Synthesis of [18f]fluororganic compounds in alcoholic vehicles

FIELD: chemistry.

SUBSTANCE: invention refers to synthesis of [18F]fluororganic compounds ensured by reaction of [18F]fluoride and relevant halogenide or sulphonate with alcoholic vehicle of formula 1 where R1, R2 and R3 represent hydrogen atom or C1-C18 alkyl.

EFFECT: possibility for mild process with low reaction time and high yield.

21 cl, 2 tbl, 27 ex

 

The technical field to which the invention relates.

The present invention relates to a method of obtaining organofluorine compounds, fluorine-18, a radioactive isotope of fluorine. More specifically, the present invention relates to a method for production of organofluorine compounds with the provision of organofluorine compounds with high yield by the interaction of fluoride containing radioactive fluorine-18, alkylhalogenide or alkylsulfonates in the presence of an alcohol of formula 1 as solvent.

Formula 1

(in which R1, R2and R3represent a hydrogen atom or a C1-C18alkyl).

The level of technology

The fluorine atom has a high polarity and hydrophobic properties and has almost the same size as the hydrogen atom. Such organofluorine compounds containing fluorine atoms possess unique chemical and physiological properties compared with General organic compounds and are used in medicine, pesticides, dyes, polymers, and the like [Gerstenberger M.R.., Haas, A., Angew. Chem., Int. Ed. Engl. 1981, 20, 647; R. Filler, In Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications; Filler, R., Ed., Studies in Organic Chemistry 48, Elsevier, New York, NY, 1993, p.1-23].

As a rule, organofluorine compounds receive substitution reactions of fluorine atom interaction al is algalogiya or alkylsulfonate with fluoride, as shown in the reaction scheme 1.

The reaction scheme 1

The halide in alkylhalogenide selected from the group consisting of Cl, Br and I, with the exception of F. Sulfonate in alkylsulfonate is a SO3R12where R12is alkyl or aryl. Alkyl preferably represents C1-C12alkylhalogenide or1-C12alkylsulfonamides, alkylsulfonate selected from the group consisting of methanesulfonate, aconsultant, isopropanolamine, chloromethanesulfonyl, triftoratsetata and chloroethanesulfonate. Aryl is preferably selected from the group consisting of phenyl, C1-C4alkylphenyl, halogenfree,1-C4the alkoxyphenyl and nitrophenyl. Preferred examples are methylphenylsulfonyl, ethylvinylacetate, chlorophenylsulfonyl, brompheniramine, methoxyphenylacetone or nitrophenylacetate.

Fluoride (MFn)as the source of fluorine atoms selected from the group consisting of alkali metal fluoride containing alkali metals such as lithium, sodium, potassium, rubidium or cesium; and fluoride of alkaline-earth metals containing alkaline-earth metals such as magnesium, calcium, strontium or barium; and ammonium fluoride containing ammonia or its derivatives, such as tetraalkylammonium.

Ka is the rule, the reaction of nucleophilic fluorination is carried out in a polar aprotic solvent such as acetonitrile (CH3CN), DMF or DMSO, to increase the solubility of fluoride and reactivity of fluoride. It is known that alcohol, being a proton solvent is not suitable for the reaction of nucleophilic fluorination. It is also known that the alcohol forms a hydrogen bond with fluoride, which is a source of fluorine atoms, and thereby reduces its reactivity in the reaction of nucleophilic fluorination [Smith M.D.; March J. Advanced Organic Chemistry, 5thed., Wiley Interscience: New York, NY, 2001, pp.389-674].

It was reported that the method of obtaining the above organofluorine compounds alkylphenyl get the interaction of fluoride with potassium alkylhalogenide in the solvent ethylene glycol [Hoffmann, F.W., J. Am. Chem. Soc., 1948, 70, 2596]. However, this method of obtaining flawed, consisting in low yield and long duration of the reaction at high reaction temperature above 140°C due to the low reactivity as a result of low solubility of potassium fluoride.

It was reported that 18-crown-6-ether, which forms strong bonds with metal ions, was used as catalyst to obtain organofluorine compounds for increasing the solubility of fluoride and reactivity of fluoride at relatively the bottom of the th temperature in the range of 80-90°C and mild reaction conditions, and the yield of the product was high [Liotta, C.L.; Harris, H.P., J. Am. Chem. Soc., 1974, 96, 2250]. However, this method has disadvantages, namely, that of 18-crown-6-ether is an expensive connection takes a lot of duration of reaction, and produces a great amount of alkene as a by-product, because the fluoride acts as a base.

It is known that when fluoride is used in obtaining organofluorine compounds, it has an adverse reaction shown in the reaction scheme 2.

The reaction scheme 2

As an example, it was reported about the use of tetrabutylammonium fluoride as fluoride, to obtain organofluorine compounds with high yield under mild reaction conditions [Cox, D.P.; Terpinsky, J.; Lawrynowicz, W.J. Org. Chem. 1984, 49, 3216]. However, tetrabutylammonium fluoride hydrate inherent problem, namely, that produce large quantities of alcohol, which is a by-product caused by the presence of water, and alkene is formed as another by-product due to the high basicity of tetrabutylammonium fluoride.

Therefore, to obtain organofluorine compounds by the interaction of fluoride with alkylhalogenide or alkylsulfonates required mode of production, which can lead to a decrease in the duration of the spine of the reaction by increasing the reactivity of fluoride and can reduce the formation of by-products, such as alkene or alcohol, by eliminating the influence of moisture and minimizing the basicity of the fluoride.

The applicants have attempted to solve the above problems. In the production method of organofluorine compounds by the interaction of alkylhalogenide or alkylsulfonate with fluoride applicants have found that the present invention should be viewed as following from the reaction presented on figure 1, but theoretically not always limited to this. Applicants have found that alcohol solvent increases the reactivity of the fluoride to nucleophilic substitution by the weakening of the ionic bonds in the fluoride between metal cations and anions of fluorine due to the formation of hydrogen bonds with the metal fluorides and reduces adverse reactions by suppressing the effect of basicity on the fluorination reaction by reducing the basicity of fluoride through the formation of hydrogen bonds fluoride, and so was made the present invention.

Disclosure

Technical solution

The purpose of this invention is the provision of a method of obtaining organofluorine compounds with high yield by the interaction of fluoride with alkylhalogenide or alkylsulfonates with increasing solubility of fluoride due to the weakening of the ionic bonds in the fluoride between metal cations and anions CFT is RA, and a simultaneous decrease in the duration of the reaction as a result of increased reactivity of fluoride. The method of obtaining can lead to increased reactivity of fluoride to nucleophilic substitution and simultaneously reducing the formation of by-products to eliminate the influence of moisture or decrease the basicity of the fluoride.

The predominant effects of the present invention

The present invention organofluorine compounds can selectively be obtained as the main products, constituting more than 90%, by suppressing the formation of by-products when using alcohol as a reaction solvent. Alcohol solvent increases the reactivity of the fluoride to nucleophilic substitution by the weakening of the ionic bonds between metal cations and anions of fluorine due to the formation of hydrogen bonds with the metal fluoride, whereby it is possible to overcome the problem of low reactivity as a result of strong ionic bonds of the fluorine atom in the usual way, to reduce the reaction time by increasing the reactivity and reaction rate of fluoride and reduce the formation of by-products by suppressing the influence of basicity by weakening the basicity of fluoride through the formation of hydrogen bonds of fluoride.

Description of the drawings

Figure 1 is a schematic depiction of the principle of how alcohol causes the weakening of the ionic bonds between metal cations and anions of fluorine through the formation of hydrogen bonds with the metal fluoride according to an exemplary variant of implementation of the present invention.

Figure 2 is a schematic depiction of the disposable cassette according to an exemplary variant of implementation of the present invention.

Description of the preferred option implementation

The present invention relates to a method for production of organofluorine compounds using alcohol of formula 1 as solvent, in which organofluorine compounds produced by interaction of fluoride with alkylhalogenide or alkylsulfonates.

Formula 1

(in which R1, R2and R3represent a hydrogen atom or a C1-C18alkyl).

Organofluorine compounds in the present invention are organofluorine compounds containing fluorine-18 and/or fluorine-19.

In the production method of organofluorine compounds of the present invention preferably R1represents a hydrogen atom or a C1-C18alkyl, preferably

R2is a hydrogen or C1-C18the alkyl, preferably R3represents a hydrogen atom or a C1-C18alkyl, more preferably R1is stands or ethyl, more preferably R2represents methyl or ethyl, more preferably R3is stands or ethyl.

In the production method of organofluorine compounds for infusion is to him the invention of the alcohol of formula 1 is preferably selected from the group consisting of primary alcohols, such as methanol, ethanol, n-propanol, n-butanol, amyl alcohol, n-hexyl alcohol, n-heptanol or n-octanol; secondary alcohols such as isopropanol, Isobutanol, isoamyl alcohol, 3-pentanol; and tertiary alcohols such as tert-butanol, tert-amyl alcohol, 2,3-dimethyl-2-butanol, 2-(trifluoromethyl)-2-propanol, 3-methyl-3-pentanol, 3-ethyl-3-pentanol, 2-methyl-2-pentanol, 2,3-dimethyl-3-pentanol, 2,4-dimethyl-2-pentanol, 2-methyl-2-hexanol, 2-cyclopropyl-2-propanol, 2-cyclopropyl-2-butanol, 2-cyclopropyl-3-methyl-2-butanol, 1-methylcyclopentanol, 1-ethylcyclopentane, 1-propylcyclohexane, 1-methylcyclohexanol, 1-ethylcyclohexane and 1-methylcycloheptane. More preferably the alcohol is selected from the group consisting of tertiary alcohols such as tert-butanol, tert-amyl alcohol, 2,3-dimethyl-2-butanol and 2-(trifluoromethyl)-2-propanol.

Salt fluoride, preferably selected from the group consisting of alkali metal fluorides containing alkali metals selected from the group consisting of lithium, sodium, potassium, rubidium and cesium; fluorides of alkaline-earth metals containing alkaline-earth metals selected from the group consisting of magnesium, calcium, strontium and barium; and ammonium fluoride. More preferably, in the method of obtaining organofluorine compounds of the present invention desirable alauderdale cesium and ammonium fluoride.

The above ammonium fluoride is preferably selected from the group consisting of fluorides, Quaternary ammonium compounds, including fluoride and tetrabutylammonium fluoride designed; fluorides tertiary ammonium, including fluoride of triethylamine and fluoride of tributylamine; fluoride secondary ammonium, including fluoride of dibutylamine and fluoride of vexillaria; and fluorides primary ammonium, including fluoride of butylamine and fluoride of hexylamine, more preferably in the method of obtaining organofluorine compounds of the present invention is desirable tetrabutylammonium fluoride.

In the production method of organofluorine compounds of the present invention of tetraalkylammonium fluoride or fluoride of an alkali metal, including cesium, preferably adsorbed on substrates selected from the group consisting of celite, molecular sieves, alumina and silica gel.

In the production method of organofluorine compounds of the present invention in the most preferred combination of fluoride and alcohol fluoride is a fluoride of a metal or of tetraalkylammonium fluoride, specifically cesium fluoride or tetrabutylammonium fluoride, and the preferred alcohol is a tertiary alcohol, such as tert-butanol and tert-amyl alcohol.

In the production method of organofluorine compounds on n the present invention the number of the above fluoride is preferably 1.0 to 10 equivalents. to alkylhalogenide or alkylsulfonate.

In the production method of organofluorine compounds of the present invention organofluorine compound, obtained using the alcohol of formula 1 as solvent is [18F]Tordesillas formula 2.

Formula 2

In the production method of organofluorine compounds of the present invention organofluorine compound, obtained using the alcohol of formula 1 as solvent is [18F]fermionization formula 3.

Formula 3

In the production method of organofluorine compounds of the present invention organofluorine compound, obtained using the alcohol of formula 1 as solvent is [18F]forestration formula 4.

Formula 4

In the production method of organofluorine compounds of the present invention organofluorine compound, obtained using the alcohol of formula 1 as solvent is [18F]ferroelasticity formula 5.

Formula 5

In the production method of organofluorine compounds of the present invention organofluorine compound, obtained with the use of alcohol is of the formula 1 as solvent, is [18F]DDNP formula 6.

Formula 6

In the production method of organofluorine compounds of the present invention organofluorine compound, obtained using the alcohol of formula 1 as solvent is [18F]fertility formula 7.

Formula 7

In the production method of organofluorine compounds of the present invention organofluorine compound, obtained using the alcohol of formula 1 as solvent is [18F]verhalen formula 8.

Formula 8

In the production method of organofluorine compounds of the present invention organofluorine compound, obtained using the alcohol of formula 1 as solvent is [18F]foretelling formula 9.

Formula 9

In the production method of organofluorine compounds of the present invention organofluorine compound, obtained using the alcohol of formula 1 as solvent is [18F]forproperty formula 10.

Formula 10

In the production method of the present invention, the alcohol solvent forms a hydrogen bond with fluoride and thereby condition the es reaction of nucleophilic substitution of fluoride. Thus, it is possible to overcome the problem of low reactivity of fluoride due to the formation of tayannah relations in the fluoride between metal cations and anions of fluorine, it is possible to reduce the reaction time and it is possible to obtain a final product of organofluorine compounds with high yield while suppressing side reactions.

The method according to the invention

Below will be described in detail exemplary embodiments of the present invention.

In the production method of organofluorine compounds by interaction of fluoride with alkylhalogenide or alkylsulfonates alcohol of formula 1 is used as a solvent. Preferably the reaction is carried out at 0-150°C for 0.5 to 24 h, more preferably the reaction is carried out for 1-10 h at 20-120°C., even more preferably the reaction is carried out at 40-100°C for 1.5-6 hours

Boiling point, the affinity to water, chemical stability and reactivity of alcohol depend on the composition of the alkyl groups in the alcohol of formula 1.

With increasing number of carbon atoms in the alcohol and alkyl substituents boiling point and melting point of the alcohol increases. Alcohol having a high boiling point and melting point, is not suitable as a solvent or in the solid state. Alcohol has a low number of carbon atoms in the alkyl or a lower amount of al is strong substituents, not suitable as a solvent, since the reactivity of the alcohol is increased by reducing steric obstacles alcohol.

Taking into account these effects R1preferably represents a hydrogen atom or a C1-C18alkyl, more preferably1-C6alkyl, more preferably methyl or ethyl.

R2preferably is a hydrogen atom or a C1-C18the alkyl, more preferably1-C6the alkyl, even more preferably stands or ethyl.

R3preferably represents a hydrogen atom or a C1-C18alkyl, more preferably1-C6alkyl, more preferably methyl or ethyl.

As examples of the alcohol described above, preferably the alcohol is selected from the group consisting of primary alcohols, such as methanol, ethanol, n-propanol, n-butanol, amyl alcohol, n-hexyl alcohol, n-heptanol or n-octanol; and secondary alcohols such as isopropanol, Isobutanol, isoamyl alcohol, 3-pentanol; and tertiary alcohols such as tert-butanol, tert-amyl alcohol, 2,3-dimethyl-2-butanol, 2-(trifluoromethyl)-2-propanol, 3-methyl-3-pentanol, 3-ethyl-3-pentanol, 2-methyl-2-pentanol, 2,3-dimethyl-3-pentanol, 2,4-dimethyl-2-pentanol, 2-methyl-2-hexanol, 2-cyclopropyl-2-propanol, 2-cyclopropyl-2-butanol, 2-cycle is propyl-3-methyl-2-butanol, 1-methylcyclopentanol, 1-ethylcyclopentane, 1-propylcyclohexane, 1-methylcyclohexanol, 1-ethylcyclohexane and 1-methylcycloheptane. More preferably the alcohol is selected from the group consisting of tertiary alcohols such as tert-butanol, tert-amyl alcohol, 2,3-dimethyl-2-butanol and 2-(trifluoromethyl)-2-propanol.

Alcohol solvent of the present invention increases the reactivity of the fluoride to nucleophilic substitution by the weakening of the ionic bonds in the fluoride between metal cations and anions of fluorine through the formation of hydrogen bonds with the metal fluoride and the fluoride of tetraalkylammonium and also suppresses the formation of by-products by reducing the basicity of fluoride.

The method according to the present invention should be considered in accordance with the reaction scheme presented in figure 1, but theoretically not always limited to this. In addition, it was found that the reaction with alkylsulfonates is more effective compared to alkylhalogenide because alcohol forms hydrogen bonds with alkylsulfonates.

In the production method of organofluorine compounds of the present invention fluoride, which is the source of fluoride ions can be selected from the group consisting of alkali metal fluorides containing alkali metals selected from the group consisting of lithium, NAT is Oia, potassium, rubidium and cesium; and fluorides of alkaline-earth metals containing alkaline-earth metals selected from the group consisting of magnesium, calcium, strontium and barium; and ammonium fluoride.

The above ammonium fluoride is preferably selected from the group consisting of Quaternary ammonium fluorides such as tetrabutylammonium fluoride and fluoride designed; and fluoride tertiary ammonium, such as a fluoride of triethylamine and fluoride of tributylamine; fluoride secondary ammonium, such as a fluoride of dibutylamine and fluoride of vexillaria; and fluorides primary ammonium, such as a fluoride of butylamine and fluoride of hexylamine, most preferably it is possible to use cesium fluoride or tetrabutylammonium fluoride.

Fluoride of an alkali metal, including cesium, and of tetraalkylammonium fluoride can be used in forms adsorbed on different substrates. For example, cesium fluoride and tetrabutylammonium fluoride adsorb on the substrate, such as celite, molecular sieve, alumina and silica gel. When using fluorine-19, the amount of fluoride is preferably 1.0 to 10 equivalents. to alkylhalogenide or alkylsulfonate, more preferably from 3.0 to 6.0 EQ. When you add a smaller amount of fluoride than the specified limits, the yield of the reaction becomes less. When to add a lot of ftory is a, than the specified limits, the yield of the reaction is higher, but the overuse of fluoride.

For the same reason in the case of fluorine-18 preferably use a trace amount of [18F]fluoride as fluoride compared with the number of alkylhalogenide or alkylsulfonate. More preferably use 1 pkg-100 ng of [18F]fluoride at 1 mg alkylhalogenide or alkylsulfonate.

On the other hand, you can get organofluorine compound comprising a label fluorine-18, the interaction of alkylhalogenide or alkylsulfonate with fluoride with positron emitting radioactive isotope fluorine-18. In this case, the fluoride in the fluoride, which is a radioactive isotope, is fluorine-18, specifically [18F]fluoride.

In the production method of organofluorine compounds by the interaction of fluoride with alkylhalogenide or alkylsulfonates organofluorine compound selectively receive high yield, comprising more than 90%, as the main product while suppressing side reactions and the use of a tertiary alcohol as the reaction solvent.

In contrast, according to a variant implementation of the present invention, in the case of acetonitrile or DMF, representing polar aprotic solvents commonly used to obtain organofluorine compounds, yhod is low due to the low solubility of fluoride. When the reaction is carried out using 1,4-dioxane or benzene, which are non-polar solvents, they do not receive organofluorine compounds (see table 1).

In conclusion, the alcohol solvent used in the present invention leads to increased reactivity of fluoride to nucleophilic substitution by the weakening of the ionic bonds between metal cations and anions of fluorine due to the formation of hydrogen bonds with alkali metal fluoride and a fluoride of tetraalkylammonium, and thus the normal way you can overcome the problem of low reactivity of the fluoride in the strong ionic bonds in fluoride, to reduce reaction time by increasing the reactivity and reaction rate of fluoride and get organofluorine compound of the present invention with a high output.

In addition, alcohol, being a proton solvent, can suppress the formation of by-products due to the effect on the basicity of the reaction of fluorination by reducing the basicity of the fluoride in the formation of hydrogen bonds with fluoride. Therefore, may decrease the formation of by-products such as alcohols and alkenes.

According to the present invention using a method of obtaining organofluorine compounds with the use of alcohol is ormula 1 as the solvent can be obtained organofluorine compounds with a higher yield, at least the duration of the reaction and in a milder conditions compared to the usual way of obtaining. It was shown that organofluorine compounds can be obtained with high yield by using another method of obtaining already disclosed by the applicants (Kim, D.W.; Song, C.E.; Chi, D.Y. J. Am. Chem. Soc., 2002, 124, 10278-10279). However, the method described in the above work has economic disadvantages because it requires expensive ionic liquid, while in the present invention are used cheap alcohol.

The above conventional method is very suitable for non-polar organofluorine compounds. For example, you can get the18F-labeled organofluorine compounds with high yield (Kim, D.W.; Choe, Y.S.; Chi, D.Y. Nucl. Med. Biol., 2003, 30, 345-350). In those cases, when really synthesize18F-labeled radioactive drugs, this method has the disadvantage that it is very difficult their separation from the ionic liquid, since most of the18F-labeled radioactive drugs are polar. Therefore, the above method cannot be used to obtain the18F-labeled radioactive drugs.

In this respect, the present invention has greater applicability in obtaining18F-Machen who's radioactive drugs. The present invention provides various applications to obtain18F-labeled radioactive drugs. Exemplary embodiments of the present invention are particularly suitable for applications in relation to existing18F-labeled radioactive drugs.

The present invention will be described in more detail with reference to the subsequent examples. Subsequent variants of implementation are examples of the present invention, and the present invention should not be construed as limited to the below options for implementation; and more data options for implementation are presented to describe the principle of the invention for specialists in this field. Obviously, the experts in this field it is clear that it is possible to make various changes in form and detail without departing from the essence and scope of the invention defined by the attached claims.

Example 1

Getting organofluorine compounds 1

280 mg (1.0 mmol) of 2-(3-methanesulfonylaminoethyl)naphthalene and 456 mg (3.0 mmol) of cesium fluoride are added to a solvent, 4,0 ml of tert-butanol. The reaction mixture was stirred for 6 h at 80°C. In the reaction mixture contribute 7 ml simple ethyl ether to remove metal salts. After filtration the filter is concentrated under reduced pressure. 188 mg (yield 92%) of 2-(3-forproperty)naphthalene get column chromatography (mixture of ethyl acetate:n-hexane = 1:20).

Example 2

Getting organofluorine compounds 2-7

The reaction is conducted in the same manner as described in example 1, except that alcohol solvents, reaction temperature and time are as shown in table 1. Organofluorine compounds are given as shown in table 1. In the reaction scheme 3 shows the 2-(3-forproperty)naphthalene (A), 2-(3-hydroxypropoxy)naphthalene (C), 2-(3-allyloxy)naphthalene (C) and 2-(3-alkoksigruppami)naphthalene (D), which are the products obtained upon receipt of organofluorine compounds.

Comparative example 1

Getting organofluorine compounds 1

280 mg (1.0 mmol) of 2-(3-methanesulfonylaminoethyl)naphthalene and 456 mg (3.0 mmol) of cesium fluoride are added to 4.0 ml of acetonitrile, is used instead of alcohol. The reaction mixture was stirred for 6 h at 80°C.

The reaction almost never occurs, and thus shows the important role of alcohol to organofluorine compounds.

Comparative example 2

Getting organofluorine compounds 2

280 mg (1.0 mmol) of 2-(3-methanesulfonylaminoethyl)naphthalene and 456 mg (3.0 mmol) of cesium fluoride are added to 4.0 ml of DMF used instead of alcohol. The reaction mixture is stirred during the 6 h at 80°C.

After the reaction is still 33% of the reacting substances. Produce large quantities of alcohol and alkene as by-products. Shows the important role of alcohol to organofluorine compounds.

Comparative examples 3-4

Getting organofluorine compounds 3-4

280 mg (1.0 mmol) of 2-(3-methanesulfonylaminoethyl)naphthalene and 456 mg (3.0 mmol) of cesium fluoride are added to 4.0 ml of benzene or 1,4-dioxane used instead of alcohol. The reaction mixture was stirred for 6 h at 80°C.

The reaction almost never occurs, and thus shows the important role of alcohol to organofluorine compounds.

Comparative examples 5-6

Getting organofluorine compounds 5-6

To confirm the increase in reactivity due to the formation of hydrogen bonds between fluoride and alcohol the reaction is carried out in the same manner as described in example 1 using potassium bromide, which does not form hydrogen bonds with alcohol, instead of fluoride.

The reaction of the synthesized almost never occurs, and thus it is shown that the formation of hydrogen bonds between the alcohol and fluoride is important for increasing the reactivity of fluoride.

The reaction scheme 3

The data presented in table 1, show that h is 2-(3-forproperty)naphthalene (A) receive (yield 92%), when using cesium fluoride as the source of fluorine atoms, and tertiary alcohols, tert-butanol or tert-amyl alcohol is used as solvent (examples 1, 3 and 4).

In cases when, as a source of fluorine atoms using tetrabutylammonium fluoride instead of cesium fluoride, the output of the main product is more than 90% (example 7). When using rubidium fluoride, the fluorination reaction proceeds, but for the reaction requires a longer time (example 5).

In the case of comparative examples 1 and 2 using polar aprotic solvent that is commonly used to obtain organofluorine compounds, and in the case of a non-polar solvent, the reaction mixture is treated within 6 h of the Reaction is not leaking or produces large quantities of by-products, and the product yield is only 48%. This result shows that the use of alcohol is important for obtaining organofluorine compounds. 2-(3-n-butoxypropyl)naphthalene (D), a by-product ester formed (30%)as solvent using n-butanol, primary alcohol. This result shows that the use of the tertiary alcohol instead of primary or secondary alcohols suppresses the formation of ethers as by-products.

In the comparative example, the 5 and 6 potassium bromide, not capable of forming hydrogen bonds, is used instead of fluoride to confirm the increase in reactivity due to the formation of hydrogen bonds between the alcohol and fluoride. It is established that the reaction of the synthesized almost does not leak, and the formation of hydrogen bonds between the alcohol and fluoride is important for increasing the reactivity of fluoride upon receipt of organofluorine compounds.

Example 8

Getting organofluorine compounds 8

356 mg (1.0 mmol) of 2-(3-toluensulfonate)naphthalene and 456 mg (3.0 mmol) of cesium fluoride are added to 4.0 ml of tert-amyl alcohol in the reaction vessel. The reaction mixture was stirred for 2 h at 90°C. Add 7 ml of a simple ethyl ether to remove the metal salt. After filtration the filtrate is concentrated under reduced pressure. 190 mg (yield 93%) of 2-(3-forproperty)naphthalene get column chromatography (mixture of ethyl acetate:n-hexane = 1:20).

Examples 9-14

Getting organofluorine compounds 9-14

The reaction is conducted in the same manner as described in example 8, except using 1.0 mmol of several alkylhalogenide or alkyl sulphonates, are presented in table 2, instead of 2-(3-toluensulfonate)naphthalene.

/tr>
T the blitz 2
Alkylhalogenide or alkylsulfonateTemperature (°C)Time (h)Output (%)
Example 890293
Example 9902473
Example 10Boiling1272
Example 11Boiling1888
Example 12903,581
Example 13902,592
Example 14251,569

As shown in table 2, the reaction carried out for 1.5-24 h at 25-110°C depending on alkylhalogenide or alkyl sulphonates. It is established that organofluorine compounds get high output.

Example 15

Getting organofluorine compounds 15

Getting [18F]Tordesillas (FDG)

A method of obtaining a [18F]Tordesillas represented in the reaction scheme 4. 10 µci of [18F]fluoride adsorb on ion-exchange resin. Adsorbed [18F]fluoride elute in the reaction vessel, a mixed solution of cesium carbonate (16 mg in 300 μl of water) and Kryptofix 222 (22 mg in 300 μl of acetonitrile) or a solution of tetrabutylammonium. [18F]fluoride is dried by acetonitrile (500 μl × 3). To the solution was added 20 mg of mannose triflate. And then to the reaction mixture is added a mixed solution of 300 μl of tert-butyl alcohol or tert-amyl alcohol and 300 μl of acetonitrile. The reaction is carried out at 100°C for 15 minutes the Solvent is removed at 95°C using nitrogen gas and then make 500 μl of 2 n NaOH solution. The hydrolysis is carried out for 2 min at room temperature and then make 3 ml of water is La dilution. The reaction mixture is successively passed through the cartridge with neutral aluminum oxide, tC18 cartridge and the cartridge IC-H+obtaining pure [18F]Tordesillas. In the experiment conducted in the above-mentioned conditions, adjusted for the weakening of the radiochemical yield is 95,1±2,7%, and the radiochemical purity is equal to 98.2±1.3 percent.

The reaction scheme 4

Example 16

Getting organofluorine compounds 16

Automated acquisition of [18F]Tordesillas (FDG)

Automated acquisition of [18F]Tordesillas carried out under the reaction conditions described in example 15. Device for automated acquisition is a GE TracerLab MX, and work programme of change to obtain a [18F]Tordesillas. Use disposable cassette for receiving and schematic representation of the cassette shown in figure 2.

After inserting a disposable cartridge for GE TracerLab MX in automatic equipment make chemical reagents as follows: 7 ml of acetonitrile into the vial V1 with a capacity of 10 ml, 20 mg of mannose triflate (1.2 ml tert-butyl alcohol or tert-amyl alcohol and 0.8 ml of acetonitrile) into the vial V2 with a capacity of 10 ml, 5 ml ethanol in a bottle V3 capacity of 10 ml, 5 ml 1 n HCl solution and buffer into the vial V4 and 2 ml of 2 n NaOH solution into the syringe a volume of 2 ml

1,00 µci of [ 18F]fluoride obtained from labeled with oxygen-18 water in the cyclotron and then [18F]fluoride is transferred into an automatic device GE TracerLab MX under pressure gaseous helium. Moved [18F]fluoride adsorb on the cartridge ion exchange resin and the oxygen-18 is removed in a tank labeled with oxygen-18 water. Adsorbed [18F]fluoride elute in the reaction vessel, a mixed solution of cesium carbonate (16 mg in 300 μl of water) and Kryptofix 222 (22 mg in 300 μl of acetonitrile) or a solution of tetrabutylammonium. Suirvey [18F]fluoride fully dried 1 ml of acetonitrile in the vial V1. After addition of mannose triflate in vial V2 in the reaction vessel containing the dried [18F]fluoride, the reaction is carried out at 100°C for 15 min, and then the solvent is completely removed. In the reaction vessel was added 1 ml of acetonitrile in the vial V1 and the mixture is then transferred into the syringe 1 in figure 2. The intermediate reaction product is diluted by adding 25 ml of water and then adsorb on the tC18 cartridge. After adding 2 n NaOH solution and 2 ml syringe to the adsorbed intermediate product of the hydrolysis of pure [18F]Tordesillas obtained after purification by passing through the cartridge with neutral alumina and tC18 cartridge. When automatic acquisition is carried out in the above conditions, with amendments is th at weakening the radiochemical yield is a 75.1±7,4%, and the radiochemical purity is equal to 98.2±1,2%.

Example 17

Getting organofluorine compounds 17

Getting [18F]formetanate (FMISO) 1

A method of obtaining a [18F]formetanate represented in the reaction scheme 5. 10 µci of [18F]fluoride adsorb on ion-exchange resin. Adsorbed [18F]fluoride elute in the reaction vessel, a mixed solution of cesium carbonate (2 mg in 300 μl of water) and Kryptofix 222 (22 mg in 300 μl of acetonitrile) or a solution of tetrabutylammonium. [18F]fluoride is dried by acetonitrile (500 μl×3). To this solution was added 10 mg of 1-(1,2-epoxypropyl)-2-intorimidazole. After adding a mixed solution containing 500 μl of tert-butyl alcohol or tert-amyl alcohol and 100 μl of acetonitrile, to the above reaction mixture, the reaction is carried out at 100°C for 15 minutes the Solvent is removed using nitrogen gas at 95°C and then the reaction vessel make 200 ál 1000 ál acetonitrile and water. Pure [18F]fermionization get high performance liquid chromatography (HPLC). Conditions for HPLC are as follows: use column Alltech Econosil C18, a mixture of water:ethanol = 95:5 is used with a flow rate of 5 ml/min, and the device has a UV detector at 254 nm and radioactive detector. In the experiment conducted in the above-mentioned conditions, adjusted for slable is their radiochemical yield is 75.4±3,1%, and the radiochemical purity is equal to 98.1±0.7 percent.

The reaction scheme 5

Example 18

Getting organofluorine compounds 18

Getting [18F]formetanate (FMISO) 2

Another way to get a [18F]formetanate represented in the reaction scheme 6. 10 µci of [18F]fluoride adsorb on ion-exchange resin. Adsorbed [18F]fluoride elute in the reaction vessel, a mixed solution of cesium carbonate (16 mg in 300 μl of water) and Kryptofix 222 (22 mg in 300 μl of acetonitrile) or a solution of tetrabutylammonium. [18F]fluoride is dried by acetonitrile (500 μl × 3). To this solution was added 10 mg of 1-(2-nitro-1-imidazolyl)-2-O-tetrahydropyranyl-3-O-colorselectiondialog. After adding a mixed solution containing 500 μl of tert-butyl alcohol or tert-amyl alcohol and 100 μl of acetonitrile, to the above reaction mixture, the reaction is carried out at 100°C for 10 minutes the Solvent is completely removed using nitrogen gas at 95°C and then the reaction vessel make 200 μl of acetonitrile and 500 μl of 1 n HCl solution. The hydrolysis is carried out at 100°C for 5 minutes Clean [18F]fermionization receive HPLC. Conditions for HPLC are as follows: use column Alltech Econosil C18, a mixture of water:ethanol = 95:5 is used with a flow rate of 5 ml/min, and the device has the UV detector at 254 nm and radioactive detector. In the experiment conducted in the above-mentioned conditions, adjusted for the weakening of the radiochemical yield is to 82.1±1,1%, and the radiochemical purity is equal to 98.1±1,5%.

A reaction scheme 6

Example 19

Getting organofluorine compounds 19

Getting [18F]forestrial (FES)

A method of obtaining a [18F]forestrial represented in the reaction scheme 7.

10 µci of [18F]fluoride adsorb on ion-exchange resin. Adsorbed [18F]fluoride elute in the reaction vessel, a mixed solution of cesium carbonate (16 mg in 300 μl of water) and Kryptofix 222 (22 mg in 300 μl of acetonitrile) or a solution of tetrabutylammonium. [18F]fluoride is dried by acetonitrile (500 μl × 3). To the solution was added 3 mg of 3-O-methoxymethyl-16β,17β-epiestriol cycloolefin. After adding a mixed solution containing 400 μl of tert-butyl alcohol or tert-amyl alcohol and 100 μl of acetonitrile, to the above reaction mixture, the reaction is carried out at 100°C for 15 minutes

The solvent is completely removed using nitrogen gas at 95°C and then the reaction vessel make 200 μl of acetonitrile and 50 μl of 1 n HCl solution and the hydrolysis is carried out in nitrogen atmosphere at 100°C for 5 minutes the above method was performed three times. Pure [18F]forestration receive HPLC. Conditions In the LC are as follows: use column Nucleosil 120 C18-5A C18, the mixture of water:ethanol = 40:60 is used with a flow rate of 4 ml/min, and the device has a UV detector at 280 nm and radioactive detector. In the experiment conducted in the above-mentioned conditions, adjusted for the weakening of the radiochemical yield is 72,1±1,1%, and the radiochemical purity is equal to 98.4±1,2%.

A reaction scheme 7

Example 20

Getting organofluorine compounds 20

Automated acquisition of [18F]forestrial (FES)

Automated acquisition of [18F]forestrial carried out under the reaction conditions described in example 19. Device for automated acquisition is a GE TracerLab MX, and work programme of change to obtain a [18F]forestrial. Use disposable cassette for receiving and schematic representation of the cassette shown in figure 2.

After inserting a disposable cartridge for GE TracerLab MX in automatic equipment make chemical reagents as follows: 7 ml of acetonitrile into the vial V1 with a capacity of 10 ml, 3 mg 3-O-methoxymethyl-16β,17β-epiestriol cycloolefin (1.5 ml tert-butyl alcohol or tert-amyl alcohol and 0.5 ml of acetonitrile) into the vial V2 with a capacity of 10 ml, 3 ml ethanol and mixed solution of 500 μl of 2 n NaOH solution and 1 ml of water in a bottle V3 capacity of 10 ml, 0.63 ml 2 n HCl and 6 ml acetonitrile in a bottle V4 and the vials placed the t in a disposable cassette.

1,0 CI [18F]fluoride obtained from labeled with oxygen-18 water in the cyclotron and then obtained [18F]fluoride is transferred into an automatic device GE TracerLab MX under pressure gaseous helium. Moved [18F]fluoride adsorb on the cartridge ion exchange resin and the oxygen-18 is removed in a tank labeled with oxygen-18 water. Adsorbed [18F]fluoride elute in the reaction vessel, a mixed solution of cesium carbonate (16 mg in 300 μl of water) and Kryptofix 222 (22 mg in 300 μl of acetonitrile) or a solution of tetrabutylammonium. Suirvey [18F]fluoride fully dried 1 ml of acetonitrile in the vial V1. After adding 3-O-methoxymethyl-16β,17β-epiestriol cycloolefin vial V2 in the reaction vessel containing the dried [18F]fluoride, the reaction is carried out at 95°C for 5 min and then the solvent is removed. The hydrolysis is carried out at 90°With the addition of a mixed solution of 2 ml of HCl and acetonitrile in a bottle V4 in the reaction vessel. This technique is repeated three times. The solvents are removed after hydrolysis. The mixed solution in the vial V3 added to the reaction vessel to dissolve the reaction mixture. Pure [18F]forestration receive HPLC. Conditions for HPLC are as follows: use column Nucleosil 120 C18-5A C18, a mixture of water:ethanol = 40:60 is used with a flow rate of 4 ml/min, and the device having the t UV detector at 280 nm and radioactive detector. In the experiment conducted in the above-mentioned conditions, adjusted for the weakening of the radiochemical yield is 42.1±5,1%, and the radiochemical purity equals 98,0±1,1%.

Example 21

Getting organofluorine compounds 21

Getting [18F]forpreparation (FP-CIT)1

A method of obtaining a [18F]forpreparation represented in the reaction scheme 8. 10 µci of [18F]fluoride adsorb on ion-exchange resin. Adsorbed [18F]fluoride elute in the reaction vessel, a mixed solution of cesium carbonate (16 mg in 300 μl of water) and Kryptofix 222 (22 mg in 300 μl of acetonitrile) or a solution of tetrabutylammonium. [18F]fluoride is dried by acetonitrile (500 μl × 3). To this solution was added 10 mg of 1,3-diethylpropane. After adding a mixed solution containing 500 μl of tert-butyl alcohol or tert-amyl alcohol and 100 μl of acetonitrile, to the above reaction mixture, the reaction is carried out at 95°C for 15 minutes the Solvent is removed using nitrogen gas at 95°C and then add 5 mg of nor-β-CIT in a mixture of 300 μl of acetonitrile and 500 μl of tert-butyl alcohol. The reaction is carried out at 135°C for 40 minutes of Pure [18F]ferroelasticity receive HPLC. Conditions for HPLC are as follows: use column µ-Bondapack C18, a mixture of phosphoric acid:acetonitrile = 40:60 IP is result a flow rate of 5 ml/min, and the device has a UV detector at 220 nm and radioactive detector. In the experiment conducted in the above-mentioned conditions, adjusted for the weakening of the radiochemical yield is 25.3±2,1%, and the radiochemical purity equals 97,2±1,3%.

A reaction scheme 8

Example 22

Getting organofluorine compounds 22

Getting [18F]forpreparation (FP-CIT)2

A method of obtaining a [18F]forpreparation represented in the reaction scheme 9. 10 µci of [18F]fluoride adsorb on ion-exchange resin. Adsorbed [18F]fluoride elute in the reaction vessel, a mixed solution of cesium carbonate (16 mg in 300 μl of water) and Kryptofix 222 (22 mg in 300 μl of acetonitrile).

[18F]fluoride is dried by acetonitrile (500 μl × 3). To the reaction solution was added 5 mg (3-methanesulfonylaminoethyl)-2β-carbomethoxy-3β-(4-itfinal)tropane or (3-toluensulfonate)-2β-carbomethoxy-3β-(4-itfinal)tropane and a mixed solution containing 100 μl of acetonitrile and 500 μl of tert-butyl alcohol or tert-amyl alcohol. The reaction is carried out at 95°C for 10 minutes the Solvent is completely removed using nitrogen gas at 95°C and then the reaction vessel make 300 μl of acetonitrile and 500 μl of water. Pure [18F]ferroelasticity receive HPLC. Conditions to perform the surveillance HPLC are as follows: use column µ-Bondapack C18, a mixture of phosphoric acid:acetonitrile = 40:60 is used with a flow rate of 5 ml/min, and the device has a UV detector at 220 nm and radioactive detector. In the experiment conducted in the above-mentioned conditions, adjusted for the weakening of the radiochemical yield is 25.3±2,1%, and the radiochemical purity equals 97,2±1,3%.

The reaction scheme 9

Example 23

Getting organofluorine compounds 23

Getting [18F]DDNP (FDDNP)

A method of obtaining a [18F]DDNP represented in the reaction scheme 10. 10 µci of [18F]fluoride adsorb on ion-exchange resin. Adsorbed [18F]fluoride elute in the reaction vessel, a mixed solution of cesium carbonate (16 mg in 300 μl of water) and Kryptofix 222 (22 mg in 300 μl of acetonitrile) or a solution of tetrabutylammonium. [18F]fluoride is dried by acetonitrile (500 μl × 3). To the solution was added 4 mg tosyl predecessor represented in the reaction scheme 9. After adding a mixed solution containing 500 μl of tert-butyl alcohol or tert-amyl alcohol and 100 μl of acetonitrile, to the above reaction mixture, the reaction is carried out at 95°C for 10 minutes the Solvent is removed using nitrogen gas at 95°C. the Reaction mixture is dissolved in acetonitrile and the radiochemical yield was determined by the use of radioisotope TLC. In about the ice, held in the above-mentioned conditions, adjusted for the weakening of the radiochemical yield is 42.3±4,1%, and the radiochemical purity equals 97,2±1,3%.

The reaction scheme 10

Example 24

Getting organofluorine compounds 24

Getting [18F]fortemedia (FLT)

Another way to get a [18F]fortemedia represented in the reaction scheme 11. 10 µci of [18F]fluoride adsorb on ion-exchange resin. Adsorbed [18F]fluoride elute in the reaction vessel, a mixed solution of cesium carbonate (16 mg in 300 μl of water) and Kryptofix 222 (22 mg in 300 μl of acetonitrile) or a solution of tetrabutylammonium. [18F]fluoride is dried by acetonitrile (500 μl × 3). To the solution add 10-40 mg of 3-N-tert-butoxycarbonyl-(5'-O-(4,4'-dimethoxytrityl)-2-deoxy-3'-O-(4-nitrobenzenesulfonyl)-β-D-trapencieris)thymine or 3-N-tert-butoxycarbonyl-(5'-O-(triphenylmethyl)-2-deoxy-3'-O-(4-nitrobenzenesulfonyl)-β-D-trapencieris)thymine and then add a mixture of 100 μl of acetonitrile and 500 μl of tert-butyl alcohol or tert-amyl alcohol. The reaction is carried out at 100-150°C for 10 minutes the Solvent is removed using nitrogen gas at 95°C and then add 200 ál of acetonitrile and 500 μl of 1 n HCl solution. The hydrolysis is carried out at 100°C for 5 minutes Clean [18F]fertilizin get In the LC. Conditions for HPLC are as follows: use column Alltech Econosil C18, a mixture of water:ethanol = 90:10 is used with a flow rate of 5 ml/min, and the device has a UV detector at 267 nm and radioactive detector. In the experiment conducted in the above-mentioned conditions, adjusted for the weakening of the radiochemical yield is 85.6±3,1%, and the radiochemical purity is equal to 98.5±1,2%.

The reaction scheme 11

Example 25

Getting organofluorine compounds 25

Getting [18F]floraline (F)

Another way to get a [18F]floralina represented in the reaction scheme 12. 10 µci of [18F]fluoride adsorb on ion-exchange resin. Adsorbed [18F]fluoride elute in the reaction vessel, a mixed solution of cesium carbonate (16 mg in 300 μl of water) and Kryptofix 222 (22 mg in 300 μl of acetonitrile) or a solution of tetrabutylammonium. [18F]fluoride is dried by acetonitrile (500 μl × 3). To the solution was added 10 mg of 1,1-di-p-toluensulfonate and then add the mixed solution containing 500 μl of tert-butyl alcohol or tert-amyl alcohol and 100 μl of acetonitrile. The reaction is carried out at 100-150°C for 10 minutes After the reaction type (N,N-dimethylaminoethanol for alkylation. Pure [18F]verhalen receive HPLC. In the experiment conducted in the above conditions, with the amendment oslablenie radiochemical yield is to 75.7±3,1%, and the radiochemical purity is equal to 97.5±1,2%.

The reaction scheme 12

Example 26

Getting organofluorine compounds 26

Getting [18F]foretelling (FE)

Another way to get a [18F]foretelling represented in the reaction scheme 13. 10 µci of [18F]fluoride adsorb on ion-exchange resin. Adsorbed [18F]fluoride elute in the reaction vessel, a mixed solution of cesium carbonate (16 mg in 300 μl of water) and Kryptofix 222 (22 mg in 300 μl of acetonitrile) or a solution of tetrabutylammonium. [18F]fluoride is dried by acetonitrile (500 μl × 3). To the solution was added 10 mg of 1,2-di-p-toluensulfonate and then add the mixed solution containing 500 μl of tert-butyl alcohol or tert-amyl alcohol and 100 μl of acetonitrile. The reaction is carried out at 100-150°C for 10 minutes After completion of the reaction, add N,N-dimethylaminoethyl for alkylation. Pure [18F]foretelling receive HPLC. In the experiment conducted in the above-mentioned conditions, adjusted for the weakening of the radiochemical yield is 67,7±8,1%, and the radiochemical purity is equal to 98.2±2,3%.

The reaction scheme 13

Example 27

Getting organofluorine compounds 27

Getting [18F]tobramicina (FP)

A method of obtaining a [18F]forproper is Lina represented in the reaction scheme 14. 10 µci of [18F]fluoride adsorb on ion-exchange resin. Adsorbed [18F]fluoride elute in the reaction vessel, a mixed solution of cesium carbonate (16 mg in 300 μl of water) and Kryptofix 222 (22 mg in 300 μl of acetonitrile) or a solution of tetrabutylammonium. [18F]fluoride is dried by acetonitrile (500 μl × 3). To the solution was added 10 mg of 1,3-di-p-toluensulfonate and then add the mixed solution containing 500 μl of tert-butyl alcohol or tert-amyl alcohol and 100 μl of acetonitrile. The reaction is carried out at 100-150°C for 10 minutes After the reaction type (N,N-dimethylaminoethanol for alkylation. Pure [18F]forproperty receive HPLC. In the experiment conducted in the above-mentioned conditions, adjusted for the weakening of the radiochemical yield is 72,4±6,1%, and the radiochemical purity is equal to 98.1±1,3%.

The reaction scheme 14

1. A method of obtaining a [18F]organofluorine compounds by the interaction of [18F]fluoride with a corresponding halide or sulfonate in the presence of an alcohol of formula 1 as solvent
Formula 1

(in which R1, R2and R3represent a hydrogen atom or a C1-C18alkyl).

2. The method according to claim 1, in which R1represents a hydrogen atom or a C1-C18alkyl; R2 is a hydrogen or C1-C18by alkyl; and R3represents a hydrogen atom or
C1-C18alkyl.

3. The method according to claim 1, in which R1represents methyl or ethyl; R2represents methyl or ethyl; and R3is stands or ethyl.

4. The method according to claim 1, wherein the alcohol of formula 1 selected from the group consisting of primary alcohols, such as methanol, ethanol, n-propanol, n-butanol, amyl alcohol, n-hexyl alcohol, n-heptanol or n-octanol; secondary alcohols such as isopropanol, Isobutanol, isoamyl alcohol and 3-pentanol; and tertiary alcohols such as tert-butanol, tert-amyl alcohol, 2,3-dimethyl-2-butanol, 2-(trifluoromethyl)-2-propanol, 3-methyl-3-pentanol, 3-ethyl-3-pentanol, 2-methyl-2-pentanol, 2,3-dimethyl-3-pentanol, 2,4-dimethyl-2-pentanol, 2-methyl-2-hexanol, 2-cyclopropyl-2-propanol, 2-cyclopropyl-2-butanol, 2-cyclopropyl-3-methyl-2-butanol, 1-methylcyclopentanol, 1-ethylcyclopentane, 1-propylcyclohexane, 1-methylcyclohexanol, 1-ethylcyclohexane and 1-methylcycloheptane.

5. The method according to claim 1, wherein the alcohol of formula 1 selected from the group consisting of tert-butanol, tert-amyl alcohol, 2,3-dimethyl-2-butanol and 2-(trifluoromethyl)-2-propanol.

6. The method according to claim 1, in which the [18F]fluoride is [18F]fluoride or cesium [18F]fluoride of tetraalkylammonium, and the alcohol is selected from the group consisting the th of tert-butanol, tert-amyl alcohol, 2,3-dimethyl-2-butanol and 2-(trifluoromethyl)-2-propanol.

7. The method according to claim 1, in which the [18F]fluoride is preferably selected from the group consisting of [18F]fluoride of alkali metals including alkali metals selected from the group consisting of lithium, sodium, potassium, rubidium and cesium; and [18F]fluoride of alkaline-earth metals, including alkali-earth metals selected from the group consisting of magnesium, calcium, strontium and barium; and [18F]ammonium fluoride.

8. The method according to claim 7, in which [18F]the ammonium fluoride is preferably selected from the group consisting of [18F]fluoride, Quaternary ammonium compounds, including [18F]tetrabutylammonium fluoride and [18F]fluoride designed; [18F]fluoride tertiary ammonium, including [18F]fluoride of triethylamine and [18F]fluoride of tributylamine; [18F]fluoride secondary ammonium, including [18F]fluoride of dibutylamine and [18F]fluoride of vexillaria; and [18F]fluoride primary ammonium, including [18F]fluoride of butylamine and [18F]fluoride of hexylamine.

9. The method according to claim 1, in which the [18F]fluoride is [18F]fluoride or cesium [18F]fluoride of tetraalkylammonium.

10. The method according to claim 9, in which [18F]fluoride or cesium [18F]of tetraalkylammonium fluoride adsorbed on the substrate, using the data from the group consisting of celite, molecular sieves, alumina and silica gel.

11. The method according to claim 1, in which the number of [18F]fluoride is a trace amount of [18F]fluoride to the corresponding halide or sulfonate.

12. The method according to claim 11, in which use 1 pkg - 100 ng of [18F]fluoride at 1 mg of the corresponding halide or sulfonate.

13. The method according to claim 1, in which the [18F]organofluorine compound is [18F]Tordesillas formula 2.
Formula 2

14. The method according to claim 1, in which the [18F]organofluorine compound is [18F]fermionization formula 3.
Formula 3

15. The method according to claim 1, in which the [18F]organofluorine compound is [18F]forestration formula 4.
Formula 4

16. The method according to claim 1, in which the [18F]organofluorine compound is [18F]ferroelasticity formula 5.
Formula 5

17. The method according to claim 1, in which the [18F]organofluorine compound is [18F]DDNP formula 6.
Formula 6

18. The method according to claim 1, in which the [18F]organofluorine compound is [18F]fertility formula 7.
Formula 7

19. The method according to claim 1, in which the [18F]organofluorine compound is [18F]verhalen formula 8.
Formula 8

20. The method according to claim 1, in which the [18F]organofluorine compound is [18F]foretelling formula 9.
Formula 9

21. The method according to claim 1, in which the [18F]organofluorine compound is [18F]forproperty formula 10.
Formula 10



 

Same patents:

FIELD: technological processes.

SUBSTANCE: invention is related to automation of technological processes and may be used in automation of process of production of loose form of powdery choline chloride from its aqueous solution. In method that provides for use of crushed and fractionated dry sugar beet pulp as active adsorbent, its mixing with previously heated aqueous solution of choline chloride, and then drying in vibration dryer by superheated steam of atmospheric pressure, separation of spent superheated steam flow into the main one, sent to vibration dryer with creation of recirculation circuit, and additional one sent for reheating of choline chloride prior to its supply for mixing, the novelty is the fact that superheating of atmospheric pressure steam is done with heating steam, at that heating steam is produced by means of steam generator with electric heating elements, feed pump and safety valve, heating steam condensate produced in this process after superheating and condensate produced during heating of aqueous solution of choline chloride is taken to condensate collector, and then in mode of closed circuit is supplied in steam generator, at that flow rate of crushed and fractionated dry pulp is measured, as well as aqueous solution of choline chloride coming for mixing, flow rate and temperature of superheated steam upstream vibration dryer, choline chloride temperature before and after its heating, pressure of choline chloride after heating, temperature and humidity of mixture of crushed and fractionated dry pulp and aqueous solution of choline chloride prior to supply for drying, amplitude and frequency of oscillations in gas-distributing grid of vibration dryer, flow rate and humidity of powdery choline chloride after drying, level of condensate in steam generator and pressure of heating steam, at that flow arte of dry sugar beet pulp after fractionation is used to set flow rate of heated choline chloride coming for mixing, and flow rate and humidity of prepared mixture of crushed and fractionated dry pulp and aqueous solution of choline chloride prior to supply for drying, flow rate and humidity of powdery choline chloride after drying are used to determine amount of evaporated moisture in vibration dryer, which is used to establish flow rate of superheated steam in the main circuit of recirculation, and its temperature is established by current value of temperature of mixture of crushed and fractionated dry pulp and aqueous solution of choline chloride by setting of specified capacity of steam generator affecting power of electric heating elements, at that in case condensate level in steam generator falls below specified value, condensate is supplied from condensate collector, and when pressure of steam in steam generator reaches upper limit value, steam pressure is released through safety valve, if flow rate of mixture of crushed and fractionated dry pulp and aqueous solution of choline chloride deviates prior to supply for drying to the side of increase from specified value, at first frequency is increased, and then amplitude of oscillations in gas-distributing grid of vibration dryer, if flow rate of mixture of crushed and fractionated dry pulp and aqueous solution of choline chloride deviates to the side of reduction from specified value, at first frequency is reduced, and then amplitude of oscillations in gas-distributing grid of vibration dryer, current values of temperature and flow rate of choline chloride prior to heating are used to set flow rate of spent superheated steam in additional recirculation circuit, at that temperature of choline chloride after heating is used to set specified pressure of choline chloride at the inlet to mixer.

EFFECT: provides for increased quality of finished product, accuracy and reliability of control, increased yield of finished product, reduced specific heat and power inputs and prime cost of finished product.

1 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns novel compounds of formula I: , where M is macrolide subunit of substructure II: , L is chain of substructure III: -X1-(CH2)m-Q-(CH2)n-X2-, D is steroid or non-steroid subunit derived from steroid or non-steroid NSAID medicines (nonsteroid anti-inflammatory drug) with anti-inflammatory effect; pharmaceutically acceptable salts and solvates of claimed compounds; methods and intermediary compounds for obtainment of claimed compounds.

EFFECT: improved therapeutic effect, application in inflammatory disease and state treatment for humans and animals.

37 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel fusidic acid derivatives of general formula [I], where X represents halogen, trifluoromethyl, C1-C7alkyl, substituted with phenyl, C2-C9alkenyl, optionally substituted with C1-C7alkyl, halogen or phenyl, phenyl, optionally substituted with one or two similar or different substituents, selected from group consisting of halogen, C1-C7alkyl, C2-C9alkenyl, phenyl, C1-C6alkoxy, nitro, C1-C6alkyltio, trifluoromethyl and cyano; or X represents naphtyl; Y and Z both represent hydrogen or together with bond C-17/C-20 form double bond between C-17 and C-20 or together represent methylene and form cyclopropane ring in combination with C-17 and C-20; A represents O, S or S(O); B represents C1-6alkyl, C2-6alkenyl, C1-6acyl, phenyl or benzoyl, where C1-6alkyl is optionally substituted with one or more halogens, hydroxy, C2-6alkenyl, phenyl, C1-4heteroaryl or C1-6alkoxy; Q1 represents -(CHOH)-, or -(CHW)-, where W represents halogen or azido; Q2 represents -(CHOH)-; to their pharmaceutically acceptable salts and easily hydrolysed esters and to pharmaceutical compositions, including said derivatives, as well as to their application in therapy.

EFFECT: application in therapy.

31 cl, 127 ex, 5 tbl

FIELD: veterinary.

SUBSTANCE: claimed is method, which allows to separate from pregnant horse urine by hard-phase extraction mixture of conjugated estrogens, depleted of phenol urine components and non-conjugated lipophilic compounds from group including non-conjugated flavonoids, non-conjugated isoflavonoides, non-conjugated norisoprenoids, non-conjugated steroids, first of all, androstane and preganane steroids, and comparable with them non-conjugates compounds.

EFFECT: improved method of obtaining extract, containing natural mixture of conjugated horse estrogens.

16 cl, 3 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns improved methods of obtaining eplerenone pharmaceutical compound: (9α,11α-epoxy-17β-hydroxypregn-4-en-3-one-7α,21-dicarbonic acid, γ-lactone, methyl ether) involving new intermediary products. Methods are implemented by Δ4,6-3-ketosteroid or its ketal transformation into respective Δ4-3-ketosteroid-7α-carbonic acid through a number of stages including oxidation, methylation, epoxydation stages.

EFFECT: reduced process stage number, high yield of product.

11 cl, 38 ex, 15 dwg

FIELD: chemistry.

SUBSTANCE: polyaminosteroid branched derivatives of general formula I are described, where R1 is saturated or unsaturated C2-C10alkyl (conjugated or branched) or methyl, R2 is COOH or branched polyamine fragments, R3 is H, OR19, where R19 is H or C1-6acyl, R4 is H, R5 is H, CH3, R6 is H, CH3, R7=R8=R9=H, R10 is H, CH3, R11 is OH,-OSO3, - O-acyl, -(Z)n-(NR-Z)p-N(R)2, Z is linear hydrocarbon diradical, n=0, 1, p=1, R-H, C1-6alkyl, C1-6aminoalkyl, possibly substituted by C1-6alkyl, R12=R13=R15=H, R16 is H, OH, R17 is H, R18 is H, CH3, possible double bond. Compounds possess bactericidal activity and can be used for prevention of bacterial infections.

EFFECT: production of polyaminosteroid derivatives, possessing bactericidal activity which can be used for prevention of bacterial infections.

27 cl, 31 ex, 1 tbl, 2 dwg

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention refers to pharmacology and medicine and concerns ethonogestrel new esters of formula 1 , 2 , 3 , applied for male and female contraception. Compositions are characterised by improved disposition profile.

EFFECT: production of composition with improved disposition profile.

3 cl, 2 dwg, 1 ex

FIELD: organic chemistry, natural compounds, medicine.

SUBSTANCE: invention describes a glycoside derivative of 4-methylergost-7-ene-3-ol of the formula (I): , method for its preparing and composition for correction of hyperglycemia. The composition represents extract from plant of Liliaceae family, preferably, from Aloe vera. Also, invention describes a medicinal agent used for correction of hyperglycemia, foodstuffs and beverages.

EFFECT: valuable medicinal and nutrient properties of derivative and composition.

14 cl, 2 tbl, 4 dwg, 8 ex

FIELD: pharmaceutical technology, pharmacy, steroids.

SUBSTANCE: invention describes a method for preparing steroid crystals showing the mean coarseness in desired limits from 1 to 25 mcm and without exceeding the required value. Method for preparing involves wetted grinding a steroid supersaturated solution in the crystallization process by using a device for carrying out this process resulting to preparing suspension of primary grains followed by its heating. Also, the claim describes crystals prepared by the proposed method and pharmaceutical composition containing these crystals based on steroid crystals.

EFFECT: improved preparing method.

12 cl, 7 tbl, 2 dwg, 11 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to improved method for production of 4,17(20)-E-pregnadiene-3,16-dione (E-guggulsterone) of formula III and 4,17(20)-Z-pregnadiene-3,16-dione (Z-guggulsterone) of formula IV including oxidation of compound of formula II , wherein C-OH or =O; ----- is optional double bond with pyridinium chlorochromate, pyridinium dichromate etc to produce 4,17(20)-E-pregnadiene-3,16-dione of formula III followed by conversion thereof by photochemical, thermochemical reaction or reaction in presence of acidic catalyst. Compounds of formulae III and IV effectively decrease increased low density lipoprotein levels and high cholesterol levels.

EFFECT: improved method for production of 4,17(20)-Z-pregnadiene-3,16-dione.

8 cl, 46 ex, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of 1-α-halogen-2,2-difluoro-2-deoxy-D-ribofuranose of the general formula (I) in solid state, where R1 is benzoyl or ; R2 is hydrogen; and X is CI, Br or I; which can be applied as intermediates in stereoselective method of gemcitabine obtainment. In addition, invention claims stereoselective method of obtaining compounds of the general formula (I), including stages of: (i) recovery of 1-oxoribose of formula to obtain lactol of formula ; (ii) interaction of compound of formula (III) with halogen phosphate compound of formula in the presence of a base to obtain 1-phosphatefuranose derivative of formula ; and (iii) interaction of compound of formula (V) (also included in the claim) with halogen source, with further recrystallisation of obtained product; where R1, R2 and X are the same as indicated above while R3 is phenyl.

EFFECT: efficient method of obtaining derivatives of the abovementioned agent.

11 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: in method of obtaining compound aminoalkyl glucosaminide 4-phosphate of formula , X represents , Y represents -O- or NH-; R1, R2 and R3, each is independently selected from hydrogen and saturated and unsaturated (C2-C24) aliphatic acyl groups; R8 represents -H or -PO3R11R11a, where R11a and R11a, each is independently -H or (C1-C4) aliphatic groups; R9 represents -H, -CH3 or -PO3R13aR14, where R13a and R14, each is independently selected from -H and (C1-C4) aliphatic groups, and where indices n, m, p, q each independently is a integer from 0 to 6 and r is independently integer from 2 to 10; R4 and R5 are independently selected from H and methyl; R6 and R7 are independently selected from H, OH, (C1-C4) oxyaliphatic groups -PO3H2, -OPO3H2, -SO3H, -OSO3H, -NR15R16, -SR15, -CN, -NO2, -CHO, -CO2R15, -CONR15R16, -PO3R15R16, -OPO3R15R16, -SO3R15 and -OSO3R15, where R15 and R16, each is independently selected from H and (C1-C4) aliphatic groups, where aliphatic groups are optionally substituted with aryl; and Z represents -O- or -S-; on condition that one of R8 and R9 represents phosphorus-containing group, but R8 and R9 cannot be simultaneously phosphorus-containing group, including: (a) selective 6-O- silylation of derivative of 2-amino-2-desoxy-β-D-glucopyranose of formula , where X represents O or S; and PG independently represent protecting group, which forms ester, ether or carbonate with oxygen atom of hydroxy group or which forms amide or carbamate with amino group nitrogen atom, respectively; by means of tri-substituted chlorosilane RaRbRcSi-Cl, where Ra, Rb and Rc are independently selected from group, consisting of C1-C6alkyl C3-C6cycloalkyl and optionally substituted phenyl, in presence of tertiary amin, which gives 6-silylated derivative; (b) selective acylation of 4-OH position of obtained 6-O-silylated derivative with 6-3-alkanoyloxyalcanoic acid or hydroxyl-protected (R)-3-hydroxyalkanoic acid presence of a carbodiimide reagent and catalytic 4-dimethylaminopyridine or 4-pyrrolidinopyridine to give a 4-O-acylated derivative; (c) selectively deprotecting the nitrogen protecting groups, sequentially or simultaneously and N,N-diacylating the resulting diamine with (R)-3-alkanoyloxyalkanoic acid or a hydroxy-protected (R)-3-hydroxyalkanoic acid in presence of peptide condensation reagent; (d) introducing a protecting phosphate group at 3-position with a chlorophosphate or phosphoramidite reagent to give a phosphotriester; and (e) simultaneous or sequential deprotecting phosphate, silyl, and remaining protecting groups.

EFFECT: method improvement.

11 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention concerns a variant of admixture extraction from composition containing extraneous matter and sucralose, which is used as a sweetener. One of the variants includes following stages: (a) first solvent extraction of the said composition containing sucralose and admixtures in the first solvent with the help of another solvent, at least partially immiscible, in order to remove admixtures to the said second solvent; (b) second solvent extraction of the said composition containing sucralose and admixtures in the first solvent with the help of the third solvent, at least partially immiscible, in order to transfer sucralose to the said third solvent; where stage (a) removes at least a part of admixtures to the second solvent; and stage (b) transports most of sucralose to the third solvent and detains most of admixtures in the first solvent.

EFFECT: efficient removal of admixtures from compositions.

34 cl, 4 tbl, 2 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: developed method of sucralose production using acyl-sucralose implies (a) adjustment of pH factor of specified supplied mixture to value ranged from 8.0 to 12.0 by alkali metal hydroxide addition; (b) buffer addition to specified base mixture in amount enough for specified pH factor stabilization within stated range over holding stage (c); (c) holding of specified base mixture at appropriate temperature over time period enough for effective transformation of specified acyl-sucralose compound into free sucralose; (d) reduction of specified pH factor of specified base mixture up to value from 4 to 8; (e) sucralose release from product of step (d) resulted thereby in released sucralose.

EFFECT: improved method of water deacylation procedure stabilization.

22 cl, 1 tbl, 1 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved solid-phase method for synthesis of radioisotope indicators, in particular, for synthesis of compounds labeled with 18F that can be used as radioactive indicators for positron- emission tomography (PET). In particular, invention relates to a method for synthesis of indicator labeled with 18F that involves treatment of a precursor fixed on resin if the formula (I): SOLID CARRIER-LINKER-X-INDICATOR wherein X means a group promoting to nucleophilic substitution by a definite center of a fixed INDICATOR with 18F- ion for preparing a labeled indicator of the formula (II): 18F-INDICATOR; to compound of the formula (Ib):

and compound of the formula (Ih): ;

to radiopharmaceutical set of reagents for preparing indicator labeled with 18F for using in PET; to a cartridge for radiopharmaceutical set of reagents for preparing indicator labeled with 18F for using in positron-emission tomography.

EFFECT: improved method of synthesis.

13 cl, 1 sch, 3 ex

FIELD: pharmaceutical technology.

SUBSTANCE: invention relates to the improved sucralose formulation and a method for its crystallization. Method involves controlling pH value of solution in the range from about 5.5 to about 8.5 in the process of formation of sucralose crystals. Invention provides the development of the improved composition comprising crystalline sucralose and possessing the enhanced stability.

EFFECT: improved preparing method, improved properties of composition.

24 cl, 4 tbl, 4 ex

The invention relates to medicine, more specifically to radiopharmaceuticals for diagnostic purposes, and may find application in positron emission tomography

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula (I), their obtaining and application as elastase inhibitors, and can be applied in medicine, where Y = CH; R№ represents H or alkyl; RІ represents phenyl or 5-6-memner heteroaryl, G1 represents phenyl; R5 represents H, halogen, alkyl, CN or fluorinated alkyl; n=1-3; R4 = H; L represents bond, O, NR29 or alkyl; or R4 and L are bound together in such way that group -NR4L- represents 5-7-member asacyclic ring; G2 represents phenyl, 5-6-member heteroaryl, cycloalkyl, C4-7-heterocycle, bicycle from two condensed, bound with direct bond or separated with O atom rings, selected from phenyl, 5-6-member heteroaryl, cycloalkyl or C4-7-heterocycle; or when L does not represent bond, G2 represents H; s = 0-2; R25 represents H, alkyl or cycloalkyl; R29 represents H or alkyl.

EFFECT: obtaining novel biologically active compounds.

10 cl, 95 ex, 1 tbl

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