Method of producing carbamide, labelled with stable 13c isotope

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method of producing carbamide with a stable 13C isotope used in medical diagnostics, involving reaction of labelled carbon dioxide and ethylene oxide at temperature 80-150°C, pressure 2.1-6 MPa in the presence of a catalyst - complex of zinc bromide and tertiary organophosphines in molar ratio of ethylene oxide to the catalyst equal to 500-5000:1, followed by extraction of the labelled ethylene carbonate and ammonolysis of the extracted ethylene carbonate at temperature 120-170°C and pressure 2.8-4.7 MPa.

EFFECT: possibility of obtaining an end product with good output using a fairly simple and technologically effective method.

4 cl, 14 ex, 2 tbl

 

The invention relates to a thin organic synthesis, synthesis of medicines and concerns a method for obtaining urea with a stable isotope of carbon13For use in medical diagnosis of diseases of the gastrointestinal tract.

To date, there are several practically implemented methods for the synthesis of urea with labeled carbon atom.

Multi-stage method for the synthesis of labeled urea through the barium cyanamide (U.S. Pat. USA 2571926, 1951, SA 1952, 46, 3561).

*CO2→VA*CO3→BaN*CN→NH2*CN→NH2*CONH2

The output of urea in the calculation of the original labeled carbon dioxide is 60%. In the stages of formation of barium cyanamide is quite specific reagent barium amide and sulfuric acid, respectively. Technically, the method is quite complex, has a low productivity (the synthesis of very long and very difficult to scale.

The known method of synthesis of labeled urea through the cyanate of ammonia, which is produced from potassium cyanide with labeled carbon atom (Haley E.E., Lambooy J.P., J. Amer. Chem. Soc., 1954, 76,2926).

K*CN→KO*CN→NH4OCN→NH2CONH2

The output of urea in the calculation of the cyanide of potassium is 70%. The method is limited by the availability and toxicity labeled potassium cyanide.

Labeled urea with quantitative o the house is also obtained from labeled phosgene(M lvin et al., Isotopic Carbon, N.Y., Wiley, 1949, p.157). However, the synthesis of phosgene from the available labeled raw material is a two-stage and a fairly complex process, so the loss of the isotope label is still inevitable.

*CO2→*; *CO+Cl2→*COCl2; *COCl2++4NH3→NH2*CONH2+2NH4Cl

Known two-stage method of obtaining13C-urea from13CO2providing a processing solution hexamethyldisilazide lithium in an organic solvent, labeled with carbon dioxide, followed by hydrolysis of the resulting13With bis(trimethylsilyl)carbodiimide water (Eurasian patent 004471, 2004).

2(Me3Si)2NLi+13CO2→Me3SiN=13C=NSiMe3+Li213CO3+(Me3Si)O2

Me3SiN=13C=NSiMe3+H2O→NH213CONH2

The total yield of labeled urea per bis(dimethylsilane)amide lithium fairly moderate - 60-72%. Output13CO2is not given, but 50% of the original13CO2spent on education (Li213CO3). It should be borne in mind that such method involves the use of expensive silicon amides of alkali metals.

Thus, the described methods of obtaining labeled urea have significant shortcomings. They feature Southsea low yield on labeled raw, extreme conditions of synthesis or include toxic reagents (potassium cyanide, cyanate, cyanamide and phosgene), which seems to be invalid in the synthesis of pharmacological drug. In addition, most methods due to technical complexity, mnogostadiinost, using specific labeled raw materials or expensive reagents are not suitable for scaling to any substantial quantity of a product, the total requirement which as a diagnostic drug can reach several hundred pounds. Given these production volumes, it should be borne in mind that the only economically viable source of isotope labels to obtain urea labeled with isotope13With is13CO2.

Closest to the proposed method is a method of synthesis of labeled urea of labeled carbon dioxide and ammonia by the reaction Bazarova:

*CO2+2NH3+H2O→NH2*CONH2+H2

The synthesis is carried out at 135°C in a sealed ampoule with a yield of 40% (Myerson.A.L., J. Amer. Chem. Soc., 1952, 74, 2436).

The disadvantages of the method should be regarded as a low output per expensive labeled raw materials and intermediate formation of toxic ammonium cyanate:

*CO2+2NH3→NH2*COONH4→N*CONH4→NH2CONH2.

the Output could be increased to 80%, if you perform the reaction at 200°C and a pressure of 196 MPa (Marra A., Williams DL, Syntheses of organic compounds with carbon isotopes. Izd-vo IL. M, 1961). Under these conditions, the formation of toxic cyanate of ammonia does not occur (Kirk-Othmer, Encyclopedy of Chem. Technology, 4thed., v.11, p.297) However, the very high pressure required to achieve acceptable output, requires special equipment that reduces the attractiveness of the method. Particularly significant from an economic point of view, it can affect the scaling to work out larger quantities of product. In addition, the reaction equilibrium, and recycling the initial reagents without technological losses of expensive labeled carbon dioxide at high pressures seem to be quite a difficult technical task.

The problem solved by the invention is to create molestating, low-waste and environmentally friendly method for the synthesis of urea labeled with a stable isotope13With, while maintaining pharmacopoeial quality product. Closest to the proposed method on raw materials used is the interaction of labeled carbon dioxide (13CO2) with ammonia by the reaction Bazarova, which can be considered as a prototype of the proposed method.

The technical result from the proposed method is to see what Genii reaction conditions, using the available labeled raw material, to improve the processability of the method, reduce the loss of isotope labels, as well as the exclusion from potentially dangerous highly toxic substances, such as cyanate that could affect the pharmaceutical quality of the product.

The technical result is achieved using the two-stage synthesis method including a preliminary interaction of labeled CO2and ethylene oxide with the formation of ethylene carbonate resulting reaction

in the presence of a catalyst at a pressure of 2.1 to 6 MPa and a temperature of 80-150°C With almost quantitative yield (stage 1), followed by separation of ethylene carbonate resulting, and ammonolysis of the selected ethylene carbonate resulting reaction

at a pressure of 2.8 to 4.7 MPa and a temperature of 120-170°C with the release of not less than 80% on the recovered ethylene carbonate resulting (stage 2). Synthesis of ethylene carbonate resulting exercise in excess of labeled carbon dioxide in the presence as catalyst complexes of zinc bromide with tertiary organophosphine, with the release of labeled ethylene carbonate resulting in the distillation or sublimation. The catalyst introduced into the reaction mixture in the form of ready-made systems or their components. When the pressure is below 2.1 MPa, there is a risk of spontaneous explosive decomposition of ethylene oxide. The use of pressure bol is 6 MPa technically infeasible, because it already exceeds the vapour pressure of liquid CO2at room temperature, which requires additional equipment for the supply of this reagent in the reactor. The reaction rate is markedly reduced at temperatures below 80°C and at temperatures above 150° C the yield of the product decreases and becomes visible decay phosphine components of the catalyst. Stage 2 can be performed in a solvent, partially dissolving the urea. At temperatures below 120° ammonolysis of ethylene carbonate resulting in proceeds very slowly, and at a temperature above 170° output of urea is small due to adverse reactions. When the pressure is below 2.8 MPa ammonolysis process (stage 2) does not occur, and the pressure increase above the 4.7 MPa does not impact positively on the performance of the process. The choice of catalyst complexes of zinc bromide with organophosphine explained by the need to ensure the absence of impurities in the intermediate ethylene carbonate resulting after its separation by distillation or sublimation, i.e. the catalyst should not be volatile and not to give volatile products of decomposition. On the other hand, the catalyst must be sufficiently active to moderate consumption to ensure quantitative conversion of ethylene oxide to ethylene carbonate resulting for technologically acceptable response time. All these conditions meet the bromide complexes of zinc with tertiary Ala aromaticheskimi organophosphine, taken in relation to the zinc bromide in a molar amount of 1:2. When implementing the invention, the catalyst can be used as a ready-made complexes, and a mixture of anhydrous zinc bromide with organophosphine. In the latter case, the true catalysts are formed directly in the reaction mixture. The molar ratio of ethylene oxide to the catalyst is 500-5000:1.

For minimizing the loss of labeled reagents in stage 1 technical result is achieved by quantitative conversion of the ethylene oxide in the labeled ethylene carbonate resulting in the course of the synthesis reactor is fed an excess of labeled carbon dioxide in comparison with the stoichiometric required. Thus, after the process is complete, the gas phase reactor contains free from ethylene oxide labeled WITH2that can be assembled and applied to reduce the consumption of fresh labeled carbon dioxide by repeating synthesis or used for any other purpose. When carrying out the invention unreacted labeled carbon dioxide can be completely removed from the reactor in any way, for example precondensation or pumped by the pump source or a separate container. After that, the product removed from the reactor and separated from the catalyst by distillation or sublimation in a high vacuum. T is some allocation method guarantees complete absence of traces of ethylene oxide in the intermediate product the ethylene carbonate resulting.

In the implementation stage 2 technical result in increasing output, easing the reaction conditions, increasing the purity of the final product and improve the manufacturability of the method is achieved by using such a solvent, in which the original ammonia, labeled a and ethylene carbonate resulting formed during the reaction of a glycol soluble and urea trudnorastvorim that allows you to shift the reaction equilibrium in the direction of end products and select the target labeled urea by simple filtration. The specified conditions are satisfied by most of the solvents of the ether type, in particular tetrahydrofuran.

The implementation of the present invention illustrate the examples below.

Example 1.

Synthesis of labeled ethylene carbonate resulting in spend in the installation, consisting of autoclave production Parr Instrument" (volume 300 ml), dosing of liquid ethylene oxide and container labeled with carbon dioxide. Installation involves attaching supply lines, argon and vacuum. To reduce technological losses labeled WITH2the volume of communications and the valve is minimized.

In the autoclave is placed 0.045 g (0.2 mmol) of anhydrous zinc bromide and 0.105 g (0.4 mmol) of triphenylphosphine. To remove atmospheric unlabeled CO2install purge with argon, after which vacuum and n is the power of the dispenser enter 17,64 g (0.4 mol, about 20 ml) of liquid ethylene oxide. Then include mixing and fed into the autoclave13CO2(isotopic purity 99.5 at.%) to the total pressure of 1.6 MPa, and then heated to 120°C and carry out the reaction. During the reaction the pressure support in the range of 2.8-3.2 MPa through batch submission13CO2. Upon completion of the reaction, the autoclave is cooled and precondensed unspent carbon dioxide in the original container by cooling with liquid nitrogen, after which the solidified reaction mixture is then removed from the autoclave. Change the mass of the cylinder is found that the chemical reaction and process losses consumed 18.2 g (9.07 nl, 0.404 mol)13CO2. The product distinguish sublimation at a residual pressure of 0.05 mm Hg (40-50°C). Get 34.815 g (0.391 mol) of labeled ethylene carbonate resulting in the form of a colorless crystalline substance, TPL 35-37°C. the Yield on consumed labeled carbon dioxide 96.8%, output loaded to ethylene oxide 97.8%. Impurities, including triphenylphosphine, according to GC is not detected (limit of sensitivity of the method is 0.01 wt.%). The isotopic purity of the product according to gas chromatography-mass spectrometry not below 98.2%.

Example 2.

Synthesis of labeled ethylene carbonate resulting carried out analogously to example 1, except that as the catalyst using 0.15 g (0.2 mmol) in advance p is iegotovlenna complex ZnBr 2(Ph3P)2. The yield on consumed labeled carbon dioxide 96.7%, output loaded to ethylene oxide 98.4%. Impurities within the sensitivity of the GC-analysis is not detected, the isotopic purity of the product is not lower than 98.5%.

Example 3

Synthesis of labeled ethylene carbonate resulting behave analogously to example 1, except that as the catalyst using 0.09 g (0.4 mmol) of anhydrous zinc bromide and 0.244 g (0.8 mmol) of Tris(p-tolyl)phosphine, and the process is carried out at 100°C. the product Yield on consumed labeled carbon dioxide 96.5%, loaded ethylene oxide 97.6%. Example 3 shows that as the catalyst for the synthesis of labeled ethylene carbonate resulting in addition to complexes of zinc bromide with triphenylphosphine can be used complexes with other organophosphine.

Example 4.

In the autoclave with a capacity of 50 ml was placed 1.1 g (12,36 mmol) labelled with carbon-13 ethylene carbonate resulting dissolved in 5 ml of fresh over sodium tetrahydrofuran. To remove air, the autoclave is rinsed with nitrogen (3×1 MPa) and with stirring to saturate the solvent with ammonia under pressure of 0.8 MPa for 30 minutes Then the total pressure in the autoclave to raise the nitrogen to 2 MPa and heated to 140°C. when heated, the pressure increases to 4.05 MPa). After soaking for 8 hours of heating and stirring off, give the wroclawiu spontaneously cooled to room temperature, transfer the contents onto porous glass filter and filtered, the insoluble product. To reduce mechanical losses autoclave rinsed 15 ml of tetrahydrofuran (3×5 ml) and washed with this amount of the product on the filter. After that, the product is additionally washed with diethyl ether (3×5 ml) and dried on the filter in a stream of air to constant weight. Analysis of the product and the mother liquor on the content of urea is conducted according to standard photocolorimetric method (CrockerC.L. Amer. J. Med. Technol., 1967, v.33, R). Get 0,711 g of urea labelled with carbon-13. The basic substance content of 96.5 wt.% (11,25 mmol), output 91,0% per loaded ethylene carbonate resulting.

Examples 5-14.

The synthesis of urea labeled with the carbon atom13With, carry out analogously to example 4 by varying the reaction temperature, duration of procedure, download and ethylene carbonate resulting in the nature of the solvent (table 1).

Table 1
# exampleDownload the ethylene carbonate, g (mmol)The temperature-RA, °CPressure-tion, MPaDissolve-telDuration of synthesis, hMass prod the KTA, gCarbamide content, wt.% (mmol)Output %
51.12 (12.58)1203,10THF80.63673.0 (7.61)60.5
61.10 (12.36)1404,0THF50.604100 (9.90)80.1
72.20 (24.72)1404,6THF81.3292 (19.91)80.5
84.40 (49.44)1404,0THF82.4695.5 (38.50)77.9
91.10 (12.36)140 4,0THF100.63598.7 (10.27)83.1
101.10 (12.36)170the 4.7THF50.49498.0 (7.94)64.2
111.10 (12.36)1704,2THF80.44694.0 (6.87)55.6
121.10 (12.36)1404,01,4-Dioxane80.73058.5 (7.00)56.6

Examples 13, 14.

The synthesis of urea labeled with the carbon atom13With, carry out analogously to example 4 except that the solvent is not used (table 2)

Table 2
no example is Download the ethylene carbonate, g (mmol)Temperature, °CPressure, MPaThe duration of synthesis, hThe product weight, gCarbamide content, wt.% (mmol)Output %
131.10 (12.36)1402,850.61099.0 (9.90)80.1
141.10 (12.36)1403,580.63096.3 (9.94)80.4

Thus the proposed method of producing urea labeled with a stable isotope13With, produces a product with a good yield (up to 91%) and with the quality that meets the requirements of the pharmaceutical product in Addition, the proposed method due to its technology can be scaled to obtain a product in more than a few hundred kg

1. A method of producing urea labeled with a stable isotope13, with the use of labeled carbon dioxide and ammonia, wherein the process is carried out in two stages: first, spend the interaction of labeled carbon dioxide and ethylene oxide at temperatures of 80-150°C., a pressure of 2.1 to 6 MPa in the presence of a catalyst complex of zinc bromide with tertiary organophosphine at a molar ratio of ethylene oxide to the catalyst 500-5000:1, followed by separation of labeled ethylene carbonate resulting in, and then spend the ammonolysis of selected ethylene carbonate resulting at a temperature of 120-170°C and a pressure of 2.8 to 4.7 MPa.

2. The method according to claim 1, characterized in that the first stage is carried out in excess of labeled carbon dioxide.

3. The method according to claim 3, characterized in that the components of the catalyst is zinc bromide and organophosphine injected into the reaction mixture in the form of individual compounds.

4. The method according to claim 1, characterized in that as the reaction medium in the second stage - use the solvent, partially dissolving labeled urea.



 

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