SK280287B6 - Method for the preparation of isocyanoethers - Google Patents

Abstract

A method of preparing isocyanoether compounds of the general formula (I), wherein R is an alkylene group containing from 2 to 8 carbons and R' is an alkyl group containing from 1 to 4 carbons and both of them having a direct or branched chain, is characterised in that amine of the general formula (III) reacts with chloroform in the presence of an alk. metal hydroxide with the proviso that both R and R' denote the same meaning. A catalyst of the phase transfer can be present as well.

Description

A process for preparing isocyanether ether compounds of formula (I) wherein R is a C 2 -C 8 alkylene group and R 'is a C 1 -C 4 alkyl group, both straight or branched chain, wherein the amine of formula (III) ), wherein R and R 'have the same meaning, react with chloroform in the presence of an alkali metal hydroxide. A phase transfer catalyst may be present.

CN-R-OR

OR-NH ₂ (III)

Technical field

The invention relates to a process for isocyanethers of general formula (I)

CN - R - OR '(I) in which it is

R is a straight chained 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

Said compounds of formula (I) are used in radiodiagnostic methods for the preparation of complexes containing ^99m Tc. These complexes have the general formula (II) [(CN-R-OR ') ₆ ^99m Tc] ⁺ A (II) in which

R 'is as defined above and R is the same meaning, this substituent may also be substituted, and A represents a monovalent anion or one equivalent of a multivalent anion. These complexes are widespread in methods for detecting myocardial disorders, see, for example, Int. J. Nucl. Med. Biol. 11, 225 (1984); J. Nucl. Med. 25, 1350 (1984) and 27, 404 (1986); and Eur. J. Nucl. Med. 12,219 (1986).

The procedure described in U.S. Pat. No. 4,452,774 and in European patent no. 233,338, said compounds of formula (I) are prepared by formylation of an amine of formula (III)

R'OR-NH ₂ (III), in which R and R 'have the same meaning as mentioned above, with formic acid or with a reactive formic acid derivative, the formyl derivative thus obtained is then dehydrated. A disadvantage of this procedure 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, realizing this stage requires considerable energy.

SUMMARY OF THE INVENTION

It is an object of the process of the present invention 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 consists in that said compounds of the general formula (I)

CN-R-OR '(I), wherein R is a C 2 -C 8 alkylene group and R' is a C 1 -C 4 alkyl group, both of which may have a straight or branched chain, is prepared by reaction of an amine of the general formula of formula (III)

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 reaction takes place within a few hours. Furthermore, this reaction can be expediently accelerated or completed by heating the reaction mixture. Said alkali metal hydroxide can also be added to the reaction mixture in the form of an aqueous solution to form a heterogeneous (biphasic) reaction medium. In these cases, it is advantageous to add a phase transfer catalyst to the reaction medium to accelerate the reaction and increase the yield. As said 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 isocyanether ether compounds of formula (I) will now be illustrated by the following practical examples which illustrate the process without limiting it.

Example 1

Preparation of 2-methoxyisobutylisocyanide

In the procedure, 60 ml of dichloromethane was added to a mixture containing 20.6 g (corresponding to 0.2 mol) of 2-methoxyisobutylamine, 24 g (corresponding to 0.2 mol) of chloroform (16 ml) and 100 mg of benzyltriethylammonium chloride and 60 ml of a 50% strength by weight aqueous sodium hydroxide solution were then added dropwise to the reaction mixture thus prepared, which was carried out at room temperature and with stirring. The reaction mixture was then heated at reflux for 2 hours at the reflux temperature of the solvent. 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, then filtered and the solvent was evaporated to give a residue which was distilled under reduced pressure. 15.3 g of 2-methoxy-isobutylisocyanide (68% yield) were prepared according to the procedure.

Boiling point: 64 ° C (3 kPa).

NMR (CDCl 3): δ 1.24 (6H, 2Cl 2). 3.23 (3H, _OCH3), 3.35 (2H, _CH2) ppm.

Example 2

Preparation of 2-methoxy-2-methylbutylisocyanide

60 ml of a 50% strength by weight aqueous solution of sodium hydroxide were used. was added dropwise at room temperature to a stirred mixture containing 23.4 g (corresponding to 0.2 mol) of 2-methoxy-2-methylbutylamine, 24.0 g (corresponding to 0.2 mol or 16 ml) of chloroform and 100 ml. mg of benzyltriethylammonium chloride as a phase transfer catalyst and 60 ml of dichloromethane. The reaction mixture was then heated under reflux for 2.5 hours at the reflux temperature of the solvent. The reaction mixture was then diluted with 150 ml of dichloromethane and washed three times with 50 ml of water. The phases were separated, the organic phase was then dried over sodium sulphate, then filtered and the solvent was evaporated to give a residue which was distilled off under reduced pressure.

2806 reduced pressure. 16.7 g of 2-methoxy-2-methylbutylisocyanide 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 , CH ₂ ) ppm.

Example 3

Preparation of 2-methoxy-2-ethylbutylisocyanide

60 ml of a 50% strength by weight aqueous solution of sodium hydroxide were used. added dropwise at room temperature to a stirred reaction solution containing 26.2 g (corresponding to 0.2 mol) of 2-methoxy-2-ethylbutylamine, 24.0 g (corresponding to 0.2 mol) of chloroform (which is 16 moles). ml), 100 mg of benzyltriethylammonium chloride as a phase transfer catalyst and 60 ml of dichloromethane. The reaction mixture was refluxed for 3 hours at the reflux temperature of the solvent, 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 then dried over sodium sulfate, filtered and the solvent was evaporated. The residue thus obtained was then distilled under reduced pressure. 18.3 g of 2-methoxy-2-ethylbutylisocyanide were prepared (yield 65%). 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-isobutylisocyanide

The procedure of Example 1 was followed except that 23.4 g (corresponding to 0.2 mol) of 2-ethoxyisobutylamine was used instead of 2-methoxy-isobutylamine. According to this embodiment, 17.27 g of 2-ethoxy-isobutylisocvanide (68% yield) was prepared.

Boiling point: 67 ° C (3 kPa).

Example 5

Preparation of 2-n-propoxyisobutylisocyanide

The procedure of Example 1 was followed except that 26.2 g (corresponding to 0.2 mol) of 2-n-propoxyisobutylamine was used instead of 2-methoxyisobutylamine. 18.47 g of 2-n-propoxyisobutylisocyanide (yield 65%) were prepared according to the procedure.

Boiling point: 69 ° C (3 kPa).

Example 6

Preparation of 2-i-propoxyisobutylisocyanide

The procedure of Example 1 was followed except that 26.2 g (corresponding to 0.2 mol) of 2-i-propoxyisobutylamine was used instead of 2-methoxyisobutylamine. 18.05 g of 2-i-propoxyisobutylisocyanide (64% yield) were prepared according to the procedure.

Boiling point: 68 ° C (3 kPa).

PATENT CLAIMS

Claims (2)

1. Process for the preparation of isocyanethers of general formula (I) CN - R - OR '(I) in which it is R is a straight chained 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 the amine compound of formula (III) is reacted. R'OR-NH ₂ (III), wherein 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. End of document