Method of producing detomidine or non-toxic pharmaceutically acceptable salts thereof

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 4-(2,3-dimethylbenzyl)-1H-imidazole, also known as detomidine, having formula I: , which involves alkylation of trimethylsilyl imidazole with a compound of formula II: , where X: CI, Br, OH, in the presence of titanium tetrachloride in the medium of a chlorine-containing organic solvent, where molar ratio of titanium tetrachloride to N-trimethylsilyl imidazole must be maximum but must not be more than 0.95.

EFFECT: novel method of producing detomidine, characterised by high output of the end product.

1 cl, 3 ex

 

The invention relates to an improved process for the preparation of 4-(2,3-dimethylbenzyl)-1H-imidazole, also known as detomidine and corresponding to the formula I

Detomidine belongs to the group of α2-presynaptic agonists and is the current top of veterinary drug Dormosedan used to sedately and/or analgesia for diagnostic or therapeutic manipulations in horses and dogs.

In US patent No. 4443466, publ. 15.02.1983 described several ways to obtain benzylamine of imidazoles, including detomidine. According to one of them chloromethylthiazole subjected to reaction with an appropriate derivative of benzene in an organic solvent with addition of a base, such as sodium carbonate. Another method is the hydrolysis of inorganic acid N-acyl derivative of benzylimidazole in the aquatic environment. You can also get detomidine reaction of formamide with the corresponding oxazolines connection. Also described method, consisting in the reaction of the imidazole-4-carbaldehyde with 2,3-phenylmagnesium, to obtain the corresponding hydroxy, which in the second stage to restore detomidine hydrogen in the presence of a hydrogenation catalyst such as platinum oxide, palladium on coal or Raney Nickel. The output of detomidine the specified patent is not specified.

In US patent No. 4584383 (publ. 22.04.1986) retrieves detomidine by the reaction of 1-benzylimidazole-5-carboxaldehyde with a Grignard reagent followed by reduction of the obtained compound. The output of detomidine in US patent No. 4584383 in the calculation of the original aldehyde is 60%.

In CN 101747280 And (publ. 23.06.2010) 1H-imidazole-4-informed subjected to the reaction with the Grignard reagent derived from 1-bromo-2,3-xylene with receipt-4-(2,3-dimethylbenzyl)imidazole, which restores and receive high output detomidine.

The disadvantages of the known methods is the use of the Grignard reagent, which has a high activity and consequently difficult using known methods in the industry, or low yield of the target compound.

The objective of the invention is to develop a new method of synthesis of detomidine distinguished by its simplicity and high yield of the target compound.

The solution of this problem is achieved by the claimed method of obtaining detomidine interaction of N-trimethylsilylimidazole with the compound of the formula II

where X Is Cl, Br, IT,

in the presence of titanium tetrachloride at room temperature in the environment of chlorine-containing organic solvents such as chloroform, methylene chloride, 1,1-dichlorethylene. When this mole is E. the ratio of titanium tetrachloride to N-trimethylsilylimidazole should be the maximum, but not to exceed 0,95.

When the molar ratio of titanium tetrachloride to N-trimethylsilylimidazole equal to 1.0 and above, there is a sharp decrease in the output of detomidine;

the increase in molar ratio of N-trimethylsilylimidazole to the compound of formula II from 1.5 to 5.0 increases the output of detomidine;

as the organic solvent can usually be used methylene chloride, chloroform, 1,1-dichlorethylene. The ratio solvent/reagent has no significant impact on the yield of the target substance;

the process temperature in the range of 0-40°C has no significant impact on the yield of the target substance.

When processing the obtained detomidine non-toxic pharmaceutically acceptable acid, such as hydrochloric acid, Hydrobromic acid, oxalic acid, can be obtained from the corresponding non-toxic pharmaceutically acceptable salt.

The experimental part.

The described method is illustrated by the following examples.

Example 1.

4-(2,3-Dimethylbenzyl)-1H-imidazol

To a solution of 56,0 g (0.40 mol) of N-trimethylsilylimidazole in 150 ml of chloroform at room temperature under stirring for 30 minutes, add a solution to 68.4 g (0.36 mol) of titanium tetrachloride in 100 ml of chloroform. Stirred the reaction mixture for 30 minutes, then add dropwise a solution of 15.5 g (0.10 mol) of 2,3-dimethylbenz is inflorida in 50 ml of chloroform. The reaction mixture is stirred for 3 hours and poured into 300 ml of ice water.

The aqueous layer was separated, alkalinized to pH>8, is treated with ethyl ether (3×100 ml), the ether layer separated.

The solvent from the chloroform solution is removed in vacuo, to the residue is added 200 ml of 10% sodium hydroxide solution, the resulting mixture is treated with ethyl ether (3×100 ml), the ether layer separated.

The combined ether extract is treated with 10% solution of acetic acid (3×50 ml), the aqueous layer was separated and alkalinized to pH>8, the released detomidine extracted with methylene chloride (3×50 ml), the organic layer dried over Na2SO4and remove the solvent. Gain of 15.3 g (82% 2,3-dimethylbenzylidene) 4-(2,3-dimethylbenzyl)-lH-imidazole in the form of a light yellow crystalline substance.

NMR H1(CDCl3): δ 2,19 (s, 3H, C6H5-CH3), is 2.30 (s, 3H, C6H5-CH3), of 3.97 (s, 2H, CH2), is 6.61 (s, 1H, Im, C-5), 7,06 (m, 3Harom), 7,47 (s, 1H, Im, C-2), of 10.50 (br s, 1H, NH); TPL153-158°C (hydrochloride).

Example 2

4-(2,3-Dimethylbenzyl)-1H-imidazol

Synthesis and secretion similar to example 1.

Instead of 2,3-dimethylbenzylamine used to 19.9 g (0.10 mol) of 2,3-dimethylbenzylamine. Yield 15.0 g of 4-(2,3-dimethylbenzyl)-1H-imidazole (detomidine) (80% 2,3-dimethylbenzylamine).

Example 3

4-(2,3-Dimethylbenzyl)-1H-imidazol

C the MES and the selection is similar to example 1.

Instead of 2,3-dimethylbenzylamine use of 13.6 g (0.10 mol) of 2,3-dimethylbenzyl alcohol. Yield 15.9 g of 4-(2,3-dimethylbenzyl)-1H-imidazole (detomidine) (85% 2,3-dimethylbenzylamine alcohol).

As can be seen from the above examples, the proposed new method of obtaining detomidine is simple and suitable to obtain the target product with high yield.

1. The method of receiving detomidine formula I

interaction of N-trimethylsilylimidazole with the compound of the formula II

where X: Cl, Br, HE
in the presence of titanium tetrachloride at room temperature in the environment of chlorinated organic solvents, and the molar ratio of titanium tetrachloride to N-trimethylsilylimidazole should be the maximum, but not to exceed 0,95.

2. The method according to claim 1, characterized in that as chlorinated organic solvents used chloroform, methylene chloride and 1,1-dichloroethylene.

3. The method according to claim 1, characterized in that the molar ratio of trimethylsilylimidazole and the compounds of formula II ranges from 1.5 to 5.0.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to a method of producing 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, also known as medetomidine, having structural formula I: , which involves alkylation of N-trimethylsilyl imidazole with 2,3-trimethylbenzyl chloride in the presence of titanium tetrachloride in the medium of chlorine-containing organic solvents with molar ratio with 2,3-trimethylbenzyl chloride: trimethylsilyl imidazole:TiCl4 equal to 1.0:4.0-5.0:3.6-4.5.

EFFECT: improved method of producing medetomidine, characterised by high output of the end product.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel cyclic N,N'-diarylthioureas or N,N'-diarylureas of general formula (1), their optic (R)- and (S)-isomers and their pharmaceutically acceptable salts - antagonists of androgenic receptors. In formula (1), where: X represents oxygen or sulfur atom; m=0 or 1, mR1 represents C1-C3alkyl; R2 and R3 represent hydrogen atom; or R2 and R3 together with carbon atom, to which they are bound, form group C=O; or represents group NH; R4 and R5 represent hydrogen atom; or R4 represents hydrogen atom, and R5 represents methyl; or R4 represents hydrogen atom, methyl, and R5 represents group Zn-Y-R6, in which n=1 or 2, Z represents CH2 or C=0 and Y- oxygen atom or N-CH3, or Y represents C=O, and Z represents CH2; R6 represents hydrogen atom, methyl, benzyl, hydroxygroup or R5 and R4 together with atoms, to which they are bound, form five or sic-member heterocycle, including, at least, oxygen or nitrogen atom, which can be substituted by methyl. Invention also relates to method of obtaining compounds.

EFFECT: invention relates to anti-cancer substance, pharmaceutical composition, medication and method of treating prostate cancer with application of invention compounds.

12 cl, 6 dwg, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) in form of a separate stereoisomer, a mixture of stereoisomers or a racemic mixture of stereoisomers and their pharmaceutically acceptable salts. In formula (I) ring A, C or D is independently completely or partially saturated; each of C1, C4, C11, C12, C15 and C16 is independently substituted with two hydrogen atoms; each of C9 and C14 is independently substituted with a hydrogen atom; R1 represents -OR7 or -N(R7)2. Values of the rest of the radicals are given in the formula of invention. The invention also relates to a pharmaceutical composition with anti-inflammatory activity and contains an effective amount of the disclosed compound and to use of the said compounds to make a medicinal agent with anti-inflammatory activity.

EFFECT: disclosed compounds have anti-inflammatory activity.

23 cl, 47 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of formula (I): and to its salts with acid, where: R1 and R2 represent hydrogen; Q represents (CH2)m-X-(CH2)n-A; A represents direct bond, O, SO2, NR5; X represents direct bond, O, SO2, C(O) or NR5; Z represents group selected from : m and n represent, each independently, 0, 1, 2, 3 or 4; p represents 1, 2, 3 or 4; q represents 0, 1 or 2; dotted line means that R8 and/or R9 can be situated in any position of benzothiophene ring; R3 and R8 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11 or NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10; when Q-Z represents n 0, 1 or 2 and p represents 1, one of R3 and R8 represents hydroxy, nitro, NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CONR10R11, and the other represents hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11 OSO2NR10R11, NR12SO2NR10R11, CO2R10; R4 and R9 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CHO; when p represents 2, 3 or 4, R9 can be similar or different; R6 and R7 represent hydrogen; each R5, R10, R11 and R12 represents hydrogen; when Z represents and p represents 1, then R8 and R9 can also together with phenyl ring form benzoxathiazine dioxide. Invention also relates to pharmaceutical composition and to application of derivatives by any of ii.1-25.

EFFECT: obtaining novel biologically active compounds which possess inhibiting activity with respect to aromatase and/or steroid-sulfatase and/or carboanhydrase.

36 cl, 67 ex, 5 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of imidazole of the formula (I):

or its pharmaceutically acceptable salts wherein X represents -CH2-(CH2)p-, -O-; R1 represents phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl wherein indicated phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl are substituted optionally with 1-3 substitutes taken independently among halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group and OH-(C1-C6)-alkyl; R2 represents hydrogen atom (H) or (C1-C6)-alkyl; R3 represents H or (C1-C6)-alkyl; R4 represents H or (C1-C6)-alkyl; R5 represents H, or R5 and R7 form in common a bond; each R6 represents independently halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group or OH-(C1-C6)-alkyl; R7 represents H, or R7 and R5 form in common a bond; each R8 represents independently -OH, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl or (C1-C6)-alkoxy group; m = 0, 1, 2 or 3; n = 0 or 1; p = 0 or 1; r = 0 or 1; t = 0. Also, invention relates to a method for preparing compounds of the formula (I) and to a pharmaceutical composition showing affinity to alpha-2-adrenoceptors based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof used in aims for treatment of neurological disturbances, psychiatric disorders or disturbances in cognitive ability, diabetes mellitus, lipolytic diseases, orthostatic hypotension or sexual dysfunction.

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

25 cl, 1 tbl, 14 ex

The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to new amino acid derivatives and their pharmaceutically acceptable salts, specifically to new amino acid derivatives and their pharmaceutically acceptable salts, which have an inhibiting activity against renin, to methods for their preparation, to pharmaceutical compositions containing them and to a method for the treatment of hypertension and heart failure in humans or animals

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of imidazole of the formula (I):

or its pharmaceutically acceptable salts wherein X represents -CH2-(CH2)p-, -O-; R1 represents phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl wherein indicated phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl are substituted optionally with 1-3 substitutes taken independently among halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group and OH-(C1-C6)-alkyl; R2 represents hydrogen atom (H) or (C1-C6)-alkyl; R3 represents H or (C1-C6)-alkyl; R4 represents H or (C1-C6)-alkyl; R5 represents H, or R5 and R7 form in common a bond; each R6 represents independently halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group or OH-(C1-C6)-alkyl; R7 represents H, or R7 and R5 form in common a bond; each R8 represents independently -OH, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl or (C1-C6)-alkoxy group; m = 0, 1, 2 or 3; n = 0 or 1; p = 0 or 1; r = 0 or 1; t = 0. Also, invention relates to a method for preparing compounds of the formula (I) and to a pharmaceutical composition showing affinity to alpha-2-adrenoceptors based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof used in aims for treatment of neurological disturbances, psychiatric disorders or disturbances in cognitive ability, diabetes mellitus, lipolytic diseases, orthostatic hypotension or sexual dysfunction.

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

25 cl, 1 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of formula (I): and to its salts with acid, where: R1 and R2 represent hydrogen; Q represents (CH2)m-X-(CH2)n-A; A represents direct bond, O, SO2, NR5; X represents direct bond, O, SO2, C(O) or NR5; Z represents group selected from : m and n represent, each independently, 0, 1, 2, 3 or 4; p represents 1, 2, 3 or 4; q represents 0, 1 or 2; dotted line means that R8 and/or R9 can be situated in any position of benzothiophene ring; R3 and R8 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11 or NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10; when Q-Z represents n 0, 1 or 2 and p represents 1, one of R3 and R8 represents hydroxy, nitro, NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CONR10R11, and the other represents hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11 OSO2NR10R11, NR12SO2NR10R11, CO2R10; R4 and R9 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CHO; when p represents 2, 3 or 4, R9 can be similar or different; R6 and R7 represent hydrogen; each R5, R10, R11 and R12 represents hydrogen; when Z represents and p represents 1, then R8 and R9 can also together with phenyl ring form benzoxathiazine dioxide. Invention also relates to pharmaceutical composition and to application of derivatives by any of ii.1-25.

EFFECT: obtaining novel biologically active compounds which possess inhibiting activity with respect to aromatase and/or steroid-sulfatase and/or carboanhydrase.

36 cl, 67 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) in form of a separate stereoisomer, a mixture of stereoisomers or a racemic mixture of stereoisomers and their pharmaceutically acceptable salts. In formula (I) ring A, C or D is independently completely or partially saturated; each of C1, C4, C11, C12, C15 and C16 is independently substituted with two hydrogen atoms; each of C9 and C14 is independently substituted with a hydrogen atom; R1 represents -OR7 or -N(R7)2. Values of the rest of the radicals are given in the formula of invention. The invention also relates to a pharmaceutical composition with anti-inflammatory activity and contains an effective amount of the disclosed compound and to use of the said compounds to make a medicinal agent with anti-inflammatory activity.

EFFECT: disclosed compounds have anti-inflammatory activity.

23 cl, 47 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel cyclic N,N'-diarylthioureas or N,N'-diarylureas of general formula (1), their optic (R)- and (S)-isomers and their pharmaceutically acceptable salts - antagonists of androgenic receptors. In formula (1), where: X represents oxygen or sulfur atom; m=0 or 1, mR1 represents C1-C3alkyl; R2 and R3 represent hydrogen atom; or R2 and R3 together with carbon atom, to which they are bound, form group C=O; or represents group NH; R4 and R5 represent hydrogen atom; or R4 represents hydrogen atom, and R5 represents methyl; or R4 represents hydrogen atom, methyl, and R5 represents group Zn-Y-R6, in which n=1 or 2, Z represents CH2 or C=0 and Y- oxygen atom or N-CH3, or Y represents C=O, and Z represents CH2; R6 represents hydrogen atom, methyl, benzyl, hydroxygroup or R5 and R4 together with atoms, to which they are bound, form five or sic-member heterocycle, including, at least, oxygen or nitrogen atom, which can be substituted by methyl. Invention also relates to method of obtaining compounds.

EFFECT: invention relates to anti-cancer substance, pharmaceutical composition, medication and method of treating prostate cancer with application of invention compounds.

12 cl, 6 dwg, 16 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to a method of producing 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, also known as medetomidine, having structural formula I: , which involves alkylation of N-trimethylsilyl imidazole with 2,3-trimethylbenzyl chloride in the presence of titanium tetrachloride in the medium of chlorine-containing organic solvents with molar ratio with 2,3-trimethylbenzyl chloride: trimethylsilyl imidazole:TiCl4 equal to 1.0:4.0-5.0:3.6-4.5.

EFFECT: improved method of producing medetomidine, characterised by high output of the end product.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 4-(2,3-dimethylbenzyl)-1H-imidazole, also known as detomidine, having formula I: , which involves alkylation of trimethylsilyl imidazole with a compound of formula II: , where X: CI, Br, OH, in the presence of titanium tetrachloride in the medium of a chlorine-containing organic solvent, where molar ratio of titanium tetrachloride to N-trimethylsilyl imidazole must be maximum but must not be more than 0.95.

EFFECT: novel method of producing detomidine, characterised by high output of the end product.

1 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a method for preparing 2-methylimidazole involving mixing 40% aqueous glyoxal, acetaldehyde and aqueous ammonia, further recovering an end product by distillation, differing by the fact using 25% ammonia, mixing acetaldehyde and ammonia at temperature 0÷5°C; adding glyoxal preliminary purified from impurities by electrodialysis at temperature no more than 60°C; the agents taken in a ratio of ammonia : acetaldehyde : glyoxal = 2:1:1; the reaction conducted at temperature 90-95°C for 3 hours; besides, the end product recovered by vacuum distillation at residual pressure 0.5-1.5 kPa and vapour temperature 120-140°C preceded by water distillation.

EFFECT: what is developed is the new method for preparing 2-methylimidazole differing by high yield and end product quality, as well as simplified process of recovering and purifying.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to benzimidazole derivatives of general formula (I) and to their pharmaceutically acceptable salts, mixed stereoisomers and enantiomers, wherein R1 is L1C(O)OL2C(O)OT; R2 is unsubstituted C1-C10alkyl; L1 is a bond; L2 is unsubstituted C2-C10alkylene; T is C1-C10alkyl. Also, the invention refers to a pharmaceutical composition of the compound of formula (I) and a method of anaesthetising on the basis of using the compound of formula (I).

EFFECT: there are prepared new imidazole derivatives effective as an anaesthetising agent.

15 cl, 9 dwg, 15 ex

FIELD: pharmacology.

SUBSTANCE: compounds of the invention are intended for manufacture of a pharmaceutical composition, kit or drug. The invention also relates to a process for preparation of compounds of the invention (versions). Compounds of the invention are intended for use in the prevention or treatment of diseases caused by RNA-containing viruses belonging to enteroviruses, metapneumoviruses or pneumoviruses.

EFFECT: amide compounds for treatment or prevention of diseases caused by RNA-containing viruses.

26 cl, 8 tbl, 5 ex

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