The way to obtain 7-bromo-1,3-dihydro-5-/2-chlorophenyl/-2h-1,4 - benzodiazepin-2-it, the intermediate compound 5-bromo-2-/2 - chloracetamide/-2'-chlorobenzophenone

 

(57) Abstract:

We propose a new way to obtain 7-bromo-1,3-dihydro-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-it (I) with high yield and purity by the interaction of aminobenzophenone with monochloracetic acid chloride of the acid with subsequent treatment of the obtained 5-bromo-2'-chloro-(2-chloroacetamido)benzophenone (II), an iodide of an alkali metal to obtain 5-bromo-2-(2-iodoacetamide)-2'-chlorobenzophenone formula III. Compound III is treated with ammonia, and then cyclist obtained 2-(2-aminoacetyl)-5-bromo-2'-chlorobenzophenone. 2 S. p. f-crystals.

The present invention relates to the synthesis of biologically active compounds, namely the method of production of 7-bromo-1,3-dihydro-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-it formula V, which is the active ingredient of a pharmaceutical product "phenazepam" [Mashkovsky M. D. Medicines.- M.: Medicine, 1993, H. 1, S. 91].

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and to the new intermediate compound of formula II

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A method of obtaining (V), described in 2 [A. V. Bogatsky Century, Andronati S. A., Valeev Y. N. and other Chemical and pharmaceutical journal, No. 11, S. 85, 1977] and used for the industrial production of this compound, which is selected as prototypical with the formation of intermediate VI in the reaction mixture and its subsequent cyclization with obtaining compounds V.

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However, this method has some significant drawbacks. Primarily used as a source of reagent salt of the acid chloride glycine, which is a very unstable compound, and for this reason there is a need to prepare it directly during the process without analytical control, which leads to the formation along with the acid chloride glycine several side products, which subsequently contaminate the target product.

In addition, due to the high reactivity of the salt of the acid chloride glycine, a high percentage of passing adverse reactions, which further leads to the presence of a large number of impurities and, consequently, to a significant decrease in purity and product yield.

Next, obtained during the synthesis of the intermediate compound VI arrives on stage cyclization without isolation from the reaction mixture and purification, due to the instability of this product, which also leads to reduction of purity and volatility of the yield of the target product V.

To obtain a pure pharmaceutical grade product technical product obtained in the described manner, it is necessary to expose multiple paracrystals costs.

The aim of the present invention is to develop a simple and feasible method of obtaining V with high yield and purity, which is an important factor when using the product in the pharmaceutical industry.

The proposed method of synthesis involves the interaction of aminobenzophenone with monochloracetic acid chloride acid to obtain 5-bromo-2-(2-chloroacetamido)-2'-chlorobenzophenone formula II, treatment of compound II with iodide of an alkali metal to obtain 5-bromo-2-(2-iodoacetamide)-2'-chlorobenzophenone formula III, the treating compound III with ammonia to obtain 2-(2-aminoacetyl)-5-bromo-2'-chlorobenzophenone formula IV, which is then cyclist, obtaining the target compound V. the Process proceeds according to the following scheme:

< / BR>
The interaction of aminobenzophenone with monochloracetic acid chloride acid is conducted in the medium of anhydrous solvent, inert under the reaction conditions, when heated from 50oC to the boiling point of the solvent.

Treatment of compound (II) with the alkali metal iodide is carried out in a medium polar solvent at boiling point. Most preferred are sodium iodide and such solvents as acetonitrile, lower alcohols and chloride and cooling from 25 to -5oC. At this stage it is preferable to use solvents such as used in the second stage of the process. The preferred temperature of the reaction temperature is from 5 to -5oC.

The cyclization of compounds IV can be performed with or without solvent at a temperature below the melting temperature IV with continuous removal of water, or in high-boiling solvent with continuous removal of water. Mainly the cyclization reaction is carried out in high-boiling solvents, forming an azeotrope with water.

Proposed in the present invention method allows to obtain the target product with high yield and purity, because in this method, the intermediate stages are obtained stable compounds with high yield, which can be isolated and purified before subsequent stages, which greatly simplifies obtaining pure pharmaceutical grade product and can virtually eliminate (at the level of sensitivity of the instrument, HPLC) in the target product impurities that are present in the product obtained by the method used in the industry.

In addition, a product with a high purity allows much of product can be reduced to a single operation, which significantly increases process yield.

The intermediate product II obtained in the first stage of the proposed method is a new product and is the subject of the present invention.

The following is a specific example of the present invention.

Example. 1. Getting 5-bromo-2-(2-chloroacetamido)-2-'-chlorobenzophenone formula II.

To a solution of 1.0 mol of 2-amino-5-bromo-2'-chlorobenzophenone in 0.7 l of toluene at boiling point add 1.0 mol of monochloracetic acid chloride acid. The reaction mass was kept for 1 hour and cooled. The precipitated crystals are separated by filtration and receive specified in the title of the product II with the release of 97%. TPL= 176,5-177,5oC. Found,%: C 46,55; H 2,50; N 3,59; Br 20,70; Cl 18,33. C15H10BrCl2NO2. Calculated,%: C 46,51; H 2,58; N 3,62; Br 20,67; Cl 18,35. IR (cm-1): 731, 769, 832, 859 (ArH); 1511, 1576, 1648 (ArNHCO); 1689 (C=O); 3055 (Ar).

2. Getting 5-bromo-2-(2-iodoacetamide)-2-'-chlorobenzophenone formula III.

Boil 1.0 mol of product II obtained in stage 1, and 1.2 mol of NaI in 0.5 ml of acetonitrile for 1 hour, filtered sodium chloride and cooled. The precipitated crystals are separated by filtration and receive specified the UB>10BrCl2INO2. Calculated,%: C 37,62; H 2,09; N 2,93; Br 16,72; Cl 7,42; I 26,54. IR (cm-1): 735, 769, 831, 860 (ArH); 1510, 1577, 1649 (ArNHCO); 1690 (C=O); 3056 (Ar).

3. Obtaining 2-(2-aminoacetyl)-5-bromo-2-'-chlorobenzophenone formula IV.

In 1.0 ml of acetonitrile saturated with ammonia under cooling to 0 : -5oC add 1.0 mol of product III obtained in example 2, and stirred for 2 hours. Then add 3.0 l of water and the precipitated crystals are separated by filtration, getting listed in title product IV with the release of 98%. TPL= 122,1-123,5oC. Found, %: C 48,92; H 3,23; N 7,65; Of 21.75 Br; Cl 9,62. C15H12BrClN2O2. Calculated,%: C 48,98; H 3,27; N 7.62mm; To 21.77 Br, Cl 9,66. IR (cm-1): 755, 770, 835, 892 (Ar); 1510, 1577 (ArNHCO); 1690 (C=O); 3221 (NH2).

4. Obtain 7-bromo-1,3-dihydro-5-(2-chlorophenyl)-2H-1,4 - benzodiazepin-2-it (V).

Boil 1.0 mol of product IV, obtained according to example 3, 3.0 l of toluene for 5 hours while continuously removing water from the reaction mass. Cool, separating the precipitated crystals by filtration, and get listed in title product of V with the release of 96%. Tpl.= 226-228oC. Found,%: C 51,60; H 2,80; N 8,11; Br 22,80; Cl There Is A 10.03. C15H10BrClN2O. Calculated.%: C 51,50; H 2,86; N 8,01; Br 22,89; Cl 10,16. IR (cm-1): 757, 772, 836, 891 (ArH); 1512, 1576 (ArNHCO); 1599 (C=N); 1692 aimogasta 2-amino-5-bromo-2'-chlorobenzophenone derived from the acid chloride of acetic acid and cyclization of the intermediate product, characterized in that 2-amino-5-bromo-2'-chlorobenzophenone subjected to interaction with the acid chloride monochloracetic acid to obtain 5-bromo-2-(2 - chloroacetamido)-2'-chlorobenzophenone, which is treated sequentially with iodide of an alkali metal, to obtain 5-bromo-2-(2 - iodated)-2'-chlorobenzophenone, and ammonia in a polar solvent at low temperature to obtain 2-(2-aminoacetyl)-5 - bromo-2'-chlorobenzophenone that cyclist when heated.

2. 5-Bromo-2-(2-chloroacetamido)-2'-chlorobenzophenone.

 

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3 cl, 8 dwg, 1 tbl, 21 ex

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45 cl, 11 dwg, 11 tbl, 206 ex

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7 cl, 4 tbl, 43 ex

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5 cl, 17 tbl, 33 ex

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or

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6 cl, 5 dwg, 3 tbl,12 ex

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1 cl, 1 ex, 1 tbl

FIELD: chemistry.

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24 cl, 4 tbl, 270 ex

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1 tbl, 8 ex

FIELD: chemistry.

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36 ex

FIELD: pharmacology.

SUBSTANCE: invention relates to new arylcycloalkylamines of the general formula

. In the general formula (I), R1, R2 are H, linear or branched alkyl (C1-C4), linear or branched alkoxy (C1-C4), halogen; Y is -CH2-O-CH2-, - (CH2)n-, where n: 1-3; X is -CO-NH-(CH2)6-, -CO-(CH2)k-, -CH2-NH-(CH2)6-, -CH(CH3)-NH-(CH2)6-, -(CO)p-(CHR5)m, where p, m-: 0, 1, k: 2, 4-7, R5: H, linear alkyl C1-C5; R3, R4 are H, linear alkyl C1-C4, -CH2-C≡CH, -(CH2)2-O-(CH2)2-NH2, cyclopropyl, cyclopropylmethyl; 4-pyridinyl, an amino acid residue of a proteinogenic acyclic or aromatic α-amino acids, γ-aminobutyric acid, ε-aminocaproic acid, β-alanine; -CHR6-CH2-OR7, where R6: H or a linear or branched alkyl C1-C4, benzyl, R7: H, linear alkyl C1-C4, or R3, R4 together with the nitrogen to which they are attached, form a pyrrolidine, 2-(hydroxymethyl) pyrolidine, 4-aminopyridinium ring; G is (C1-C4) carboxylic acid, methanesulfonic acid or a mineral acid or water. As an acyclic or aromatic α-amino acid residue, they contain a proteinogenic α-amino acid residue. As (C1-C4) carboxylic acid, they contain at least one compound from the group consisting of acetic, fumaric, succinic, tartaric, malic and maleic acids. As a mineral acid, they contain at least one compound from the group consisting of hydrochloric, phosphoric, sulfuric acids. The preferred compounds are arylcycloalkylamine derivatives of the general formula , wherein Y: -CH2-O-CH2-, -(CH2)2-. The invention also relates to a pharmaceutical composition which can be a combination of arylcycloalkylamine derivatives and at least one substance from the group comprising levodopa, palmitoyle ethanolamide, N-(2-aminoethyl) palmitamide hydrochloride, rasagiline, risperidone, toloxaton, quetiapine, gamma-aminobutyric acid, sodium valproate, amitriptyline, clomepramine, fluoxetine, paroxetine, sertraline, phenylephrine, dexamethasone, prednisolone. The composition may be in the form of a tablet, capsule, pellet, powder for preparation of a solution for enteral administration, a solution for parenteral administration, a powder for preparation of a solution for parenteral administration.

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11 cl, 13 tbl, 96 ex

FIELD: chemistry.

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EFFECT: improved method of producing a compound which is an intermediate compound in synthesis of compounds with affinity for the GABAA receptor.

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one - active ingredient of original domestic sedative agent "Phenazepam".

EFFECT: disclosed is a novel simpler method of producing 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one by formation from N-[4-bromo-2-(2-chlorobenzoyl)phenyl]-2-chloroacetamide and subsequent cyclocondensation of 2-amino-N-[4-bromo-2-(2-chlorobenzoyl)phenyl]acetamide.

1 cl

FIELD: chemistry.

SUBSTANCE: stabilising composition is described, containing (A) compound of 2,4-bis-(4-phenylphenyl)-6-(2-hydroxyphenyl)-1,3,5-triazine series by formula (I), and (B) one or more compounds chosen from group, which include benzotriazoles by formula (IIa), 2-hydroxybenzophenones by formula (IIb), oxanilides by formula (IIc), 2-hydroxyphenyltriazines by formula (IId), cinnamates by formula (IIe), and benzoates by formula (IIf). There are also described: composition, containing stabiliser composition and organic material; method for organic material stabilisation; and application of stabiliser composition to organic material stabilisation.

EFFECT: increase in efficiency of labile organic materials stabilisation.

17 cl, 19 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one - active ingredient of original domestic sedative agent "Phenazepam".

EFFECT: disclosed is a novel simpler method of producing 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one by formation from N-[4-bromo-2-(2-chlorobenzoyl)phenyl]-2-chloroacetamide and subsequent cyclocondensation of 2-amino-N-[4-bromo-2-(2-chlorobenzoyl)phenyl]acetamide.

1 cl

FIELD: chemistry.

SUBSTANCE: invention relates to processes of preparing aromatic or fatty-aromatic ketones by reaction of aromatic chlorides or bromides or iodides with an aliphatic or aromatic nitriles, including intramolecular reactions containing nitrile group of aromatic chlorides, bromides or iodides, initially resulting compound with bond C=N undergoes subsequent hydrolysis to form the desired product. In particular, a process of preparing aromatic or aliphatic-aromatic ketones of the general formula R1C(O)R2, where R1 - aryl or hetaryl, and R2 - aryl or hetaryl or alkyl comprises reacting aromatic halide R1X, wherein R1 - aryl or hetaryl, and X=Cl, Br, I with nitriles R2CN, where R2 - aryl or hetaryl, or alkyl, which is carried out in the presence of a catalyst comprising nickel atom coordinated with a chelate ligand containing 1,4-diazabutadiene fragment (N=C-C=N), and a reducing agent in an ether solvent at molar ratios: R1X:R2CN, located within the range of from 2:1 to 1:20, Ni:(chelating ligand) is located within the range of from 1:1 to 1:2, Ni:R1X, is located in the range of from 1:200 to 1:2, the reducing agent: R1X, is located in the range of from 1:2 to 10:1, and the volume of the solvent with respect to the amount of the halide R1X is in the range of 0.5 to 20 ml/mmol, at a reaction temperature of 0-120°C, and the subsequent hydrolysis of the initially formed compound with the connection of C=N.

EFFECT: expansion of the arsenal of tools, the use of compounds as starting aryl bromides and aryl chlorides, cheaper and more readily available; use of at least twice lower catalyst loads; possibility of carrying out the reaction at a lower temperature; the possibility of carrying out the reaction in a shorter time.

18 cl, 40 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new photoinitiators, method of their obtainment, compositions hardening with irradiation, and application of those compositions in coating preparation. Invention claims photoinitiators of formulae I , where R1, R2, R3 and R4 are independently C1-C8alkyl or benzyl; or R1 and R2 together and/or R3 andR4 together are cyclohexyl; R5 is hydrogen; A is OH, Br, -O-C1-C12alkyl, -O-R7, where R7 is linear or forked C2-C21hydroxyalkyl carbon chain interrupted by 1 to 9 oxygen atoms; or -NR8R9, where R8 and R9 are independently C1-C21alkyl or C2-C4alkyl substituted by one or more OH groups; A' is -O-; X and Y are independently -OH or -N(CH3)2; n is 2; R6 is linear or forked divalent -CO-NH-(C2-C16alkylene)-(NH-CO)- radical or linear or forked -CO-NH-(C0-C9alkylene)-(NH-CO)- which can be interrupted by phenylene, or linear or forked divalent -C2-C50alkylene radical with carbon chain interrupted by 1 to 15 oxygen atoms.

EFFECT: efficient method of obtaining new organic photoinitiators.

11 cl, 20 cx

FIELD: chemistry.

SUBSTANCE: invention refers to production method of 1-(4-chlorophenyl)-2-cyclopropylpropane-1-one being a by-product for making biologically active substances, as well as to production method for 1-(4-chlorophenyl)-2-methyl-3-butene-1-one being a by-product for making 1-(4-chlorophenyl)-2-cyclopropylpropane-1-one. Production method for 1-(4-chlorophenyl)-2-cyclopropylpropane-1-one consists that 4-chlorobenzonitrile reacts with crotyl chloride or bromide and zinc in organic solvent and optionally with aluminium chloride. Hydrolysis of reaction mixture 2M with hydrochloric acid results in separation 1-(4-chlorophenyl)-2-methyl-3-butene-1-one thereafter purified. It reacts dibromomethane, zinc and copper monochloride in organic solvent with catalyst added or in ultrasonic bath. It is followed with separation of end product by common method.

EFFECT: simple and cheaper end production methods.

4 cl, 2 dwg, 9 ex

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