Method of producing 5-(4-methyl-1h-imidazol-1-yl)-3-(trifluoromethyl) benzamine (versions)

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzamine , involving reaction of 4-methyl-1H-imidazole or salt thereof with a compound of formula , where X denotes a halogen and Y denotes NH2, in the presence of a suitable base or corresponding transition metal as a catalyst or combination thereof in a suitable solvent. The invention also relates to other versions of the method of producing a compound of formula (I) and intermediate compounds used.

EFFECT: new versions of the method of producing 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzamine (I), which is an intermediate compound in synthesis of biologically active compounds.

9 cl, 14 ex

 

Background of invention

The present invention offers an effective, safe and commercially available way to obtain 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzamine having the formula (I):

which is an intermediate compound for obtaining substituted pyrimidinediamine formula (II):

The compounds of formula (II) described in the publication W.Breitenstein et al. WO 04/005281 A1, which is included in the text of this application by reference. It was found that these compounds inhibit one or more of tyrosinekinase, such as c-Abl, Bcr-Abl, the receptor tyrosinekinase PDGF-R, Flt3, VEGF-R, EGF-R and c-Kit. Consequently, the compounds of formula (II) can be used for the treatment of certain neoplastic diseases such as leukemia.

Previously known method of obtaining compound (I) is chetyrehstoronny synthesis, starting with the reaction of aromatic substitution compound (III) compound (IV), which requires the use of high temperature (150°C) (scheme 1).

Scheme 1

In addition, the conversion of compound (VI) to the compound (VII) with rearrangement of kurzius is carried out using unsafe reagent such as diphenylphosphoryl. The result of this reaction the outputs andáquality product features are not permanent, and remove diphenylphosphinic acid formed as a by-product, causes difficulties. The resulting carbamate (VII) requires chromatographic purification, which is costly and time-consuming procedure.

The present invention is the provision of an effective and alternative methods for obtaining the compounds of formula (I) with high output.

The next object of the present invention is to obtain the compounds of formula (I) from a cheaper source of chemicals and reagents.

Another object of the present invention is a method for obtaining compounds of formula (I) using less hazardous reagents.

Next goal - reduction cycles of heating and cooling, leading to a decrease in decomposition and a more pure running reactions, is achieved through the use of microwave irradiation, or additional heat exchange capacity heating the reaction vessels of the devices, or through the use of the reaction equipment for continuous reaction.

The present invention overcomes the problems of the reaction represented above in figure 1.

The present invention also includes an intermediate compound (XVIII) and its receipt.

Summary of the invention

the present invention provides new synthetic methods for obtaining 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzamine, having the formula (I):

The compound of formula (I) is an intermediate compound for obtaining substituted pyrimidinediamine formula (II):

The compounds of formula (II) described in the publication W.Breitenstein et al. WO 04/005281, which was published January 15, 2004 and is incorporated into this description by reference. The preferred compound of formula (II) is 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide. The compounds of formula (II) can be used for the treatment of certain neoplastic diseases such as leukemia.

More preferably, the present invention provides a General method of obtaining the compound (I)represented by the following diagram:

Scheme 2

where

X denotes halogen, sulfonate or NO2; and

Y represents NH2, NO2, halogen or CN.

The General reaction scheme involves the reaction of compounds (A) with compound (III) in the appropriate reaction conditions to obtain compound (B). When Y represents NH2then (B) denotes a compound of formula (I). When Y denotes NO2or CN, or X and Y are both halogen, required an additional stage of the process, as shown below.

Detailed description izobreteny the

The General reaction scheme according to the invention can be illustrated by the following embodiments of the invention.

The first variant is represented in reaction scheme 3.

Scheme 3

where Y connection And indicates NO2:

X may denote halogen, sulfonate or NO2.

When X denotes Br, stage And involves the use of a transition metal as a catalyst and base (medium to strong), and stage B involves the reaction of recovery using a transition metal as a catalyst in a suitable polar solvent.

When X represents hydrogen, reaction of modify in accordance with scheme 4:

Scheme 4

This process includes:

(i) treatment with 1-nitro-3-triptoreline (X) brainwashin agent, preferably 1,3-dibromo-5,5-dimethylhydantoin (1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione), in the presence of a strong acid, preferably concentrated sulfuric acid, in an inert solvent, preferably dichloromethane, at a temperature in the range from 25 to 40°C., preferably at a temperature of 35°C, to obtain 1-bromo-3-nitro-5-triptoreline (XI) as the main product,

(ii) the interaction of 1-bromo-3-nitro-5-triptoreline (XI) and 4-methyl-1H-imidazo is and in the presence of a transition metal as a catalyst such as compounds of copper, palladium or Nickel, preferably copper(I) salts, and bases (from moderately strong to medium), preferably carbonate, alkanoate or bicarbonate salt, and optional coordinating additives such as 1,2-diamine, preferably Ethylenediamine, in a dipolar aprotic solvent, preferably N,N-dimethylformamide or 1-methyl-2-pyrrolidinone, at elevated temperature, preferably at a temperature of from 100 to 120°C., to obtain 4-methyl-1-(3-nitro-5-triptoreline)-1H-imidazole (IX) as the main product,

(iii) recovery 4-methyl-1-(3-nitro-5-triptoreline)-1H-imidazole (IX), preferably using hydrogen in the presence of a transition metal as a catalyst, in a polar solvent, preferably methanol or ethanol, preferably at elevated temperature, to obtain 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzamine (I). The parent compound 1-nitro-3-triptoreline (X) and 4-methyl-1H-imidazol commercially available.

When X represents iodine in the diagram above, 3, stage And involves the use of a transition metal as a catalyst and medium to strong bases, and stage B includes a step of recovery using a transition metal as a catalyst in the corresponding polar process is the, as shown in the following scheme 5:

Scheme 5

The compound (I) can be produced from 1-iodine-3-nitro-5-triptoreline (XII)using the methods of steps (ii) and (iii)described above. Getting 1-iodine-3-nitro-5-triptoreline (XII) described in J Med Chem, vol.44, p.4641 (2001).

When X represents F in the diagram above, 3, stage And includes the use from the strong to the middle base in the solvent at elevated temperature in the range from 70 to 130°C. and phase B includes a step of recovery using a transition metal as a catalyst in an appropriate polar solvent, as follows:

Scheme 6

This process includes:

(i) a reaction mixture of 1-fluoro-3-nitro-5-triptoreline (XIII) with 4-methyl-1H-imidazole in the presence of moderately strong to medium base, preferably a carbonate or bicarbonate salt in an appropriate solvent, preferably N,N-dimethylformamide, N,N-dimethylacetamide or 1-methyl-2-pyrrolidinone, at a temperature in the range from 70 to 130°C., preferably at 75-100°C., to obtain 4-methyl-1-(3-nitro-5-triptoreline)-1H-imidazole (IX) as the main product; and

(ii) recovery 4-methyl-1-(3-nitro-5-triptoreline)-1H-imidazole (IX), preferably using odorata in the presence of a transition metal as a catalyst, in an appropriate polar solvent, preferably methanol or ethanol, preferably at elevated temperature to obtain 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzamine (I). This option may also be a reaction of condensation.

In addition, each of the methods described above may not necessarily include the conversion of compound (IX) in the salt of the formula (XV), for example, for cleaning, as illustrated in the following diagram:

Scheme 7

According to this scheme, the solution of the compound (IX) is treated with acid or acid solution in water or an organic solvent, followed by separation of salt (XV), for example, by filtration. The compound (IX) is then obtained from the processing of salt (XV) a base, preferably aqueous sodium hydroxide solution, and the release of free bases (IX) by extraction or crystallization.

For the first variant base (from strong to medium) is preferably a carbonate, alkanet or hydrogen; more preferably a potassium alkoxide, sodium alkoxide, lithium alkoxide, potassium hydride, sodium hydride or the carbonates of lithium, sodium, potassium or cesium.

The second option scheme 2 is when Y represents NH2. When the first sub-option X denotes halogen. When X denotes Br, the reaction of anywayse scheme 8:

Scheme 8

This reaction involves reacting 3-bromo-5-triptoreline (XVI) with 4-methyl-1H-imidazole in the presence of a transition metal as a catalyst such as copper, palladium or Nickel, preferably copper(I) salt, and from strong to medium base, preferably carbonate, alkanoate or bicarbonate salt, and optional coordinating additives such as, preferably, cyclohexanediamine, in a dipolar aprotic solvent, preferably diglyme, N,N-dimethylformamide or 1-methyl-2-pyrrolidinone, at elevated temperature, preferably in the interval from 100 to 150°C., to obtain 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzamine (I) as the main product.

When X represents F, an alternative synthesis of compounds (XIX) and (I) provides for the use of inexpensive starting compound 2-bromo-5-fermentatively (XVII). In addition, the compound of formula (I) can be synthesized according to the following scheme:

Scheme 9

Nitration of commercially readily available 2-bromo-5-fermentatively (XVII) potassium nitrate and sulfuric acid leads to a new connection, 2-bromo-5-fluoro-1-nitro-3-triptoreline (XVIII). The reduction of compound (XVIII) by hydrogenation catalyst palladium/wholiday 3-fluoro-5-triptorelin [compound (XIX)], which reacts with the sodium salt of 4-methylimidazole in obtaining compound (I). The crude compound (I) includes the desired product as a primary product and at least one isomer provisions (regioisomer) as a by-product. The crude product (I) can be recrystallized from toluene to obtain pure compound (I) with >and 99.8%purity (by area) according to HPLC.

It should be noted that 3-fluoro-5-triptorelin (XIX) are also commercially available in small quantities, for example, by ABCR. Synthetic path described in this application represents a new way of obtaining compound (XIX) from the new universal compound (XVIII). 3-Fluoro-5-triptorelin (XIX)obtained by this method were identical to the commercial sample, purchased from the firm ABCR (ABCRF 01075).

New connection (XVIII)described in this text is the universal connection and can be used for synthesis of a number of interesting tripterocalyx compounds, which are intermediate compounds for obtaining substituted pyrimidinediamine (II)that, as installed, have antilysozyme properties (see WO 04/005281).

The third option scheme 2 is when X denotes F, and Y represents CN. Reaction (cleavage by Hoffman) presented on either privedennoi scheme 10:

Scheme 10

In the fourth scheme version 2 as X and Y are both halogen. This reaction is represented in the following diagram:

Scheme 11

According to this method, 3-bromo-5-fluoro-benzotrifluoride (XXV) is injected into the reaction with 4-methylimidazole (III) at a temperature of 25°C in the presence of a strong base such as sodium hydride, obtaining in this way the crude compound (XXVI) [containing 16% regioisomer]. The crude compound (XXVI) can be recrystallized from heptane and turned into pure premarin (XXVI) no program number of regioisomer. Arylamidine compounds (XXVI) diphenylamine (XXVII) in the presence of a palladium catalyst, a phosphine ligand and a base such as a combination of Pd(SLA)2/Xanthos/tert-piperonyl sodium or Pd(OAc)2/BINAP/tert-piperonyl sodium leads to the compound (XXVIII). The content of residual palladium compound (XXVIII) can be increased to 3.4 ppm after treatment for PICA coal. Hydrolysis of compound (XXVIII) with an aqueous solution of hydrochloric acid gives compound (I) in the form of its hydrochloride. This salt can be converted to free base [compound (I)] by treatment with potassium bicarbonate with obtaining thus a pure compound (I) high quality: purity according to HPLC is >99%; soda is a palladium content of 0.5 ppm The method according to the present invention is safer, practical and commercially acceptable, compared to the previously used synthetic method (scheme 1). Other palladium catalyst used in the above reaction include tetrakis(triphenyl)phosphine palladium(0); Tris(dibenzylideneacetone)dipalladium(0) or palladium chloride, and other catalysts known to specialists in this field of technology. Other ligands used in the above reaction include triphenylphosphine or trialkylphosphine.

The following examples serve only to illustrate the present invention in no way limiting its scope.

Examples

Example 1: Synthesis of 1-[3-bromo-5-(trifluoromethyl)phenyl]-4-methyl-1H-imidazole (XXVI)

Scheme 12

In a two-liter, 4-necked, round-bottom flask equipped with a mechanical stirrer, digital thermometer, heating/cooling capacity, addition funnel and a device for input/output of nitrogen, was placed 1-methyl-2-pyrrolidinone (113 g) and sodium hydride (8.0 g, 60%in oil) under nitrogen atmosphere. The mixture is stirred at 20-25°C for 15 minutes a Solution of 4-methylimidazole (17.6 g) and 1-methyl-2-pyrrolidinone (181 g) slowly bring the mixture for 30 min, maintaining the bath temperature in the range from 20 to 25°C. After addition the mixture plumage is eshivot at a temperature of from 20 to 25°C for 2 hours Then to the reaction mixture slowly add a solution of 3-bromo-5-fermentatively (XXV) (40 g) and 1-methyl-2-pyrrolidinone (76 g) for 10 min, maintaining the bath temperature in the range from 20 to 25°C. the mixture is Then stirred at a temperature of from 20 to 25°C for 16 hours

Water (720 g) is added slowly to the mixture over 3 hours, maintaining the bath temperature in the range from 20-25°C. After the addition the mixture is stirred at 20-25°C for 1 h, the Solid is allocate by filtration, washed with a solution of 1-methyl-2-pyrrolidinone (41 g), and then washed with water (100 g). The solid is dried in air over within 1 hour

In a two-liter, 4-necked, round bottom flask in an atmosphere of nitrogen loads resulting solid substance (about 50 g) and ethyl acetate (361 g). The mixture is stirred for 5 min at 20-25°C until dissolution. The solution was washed with water (twice 100 g). The organic layer distil at 100 mm Hg at 40°C up until the residual volume will not be 100 ml. Then add heptane (342 g) and the mixture distil at 400 mm Hg at 60°C up until the residual volume is the amount of 300 ml of This operation is repeated several times. The residue is cooled from 55°C to 20°C for 5 h and additionally stirred for 1 h at 20°C. the mixture is Then cooled to 5°C for 1 h and optionally peremeshivayte for 1 h at 5°C. Solid allocate by filtration and washed with cold (5°C) heptane (68 g), then dried under 5 mm Hg/20-25°C for 4 h, obtaining the compound (XXVI) (24.3 g, 48% yield) as white solids:

1H NMR (300 MHz, DMSO-d6): δ to 8.45 (s, 1H), 8.30 to (s, 1H), 8,10 (s, 1H), of 7.90 (s, 1H), of 7.70 (s, 1H), 2,10 (s, 3H).

Example 2: 5-(4-Methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzamid (I)

Scheme 13

In a 1-liter, 4-necked, round-bottom flask equipped with a mechanical stirrer, digital thermometer, heating/cooling capacity, refrigerator, drip funnel and a device for input/output of the nitrogen load toluene (400 ml) under nitrogen atmosphere. Toluene is heated to a temperature of 113°C., stirred at this temperature for an additional 1 h, and then cooled to a temperature of 20-25°C. In a separate 1-liter, 4-necked, round-bottom flask equipped with a mechanical stirrer, digital thermometer, heating/cooling capacity, refrigerator, drip funnel and a device for input/output of the nitrogen load connection (XXVI) (40 g) and degassed as described above, toluene (240 ml). The suspension is stirred at 20-25°C for 5 min, thus obtaining a clear solution. Make a mixture of tert-piperonyl, sodium (17.6 g), and then a mixture of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.5 g), palladium(II) acetate (0.3 g) and money is sarounova toluene (120 ml). Then add a solution benzophenone (XXVII) (26,4 g) and degassed toluene (40 ml). The mixture is heated to a temperature of from 97 to 103°C. and stirred at this temperature additionally for 3 h, and then cooled to 60°C. Add water (200 ml), maintaining a temperature in the range from 20 to 40°C. Then the organic layer separated.

Suspension PICA P1400 activated carbon (8 g) in toluene (80 ml) contribute to the organic layer. The resulting suspension is heated to a temperature of 80-85°C. and stirred additionally for 5 hours the Mixture is cooled to 20-25°C. and stirred at this temperature for 1 h the mixture is Then filtered through a Hyflo filter Super Celite (4 g) and washed with toluene (160 ml). The same operations that are conducted in the previous method, repeat several times. The organic solution was concentrated in vacuo until the volume average of 200 ml. To this residue is added acetone (600 ml) and heat the mixture to a temperature of 35±3°C. Then add concentrated (37%) hydrochloric acid (14.2 g), maintaining a temperature below 40°C. the Mixture is stirred at a temperature of 35-40°C for 2 h, cooled to 20-25°C and additionally stirred for 1 h, the Solid is separated by filtration, washed with acetone (40 ml) and dried at 60°C/5 mm Hg for 8 hours, getting hydrochloric alaeddine (I) (31,2 g) as a white solid. The solid is dissolved in methanol (312 ml) at 40°C. Then add a solution of potassium bicarbonate (15.7 g) in water (936 ml) for 2 h, maintaining a bath temperature at 30°C. then the mixture is cooled to 20°C. and optionally stirred at a temperature of 20°C for 1 h, the Solid is separated by filtration, washed with water (80 g) and dried at a temperature of 60-75°C/5 mm Hg for 16 h, obtaining the compound (I) (23,5 g, yield 74%) as white solids:

1H NMR (300 MHz, DMSO-d6): δ with 8.05 (s, 1H), 7,40 (s, 1H), 7,00 (s, 1H), 6,95 (s, 1H), 6,85 (s, 1H), 5,90 (s, 2H), of 2.15 (s, 3H).

Example 3: Obtain 2-bromo-5-fluoro-1-nitro-3-cryptomelane, the compound of formula (XVIII)

2-Bromo-5-fermentatively (XVII) (50 g, obtained from the company ABCR, F01421) is dissolved in 750 ml of dichloromethane. With stirring, add the potassium nitrate (they accounted for 60,54 g), and then slowly add sulfuric acid (587,3 g of 20% SO3, Riedel de Haen 30736). The temperature of the reaction medium during the addition of sulfuric acid support at 25-30°C by gentle cooling. The reaction mixture is then additionally stirred for 25 h at room temperature, then according to IPS conversion is >97%. Next, the layers are separated and the acid layer is extracted with dichloromethane under stirring (twice 300 ml). Dichloromethane phases are combined and on sledovatelno washed with 1000 ml of a saturated aqueous solution of NaHCO 3, 1000 ml of an aqueous solution of sulfamic acid (5 wt.%), 1000 ml of a saturated aqueous solution of NaHCO3and 1000 ml of water. The dichloromethane solution is dried over anhydrous MgSO4and the solvent is removed in vacuum, obtaining 2-bromo-5-fluoro-1-nitro-3-triptoreline (XVIII) as a yellow liquid. GC-MS: m/z: 287, 268, 257, 241, 229. These MS peaks are accompanied by corresponding isotope peaks characteristic of bromodomain compounds. IR (thin layer): 3101, 1618, 1591, 1554, 1454, 1423,1365, 1319, 1232, 1186,1153, 1113, 883 cm-1.

1H-NMR (400 MHz, DMSO-d6): δ 8,13 (dd, J=8.5 and J=2.5 Hz), 8,42 (dd, J=7.6 and J=3.0 Hz).

Example 4: 3-Fluoro-5-triptorelin, the compound of formula (XIX)

2-Bromo-5-fluoro-1-nitro-3-triptoreline (XVIII) (55,5 g) dissolved in 500 ml of ethanol. Add a solution of triethylamine (quintiles these figures were 19.63 g) and palladium on coal (6 g Pd/C 10%, Engelhard 4505) and the mixture hydronaut at 20-25°C. After 20 hours from the start of the reaction, the absorption of hydrogen ceases. The supply of hydrogen is stopped and the solution is separated from the catalyst by filtration on Cellflock. The filter cake containing the catalyst, washed with ethanol (twice 100 ml). The filtrate and washing fractions are combined and the resulting solution concentrated at a temperature of 45°C under reduced pressure to a final volume of about 400 ml After adding toluene (400 ml) forming the HSIA solution concentrated to a final volume of about 250 ml, getting the suspension. The precipitate was separated by filtration and washed his toluene (twice 100 ml). The solution is again concentrated to a final volume of 200 ml and the precipitate again separated by filtration. The filter cake is washed with toluene (three times 50 ml). The process of dilution with toluene, concentrated and filtered again up until in toluene solution is not found no significant traces of sediment. Finally, the solvent is evaporated at a temperature of 45-50°C and reduced pressure, and the residue is dried in vacuum at 45°C receives 3-fluoro-5-triptorelin in the form of a yellow oil. GC-MS: m/z: 179, 160, 151, 140, 132. The product is identified (according to GC and HPLC) sample of 3-amino-5-fluoro-benzotrifluoride obtained from the company ABCR (ABCR F01075). The NMR spectrum is also identical to the sample obtained from the company ABCR.

Example 5: 3-(4-Mei-1-yl)-5-triptorelin (I)

Sodium hydride (12,18 g, 55-65 wt.%, Fluka 71620) suspended in tetrahydrofuran (60 ml) and a solution of 4-methylimidazole (24.5 g) in tetrahydrofuran (65 ml) is added slowly to the stirred suspension at a temperature of 20-25°C. in Order to maintain the temperature at 20-25°C during the addition, it is necessary to use a mild cooling. After addition, the reaction mixture is stirred for additional 15 min at 20-25°C until the closing is utitsa gas. A solution of 3-fluoro-5-triptoreline (XIX) (25 g) in 1-methyl-2-pyrrolidone (125 ml) slowly bring in the reaction mixture, and optionally continue stirring for 15 min at 20-25°C. Then the reaction mixture is heated on an oil bath at a temperature of 100°C. to remove volatile solvent (tetrahydrofuran). Finally, the temperature was raised to 165°C. (oil bath) and the reaction mixture is stirred for 22 h at this temperature. After that the reaction mixture is transferred into water (500 ml) and the aqueous phase is extracted with tert-butylmethylamine ether (twice 500 ml). The ether phases are combined and extracted with water (twice 500 ml). The organic layer is dried over anhydrous magnesium sulfate (19 g) and the solvent is evaporated at a temperature of 45°C and reduced pressure to give crude 3-(4-methyl-imidazol-1-yl)-5-triptorelin in the form of a yellowish solid. The crude product containing at least 1 regioisomer, dissolved in toluene (93,4 g) at a temperature of 80-90°C and the solution is left to cool spontaneously to room temperature. This is followed by crystallization of the product at a temperature of about 35-40°C. Then the suspension is stirred additionally for 2 hours at room temperature and the product produce by filtration. The filter cake was washed with ice toluene (25 ml) and dried vacuume at a temperature of 50°C, getting pure 5-(4-Mei-1-yl)-3-triptorelin (I). GC-MS: m/z 241, 222, 213, 200, 186, 172, 160.

1H-NMR (400 MHz, DMSO-d6): δ 2,15 (3H), of 5.85 (2H), 6,79 (1H), 6,91 (1H), 6,95 (1H), 7,34 (1H), 8,04 (1H).

In particular, as described above, the substituent (bromine) can be selectively removed with 3-fluoro-5-nitrobenzotrifluoride (XIII). Synthesis of compound (I) from compound (XIII) shown above in scheme 6.

Scheme 15

Example 6: 5-(4-Mei-1-yl)-3-cryptomathematical (XXII)

A solution of 4-methyl-1H-imidazole (1.98 g, 24,11 mmole) in N-methylpyrrolidinone (N-MP) (18 ml) was added to a solution of sodium hydride (about 0.82 g, 60%, of 20.5 mmole) in N-MP (18 ml) at 20-25°C in nitrogen atmosphere. The mixture is stirred for 1 h before adding a solution of 3-fluoro-5-triftormetilfosfinov (XXI) (3.2 g, a 16.4 mmole) in N-MP (8 ml). The reaction mixture was stirred for 2 h at 20-25°C, then add water (120 ml) at 20-minute intervals and the resulting suspension is stirred for 16 hours

The precipitate is filtered off, washed with water (20 ml), dissolved in ethyl acetate (70 ml) and the organic layer washed with water (50 ml). The aqueous phase is extracted with ethyl acetate (twice 40 ml) and the combined organic layers evaporated in vacuo to a volume of a mixture of 50 ml After adding heptane (68 ml) is Krista is the zation of the product. The suspension is cooled to 0°C and stirred for 2 h before being filtered. The filter cake was washed with cold heptane (twice 15 ml) and dried in vacuum, obtaining 3.1 g named the title compound (yield 75,3%) as white crystals (purity of the product is 73,7% according to HPLC).

Example 7: 3-(4-Mei-1-yl)-5-cryptomelane (XXIII)

A solution of 5-(4-Mei-1-yl)-3-triftormetilfosfinov (3.5 g, 13,93 mmole) in N-MP (28 ml) is treated with an aqueous ammonia solution (9.8 ml, 25%) and aqueous hydrogen peroxide (3.5 ml, 30%). The resulting mixture is stirred for 1 h at 20-25°C, and then transferred to a chilled water (420 ml). The resulting suspension is filtered, the filter cake washed with water (50 ml) and dried in vacuum at 50°C, obtaining 3.2 g named the title compound (XXIII) (yield of 85.4%) as white crystals (purity 98% according to HPLC).

Example 8: 5-(4-methyl-1H-imidazol-1-yl)-3-triptorelin (I)

A solution of 3-(4-Mei-1-yl)-5-cryptomelane (XXIII) (1 g, 3,71 mmole) in tert-butanol (10 ml) and water (3.8 ml) is treated with aqueous solutions of sodium hypochlorite (3,7 ml, 9%) and sodium hydroxide (1.5 ml, 30%). The reaction mixture was stirred for 16 h at 60°C, then add the Hydrosulphite solution is the atrium (2 ml, 10%). The organic phase is separated and treated with toluene (5 ml) and water (2.5 ml), and then add 2-molar aqueous solution of Hcl (5 ml). The resulting suspension is stirred for 1.5 h, cooled to 0°C and filtered. The filter residue is washed with toluene (3 ml) and dried in vacuum, obtaining 0.39 g of the hydrochloride named the title compound (yield 43,2%) as orange crystals (purity of 99.7% according to HPLC). For the separation of aniline product is treated with an aqueous solution of potassium bicarbonate (2.2 ml, 5%) in ethanol (1 ml) at 45°C for 0.5 hours, the Reaction mixture was then cooled to 0°C for 1 h and stirred for 2 hours the Product produce by filtration, washed with ethanol (twice 0.75 ml) and dried in vacuum at 50°C receives 0.27 g named the title compound (I) (exit 32,8%) in the form of almost white crystals (purity >99.9% of according to HPLC).

Example 9: 5-(4-Methyl-1H-imidazol-1-yl)-3-triptorelin (I)

In odnogolosy flask equipped with fridge, added CuI (89,5 mg of 0.47 mmole), cyclohexadienyl (107,3 mg of 0.94 mmole) and diglyme (10 ml). The mixture is stirred for 10 min at room temperature. To a heterogeneous mixture of purple color add 3-bromo-5-triptorelin (XVI) (1.13 g, 4.7 mmole), 4-methyl-1H-imidazole (0,77 g, 9.4 mmole) and Cs2CO3(1,53 g ,7 mmole). The mixture is heated at a temperature of 150°C and additionally stirred for 24 h Then the mixture is cooled to 25°C and purified by column chromatography (silica gel; EtOAc/MeOH in a ratio of 95:5)to give compound (I) as the main product (yield 840 mg).

Example 10: Obtain 4-methyl-1-(3-nitro-5-triptoreline)-1H-imidazole (IX) (obtained through the catalytic condensation)

To a stirred suspension of 1-bromo-3-nitro-5-triptoreline (of 4.05 g, 15 mmole), 4-methyl-1H-imidazole (2,01 g, 24 mmole, 98%) and potassium carbonate (of 3.73 g, 27 mmole) in N,N-dimethylformamide (10 ml) add diethylamine (0,141 ml, 2.1 mmole) and copper iodide(I) (0,204 g, 1.05 mmole). The mixture with vigorous stirring and heated to a temperature of 110°C for 23 hours After that, a large part of 1-bromo-3-nitro-5-cryptomelane time to react, and the suspension is left to cool spontaneously to room temperature. The mixture is then diluted with tert-butylmethylamine ether (30 ml) and add 5%aqueous NaCl solution (30 ml) and isopropylacetate (15 ml). The aqueous layer was separated and extracted with tert-butylmethylamine ether (10 ml) and isopropylacetate (5 ml). The organic layers are combined and filtered. The filtrate is washed with water (10 ml), treated for 5 min with Ethylenediamine (0,303 ml), washed with water (10 ml), 5%aqueous solution of metabase is theta sodium (10 ml) and water (10 ml), then treated with charcoal (1.2 g) at room temperature for 1 h Then the suspension is filtered using accelerator filtration and the filtrate is evaporated without dried under reduced pressure, obtaining a transparent, reddish-brown oil which becomes solid upon standing at room temperature. The obtained solid is purified by column chromatography on silica gel, elwira mixture (in the ratio 4:5) ethyl acetate and hexane (in the presence of 0.5% vol. of triethylamine) to give as the main matter 4-methyl-1-(3-nitro-5-triptoreline)-1H-imidazole as a pale yellow solid. Output: 21,1% (purity according to HPLC: 96,7%). TPL: 118-119°C.

Example 11: 3-(4-Mei-1-yl)-5-triptorelin (I)

In the autoclave process before hydrogenation suspension of 5%palladium on charcoal (0.6 g) in 94%aqueous ethanol (200 ml). Then add 4-methyl-1-(3-nitro-5-triptoreline)-1H-imidazole (6.0 g, 22,1 mmole) and the mixture hydronaut at a temperature of 70°C and a pressure of 4 bar for 3 hours During this time much of the original substance has time to react. The suspension is filtered using accelerator filtering. The filtrate is slowly transferred into water (250 ml) at a temperature of 0-5°C. the Resulting mixture koncentriruyutsa weight 270 g stirred, cooled to 0°C and again stirred for about 3 hours the Formed solid is filtered, washed with water (20 ml) and dried at 50°C and reduced pressure, obtaining 3-(4-Mei-1-yl)-5-triptorelin as an almost white solid. Output: 85,8% (purity according to HPLC 94%), TPL 123-124°C.

Example 12: Salt of 4-methyl-1-(3-nitro-5-triptoreline)-1H-imidazole with methanesulfonic acid (XXIX)

Crude 4-methyl-1-(3-nitro-5-triptoreline)-1H-imidazole (IX) (1.85 g, 6 mmole, purity 88% by HPLC) was dissolved in ethyl acetate (6 ml) at a temperature of about 50°C. To the resulting black solution while mixing, slowly add methansulfonate acid (0,397 ml, 6 mmole) at a temperature of about 50°C. At the end of the add starts falling shiny solids. The mixture is left to cool spontaneously to room temperature and continue stirring at a temperature of about 5°C for 75 minutes the Formed solid is filtered off, washed with ethyl acetate (4 ml) and dried at room temperature and reduced pressure. A suspension of the resulting substance is stirred in 2-propanol (5 ml) at 50°C for 90 minutes, leave to cool spontaneously to room temperature, and then stirred the air for 1 h and further at a temperature of 0-5°C. for another 1 h The formed solid is filtered off, washed with cold 2-propanol (5 ml) and dried at room temperature and reduced pressure, obtaining salt methanesulfonic acid and 4-methyl-1-(3-nitro-5-triptoreline)-1H-imidazole in the form of a beige solid. Output: 54,1% (purity by HPLC: 99.5%pure), TPL 208-213°C.

Example 13: Obtain 4-methyl-1-(3-nitro-5-triptoreline)-1H-imidazole (IX) (via aromatic substitution)

4-Mei (10.5 g, output reached 125.5 mmole) and potassium carbonate (12.0 g, 119,6 mmole) is suspended in N,N-dimethylformamide (80 ml) and stirred at 100°C for 1 h, then add a solution of 1-fluoro-3-nitro-5-triptoreline (12.5 g, 59,8 mmole) in N,N-dimethylformamide (20 ml) for 10 min. the Mixture was stirred at the temperature of the reaction mixture 108°C for 3 hours HPLC analysis confirms full membership in the reaction of the starting compound. The mixture is cooled to a temperature of approximately 20°C. and add water (200 ml) for 1 h the Resulting suspension is filtered, receiving of 17.5 g of wet solid (HPLC: 88.8% of the desired isomer, 8.9% of the undesired isomer/by-product).

A suspension of the resulting product in water (100 ml) is stirred for 1 h at room temperature. The solid is filtered off, washed with water (100 ml) and dried p and a temperature of 50°C and reduced pressure, receiving the crude product by HPLC analysis, which consists of 90% of the desired product. The recrystallization is carried out by treatment of a solution of the above crude product (9.5 g) in ethyl acetate (50 ml) for 2 h at 70°With activated charcoal (1 g) and the accelerator filtering (1 g), and then filtered, and the filtrate is evaporated without dried, obtaining 11.1 g of residue which is dissolved in ethyl acetate (3.25 g) and heptane (50 ml) at reflux. In the solution contribute seed 4-methyl-1-(3-nitro-5-triptoreline)-1H-imidazole at a temperature of 65°C and left to cool spontaneously to room temperature overnight, and then stirred at 0°C for 3 hours the Formed solid is filtered off, washed with heptane (20 ml) and dried at 50°C under reduced pressure, obtaining 4-methyl-1-(3-nitro-5-triptoreline)-1H-imidazole in the form of solids. Total output is 53,3% (purity by HPLC to 98.2%), TPL 117-118°C.

Example 14: 1-Bromo-3-nitro-5-triptoreline (XI)

To a solution of 1-nitro-3-triptoreline (41,1 ml, 300 mmol, 97%received from the firm Aldrich) in dichloromethane (240 ml) was added 98%sulfuric acid (45,7 ml, 840 mmole) for 10 minutes With vigorous stirring biphasic mixture is heated to a temperature of 35°C and six equal portions in osat 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (53,1 g, 180 mmole) for 5 hours the Mixture is additionally stirred at 35°C for 19 hours After that more than 97% of the original substance reacts according to the HPLC analysis. The reaction mixture is left to cool spontaneously to room temperature and then for 20 min with stirring 2-molar aqueous NaOH solution (210 ml) under cooling in a water bath to 0-5°C. the Internal temperature rises temporarily to 35°C. Then separate the two layers and the aqueous layer was extracted with hexane (three times 200 ml). The combined organic layers washed with water (200 ml), 5%aqueous solution of sodium metabisulfite (twice 200 ml), 8%aqueous solution of NaHCO3(200 ml) and 10%aqueous NaCl (200 ml). After that, the solvent is evaporated under reduced pressure and a temperature of 45°C. the Remaining liquid is distilled at a pressure of 0.71 mbar and a bath temperature of 70-80°C receives 1-bromo-3-nitro-5-cryptomaterial in the form of a pale yellow liquid. Output: 89,6% (purity1H-NMR 95%).

1H-NMR (400 MHz, CDCl3): 8,11 ppm (m, 1H), 8,45 ppm (m, 1H), 8,58-8,59 ppm (m, 1H). T Kip. 68°C at 0.71 mbar.

1. The way to obtain 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzamine (I), namely, that 4-methyl-1H-imidazole or its salt is introduced into reaction with the compound of the formula

where X denotes halogen and
Y represents NH2,
in the presence of a suitable base or the corresponding transition metal as a catalyst, or combinations thereof, in an appropriate solvent.

2. The way to obtain 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzamine (I), which consists in carrying out the following stages:
a) nitration of 2-bromo-5-fermentatively potassium nitrate and sulfuric acid to obtain 2-bromo-5-fluoro-1-nitro-3-triptoreline (XVIII);
b) 2-bromo-5-fluoro-1-nitro-3-cryptomelane by hydrogenation catalyst palladium/charcoal with 3-fluoro-5-triptoreline and
(C) interaction of 3-fluoro-5-triptoreline with the sodium salt of 4-methylimidazole in obtaining compound (I).

3. The compound of the formula
.

4. The way to obtain 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzamine (I), consisting in the implementation of the following reactions:

using sodium hydride in N-methylpyrrolidinone (N-MP) in the first reaction stage and
with the use of aqueous ammonia and aqueous hydrogen peroxide in N-methylpyrrolidinone (N-MP) in the second reaction stage.

5. The way to obtain 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzamine (I), which consists in carrying out the following stages:
a) reaction of 3-bromo-5-is corbettreport with 4-methylimidazole in the presence of a strong base;
b) recrystallization from heptane crude compound obtained in stage (a);
C) arylamidine compounds obtained in stage (b), and diphenylamine in the presence of a palladium catalyst, a phosphine ligand and base;
d) hydrolysis of the product of stage (b) with an aqueous solution of hydrochloric acid to obtain 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzamine (I) in the form of its hydrochloric salt and
d) optional conversion of salts of 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzamine (I) in free base.

6. The method according to claim 5, where at the stage (C) a catalyst selected from Pd(OAc)2;
tetrakis(triphenyl)hasfinally(0);
Tris(dibenzylideneacetone)diplegia(0) or palladium chloride and where the ligands are selected from Xanthos, BINAP, triphenylphosphine and trialkylphosphines.

7. The way to obtain 1-bromo-3-nitro-5-cryptomelane involved in the processing of 1-nitro-3-cryptomelane brainwashin agent in the presence of a strong acid.

8. The method according to claim 7, in which the processing of 1-nitro-3-cryptomelane brainwashin agent selected from 1,3-dibromo-5,5-dimethylhydantoin (1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione), in the presence of a strong acid in an inert solvent at a temperature of from 25 to 40°C To produce 1-bromo-3-nitro-5-cryptomelane.

9. The compound 1-bromo-3-nitro-5-triptorelin the ol of the formula
.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a new improved method of producing onium tetrafluoroborates through reaction of an onium halide with trialkyloxonium tetrafluoroborate, trialkylsulphonium tetrafluoroborate or triphenylcarbonium tetrafluoroborate, characterised by that the halide has formula (1) [XR4]+ Hal-, where X denotes N, P, Hal denotes Cl, Br or I and R in each case independently denotes a linear alkyl having 1-8 C atoms, or the halide has formula (2) [(R1R2N)-C(=SR7)(NR3R4)]+ Hal- (2), where Hal denotes Br or I R1-R7 each independently denotes a linear alkyl having 1-8 C atoms, or the halide has formula (3) [C(NR1R2)(NR3R4)(NR5R6)]+ Hal- (3), where Hal denotes CI, Br or I and R1-R6 each independently denotes a linear alkyl having 1-8 C atoms, or the halide has formula (4) [HetN]+ Hal- , where Hal denotes CI, Br or I and HetN+ denotes a heterocyclic cation selected from a group comprising imidazolium pyrrolidinium pyridinium where each of substitutes R1' - R4' independently denotes hydrogen, CN, linear or branched alkyl having 1-8 C atoms, dialkylamine containing alkyl groups having 1-4 C atoms but which is not attached to he heteroatom of the heterocyclic ring.

EFFECT: method enables to obtain products with low content of halides with high purity and high output.

5 cl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is described a compound of formula I: or its pharmaceutically acceptable salt, where R2 represents (CR3R4)n-NR5R6 and m, p, q, Ar, R1, R3, R4, R5 and R6 are those as specified in the patent claim and defined as selective 5-NT6 and/or 5-NT2A antagonists. There is also described a pharmaceutical composition containing this compound, and application thereof in preparing drugs for treating diseased conditions of central nervous system chosen from psychoses, schizophrenia, manic depressions, neural disorders, memory impairment, attention deficient syndrome, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, malnutrition and Huntington's disease.

EFFECT: preparation of the compounds which can find application in treatment of a diseased condition of central nervous system.

27 cl, 1 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts and esters. The disclosed compounds have LXR-alpha and/or LXR-beta agonist properties. In formula (I) R1 is hydrogen, halogen; R2 is lower alkyl, flouro-lower alkyl; R3 is hydrogen, phenyl; R4 is hydrogen, hydroxy; R5 is hydrogen; phenyl; R6 is phenyl, a 5-6-member heteroaryl with one or two heteroatoms selected from nitrogen and sulphur, a 9-member bicyclic heteroaryl with a sulphur atom as a heteroatom, which can be optionally substituted with a halogen, or R6 is , R7 is a lower alkyl; R8 is phenyl which is optionally substituted with one substitute selected from a group consisting of halogen, fluoro-lower alkyl, R9-O-C(O)-, R10R11NC(O)-, phenyl-lower alkoxy; R9, R10, R11 independently represent hydrogen or lower alkyl; L is a single bond, lower alkylene or lower alkenylene; m assumes values from 0 to 3; n is equal to 0 or 1.

EFFECT: obtaining a new compound and a pharmaceutical composition which contains the disclosed compound as an active ingredient for therapeutic and/or preventive treatment of diseases.

23 cl, 47 ex

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

FIELD: chemistry.

SUBSTANCE: invention relates to new displaced heterocyclic derivatives that can be used in treatment of diabetes and to reduce the content of cholesterol. In formula m is 1; n is 1; Q is C; A is -(CH2)x2-0-(CH2)x3-, where x2 varies from 1 to 3 and x3 is 0; B is a bond or it is (CH2)x4, where x4 varies from 1 to 2; X represents CH or N; X2, X3, X4, X5, X6 represent C, N, O; provided that one from X2 X3 X4 X5 and X6 represents N; and at least one of X2, X3, X4, X5, and X6 represents C; R1 represents H or C1-C6alkyl; R2 is H; R2a, R2b and R2c can be equal or different and selected from H, C1-C6alkyl, C1-C6alkoxy, halogen or thyano; R3 is selected from phenyloxycarbonile, C1-C6alkyloxycarbonile, phenylcarbinol, phenyl, alkoxy; Y represents CO2R4 (where R4 represents H or C1-C6alkyl); (CH2)m can be not necessarily displaced by 1 substitute.

EFFECT: produced are pharmaceutical composition for treatment of diabetes and to reduce the content of cholesterol.

13 cl, 2 tbl, 22 dwg, 88 ex

FIELD: chemistry of organophosphorus compounds, chemical technology.

SUBSTANCE: invention describes a method for synthesis of monohydroperfluoroalkanes, bis-(perfluoroalkyl)phosphinates and perfluoroalkylphosphonates. Method involves treatment of at least one perfluoroalkylphosphorane with at least one base wherein base(s) are chosen from group consisting of alkali-earth metal hydroxides, metalloorganic compound in useful solvent or at least one organic base and an acid in useful reaction medium. Also, invention describes novel perfluoroalkylphosphonates and bis-(perfluoroalkyl)phosphinates, using novel perfluoroalkylphosphonates and bis-(perfluoroalyl)phosphinates as ionic liquids, catalysts of phase transfer or surfactants.

EFFECT: improved method of synthesis.

18 cl, 19 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to using phenylethenyl- or phenylethynyl-derivatives as antagonists of glutamates receptors. Invention describes using compound of the general formula (I):

wherein each among R1, R2, R3, R4 and R5 means independently of one another hydrogen atom, (C1-C6)-alkyl, -(CH2)n-halogen, (C1-C6)-alkoxy-group, -(CH2)n-NRR', -(CH2)n-N(R)-C(O)-C1-C6)-alkyl, phenyl or pyrrolyl that can be unsubstituted or substituted with one or more (C1-C6)-alkyl; each among R, R' and R'' means independently of one another hydrogen atom or (C1-C6)-alkyl; A means -CH=CH- or C≡C; B means ,, , , or wherein R6 means hydrogen atom, (C1-C)-alkyl, -(CH2)n-C(O)OR, or halogen atom; R7 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-C(O)OR', halogen atom, nitro-group or oxodiazolyl group that can be unsubstituted or substituted with (C1-C6)-alkyl or cycloalkyl; R8 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-OH, -(CH2)n-C(O)OR'' or phenyl; R9 means (C1-C6)-alkyl; R10 and R11 mean hydrogen atom; R12 means -(CH2)n-N(R)-C(O)-(C1-C6)-alkyl; R13 means hydrogen atom; each R14, R15, R16 and R17 independently of one another means hydrogen atom or (C1-C6)-alkoxy-group; each R18, R19 and R20 independently of one another means hydrogen atom; R21 means hydrogen atom or (C1-C6)-alkyl; R22 means hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkyl comprising one or more substitutes chosen from groups hydroxy- or halogen atom; R23 means hydrogen atom, (C1-C6)-alkanoyl or nitro-group; each among R24, R25 and R26 independently of one another means hydrogen atom or (C1-C6)-alkyl; n = 0, 1, 2, 3, 4, 5 or 6; X means -O- or -S-; Y means -CH= or -N=, and its pharmaceutically acceptable salts used in preparing medicinal agents designates for treatment or prophylaxis of disorders mediated by mGluR5-receptors. Also, invention describes compounds of the formula (I-A), compound of the formula (I-B-1) given in the invention description, and a medicinal agent used in treatment or prophylaxis of disorders mediated by mGluR5-receptors.

EFFECT: valuable medicinal properties of compounds.

44 cl, 1 tbl, 44 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of adamantine, in particular, to a new method for preparing adamant-1-yl-containing azoles of the general formula I-VIII: wherein R1 means ; R2 means ; R3 means ; R4 means ; R5 means ; R6 means ; R7 means , and R8 means . Indicated derivatives of adamantine are semifinished products used in synthesis of biologically active substances. Proposed method for preparing these compounds involves using a new method for synthesis of adamant-1-yl-containing azoles that includes the addition reaction of azoles: 2-methylimidazole, 3(5)-methylpyrazole and 4-methylpyrazole, 3,4-dinitropyrazole, 1,2,4-triazole, 3-methylpyrazole, 3-nitro-1,2,4-triazole and 5-methyltetrazole to 1,3-dehydroadamantane in the mole ratio of 1,3-dehydroadamantane to azole = 1:1 in diethyl ether medium at temperature 100°C for 4-5 h.

EFFECT: improved preparing method.

8 ex

The invention relates to imidazole derivative of General formula I, where n=0 or 1, R1is hydrogen, alkyl, R2is hydrogen or R2and R3form a double bond, R3is hydrogen, alkyl, R4is hydrogen, alkyl, hydroxy-group, alkoxy, R5is hydrogen or alkyl, or R4and R5form a carboxyl group, R6, R7, R8is hydrogen, alkyl, hydroxy-group, alkoxy, hydroxyalkyl, halogen, X-CHR9-(CHR10)m-, m = 0 or 1, R9and R10is hydrogen or alkyl

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of adamantine, in particular, to a new method for preparing adamant-1-yl-containing azoles of the general formula I-VIII: wherein R1 means ; R2 means ; R3 means ; R4 means ; R5 means ; R6 means ; R7 means , and R8 means . Indicated derivatives of adamantine are semifinished products used in synthesis of biologically active substances. Proposed method for preparing these compounds involves using a new method for synthesis of adamant-1-yl-containing azoles that includes the addition reaction of azoles: 2-methylimidazole, 3(5)-methylpyrazole and 4-methylpyrazole, 3,4-dinitropyrazole, 1,2,4-triazole, 3-methylpyrazole, 3-nitro-1,2,4-triazole and 5-methyltetrazole to 1,3-dehydroadamantane in the mole ratio of 1,3-dehydroadamantane to azole = 1:1 in diethyl ether medium at temperature 100°C for 4-5 h.

EFFECT: improved preparing method.

8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to using phenylethenyl- or phenylethynyl-derivatives as antagonists of glutamates receptors. Invention describes using compound of the general formula (I):

wherein each among R1, R2, R3, R4 and R5 means independently of one another hydrogen atom, (C1-C6)-alkyl, -(CH2)n-halogen, (C1-C6)-alkoxy-group, -(CH2)n-NRR', -(CH2)n-N(R)-C(O)-C1-C6)-alkyl, phenyl or pyrrolyl that can be unsubstituted or substituted with one or more (C1-C6)-alkyl; each among R, R' and R'' means independently of one another hydrogen atom or (C1-C6)-alkyl; A means -CH=CH- or C≡C; B means ,, , , or wherein R6 means hydrogen atom, (C1-C)-alkyl, -(CH2)n-C(O)OR, or halogen atom; R7 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-C(O)OR', halogen atom, nitro-group or oxodiazolyl group that can be unsubstituted or substituted with (C1-C6)-alkyl or cycloalkyl; R8 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-OH, -(CH2)n-C(O)OR'' or phenyl; R9 means (C1-C6)-alkyl; R10 and R11 mean hydrogen atom; R12 means -(CH2)n-N(R)-C(O)-(C1-C6)-alkyl; R13 means hydrogen atom; each R14, R15, R16 and R17 independently of one another means hydrogen atom or (C1-C6)-alkoxy-group; each R18, R19 and R20 independently of one another means hydrogen atom; R21 means hydrogen atom or (C1-C6)-alkyl; R22 means hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkyl comprising one or more substitutes chosen from groups hydroxy- or halogen atom; R23 means hydrogen atom, (C1-C6)-alkanoyl or nitro-group; each among R24, R25 and R26 independently of one another means hydrogen atom or (C1-C6)-alkyl; n = 0, 1, 2, 3, 4, 5 or 6; X means -O- or -S-; Y means -CH= or -N=, and its pharmaceutically acceptable salts used in preparing medicinal agents designates for treatment or prophylaxis of disorders mediated by mGluR5-receptors. Also, invention describes compounds of the formula (I-A), compound of the formula (I-B-1) given in the invention description, and a medicinal agent used in treatment or prophylaxis of disorders mediated by mGluR5-receptors.

EFFECT: valuable medicinal properties of compounds.

44 cl, 1 tbl, 44 ex

FIELD: chemistry of organophosphorus compounds, chemical technology.

SUBSTANCE: invention describes a method for synthesis of monohydroperfluoroalkanes, bis-(perfluoroalkyl)phosphinates and perfluoroalkylphosphonates. Method involves treatment of at least one perfluoroalkylphosphorane with at least one base wherein base(s) are chosen from group consisting of alkali-earth metal hydroxides, metalloorganic compound in useful solvent or at least one organic base and an acid in useful reaction medium. Also, invention describes novel perfluoroalkylphosphonates and bis-(perfluoroalkyl)phosphinates, using novel perfluoroalkylphosphonates and bis-(perfluoroalyl)phosphinates as ionic liquids, catalysts of phase transfer or surfactants.

EFFECT: improved method of synthesis.

18 cl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new displaced heterocyclic derivatives that can be used in treatment of diabetes and to reduce the content of cholesterol. In formula m is 1; n is 1; Q is C; A is -(CH2)x2-0-(CH2)x3-, where x2 varies from 1 to 3 and x3 is 0; B is a bond or it is (CH2)x4, where x4 varies from 1 to 2; X represents CH or N; X2, X3, X4, X5, X6 represent C, N, O; provided that one from X2 X3 X4 X5 and X6 represents N; and at least one of X2, X3, X4, X5, and X6 represents C; R1 represents H or C1-C6alkyl; R2 is H; R2a, R2b and R2c can be equal or different and selected from H, C1-C6alkyl, C1-C6alkoxy, halogen or thyano; R3 is selected from phenyloxycarbonile, C1-C6alkyloxycarbonile, phenylcarbinol, phenyl, alkoxy; Y represents CO2R4 (where R4 represents H or C1-C6alkyl); (CH2)m can be not necessarily displaced by 1 substitute.

EFFECT: produced are pharmaceutical composition for treatment of diabetes and to reduce the content of cholesterol.

13 cl, 2 tbl, 22 dwg, 88 ex

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

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts and esters. The disclosed compounds have LXR-alpha and/or LXR-beta agonist properties. In formula (I) R1 is hydrogen, halogen; R2 is lower alkyl, flouro-lower alkyl; R3 is hydrogen, phenyl; R4 is hydrogen, hydroxy; R5 is hydrogen; phenyl; R6 is phenyl, a 5-6-member heteroaryl with one or two heteroatoms selected from nitrogen and sulphur, a 9-member bicyclic heteroaryl with a sulphur atom as a heteroatom, which can be optionally substituted with a halogen, or R6 is , R7 is a lower alkyl; R8 is phenyl which is optionally substituted with one substitute selected from a group consisting of halogen, fluoro-lower alkyl, R9-O-C(O)-, R10R11NC(O)-, phenyl-lower alkoxy; R9, R10, R11 independently represent hydrogen or lower alkyl; L is a single bond, lower alkylene or lower alkenylene; m assumes values from 0 to 3; n is equal to 0 or 1.

EFFECT: obtaining a new compound and a pharmaceutical composition which contains the disclosed compound as an active ingredient for therapeutic and/or preventive treatment of diseases.

23 cl, 47 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is described a compound of formula I: or its pharmaceutically acceptable salt, where R2 represents (CR3R4)n-NR5R6 and m, p, q, Ar, R1, R3, R4, R5 and R6 are those as specified in the patent claim and defined as selective 5-NT6 and/or 5-NT2A antagonists. There is also described a pharmaceutical composition containing this compound, and application thereof in preparing drugs for treating diseased conditions of central nervous system chosen from psychoses, schizophrenia, manic depressions, neural disorders, memory impairment, attention deficient syndrome, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, malnutrition and Huntington's disease.

EFFECT: preparation of the compounds which can find application in treatment of a diseased condition of central nervous system.

27 cl, 1 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a new improved method of producing onium tetrafluoroborates through reaction of an onium halide with trialkyloxonium tetrafluoroborate, trialkylsulphonium tetrafluoroborate or triphenylcarbonium tetrafluoroborate, characterised by that the halide has formula (1) [XR4]+ Hal-, where X denotes N, P, Hal denotes Cl, Br or I and R in each case independently denotes a linear alkyl having 1-8 C atoms, or the halide has formula (2) [(R1R2N)-C(=SR7)(NR3R4)]+ Hal- (2), where Hal denotes Br or I R1-R7 each independently denotes a linear alkyl having 1-8 C atoms, or the halide has formula (3) [C(NR1R2)(NR3R4)(NR5R6)]+ Hal- (3), where Hal denotes CI, Br or I and R1-R6 each independently denotes a linear alkyl having 1-8 C atoms, or the halide has formula (4) [HetN]+ Hal- , where Hal denotes CI, Br or I and HetN+ denotes a heterocyclic cation selected from a group comprising imidazolium pyrrolidinium pyridinium where each of substitutes R1' - R4' independently denotes hydrogen, CN, linear or branched alkyl having 1-8 C atoms, dialkylamine containing alkyl groups having 1-4 C atoms but which is not attached to he heteroatom of the heterocyclic ring.

EFFECT: method enables to obtain products with low content of halides with high purity and high output.

5 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzamine , involving reaction of 4-methyl-1H-imidazole or salt thereof with a compound of formula , where X denotes a halogen and Y denotes NH2, in the presence of a suitable base or corresponding transition metal as a catalyst or combination thereof in a suitable solvent. The invention also relates to other versions of the method of producing a compound of formula (I) and intermediate compounds used.

EFFECT: new versions of the method of producing 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzamine (I), which is an intermediate compound in synthesis of biologically active compounds.

9 cl, 14 ex

FIELD: chemistry.

SUBSTANCE: present invention discloses a method of producing oligonucleotides, involving the following steps: a) providing a hydroxyl-containing compound of formula (A) wherein B is a heterocyclic base and i) R2 is H, a protected 2-hydroxyl group, F, protected amino group, O-alkyl group, O-substituted alkyl, substituted alkylamino or C4'-O2' methylene bridge; R3 is OR'3, NHR"3, NR"3R'"3, wherein R'3 is a group, protected hydroxyl, protected nucleotide of protected oligonucleotide, R"3, R'"3 are independently amine-protecting groups, and R5 is OH or ii) R2 is H, protected 2'-hydroxyl group, F, protected amino group, O-alkyl group, O-substituted alkyl, substituted alkylamino, C4'-O2' methylene bridge; R3 is OH, and R5 is OR5 and R'5 is a hydroxyl-protecting group, protected nucleotide or protected oligonucleotide or iii) R2 is OH, R3 is OR'3, NHR"3, NR"3R'"3, wherein R3 is a hydroxyl-protecting group, protected nucleotide or protected oligonucleotide, R"3, R'"3 are independently amine-protecting groups, and R5 is OR'5 and R'5 is a hydroxyl-protecting group, protected nucleotide or protected oligonucleotide; b) reaction of said compound with a phosphitylation agent in the presence of an activator of formula (I) (activator I), wherein R is alkyl, cycloalkyl, aryl, aralkyl, heteroalkyl, heteroaryl; R1, R2 is H or together form a 5-6-member ring; X1, X2 are independently N or CH; Y is H or Si(R4)3, where R4 is alkyl, cycloalkyl, aryl, aralkyl, heteroalkyl, heteroaryl; B is a deprotonated acid, to obtain a phosphitylated compound; c) reaction of said phosphitylated compound without separation thereof from a second compound of formula (A), wherein R5, R3, R2, B are independently selected but have the same values as given above, in the presence of an activator II other than I.

EFFECT: improved method.

9 cl, 14 ex, 1 dwg

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