1-¹³c-caprylic acid synthesis method

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 1-¹³C-caprylic acid which is used as a diagnostic preparation when diagnosing motor-evacuation functions of the stomach. The method involves hydrocarboxylation reaction of 1-heptene with carbon monoxide ¹³CO and water at temperature 100-170°C and pressure not above 5 MPa, in the presence of a solvent and a catalyst system which contains a complex compound of palladium and triphenylphosphine in ratio ranging from 1:2 to 1:100, where the solvent used is dioxane and/or aromatic hydrodrocarbon.

EFFECT: obtaining 1-¹³C caprylic acid with high isotope purity, increased cost-effectiveness of the process owing to increased degree of utilisation of isotope material.

5 cl, 9 ex

The invention relates to organic chemistry, in particular to methods for saturated aliphatic carbolic acid containing stable carbon isotopes¹³With, and in particular 1-¹³With Caprylic acid. This compound is used as a diagnostic drug for the diagnosis of motor-evacuation function of the stomach.

Analysis of scientific literature shows that there is a method of obtaining enanthic acid containing a radioactive isotope of carbon¹⁴In position 1 the molecules of acid (carbonyl carbon atom) (see, for example, Ammara, Delwilliams. "Syntheses of organic compounds with carbon isotopes". M., 1961, p.39). The known method is a multistage process of interaction of methyl iodide-¹⁴With dihydroisoquinolin potassium with the formation of 2-methyl-¹⁴C-dehydroretinal and then restoring it with a solution containing sodium hydroxide, diethylene glycol and 85%hydrazinehydrate with the formation of the 1¹⁴With-enanthic acid with access to 39.6%, based on methyl iodide-¹⁴C.

Unfortunately, there is a method of obtaining carboxylic acids is complicated by the fact that consists of several stages, and also the use of compounds with radioactive isotope of carbon¹⁴C. Another disadvantage of this method is low Ihad target product isotope raw materials.

Previously we have proposed a method of obtaining the 1¹³With Caprylic acid (U.S. Pat. RF 2311402, MKI⁷SS 51/14, 2007) reaction hydrocarbonsoluble 1-Heptene - its interaction with carbon monoxide¹³And water at a temperature of 100-170°C. and a pressure of not more than 5.0 MPa, in a mixed solvent - propionic acid and o-xylene in the presence of a catalytic system containing a compound of palladium in the form of a complex PdCl₂(PPh₃)₂and triphenylphosphine h₃taken in the ratio range of from 1:2 to 1÷100 respectively. Selectivity for Caprylic acid is 98%. Output 1-¹³With Caprylic acid in the calculation of the absorbed¹³WITH 100%. At the same time, the degree of isotopic enrichment was 80%, so the yield of the desired acid¹³WITH at 78.4% of theoretical.

It is known that carboxylic acids in the conditions of the carbonylation of olefins in solution complexes of palladium and rhodium may be subject to decomposition (decarbonylation) with the release of carbon monoxide (J.Tsuji. Palladium. Reagents and Catalysts. Chichester: John Wiley & Sons: 1998, p.385, 537). In this case formed WITH unlabeled will also interact with the original olefin with the formation of the corresponding carboxylic acid, which could cause a reduction in the degree of isotopic enrichment (isotopic purity) in the pre is its us the way. The yield of 1-¹³With Caprylic acid source¹³WITH will be lower due to the decline in the share of initial reagents into the target 1-¹³With Caprylic acid.

Thus, the disadvantage of this method is the low degree of isotopic enrichment of the 1¹³With Caprylic acid.

In the framework of the present invention solves the task of developing a one-step method of obtaining Caprylic acid with a stable isotope of carbon¹³In position 1 the molecules of acid (carbonyl carbon atom) with isotopic purity not less than 98%, increased yield of the desired acid in the calculation of the isotopic raw materials, improve the economic efficiency of the process.

The problem is solved in that Caprylic acid stable isotope of carbon¹³In position 1 is obtained by reaction of hydrocarbonsoluble 1-Heptene - its interaction with carbon monoxide¹³And water at a temperature of 100-170°C. and a pressure of not more than 5.0 MPa, in the solution of a catalytic system containing a complex compound of palladium and triphenylphosphine h₃taken in the ratio range of from 1:2 to 1:100, using as solvent dioxane, or aromatic hydrocarbons - benzene, toluene, xylene or their mixtures with dioxane.

The problem is solved also by the fact that the use of giving is giving ¹³WITH from 0.5 to 1.0 MPa.

The problem is solved by using the temperature from 140 to 160°C.

The problem is solved also by the fact that use of the catalytic system with a ratio of complex compounds of palladium and triphenylphosphine in the range from 1:10 to 1:40.

The task is solved in that the reaction mixture is further added hydrochloric acid.

When carrying out the process at temperatures below 140°C, the reaction proceeds slowly, and at temperatures above 160°C breaks down complex compounds of palladium with separation of metallic palladium.

At pressures below 0.5 MPa decreases the speed of the process, and when the pressure is higher than 1.0 MPa decreases the selectivity of the process.

When the ratio of the complex compound of palladium:triphenylphosphine less than 1:10 decreases the stability of the catalyst, and when the ratio is about 1:40 decreases the speed of the process.

The invention is illustrated by the following examples.

Example 1

In a stainless steel autoclave with a volume of 200 ml, placed on the table of the magnetic prevented, put 0.07 g PdCl₂(PPh₃)₂, 2,62 g PPh₃and 5.7 ml of 1-Heptene, 0,36 ml of N₂O. as solvent a mixture consisting of 9.6 ml of o-xylene and 4.7 ml of dioxane. The autoclave is pressurized, vacuum, fill with carbon monoxide¹³CO and heated on the temperature of 150°C. Then bring pressure to work (0.5 MPa) and constant support during the whole experience. After 3 hours, turn off the stirring and heating, the autoclave is cooled to room temperature and relieve pressure. The autoclave unload and analyzing the reaction mixture by gas chromatography (GC).

Chromatographic analysis of the products of the synthesis is performed on a gas chromatograph with a flame ionization detector; use metal column size 3 m×3 mm, filled with Chromaton N-AW-DMCS (0,16-0,20 mm) with 3% H₃RHO₄soaked in 10% polyethyleneglycoladipinate. As an internal standard using hexadecane.

To determine the isotopic purity of the 1¹³With Caprylic acid it is recovered from the reaction mass by vacuum distillation and analyzed by the method of NMR nuclei¹³With (25°C, the solution in CDCl₃). Use the NMR spectrometer AM-360 (Bruker) with an operating frequency of 360 MHz.

The selectivity of the reaction by Caprylic acid was 95.5%, while the degree of transformation¹³WITH close to 100%. The isotopic purity of the target 1-¹³With Caprylic acid is 99%, and its yield per absorbed¹³CO - 94.5% of theoretical. During the reaction the catalyst is stable and is not destroyed with the release of metallic palladium.

Example 2

The reaction is carried out in the same way as the example 1, however, in the original mixture of 0.02 ml of Hcl conc. and conduct a reaction for 4 hours.

The selectivity of the reaction by Caprylic acid were 96.7%. The isotopic purity of the obtained 1-¹³With-Caprylic acid - 99%, and its output at full conversion¹³CO - 95,7% of theoretical. The catalyst is not destroyed.

Example 3

The reaction is carried out as in example 1, however, the operating pressure of carbon monoxide¹³WITH is 1.0 MPa.

The selectivity of the reaction by Caprylic acid increased by 91.9%. Output 1-¹³With Caprylic acid per¹³CO - 90,1% of theoretical, its isotopic purity 98%. In the process, the catalyst is stable.

Example 4

The reaction is carried out as in example 1, but in the solvent used to 14.3 ml of dioxane, and conducting the reaction for 6 hours.

The selectivity of the reaction by Caprylic acid amounted to 94.5%. The isotopic purity of the obtained 1-¹³With Caprylic acid is 99%, and its output at full conversion¹³CO - 93.6% of theoretical. The catalyst is stable and is not destroyed with the release of metallic palladium.

Example 5

The reaction is carried out as in example 1, but in the solvent used to 14.3 ml of o-xylene and conducting the reaction for 11.5 hours.

The selectivity of the reaction by Caprylic acid was 81.0%. Output 1-¹³With Aprilovo acid per ¹³WITH no absorption - 79,4% of theoretical, its isotopic purity 98%. During the reaction the catalyst is stable.

Example 6

The reaction is carried out as in example 1, but in the solvent used to 14.3 ml of benzene and conduct a reaction for 8 hours.

The selectivity of the reaction by Caprylic acid amounted to 92.2 per cent. The isotopic purity of the obtained 1-¹³With Caprylic acid is 99%, and its output per¹³CO - 91,3% of theoretical. The catalyst is stable.

Example 7

The reaction is carried out as in example 1, but in the solvent used to 14.3 ml of toluene and conduct a reaction for 5 hours.

The selectivity of the reaction by Caprylic acid amounted to 94.8%. Output 1-¹³With Caprylic acid per¹³WITH no absorption - 92.9% of theoretical, its isotopic purity 98%. During the reaction the catalyst is stable.

Example 8

The reaction is carried out as in example 1, but in the solvent used to 14.3 ml of n-xylene and carry out reaction for 10 hours.

The selectivity of the reaction by Caprylic acid was 81,5%. Output 1-¹³With Caprylic acid per¹³WITH no absorption - 80.7% of theoretical, its isotopic purity 99%. The catalyst is not destroyed during the process.

Example 9

The reaction is carried out in the same way, to the to in example 1, however, as the catalytic system using 0.07 g of the complex PD(SLA)₂(h₃)₂and 1.31 g h₃and conduct the reaction at a temperature of 110°C for 4 hours.

The selectivity of the reaction by Caprylic acid made 94.0%. The isotopic purity of the obtained 1-¹³With Caprylic acid is 99%, and its output at full conversion,¹³CO - 93.1% of from theoretical. The catalyst is stable and is not destroyed with the release of metallic palladium.

The advantage of this method is that it allows a single stage, and in a fairly mild conditions (0.3 to 1.0 MPa) to obtain 1-¹³With Caprylic acid with high isotopic purity of 98-99% is due to the replacement of propionic acid used as a component of the solvent, dioxane, or an aromatic hydrocarbon from a number of: benzene, toluene, xylene, or a mixture of dioxane. The method allows to increase the economic efficiency of the process of obtaining the 1¹³With Caprylic acid by increasing the degree of usage (output) isotopic raw¹³WITH. Furthermore, the method allows to obtain isotopic diagnostic preparations, not containing dangerous radioactive isotopes.

1. The method of obtaining Caprylic acid with a stable isotope of carbon (1-¹³C) reaction of hydrocarbonsoluble 1-Heptene with carbon monoxide^{13 And water at a temperature of 100-170°C. and a pressure of not more than 5 MPa, in the presence of solvent and catalyst system comprising a complex compound of palladium and triphenylphosphine in the value taken from the range from 1:2 to 1:100, characterized in that the solvent used dioxane and/or aromatic hydrocarbon.}

^{2. The method according to claim 1, characterized in that the process is carried out at 140-160°C.}

^{3. The method according to claim 1, characterized in that the process is performed under a pressure of 0.5-1.0 MPa.}

^{4. The method according to claim 1, characterized in that the ratio between the complex compound of palladium and triphenylphosphine taken from the range from 1:10 to 1:40.}

^{5. The method according to claim 1, characterized in that the reaction mixture is further added hydrochloric acid.}