy-2-ethylbutylisonitrile

60 ml of 50% strength aqueous sodium hydroxide solution was added dropwise at room temperature to a stirred reaction solution containing 26.2 g (0.2 mol) of 2-methoxy-2-ethylbutylamine, 24 ml. grams (corresponding to 0.2 mol) of chloroform (16 ml), 100 milligrams of benzyltriethylammonium chloride as a phase transfer catalyst and 60 ml of dichloromethane. The reaction mixture was heated to reflux for 3 hours, diluted with 150 ml of dichloromethane and washed three times with 50 ml of water each time. 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. 18.3 g of 2-methoxy-2-ethylbutylisonitrile (65% yield) were prepared.

Boiling point: 87 ° C (3 kPa).

NMR (CDCl ₃ ): δ 0.85 (6H, 2CH ₃ ), 2.14 (4H, 2CH ₂ ), 2.91 (3H, OCH ₃ ), 3.17 (2H, CH ₂ ) 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-methoxy-isobutylamine. 17.27 grams of 2-ethoxyisobutylisonitrile (68% yield) was prepared.

Boiling point: 67 ° C (3 kPa).

-3GB 286794 B6

Example 5

Preparation of 2-n-propoxyisobutylisonitrile

The procedure of Example 1 was followed except that 26.2 g (0.2 mol) of 2-n-propoxyisobutylamine was used instead of 2-methoxy-isobutylamine. 18.47 g of 2-n-propoxyisobutylisonitrile (65% yield) were prepared.

Boiling point: 69 ° C (3 kPa).

Example 6

Preparation of 2-i-propoxyisobutylisonitrile

The procedure of Example 1 was followed 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 (64% yield) were prepared.

Boiling point: 68 ° C (3 kPa).

Claims (2)

PATENT CLAIMS A process for the preparation of isonitrile ethers of formula I CN-R-OR '(I) wherein R is a straight or branched alkylene group containing 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 RO-R-NH ₂ (ΙΠ) in which R and R 'are as previously defined, with chloroform in the presence of an 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.