Method of quantitative analysis of the crude vermeil-1,1,1, 3,3,3-hexafluoroisopropyl ester and method for producing vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether

 

(57) Abstract:

In the invention, a method of quantitative determination of the sample composition containing organic compound and unreacted hydrogen fluoride, without the threat of damage to the gas chromatograph with a capillary column containing cross-linked cenopopulations, which can be used to separate very small amounts of impurities and quantify unreacted educt and by-products having a boiling point within a wide range. The invention is also a method of control of the technological process of production of sevoflurane, characterized in that on one of the following steps define the content of a specific component, which is variable, and depending on this content regulate conditions for this stage: 1) stage of the interaction 1,1,1,3,3,3-hexafluoroisopropyl alcohol, formaldehyde or paraformaldehyde and hydrogen fluoride in the presence of sulfuric acid, 2) the stage of interaction of the crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether with an aqueous solution of alkali and/or water, 3) the stage of distillation of the crude "sevoflurane". Technical iza and simplify the method of receipt. 2 S. and 19 C.p. f-crystals, 1 Il., table 1.

The invention relates to gas chromatography analysis of the impurities contained in vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether (hereinafter referred to as "sevoflurane"), used as pharmaceuticals, agrochemicals or intermediate substances to obtain these tools, as well as concerns control over the content of impurities in the production process "sevoflurane" and based on the method of process control.

"Sevoflurane" receive in accordance with the method described in U.S. patent 4250334, interaction 1,1,1,3,3,3-hexafluoroisopropyl alcohol (hereinafter GFIS) and the reaction mixture containing concentrated sulfuric acid, hydrogen fluoride and paraformaldehyde. Received sevoflurane contains unreacted alcohol and the number of by-products. Because "sevoflurane" used as an inhaled anesthetic, it is necessary to clearly identify the contained impurities and to determine their number.

Now for the quantitative determination of fluorine-containing compounds having a relatively low boiling point, using a gas chromatograph with different speakers. Napryjenay oligomer, for example DAIFLOID#50, or columns with porous polystyrene resin, such as PORAPAK Q as the stationary phase. However, they are not efficient enough for microanalysis of impurities in drugs. From the point of view of microanalysis effective capillary column. However, when using a capillary column containing the stationary phase methylsiloxane, phenylsilanes, etc. proved impossible to achieve a sufficient degree of separation, particularly in respect of low-boiling by-products, in particular, cause problems for the "sevoflurane".

In addition, when the control of technological processes of synthesis, purification and so on, it is necessary to analyze not only the samples containing admixture with close boiling points. It is also necessary to analyze substances with high boiling point, for example, unreacted educt, etc. However, the above speakers do not comply with these requirements.

In the production of fluorinated organic compounds often as a fluorinating agent for organic compounds using hydrogen fluoride (HF). For example, in U.S. patent 4766260 describes the interaction of tetrachloride ethylene and hydrogen fluoride is the atur from 300 to 450oC to obtain 1,1,1-trichotillomania and 1,1,1,2-tetrafluorochloroethane.

In this scenario, when you try to analyze unpurified fluorine-containing organic substances or of the reaction mixture using a gas chromatograph is corrosion of the column and detector under the action contained in a sample of hydrogen fluoride. A similar problem occurs when the allocation of the hydrogen fluoride in the reaction between the fluorine-containing organic substances and other compounds.

At the same time, it is known that low molecular weight hydrocarbons (methane, ethane, Tilford, propane, n-hexane, and so on) contained in anhydrous hydrogen fluoride at concentrations from 1 to 1000 µg/g, can be extracted by carbon tetrachloride, followed by quantitative analysis (threshold 0.5 μg/g) using a gas chromatograph [W. P. Cotton, D. Z. Stelz. , Anal.Chem., 52(13), 2073 (1980)].

Set [A. V. Gubarev, A. G. Surikov., S. A., 108(4), 30834r (1986)] that in the analysis of flow of the products of the decomposition reaction of silicon tetrafluoride with sulfuric acid using a gas chromatograph, in which all parts are made of polytetrafluoroethylene, and the detector is covered with a fluoride-containing paint, tetraploid silicon is decomposed under the action of the about can only be used to analyze the flow of dry gas.

It is also known that in the analysis of halogenated metal using gas chromatograph with hydrogen flame-ionization detector (PID) flame PID formed hydrogen fluoride, and the detector corrode, so you have instead of hydrogen to use carbon monoxide [C. B. Baddiel, C. F. Cullis, Chem. and Ind., 1150 (1960)].

The closest analog of the claimed invention method is the method described in U.S. patent 4250334. Collect the gas produced by adding dropwise 1,1,1,3,3,3-hexafluoroisopropyl alcohol (hereinafter GFIS) to the heated reaction mixture containing concentrated sulfuric acid, hydrogen fluoride and paraformaldehyde, and get "sevoflurane" together with unreacted alcohol and such organic substances as formal, acetal, etc., formed as by-products. As often happens in a single reactor, multiple reactions, in this case fluorination reactions and formation of simple ether in the reaction system in small quantities produces a lot of isomers of the products of disproportionation, etc., Most of these side products can be almost completely removed by water washing, alkali washing, pureheart with him azeotropy. So get "sevoflurane" may be contaminated with these impurities.

The purpose of this invention is to provide such a method of obtaining "sevoflurane", in which the target product essentially does not contain impurities which are not separated by conventional means, and method of analysis in order to determine the content of such impurities.

The problem is solved in that a method for separation of sevoflurane and impurities from low-boiling to high boiling point, in the same column when performing gas chromatographic analysis containing impurities "sevoflurane", obtained by the interaction GFIS, formaldehyde or paraformaldehyde and hydrogen fluoride in the presence of sulfuric acid,

A method of quantitative analysis of the crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether containing fluorinated simple ether as a by-product, including stage gas chromatography analysis of the crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether, in which gas chromatographic analysis is performed using a capillary column containing cross-linked cenopopulations, emitting fluorinated simple ether as poboon column for the separation of very small quantities of impurities and quantitative determination of unreacted starting compounds and by-products in a wide range of their boiling points, as well as the method of analysis of the product containing organic matter and unreacted hydrogen fluoride, in the absence of damage to the unit, and method of control of technological process of obtaining of sevoflurane using these analytical methods.

Method for obtaining vermeil-1,1,1,3,3,3 - hexafluoroisopropyl ether, which includes stages of interaction 1,1,1,3,3,3-hexafluoroisopropyl alcohol, hydrogen fluoride and a component selected from the group comprising formaldehyde or paraformaldehyde in the presence of sulfuric acid, with the first crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether containing the first fluorinated simple ester, which additionally includes the stage

the interaction of the first crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether component selected from the group comprising aqueous alkali solution and water to remove the acidic component or 1,1,1,3,3,3-hexafluoroisopropyl alcohol remaining after the stage of interaction 1,1,1,3,3,3 - hexafluoroisopropyl alcohol, hydrogen fluoride and formaldehyde or paraformaldehyde, from the first crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether, poluchennyi simple ester,

the second distillation the crude vermeil-1,1,1,3,3,3 - hexafluoroisopropyl ether to obtain in this formetal - 1,1,1,3,3,3-hexafluoroisopropyl ester,

this produces an adjustment of at least one of the stages, including the stage of interaction 1,1,1,3,3,3 - hexafluoroisopropyl alcohol, hydrogen fluoride and formaldehyde or paraformaldehyde, and the stage of interaction of the first crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether with an aqueous alkali solution or water, and the adjustment on the stage of the interaction 1,1,1,3,3,3-hexafluoroisopropyl alcohol, hydrogen fluoride and formaldehyde or paraformaldehyde is performed during the implementation of the first gas chromatographic analysis of the first crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether using capillary column containing cross-linked cyanopropyl-methylphenylsiloxane, to determine the first content of the first fluorinated simple ether with subsequent adjustment at this stage based on the first content to reduce the first content, and the adjustment at the stage of interaction of the first crude vermeil-1,1,1,3,3,3 - hexafluoroisopropyl ether with an aqueous solution of alkali sludge is 1,1,1,3,3,3 - hexafluoroisopropyl ether using capillary column containing cross-linked cyanopropionic, to determine a second content of the second fluorinated simple ether with subsequent adjustment at this stage depending on the second content to reduce the second content.

When studying the way to obtain "sevoflurane" containing at least three stages, the authors conducted a study of the method for adjusting operating parameters of each stage, influencing the content of the target substances in the raw "sevoflurane". It was found that the adjustment method allows one to obtain reliable data analysis using gas chromatograph with a special separation column and with pretreatment of the sample. Thus was made the invention.

Consider the following stage.

(1) stage of interaction GFIS, formaldehyde or paraformaldehyde and hydrogen fluoride in the presence of sulfuric acid.

(2) the stage of interaction untreated "sevoflurane" with a water solution of alkali and/or water.

(3) the stage of distillation of the crude "sevoflurane".

It is believed, is the temperature of boiling "sevoflurane", which are difficult to separate and quantitatively determined by gas chromatograph. When the process control and product quality is extremely important to accurately identify these impurities.

Stage 1 represents the stage of synthesis of sevoflurane, which as byproducts of various fluorinated ethers. Impurities such as misformation ether, methyl-1,1,1,3,3,3-exattorney ether, etc., with boiling points close to the boiling point "sevoflurane", and forming with it azeotropy, can be a problem when the production of "sevoflurane". Reaction conditions are determined mainly by the reaction temperature and the ratio of components in the reactor containing GFIS, formaldehyde or paraformaldehyde, hydrogen fluoride and sulfuric acid. Pressure does not have much influence on the reaction products.

As formaldehyde can use, for example, paraformaldehyde, because in this form it is available in industry, and in the description of this invention, the formaldehyde is listed formaldehyde or paraformaldehyde. As sulfuric acid can be used fuming sulfuric acid, concentrated sulfuric collateralportfolio is from 30 to 80oC. More preferably, it ranges from 50 to 70oC. In this temperature range it is possible to drive away from the reaction system received sevoflurane, together with by-products and unreacted original substances. Therefore it is preferred. If the reaction temperature is high, it increases the output misformation ether, depending on other conditions. If the temperature does not exceed 30oC, the reaction is hardly taking place. Accordingly, it may not be preferred.

It is necessary that hydrogen fluoride was in excess relative to GFIS. The excess must be from 1 to 20 mol. in relation to GFIS preferably from 6 to 10. If it does not exceed 1 mole per mole GFIS, the reduced conversion GFIS. If it is higher than 20 moles per mole GFIS, from the point of view of the reaction is not a problem. However, increasing the flow of unreacted hydrogen fluoride or increase the size of the apparatus. Accordingly, it is not preferable. The molar ratio of (pair)formaldehyde and GFIS is from 0.5 to 5, preferably from 0.8 to 2. If it is below 0.5, the reduced conversion GFIS. If it is above 5, increases the output misformation ether. This is not prepoo less than 0.5, it decreases the reaction rate. Acceptable, so that it was above 20. However, this is inefficient.

The selection of the above reaction conditions it is possible to reduce the proportion formed as by-products of fluorinated ethers - misformation ether and methyl-1,1,1,3,3,3-geksaftorsilikatov ether. Preferably, the ratio misformation ether/"sevoflurane" (hereinafter - the ratio of the areas of the corresponding peaks in the chromatograms) does not exceed 0.03, and the ratio of methyl-1,1,1,3,3,3-exattorney ether/sevoflurane did not exceed 0,0003, better - 0,00005. In other words, it is possible to determine the fraction of each component by gas chromatographic analysis of the gas at the outlet of the reactor at the stage of synthesis of condensed reaction product in liquid form, the condensed liquid of the reaction product in the separator or on the exit. It is possible to select the reaction conditions, taking into account the conversion GFIS.

In stage 2 there is an interaction of the crude sevoflurane containing acid component remaining in stage 1 or submitted for other purposes, with water or aqueous alkali solution, removing the acid component or dissolve and remove unreacted GFIS.I sodium carbonate, sodium bicarbonate, etc., But it is also possible to use compounds of alkaline earth metals such as calcium hydroxide, magnesium hydroxide, etc.

The concentration of the aqueous alkali solution used for the alkali washing is not critical. Easy to use concentration is from 0.001 to 10 wt. %. Treatment temperature is usually from 0 to 60oC. you Must pay attention to the temperature treatment, because "sevoflurane" can be degraded depending on the concentration.

In this case, as a decomposition product along with other fluorinated ethers formed vermeil-1,1,3,3,3 - pentafluoropropyl ether. This ether has a boiling point close to the boiling point "sevoflurane". Therefore, it is impossible to separate and quantify vermeil-1,1,3,3,3 - pentafluoropropyl ether using a gas chromatograph with a regular column. However, when using the analytical method proposed in this invention, it becomes possible quantitative determination of the content of vermeil-1,1,3,3,3 - pentafluoropropyl ether in the reaction product to regulate, depending on atakuje is generally preferable, to the ratio of vermeil-1,1,3,3,3-pentafluoropropyl ether/sevoflurane did not exceed 0,0003.

In stage 3 it is enough to have an ordinary distillation. It is possible, however, to use a substance that binds acid and a stabilizing agent to prevent the formation of acid.

In the process of getting "sevoflurane" an effective complement to its next stage:

(4) the stage of interaction untreated "sevoflurane" containing bestattorney.com ether, with acids of Bronsted, Lewis acids or acid attached to the resin or similar substances (hereinafter - acid or similar substances).

In stage 4 you can delete misformation ether. As examples of acids Bronsted, Lewis acids or mounted on the resin acids can lead sulfuric acid, fuming sulfuric acid, sulfuric anhydride, hydrogen bromide, hydrogen iodide, triperoxonane acid, cryptomaterial acid, boron TRIFLUORIDE, tetraploid titanium, resin "Nafion (manufactured by DuPont Co.) etc. Acids of Bronsted or Lewis used in an amount of from 0.2 to 20 moles per mole misformation ether contained in the raw "sevoflurane", preferably from 1 to 20 mol/mol. If this is m The use of excess acid has no significant restrictions. However, it is preferable to use smaller amounts of acid to speed up the operations division and alkaline washing after treatment with acid. Temperature when processing is from 0 to 100oC, preferably from 10 to 60oC, more preferably from 20 to 40oC. If it does not exceed 0oC, the processing proceeds a long time. If it exceeds 100oC, undesired decomposition of a small part of the "sevoflurane". When processing at a pressure close to normal, it is most preferable, from the viewpoint of equipment and the absence of the above decomposition, to carry it out at temperatures from 20 to 40oC, which is close to the ambient temperature.

With this processing, it is preferable to select the temperature, duration, pressure in the apparatus and the ratio of the crude sevoflurane and acid so that the ratio misformation ether and sevoflurane did not exceed 0,0001, depending on the content misformation ether processed "sevoflurane".

The authors have studied conditions for gas chromatographic analysis and pre-processing of OBRs selection conditions of synthesis or processing. It was found that the separation and determination of fluorinated ethers, formed as by-products in the crude "sevoflurane", is possible with quantitative analysis using gas chromatograph with capillary column containing cross-linked cyanopropionic, after pre-treatment of samples, depending on the situation, a compound of an alkali metal or a compound of alkaline earth metal.

In the production of "sevoflurane" compounds such as GFI - starting material, formal, acetal, etc. as by - products, have a high boiling point compared with sevoflurane". Therefore, it is necessary to carry out the separation at a relatively high temperature for analysis by gas chromatograph. In this case, the capillary column containing methylsilicon and penicilian, effective, but they are not suitable for the separation of low-boiling components, such as misformation ether.

At the same time, it is known that most of the fluorine-containing organic compounds, such as sevoflurane have a low boiling point, because the intermolecular interaction is small because of the characteristics of the fluorine atom. Most the majority of which are close to the properties of sevoflurane. So with this column, it is impossible to determine the content of fluorine-containing ethers, formed as by-products, with the precision necessary for process control.

In particular, to control the amount and process control it is desirable that formetal-1,1,3,3,3-pentafluoropropyl ether (hereinafter also referred to as "analog 1"), methyl-1,1,1,3,3,3-exattorney ether (hereinafter also "analog 2"), and misformation ether, which are analogues of sevoflurane, would be separated from him, and that at the same time it was possible to determine the content of the original GFIS and high-boiling analogues, such as acetal and formal, formed as by-products.

Capillary column of fused silica are slightly polar, srednevoljskogo and silnopologo type depending on the type contained therein, a cross-linking agent. On columns silnopologo type, it is impossible to determine the high-boiling analogues. Therefore, you cannot use these columns for the analysis of sevoflurane. When using a polar column type (for example, a column containing cross-linked phenilmethylsulfoxide) it is difficult to separate low-boiling counterparts, and absolutely is necessary to improve the degree of separation by conducting analysis at a low temperature, not exceeding room temperature. For example, even when conducting the analysis at 10oC analogues 1 and 2 are separated with difficulty. In addition, under such conditions required to raise the temperature to a level sufficient for evaporation of high boiling substances. Therefore, you need a special device which can be used both at low and at high temperatures. This is uneconomical.

Therefore, the only type of columns for this purpose can be column srednevoljskogo type. However, even on such a column is extremely difficult to separate analogues 1 and 2, or it is difficult to determine the high-boiling counterparts.

In addition, analogues of 1 and 2 can be divided, for example, capillary column average polarity containing cross-linked diisodecylphthalate. However, thermostability of a cross-linking agent is limited. Therefore, it is impossible to analyze at high temperature and, therefore, to determine the high-boiling counterparts. For process control and product quality it is necessary that the degree of separation of any analogues was at least equal to 2.

The authors, however, thoroughly researched Vzmorye column for the simultaneous separation analogues, substances derived from the source connections phenylsilanes. is especially effective and has a degree of separation, unmatched by conventional capillary column of fused quartz.

In capillary column containing cross-linked cenopopulations, the inner surface of the column of fused silica coated with cyanopropylsilane with subsequent curing. Such columns are widely used in the analysis of trihalomethanes, chlorinated hydrocarbons, dioxins, residual chlorine-containing drugs, agrochemicals, etc., as commercial products may be mentioned, for example, Halomatics-624 manufactured by Quadrex With. Preferably the use of these products.

Separation of analog 1, analog 2, "sevoflurane" and GFIS was determined under the following conditions. The results are shown in the table. Separation significantly exceeds 2.0. Thus, it was found that the accuracy of the analysis is sufficient for quality control and process.

Condition analysis:

Gas chromatograph: Hewlett Packard HP-5890 type II.

Column Halomatics-624 (30 m 0.32 mm EXT. diameter 3 μm).

The column temperature: 40oC (maintained for 10 min), 200oC (the rate of temperature rise of 10oC in m is>/P>Volume of sample: 0,5 µl.

The dividing ratio of flux: 1/80.

Detector: PID, 200o.

Integrator: Hewlett Packard HP-3396 type II

The degree of separation required for quantitative analysis, is at least a 2.0, and is expressed by the following formula:

Separation = 2(T1-T2)/(W1+W2)

where T1and T2the retention time of components 1 and 2, respectively (min);

W1and W2- width of peaks 1 and 2, respectively (min.)

Typically, the test substances when carrying out fluorination contains, along with organic compounds hydrogen fluoride. Therefore, it should be noted that when using a capillary column containing cross-linked cenopopulations, gas chromatograph as an analytical device subjected to corrosion. Obviously, corrosion affects all parts in contact with the sample. It is especially evident in the capillary column of fused silica. The destruction of the column due to corrosion comes to instability analysis results over time.

This is clearly caused by the presence of hydrogen fluoride. So effective is the method in which to remove hydrogen fluoride connections, including by-products, and is not acting on the catalyst. Particularly effective was the interaction of the sample with compounds of alkali metals or alkaline earth metals prior to its entry into the gas chromatograph in order to reduce the content of hydrogen fluoride with a few percent to a level (for example, not more than 100 million hours), generally do not affect the carrying out gas chromatography analysis.

As compounds of alkali metal preferably sodium fluoride (NaF, melting point 995oC and potassium fluoride. As compounds of alkaline earth metals, it is preferable to use compounds of magnesium, such as magnesium carbonate, magnesium oxide, calcium, such as calcium carbonate, calcium chloride, calcium hydroxide, calcium oxide, compounds of strontium, for example, strontium carbonate, and compounds of barium, for example, barium carbonate.

This method of binding the hydrogen fluoride can be applied, if "sevoflurane" is in the liquid phase or in the gas phase. In the case of the liquid phase interaction is carried out at a temperature from 0 to 60oC. In the case of the gas phase is carried out at a temperature from 0 to 300oC. In the case of the liquid phase in the sustained way.

Reaction mechanisms linking fluoride hydrogen compound of the alkali metal and alkaline earth connection of the metal variety. To connect alkali metal it is expressed by the reaction scheme

NaF + HF - HF NaF; (TV.),

(CF3)2CHOH + (HCHO)n+ HF (CF3)2CHOCH2F + H2O

Received "sevoflurane" out of the reactor together with unreacted hydrogen fluoride, GFIS and other substances, and then condensed in a water condenser 2, polytetrafluoroethylene-coated, the temperature of which is maintained equal to the 20oC, and then select the separator 3, coated with polytetrafluoroethylene.

Received "sevoflurane" dropwise served in the separator in a layer of ion-exchange water flowing through the pipe, coated with polytetrafluoroethylene. At this remove most of the hydrogen fluoride from the organic layer, and containing "sevoflurane" (specific gravity of 1.54) the organic layer becomes the bottom layer. This organic layer sevoflurane contains about 0.1-0.2 wt. %. dissolved water and about 1% of hydrogen fluoride. This crude sevoflurane from the separator through the pipeline served in the wash tank. In the middle of this pipeline has a sampling hole is granular sodium fluoride. Then it is analyzed by gas chromatograph (GC) connected to the controller process (RP) 6, having as a separation column, a capillary column containing cross-linked cenopopulations. Using chromatograph determine the content misformation ether and/or methyl-1,1,1,3,3,3-geksaftorsilikatov ether. On the basis of the values obtained using the built-in RP arithmetic circuit are optimizing the supply GFIS by adjusting the degree of opening of the feed pump GFIS.

The organic phase from the lower layer of the separator is served in the washing unit 4 is equipped with a mixing device 10, through the pipe with a coating of polytetrafluoroethylene, and with stirring, washed with wash water (4% aqueous solution of caustic soda). A sample of untreated "sevoflurane" selected through the sampling hole at the outlet of the flushing apparatus 4. Further, it is passed through the granular sodium fluoride. Then it is analyzed by gas chromatograph (GC) connected to the controller process (RP) 7, having as a separation column, a capillary column containing cross-linked cenopopulations, and determine the content hermetically chains are optimizing the supply wash liquid by adjusting the degree of opening of the feed pump wash liquid.

Washed "sevoflurane" later served in the distiller 5 through the pipe with a coating of polytetrafluoroethylene, and select sevoflurane as the main fraction after distillation of low-boiling component.

The figure schematically depicts an example implementation of the process of obtaining "sevoflurane".

1 - reactor, 2 - condenser 3 - separator, 4 - washing machine, 5 - distiller, 6 and 7 regulators process, 8 and 10 - stirrers, 9 - heater.

Example 1.

In a reactor of 500 ml was loaded with 50 ml of 98% sulfuric acid, 100 g (5 moles) of hydrogen fluoride and 30 g (1 mol) of paraformaldehyde. The reaction mixture was heated to 65oC. and Then added dropwise filed 134 g (0,8 mol) GFIS within 2 hours Received during the reaction vapors are condensed using water. The obtained 140 g of the crude "sevoflurane".

10 g of the crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether was extracted three times with 100 ml of water followed by analysis using ion chromatograph under the following conditions. It was found that the product contained 1.2 wt. %. fluoride hydrogen.

Condition analysis: Ion chromatograph: Yokogawa IC-7000

Column: Exceilpak ICS-A35

The temperature of thermostat is idcast: 15 mmol/l aqueous solution of H2SO4< / BR>
To the crude "sevoflurane" was added an equal volume of NaF pellets. The mixture was stirred without stirring for 1 minute, Then it was analyzed using a liquid chromatograph under the same conditions. It was found that the concentration of hydrogen fluoride is sharply decreased to 71 million hours

Example 2.

To 5 g obtained in example 1 crude "sevoflurane", containing 1.2 wt. %. the hydrogen fluoride was added to 0.13 g of NaF powder (1.0 mol per mol of contained in the product hydrogen fluoride). The mixture was shaken for 30 seconds and filtered. Then the product was extracted three times with 10 ml water. Then determined the concentration of hydrogen fluoride under the same conditions as in example 1. Found that it amounted to 45 million hours

Example 3.

To 5 g obtained in example 1 crude "sevoflurane", containing 1.2 wt. %. the hydrogen fluoride was added to 0.38 g of NaF powder (3.0 mol per mol of contained in the product hydrogen fluoride). The mixture was shaken for 30 seconds and filtered. Then the product was extracted three times with 10 ml water. Then determined the concentration of hydrogen fluoride under the same conditions as in example 1. Found that it amounted to 40 million hours

Example 4.

To 5 g?? KF (2.0 mol per mol of contained in the product hydrogen fluoride). The mixture was shaken for 30 seconds and filtered. Then the product was extracted three times with 10 ml water. Then determined the concentration of hydrogen fluoride under the same conditions as in example 1. Found that it was 35 million hours

Example 5.

To 5 g obtained in example 1 crude "sevoflurane", containing 1.2 wt. %. the hydrogen fluoride was added 0.66 g of powder CaCl2(2.0 mol per mol of contained in the product hydrogen fluoride). The mixture was shaken for 30 seconds and filtered. Then the product was extracted three times with 10 ml water. Then determined the concentration of hydrogen fluoride under the same conditions as in example 1. Found that it was 35 million hours

Comparative example 1.

To 5 g obtained in example 1 crude "sevoflurane", containing 1.2 wt. %. the hydrogen fluoride was added 0.06 g of NaF powder (0.5 mol per mol of contained in the product hydrogen fluoride). The mixture was shaken for 30 seconds and filtered. Then the product was extracted three times with 10 ml water. Then determined the concentration of hydrogen fluoride under the same conditions as in example 1. It is established that she was 0.36%.

In the above-described processing, the concentration of hydrogen fluoride in neojidannaia. Therefore, after processing the spent gas chromatographic analysis of the crude "sevoflurane".

Example 6.

In a glass flask with a volume of 100 ml were placed 20 g of sevoflurane, received the same reaction under the same conditions as in example 1 and 12.5 4% aqueous sodium hydroxide solution, and stirred with a magnetic stirrer at 40oC for 2 h Treated in this way raw "sevoflurane" analyzed under the following conditions. Contents misformation ether was 1.5%, vermeil-1,1,3,3,3-pentafluoropropyl ether - 230 million hours, methyl-1,1,1,3,3,3-hexafluoroisopropyl ether - 40 million hours Each gas chromatogram was sufficiently separated from the other.

Condition analysis:

Gas chromatograph: Hewlett Packard HP-5890 type II.

Column Halomatics-624 (30 m 0.32 mm EXT. diameter 3 μm)

The column temperature: 40oC (maintained for 10 min), 200oC (the rate of temperature rise of 10oC per minute).

The evaporator temperature: 200oC.

Carrier gas: helium pressure of 40 kPa.

Volume of sample: 0,5 µl.

The dividing ratio of flux: 1/80

Detector: PID, 200oC.

In the a", containing 45 million hours of forida hydrogen after treatment in the conditions of example 2. It was found to reduce the degree of separation and sensitivity caused by the destruction of the column.

Comparative example 2.

Conducted analysis obtained in example 1, the crude sevoflurane containing 1.2 wt. %. fluoride hydrogen under the same conditions as in example 6, without conducting any treatment to remove hydrogen fluoride. When you re-analysis of the peak on the chromatogram was wide, which clearly pointed to the destruction of the column. After this analysis was impossible. Gas chromatograph with capillary column containing cross-linked cyanopropionic, as a separation column, has a high efficiency in the analysis of by-products of the production of "sevoflurane". Before analysis of the sample using a gas chromatograph conduct its interaction with the compound of alkali metal or alkaline earth connection of the metal. Thus it is possible to reduce the content in a sample of hydrogen fluoride to a level that does not cause visible damage to the column. When implementing this analytical method can very easily determine the content of impurities nom level.

Literature

1. Pat. USA 4250334, C 07 C 41/01.

1. Method of quantitative analysis of the crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether containing fluorinated simple ether as a by-product, including stage gas chromatography analysis of the crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether, characterized in that the gas chromatographic analysis is performed using a capillary column containing cross-linked cenopopulations, emitting fluorinated simple ether as a by-product and its quantitative analysis.

2. The method according to p. 1, characterized in that in the presence of hydrogen fluoride in the crude vermeil-1,1,1,3,3,3-hexafluoroisopropanol the air before gas chromatographic analysis of the crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether spend the interaction of the crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether compound of an alkali metal or a compound of alkaline earth metal so as to essentially remove hydrogen fluoride from the crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether.

3. The method according to p. 2, characterized in that the compound of melocanna alkaline earth metal is a compound, selected from the group comprising magnesium carbonate, magnesium oxide, calcium carbonate, calcium chloride, calcium hydroxide, calcium oxide, strontium carbonate and barium carbonate.

4. The method according to p. 2, characterized in that are in contact crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether compound of an alkali metal or a compound of alkaline earth metal at a temperature from 0 to 60oIn conditions, when the crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether is a liquid, and at a temperature of from 0 to 300oIn conditions, when the crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether is a gas.

5. The method according to p. 2, characterized in that the binding agent of hydrogen fluoride (compound of the alkali or alkaline earth metal) is used in excess with respect to hydrogen fluoride.

6. The method of obtaining vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether, including the implementation phase reaction of 1,1,1,3,3,3-hexafluoroisopropyl alcohol, hydrogen fluoride and a component selected from the group comprising formaldehyde or paraformaldehyde in the presence of sulfuric acid, with the first crude vermeil-1,1,1,3,3,3-hexaferrite includes the implementation phase of contact of the first crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether component, selected from the group comprising aqueous alkali solution and water to remove the acidic component or 1,1,1,3,3,3-hexafluoroisopropyl alcohol remaining after the reaction 1,1,1,3,3,3-hexafluoroisopropyl alcohol, hydrogen fluoride and formaldehyde or paraformaldehyde, from the first crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether, to obtain a second raw vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether containing a second fluorinated simple ether, distillation of the second crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether to obtain in this formetal-1,1,1,3,3,3-hexafluoroisopropyl ether, thus producing the adjustment of at least one of the stages, including the stage of reaction of 1,1,1,3,3,3-hexafluoroisopropyl alcohol, hydrogen fluoride and formaldehyde or paraformaldehyde, and the stage of contact of the first crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether with an aqueous alkali solution or water, and the adjustment on the stages of the reaction 1,1,1,3,3,3-hexafluoroisopropyl alcohol, hydrogen fluoride and formaldehyde or paraformaldehyde is performed during the implementation of the first gas chromatographic analysis of the first crude vermeil-1,1,1,3,3,3-Hexapla is h, to determine the first content of the first fluorinated simple ether with subsequent adjustment at this stage based on the first content to reduce the first content, and the adjustment at the stage of contact of the first crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether with an aqueous alkali solution or water is carried out at the implementation of the second gas chromatographic analysis of the second crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether using capillary column containing cross-linked cyanopropionic, to determine a second content of the second fluorinated simple ether with subsequent adjustment at this stage depending on the second content to reduce the second content.

7. The method according to p. 6, wherein the second fluorinated simple ether is formetal-1,1,3,3,3-pentafluoropropyl ether, and the adjustment at the stage of contact of the first crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether with an aqueous alkali solution or water is carried out by setting the duration of this stage, the temperature of this stage or the alkali concentration in the aqueous solution in this study is such peaks vermeil-1,1,3,3,3-pentafluoropropyl ether and vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether did not exceed 0,0003.

8. The method according to p. 6, characterized in that the first fluorinated simple ether is a methyl-1,1,1,3,3,3-hexafluoroisopropyl ether, and the adjustment on the stages of the reaction 1,1,1,3,3,3-hexafluoroisopropyl alcohol, hydrogen fluoride and formaldehyde or paraformaldehyde is carried out by setting the temperature of this stage, the pressure at this stage or the relative amounts of the reaction of 1,1,1,3,3,3-hexafluoroisopropyl alcohol, hydrogen fluoride and formaldehyde or paraformaldehyde to get at the first gas chromatographic analysis of the ratio of the areas of gas chromatographic peaks methyl-1,1,1,3,3,3-hexafluoroisopropyl ether and vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether did not exceed 0,0003.

9. The method according to p. 6, characterized in that the first fluorinated ether is misformation ether, and the adjustment on the stages of the reaction 1,1,1,3,3,3-hexafluoroisopropyl alcohol, hydrogen fluoride and formaldehyde or paraformaldehyde is carried out by setting the temperature of this stage, the pressure at this stage or the relative amounts of the reaction of 1,1,1,3,3,3-hexafluoroisopropyl alcohol, hydrogen fluoride and formaldehyde or paraformaldehyde to get prgo ether and vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether does not exceed 0.03.

10. The method according to p. 6, characterized in that it further includes another stage of interaction of the first crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether, obtained at the stage of interaction 1,1,1,3,3,3-hexafluoroisopropyl alcohol, hydrogen fluoride and formaldehyde or paraformaldehyde, acid selected from the group comprising acid Bronsted, Lewis acid and deposited on a resin acid, in which the first fluorinated ether is misformation ether, and the adjustment at this stage is carried out at the implementation of the third gas chromatographic analysis of the first crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether using capillary column containing cross-linked cyanopropionic, to determine the content misformation ether, followed by setting the temperature of this stage, the duration of this stage, the pressure at this stage or the ratio of the crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether and acid so obtained with the third gas chromatographic analysis of the ratio of the areas of gas chromatographic peaks beforeinvoke ether and vermeil-1,1,1,3,3,3-hexafluoroisopropanol Eiendom vermeil-1,1,1,3,3,3-hexafluoroisopropanol the air before the first gas chromatographic analysis shall contact the crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether compound of an alkali metal or alkaline earth metal so to essentially remove hydrogen fluoride from the crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether.

12. The method according to p. 6, characterized in that the step of the reaction 1,1,1,3,3,3-hexafluoroisopropyl alcohol, hydrogen fluoride and formaldehyde or paraformaldehyde is carried out at a temperature of from 30 to 80oC.

13. The method according to p. 6, characterized in that the reaction 1,1,1,3,3,3-hexafluoroisopropyl alcohol, hydrogen fluoride and formaldehyde or paraformaldehyde in the molar ratio of fluoride Podoroga and 1,1,1,3,3,3-hexafluoroisopropyl alcohol is from 1 to 20.

14. The method according to p. 6, characterized in that the reaction 1,1,1,3,3,3-hexafluoroisopropyl alcohol, hydrogen fluoride and formaldehyde or paraformaldehyde in the molar ratio of formaldehyde or paraformaldehyde and 1,1,1,3,3,3-hexafluoroisopropyl alcohol is from 0.5 to 5.

15. The method according to p. 6, characterized in that the reaction 1,1,1,3,3,3-hexafluoroisopropyl alcohol, hydrogen fluoride and formaldehyde or paraformaldehyde in the molar ratio of sulfuric acid and 1,1,1,3,3,3-hexafluoroisopropyl alcohol is from 0.5 to 20.

16. The method according to p. 6, characterized in that at the stage of first contact is not the R alkali is an aqueous solution of at least one base, selected from the group comprising sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, calcium hydroxide and magnesium hydroxide.

17. The method according to p. 6, characterized in that at the stage of contact of the first crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether with an aqueous alkali solution or water aqueous alkali solution has a concentration of from 0.01 to 10 wt.%, when this stage is carried out at a temperature from 0 to 60oC.

18. The method according to p. 7, characterized in that at the stage of contact of the first crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether with an aqueous alkali solution or water adjustment this stage is carried out by setting the concentration of alkali in the aqueous alkali solution.

19. The method according to p. 10, characterized in that at the stage of interaction of the first crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether with the acid, the molar ratio of acid and misformation ether is from 0.2 to 20.

20. The method according to p. 10, characterized in that the stage of interaction of the first crude vermeil-1,1,1,3,3,3-hexafluoroisopropyl ether with the acid is carried out at temperatures from 0 to 100oC.

21. The method according to p. 6 different which of paraformaldehyde by mixing formaldehyde or paraformaldehyde, of hydrogen fluoride and sulfuric acid to obtain a mixture, and then incrementally adding 1,1,1,3,3,3-hexafluoroisopropyl alcohol to this mixture, while the adjustment of this phase is carried out by setting the speed of adding 1,1,1,3,3,3-hexafluoroisopropyl alcohol based on the first contents of the first fluorinated simple ether.

 

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FIELD: petrochemical processes.

SUBSTANCE: process comprises consecutively performed catalytic conversion of synthesis gas in methanol synthesis reactor(s) and synthesis products in methanol dehydration reactor(s). Resulting liquid phase containing methanol, dimethyl ether, and water is separated in two distillation steps to give dimethyl ether in the first step and methanol-water mixture in the second step. Methanol-water mixture is divided into two streams, one being used as absorbent when washing flushing gas and the other being routed to the second distillation step. Gas phase contains unconverted synthesis gas and dimethyl ether. A part of gas phase is combined with initial synthesis gas and the other part (flushing gas) is washed to remove dimethyl ether. Dimethyl ether-charged absorbent is supplied to first distillation step. Methanol from second distillation step is returned to cycle between methanol synthesis reactor(s) and methanol dehydration reactor(s). Preferably, absorbent is used washing stage in amount 20 to 100% of the weight of liquid phase.

EFFECT: increased degree of synthesis gas-into-dimethyl ether conversion, reduced level of dimethyl ether in flushing gas, and simplified process flowsheet.

1 dwg, 3 tbl, 3 ex

FIELD: chemical technology.

SUBSTANCE: invention relates to a method for synthesis of symmetric di-(polyfluoroalkyl) esters of the formula: [H(CF2)nCH2]2O (wherein n = 2, 4, 6) from corresponding polyfluorinated alcohols in the presence of N,N-dimethylformamide as a catalyst. Method involves mixing reagents at temperature (-15)-(-10)0C followed by their interaction wherein mixture of polyfluorinated alcohol with catalyst interacts with thionyl chloride in the mole ratio of reagents = 1:(0.005-0.009):(1-1.1), respectively, at step-by-step increase of temperature: firstly at 20-300C for 1-2 h and then at 30-500C for 3-6 h, and evolving sulfur dioxide and hydrogen chloride are blown off with inert gas. Method provides synthesis of symmetric di-(polyfluoroalkyl) esters with high yield for a single step.

EFFECT: improved method of synthesis.

1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to the method of obtaining (per)fluorohalogenethers with general formula (I): (R)nC(F)mOCAF-CA'F2 (I), which are used in obtaining fluorinated vinyl ethers, which are a class of essential monomers for obtaining various polymers. In formula (I) A and A' are the same or different, represent Cl or Br or one of A and A' represents hydrogen, and the other a halogen, chosen from CI, Br; R=F or fluorinated, preferably perfluorinated, substitute, chosen from the following groups: linear or branched C1-C20alkyl; C3-C7 cycloalkyl; C6-C10aromatic group, C6-C10arylC1C20alkyl, C1-C20alkylC6-C10aryl, or C6-C20alkyl C5-C10hetertocycle; if R represents fluorinated or perfluorinated alkyl, cycloalkyl, arylalkyl, alkylaryl, then it can optionally contains in a chain, one or more oxygen atoms; if R represents a fluorinated substitute, it can optionally contain one or more H atoms and/or one or more halogen atoms, except F; n is an integer, equal to 1 or 2; m is an integer, equal to 3-n. The method involves reaction of carbonyl compounds with formula (II): (R)pC(F)q(O) (II), where p is an integer, equal to 1 or 2; q is an integer, equal to 0 or 1, under the condition that, if p=2, then q=0; if p=1, then q=1; in the liquid phase with elementary fluorine and olefinic compounds with formula (III): CAF=CA'F (III).

EFFECT: invention allows obtaining fluorohalogenethers with improved selectivity.

8 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention concerns method of obtaining adamantylphenyl ethers of the general formula: R1=R2=H, R3=CH3 (1); R1=OH, R2=R3=H (2); R1=R3=H, R2=OH (3); R1=R2=H, R3=OH (4); R1=R2=H, R3=NO2 (5); R1=OCH3 R2=H,R3=C2H5 (6), which are semiproducts for bioactive substance synthesis. Method involves interaction of adamantane derivative with phenol derivative. 1,3-dehydroadamantane is used as adamantane derivative, and compounds from the range of n-cresol, pyrocatechin, resorcin, hydroquinone, n-nitrophenol, 4-ethylguaiacol are used as phenol derivative, at component mol ratio of 1:(1.5-2) in diethyl ether medium at its boiling temperature for 20-30 minutes.

EFFECT: high output of adamantylphenyl ethers.

6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 1-(2-propenyloxy)- or 1-(phenylmethoxy)-1,2-dihydro[60]fullerene of general formula (1) , which can be used as complexing agents, sorbents, biologically active compounds, as well as in making new materials with given properties. The method involves reacting fullerene C60 with allyl or benzyl alcohol in the presence of a titanocene dichloride catalyst in molar ratio C60 : R-CH2-OH : Cp2TiCl2 equal to 0.01 : (5-10) : (0.0015-0.0025), in a toluene medium as a solvent at temperature ranging from 70 to 90°C for 3 to 7 hours.

EFFECT: method allows for selective production of end products with high output 62-80%.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing 1-phenoxy-1,2-dihydrofullerene of formula (1) which can be used as a complexing agent, sorbent, biologically active compound, as well as in making new materials with given electronic, magnetic and optical properties. The method involves reacting fullerene C60 with phenol in the presence of a hafnocene dichloride catalyst in molar ratio C60: Ph-OH:Cp2HfCl2 equal to 0.01:(5-10):(0.0015-0.0025), in a toluene medium as a solvent at temperature 130-180°C for 5-7 hours.

EFFECT: method enables selective production of the end product with output of 63-88%.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing 1-alkyl-1-alkoxy-2-arylcyclopropanes of general formula (1): where Ar = Ph, o-MeC6H4, p-MeC6H4; R=CH3, C2H5, C4H9; R'=CH3, C2H5, which can be used in fine organic synthesis, particularly synthesis of biologically active compounds, having pyrethroid, acaricidal, pesticidal, growth-regulating, fungicidal and antibacterial activity. The method involves reacting arylethylene of general formula Ar-CH=CH2, where Ar=Ph, o-MeC6H4, p-MeC6H4, with an equimolar amount of an ester of general formula RCO2R', where R=CH3, C2H5, C4H9; R'=Me, Et, in the presence of diethylaluminium chloride (Et2AlCl), magnesium (Mg, powder) and a Cp2ZrCl2 catalyst in molar ratio Ar-CH=CH2: RCO2R': Et2AlCl : Mg : Cp2ZrCl2 = 10 : 10 : (20-30) : (10-14) : (0.8-1.2) in an argon atmosphere at temperature 20-22°C and atmospheric pressure for 8-12 hours.

EFFECT: method enables to obtain desired products with high regioselectivity.

14 ex, 1 tbl

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