SK323791A3 - Method for the preparation of isocyano 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

Process for preparing isocyanethers

Technical field

The invention relates to a process for the preparation of isocyanethers 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 radiodiagnostic methods to prepare complexes containing ^99m Tc. These complexes have the general formula II [(CN-R-OR ') ₆ ^m Tc] ⁺ A' (II), in which:

R 'is as defined above and R is the same meaning, this substituent may also be substituted, and A' is a monovalent anion or one anion equivalent. These complexes are very polyvalent 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, the above compounds of formula I are prepared by formylation of an amine of formula III

R 10 -R-NH ₂ (III), in which R and R 'have the same meaning as above, with the presence of formic acid or 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 (e.g. ranging from 0.5 to 30 hours). 1 MPa). Therefore, realizing this stage requires considerable energy.

SUMMARY OF THE INVENTION

It is an object of the process according to the invention to be carried out in a rapid manner with a low energy consumption, the resulting product of the 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 '(I) in which R is a C 2 -C 8 alkylene group and R' is a C 1 -C 4 alkyl group, both of which may be straight or branched, is prepared by reaction of an amine of general formula of formula III

R'O-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, 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 preferred according to the invention 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 isocyanether ether compounds of formula (I) will be illustrated by the following practical examples which illustrate the process without limiting it.

Example 1 ictuz

Preparation of 2-methoxyisobutylisocyanB

In the procedure of this example, 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, 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-isobutylisocyanate (yield 68%) were prepared as described in this example. 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-methylbutylisocyanate

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 at reflux for 2.5 hours. The reaction mixture was diluted with 150 mL of dichloromethane and washed three times with 50 mL of water. The phases were separated and the organic phase was dried over sodium sulfate, then filtered and the solvent was evaporated to give a residue which was distilled under reduced pressure. 16.7 g of .beta.-methoxy-.beta.-methylbutylisocyanate was obtained according to this embodiment (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, _OCH3), 3.28 (2H, _CH2) ppm.

Example 3

ÍCÍUz

Preparation of 2-methoxy-2-ethylbutylisocyanate

60 ml of a 50% strength by weight aqueous solution of sodium hydroxide were used. was 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 (16 mg). 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 and the organic phase was dried over sodium sulfate, filtered and the solvent was evaporated. Thus i

the residue obtained was then distilled under reduced pressure. 18.3 g of 2-methoxy-4-ethylbutylisocyanate (yield 65%) were prepared according to the procedure.

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-isobutylisocyanate

The procedure of Example 1 was followed except that 23.4 g (corresponding to 0.2 mol) of 2-ethoxy-isobutylamine was used instead of 2-methoxy-isobutylamine. According to this embodiment, 17.27 g of 2-ethoxyisobutylisocyanate (68% yield) were prepared. Boiling point: 67 ° C (3 kPa).

Example 5

Preparation of 2-n-propoxyizobutylizokyän ^ ^U '

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-propoxyisobutylisocyanate (yield 65%) were prepared as described in this example.

Boiling point: 69 ° C (3 kPa).

Example 6

ICAM /

Preparation of 2-i-propoxyisobutylisocyanine

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. Following the procedure of this example was prepared by 18.05 g of 2-i-propoxyizobutylizokyäm ^ ^{J <(yield} 64%).

Boiling point: 68 ° C (3 kPa).

323ι / 323? - ??

Claims (2)

Patent Claims' A process for the preparation of isocyanethers 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, characterized in that an amine compound of formula III is reacted R 10 -R-NH ₂ (III), wherein R and R 'are as previously defined, with chloroform in the presence of an alkali metal hydroxide. Process according to claim 1, characterized in that 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.