The way to obtain hydrochloride of 1-phenyl-1-p-nitrobenzoyl - amino-5-n,n-diethylaminopentane and 1-phenyl-1-amino-5-n,n - diethylaminopentane

 

(57) Abstract:

The inventive product 1: hydrochloride of 1-phenyl-n-nitrobenzoyl-Mino-5-N, N-diethylaminopentane. Reagent 1: 1-phenyl-1 amino-5-N, N-diethylaminopentane. Reagent 2: n-nitrobenzanthrone. Reaction conditions: in a medium of anhydrous aprotic solvent at a temperature of from 0oC to the boiling point. Product 2: 1-phenyl-amino-5-N, N-diaminopentane. Reagent 1: 1-phenyl-1-cyan-1-carbethoxy-5-bromopentane. Reagent 2: dietionin. Reaction conditions: boiling and subsequent saponification and decarboxylation of the resulting product, acid or alkaline hydrolysis of the resulting 1-phenyl-1-cyan-5-N, N-diethylaminopentane, processing the obtained product with bromine in the environment of methanol in the presence of sodium methylate at a temperature of from (-1)oC to the boiling point, or bromosuccinimide in the presence of acetate of mercury in a mixture of DMF and methanol and boiling the resulting product in spirit and alkaline environment. 2 C. and 8 C. p. F.-ly, 1 table.

The invention relates to the chemistry of N-substituted amides of aromatic carboxylic acids and substituted amines, and related specifically to improvements in the method of obtaining the hydrochloride of 1-phenyl-1-n-nitrobenzylamine-5-N,N-diatreme - Nomentana formula is bretania way to obtain compound I.

The essence of the proposed method lies in the fact that the target product I is obtained directly by reacting the parent compound 1-phenyl-1-amino-5-N,N-diethylaminopentane n-nitrobenzotrifluoride in the medium of anhydrous aprotic solvent.

The inventive method of obtaining the compound I is that 1-phenyl-1-amino-5-N, N-diethylaminopentane subjected to interaction with n-nitrosoethylurea in the medium of anhydrous aprotic solvent in the temperature range from 0aboutC to the boiling temperature of the reaction mass.

Target product I produce in the usual way. Get the connection I in the form of light yellow or light yellow with a greenish tinge crystalline powder, soluble in water, chloroform and alcohol, almost insoluble in ether with so pl. 165-167aboutC (from isopropanol) with access 73,1-92,6% counting 1-phenyl-1-amino-5-N,N-diethylaminopentane.

Scheme of the proposed method for obtaining compounds I

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I 92,6%

As an anhydrous aprotic solvent used aromatic hydrocarbons such as benzene, esters such as ethyl acetate, ketones, such as acetone, preferably NITRILES, for example acetonitrile.

The presence of the interaction with n-nitrobenzofurazan can pass through the tertiary amine group with the formation of Quaternary allievo derivative, and the process could stop at this stage, however, this was not observed. So the result was not obvious.

Physico-chemical characteristics of the target product I are given in the table.

The second object of the invention is a new method to produce 1-phenyl-1-amino-5-N,N-diethylaminopentane (VII).

The purpose of the invention, the source compound for the synthesis of compound I.

This goal is achieved by the proposed method for obtaining compounds VII, namely, that 1-phenyl-1-cyan-1-carbethoxy-5-bromopentane (II) is treated with diethylamino boiling (65-75about(C) obtained 1-phenyl-1-cyan-1-carbethoxy-5-N,N-diethylaminopentane (III) amyraut and decarboxylases, the resulting 1-phenyl-1-cyan-5-N,N-diethylaminopentane (IV) is subjected to acid or alkaline hydrolysis, the obtained 1-phenyl-1-carbamide-5-N,N-diethylaminopentane (V) is treated with bromine in the environment of methanol in the presence of sodium methylate in the temperature range from (-1)aboutC to the boiling temperature of the reaction mass or bromosuccinimide in the presence of acetate of mercury in a mixture of dimethylformamide (DMF) and methanol, the resulting 1-phenyl-1-carbomethoxyamino-5-N, N-diethylamino - tan (VI) is boiled in spirit and y is C.

Get the compound VII in the form of colorless or colorless to light yellow oily liquid with so Kip. 117aboutWhen 0,022 mm RT.article.

Output connections VII 25,3% 42,3% counting on II.

Diagram of the inventive method of producing 1-phenyl-1-amino-5-N,N-diethylaminophenyl - (VII).

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Saponification and decarboxylation of 1-phenyl-1-cyan-1-carbethoxy-5-N,N-diethyl - aminoindane (III) conduct, as by boiling with sodium ethylate in ethanol or with the chloride of an alkali metal, e.g. sodium chloride or lithium chloride, in aqueous dimethyl sulfoxide (DMSO) and water solution of caustic alkali in the presence of a phase transfer catalyst, for example, Tabaha, as in the environment of aromatic solvent and in the temperature interval from room temperature to 50aboutC.

Acid hydrolysis of 1-phenyl-1-cyan-5-N,N-diethylaminopentane (IV) is conducted in the presence of hydrochloric acid in the temperature range from room temperature to 50aboutWith or in the presence of sulfuric acid at 0-50aboutC.

Alkaline hydrolysis of compound IV is carried out in the presence of caustic alkali and hydrogen peroxide in the environment of DMSO in the temperature interval from 5aboutTo canoe, not previously described.

Synthesis of compound (II) based on known reactions obtain the sodium salt of ethyl ether vanillaness acid with subsequent alkylation of 1,4-dibromobutane at room temperature or when heated.

Compound II is obtained by interaction of benzyl cyanide with diethylmalonate in the presence of ateleta sodium boiling formed corresponding sodium salt of ethyl ether vanillaness acid is treated with 1,4-dibromobutane according to the following scheme:

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Get connection II with the release of 86,3% counting on benzyl cyanide.

As starting compounds for obtaining the compound (II) use produced by domestic industry benzyl cyanide and diethylcarbamyl. Intermediates III, IV, V, VI new, undescribed in the literature connection.

Physico-chemical characteristics of the compounds II-VII shown in the table.

Examples illustrating the inventive method to obtain 1-phenyl-1-amino-5-N, N-diethylaminopentane (VII), and use it as a starting product for the synthesis of hydrochloride of 1-phenyl-1-n-nitrobenzylamine-5-N,N-diethylaminopentane (I), given in the Appendix.

the tion potential of the drug (compound I), possessing antiarrhythmic and antifibrillatory activity.

P R I m e R 1. Obtain hydrochloride of 1-phenyl-1-n-nitrobenzylamine-5-N, N-di - ethylaminoethanol (I).

I. In the medium of anhydrous acetonitrile.

1) To 20 g of 90% or 18 g (0,0768 mol) 100% 1-phenyl-1-amino-5-N, N-diethylaminopentane poured 20 ml of anhydrous acetonitrile, stirred for 10 minutes at room temperature, then cooled to 0-5aboutC and at this temperature, add a solution 16,63 g of 90% or 14,97 g (0,0807 mol) of 100% n-nitrobenzotrifluoride in 46 ml of anhydrous acetonitrile. After downloading n-nitrobenzotrifluoride the reaction mass is stirred for 4 h at 0-5aboutC. the precipitation is filtered off, washed with 30 ml of absolute isopropanol and dried to constant weight.

Get 29,96 g (93%) 99,5% of the hydrochloride of 1-phenyl-1-n-nitrobenzylamine-5-N,N-diethylaminopentane (I) or 29,81 g (92.6 per cent) in terms of 100% content of I, counting 1-phenyl-1-amino-5-N,N-diethylaminopentane. So pl. 165-167about(Of absolute isopropanol).

2) To 20 g of 90% or 18 g (0,0768 mol) 100% 1-phenyl-1-amino-5-N, N-diethylaminopentane poured 20 ml of anhydrous acetonitrile, stirred for 10 min at room temperature the reed in 46 ml of anhydrous acetonitrile. Then the reaction mass is heated to boiling (80-81aboutC) is boiled under stirring for 30 minutes, cooled to room temperature and stirred for 1 h

The precipitation is filtered off, washed with 30 ml of absolute isopropanol and dried to constant weight.

Get 29,73 g (92,3%) 99,5% of the hydrochloride of 1-phenyl-1-n-nitrobenzylamine-5-N, N-detailmonitor (I) or 29.58 g (91,9%) in terms of 100% content of I, counting 1-phenyl-1-amino-5-N,N-diethylaminopentane. So pl. 165-167about(Of absolute isopropanol).

II. In the medium of anhydrous acetone.

To 20 g of 90% or 18 g (0,0768 mol) 100% 1-phenyl-1-amino-5-N, N-diethylaminopentane poured 20 ml of anhydrous acetone, stirred for 10 min at room temperature and at this temperature, add 16,63 g of 90% or 14,97 g (0,0807 mol) of 100% n-nitrobenzotrifluoride. After downloading n-nitrosoethylurea the reaction mass is stirred for 2 h at room temperature. The precipitation is filtered off, washed with 30 ml of absolute isopropanol and dried to constant weight.

Get 28,54 g (88,6%) 99,5% of the hydrochloride of 1-phenyl-1-n-nitrobenzylamine-5-N, N-diethylaminopentane (I) or 28.4 g (88,2%) in terms of 100% retained is glendorado.

To a solution of 20 g of 90% or 18 g (0,0768 mol) 1-phenyl-1-amino-5-N,N-diethylaminopentane (VII) in 40 ml of benzene with stirring at room temperature was added dropwise a solution of 16.78 in g of 90% or 15,10 g (0,0814 mol) of 100% n-nitrobenzotrifluoride in 60 ml of benzene. The reaction mass is heated to boiling (80aboutC) is boiled under stirring for 3 h and cooled to room temperature. The precipitation is filtered off.

Get 23,93 g (74.3 per cent) 98,8% of the hydrochloride of 1-phenyl-1-n-nitrobenzylamine-5-N,N-diethylaminopentane (I) or 23,64 g (73.4%) in terms of 100% content of I, counting on VII. So pl. 165-167about(Of absolute isopropanol).

IV. In the environment of ethyl acetate.

Similar to the previous paragraph VIII the reaction is carried out in a solution of ethyl acetate at the boiling temperature of the solvent.

Get 25,53 g (79.3 percent) of 92.2% of the hydrochloride of 1-phenyl-1-n-nitrobenzylamine-5-N,N-diethylaminopentane (I) or 23,54 g (73.1 per cent) in terms of 100% content of I, counting on VII, so pl. 165-167about(Of absolute isopropanol).

The data of elemental analysis of the synthesized compounds I correspond to the calculated.

P R I m m e R 2. Obtain 1-phenyl-1-amino-5-N,N-diethylaminopentane (VII).

Stage I. Obtaining 1-fan 1-carbethoxy-5-bromopentane (II) poured 112 ml (79,8 g) to 98.4% (78,55 g (1,074 mol) 100%) diethylamine, heated to boiling (62-65aboutC) and incubated with stirring for 2 h while the temperature of the reaction mass rises to 75aboutC. To the reaction mixture is poured 60 ml of toluene, stirred and cooled to room temperature. Fallen in sediment bromohydrin of diethylamine filtered off, washed with toluene (2x20 ml). The filtrate is evaporated. Get the remainder in the form of oily yellowish-brown liquid in the amount of 115 g of 94.5% content of 1-phenyl-1-cyan-1-carbethoxy-5-N,N-diethylaminopentane (III) or 108,67 g (95.9 per cent) in terms of 100% content of the basic substance III, counting on II.

Stage II. Obtain 1-phenyl-1-cyan-5-N,N-diethylaminopentane (IV).

1. Using ethylate sodium.

To 150 ml of absolute ethanol under stirring portions are added and 3.31 g (0,1439 g) of metallic sodium. To the resulting solution ethylate sodium with stirring, poured the solution 25,49 g (0,0805 mol) 1-phenyl-1-cyan-1-carbethoxy-5-N, N-diethylaminopentane in 25 ml of absolute ethanol. The reaction mass is heated to boiling (78-80aboutC) and maintained at boiling and stirring for 4 hours Evaporated. To the residue add 100 ml of water and extracted with toluene (ether) (x ml). Toluene solution is dried over OS is and. The toluene evaporated. The residue is distilled in vacuum. Collect the fraction with so Kip. 150-160aboutWith 1 mm RT.article in the form of an oily liquid yellow.

Get 17,59 g (89,33%) 95,96% 1-phenyl-1-cyan-5-N,N-diethylaminopentane (IV) or 16.88 in g (88%) in terms of 100% content of IV, counting on III.

2. With the use of alkali metal chloride (NaCl) in aqueous dimethyl sulfoxide (DMSO).

To 300 ml of DMSO with stirring, add 20 ml of water, 5,15 g (0,088 mol) of sodium chloride and 27,75 g (0,088 mol) 1-phenyl-1-cyan-1-carbethoxy-5-N, N-diethylaminopentane (III). The mixture is heated to boiling (146-147aboutC) and boiled for 2 h

The reaction mass is mixed with water and extracted with toluene (g ml). Toluene solution is dried over anhydrous magnesium sulfate. The inorganic precipitate is filtered off, washed with 50 ml of toluene. The toluene evaporated. The residue is distilled in vacuum. Collect the fraction with so Kip. 150-160aboutWith 1 mm RT.article in the form of an oily liquid yellow.

Get of 17.35 g (80,96%) 95,46% 1-phenyl-1-cyan-5-N,N-diethylaminopentane (IV) or 16,56 g (77.3 per cent) in terms of 100% content of IV, counting on III.

3. Using interphase catalyst triethylmethylammonium chloride (TEBAH) and vodno is 0.5 mol) of sodium hydroxide. To the resulting solution at 25-46aboutWith stirring, 0.34 g (0,0015 mol) Tabaha and 34,03 g 93% or 31,65 g (0.1 mol) 100% 1-phenyl-1-cyan-1-carbethoxy-5-N, N-diethylaminopentane (III). The reaction mass is maintained at 45-50aboutC and stirring for 1 h, then add 67 ml of toluene, stirred for 2-3 min, poured 50 ml of water and cooled to room temperature. The mixture is extracted with toluene (g ml). The combined toluene extracts are washed with water (I ml) to pH 7-8, dried over a drying agent, for example anhydrous sodium sulfate. The inorganic precipitate is filtered off, washed with 50 ml of toluene. The toluene evaporated. The residue is distilled in vacuum. Collect the fraction with so Kip. 150-160aboutWith 1 mm RT.article in the form of an oily liquid yellow.

Get 21,71 g (88,8%) of 99.4% 1-phenyl-1-cyan-5-N,N-diethylaminopentane (IV) or 21,58 g (88.3 per cent) in terms of 100% content of IV, counting on III.

4. Using interphase catalyst triethylmethylammonium chloride (TEBAH), an aqueous solution of alkali in the environment of aromatic hydrocarbon.

a) In 20 ml of water under stirring to dissolve 20 g (0,3564 mol) of potassium hydroxide or 20 g (0.5 mol) of sodium hydroxide. To the obtained solution of alkali at 25-45aboutAnd periacti-5-N,N-diethylaminopentane (III) in 33 ml of toluene. The reaction mass is maintained at 45-50aboutC and stirring for 1 h, poured 40 ml of water and cooled to room temperature.

The mixture is extracted with toluene (2x20 ml). The combined toluene extracts are washed with water (I ml) to pH 7-8 and dried over anhydrous sodium sulfate. The inorganic precipitate is filtered off, washed with 50 ml of toluene. Evaporated. The residue is distilled in vacuum. Collect the fraction with so Kip. 150-160aboutWith 1 mm RT.article in the form of an oily liquid yellow.

Get 21,53 g (88.1 per cent) 97,54% 1-phenyl-1-cyan-5-N,N-diethylaminophenol (IV) or 21,0 g (85,93%) in terms of 100% content of IV, counting on III.

b) In 10 ml of water with stirring, dissolve 10 g (0,1782 mol) of potassium hydroxide and 10 g (0,2500 mol) of sodium hydroxide. To the obtained solution of alkali at 25-45aboutWith and with stirring was added 0.17 g (0,0007 mol) Tabaha and the solution of 16.66 g of 95% or 15,83 g (0,0500 mol) 100% 1-phenyl-1-cyan-carbethoxy-5-N,N-diethylaminopentane (III) in 17 ml of benzene. The reaction mixture was kept at 45-50aboutC and stirring for 1 h, poured in 35 ml of water and cooled to room temperature. Then the reaction mass is treated similarly 4A.

Get of 10.76 g (88%) 91% 1-phenyl-1-cyan-5-N,N-diethylaminopropylamine-5-N,N-diethylaminopentane (V).

1. In the presence of hydrochloric acid.

A solution of 13.4 g (0,0511 mol) 1-phenyl-1-cyan-5-N,N-diethylaminopentane (IV) in 70 ml of concentrated hydrochloric acid with stirring, heated to 50aboutC and maintained at 50aboutWith 4 hours the Reaction mass is then cooled to room temperature, poured into 100 g of ice and add 40% NaOH to a pH of 10.0. The alkaline solution is extracted with toluene (g ml), toluene extract was washed with 100 ml of water and dried over anhydrous sodium sulfate. The inorganic precipitate is filtered off, washed with 50 ml of toluene. Evaporated. The remainder zakristallizuetsya in hexane. The precipitate is filtered off, washed with hexane, dried in the air.

Obtain 9.5 g (66%) 99,76% 1-phenyl-1-carbamide-5-N,N-diethylaminopentane (V) or 9,48 g (65,9%) in terms of 100% content of V, counting on IV. So pl. 70-73aboutC (from hexane).

IR spectrum , cm-1: 3370, 3160 (NH2), 1640, 1490 (C O CH CH arene CH2).

2. In the presence of sulfuric acid.

To 6 g 97,2% or of 5.83 g (0,0239 mol) 100% 1-phenyl-1-cyan-5-N, N-diethylaminopentane (IV) under cooling (0aboutWith ice and stirring was added dropwise 10.9 ml of concentrated sulfuric acid. The reaction mass is heated to 45aboutC and maintained under stirring and iaut sodium hydroxide solution to a pH of 10-11. The alkaline solution is extracted with toluene (g ml), toluene extract is washed with water to pH 9 and dried over anhydrous sodium sulfate. The inorganic precipitate is filtered off, washed with 30 ml of toluene. Evaporated. The remainder zakristallizuetsya in hexane. The precipitate is filtered off, washed with hexane, and dried.

Get to 3.89 g (62%) of 97.3% 1-phenyl-1-carbamide-5-N,N-diethylaminophenyl - on (V) or of 3.78 g (60%) in terms of 100% content of V, counting on IV.

3. In the presence of alkali in the environment DMSO.

a). To 74,55 g 99,4% or 74,10 g (0,3032 mol) 100% 1-phenyl-1-cyan-5-N,N-diethylaminopentane (IV), 9.3 g (0,1654 mol) of potassium hydroxide in 400 ml of dimethyl sulfoxide (DMSO) under stirring and cooling (5 to 10aboutC) was added dropwise 80 ml of 30% hydrogen peroxide. The temperature of the reaction mixture should not exceed 30aboutC. the Reaction mixture was kept under stirring at room temperature for 1 h Control reactions carried out by TLC. Upon completion of the reaction add 530 ml of water and extracted with toluene (3x400 ml). The combined toluene extracts are washed with 270 ml of water and dried over anhydrous sodium sulfate. The inorganic precipitate is filtered off, washed with 200 ml of toluene. Evaporated. The remainder secretaryship enyl-1-carbamide-5-N,N-diethylaminophenyl - on (V) or 59,26 g (74.4 per cent) in terms of 100% content of V, counting on IV.

b). From 14,4 g 97,3% or 14 g (0,05723 mol) 100% 1-phenyl-1-cyan-5-N, N-diethylaminopentane (IV), 2.24 g (0,0560 mol) of sodium hydroxide, 75 ml of DMSO and 25 ml of 30% H2ABOUT2by the method similar to the previous paragraph (a) obtain 10.8 g (72%) 93% 1-phenyl-1-carbamide-5-N,N-diethylaminopentane (V) or 10,04 g (66,8%) in terms of 100% content of V, counting on IV.

4. In the presence of potassium tert-butylate.

To a solution of 2.28 g 86,6% or 1.97 g (0,0081 mol) 100% 1-phenyl-1-cyan-5-N,N-diethylaminopentane (IV) in 25 ml of tert-butyl alcohol was added with stirring 2,12 g (0,0378 mol) of powdered potassium hydroxide. The reaction mass is heated to 83aboutC and boiled for 7 hours Control reactions carried out by TLC.

The reaction mixture was poured into 50 g of ice, extracted with toluene (g ml), washed with a saturated solution of sodium chloride (g ml), dried over anhydrous sodium sulfate. The inorganic precipitate is filtered off, washed with 25 ml of toluene. Evaporated. The remainder zakristallizuetsya in hexane. The precipitate is filtered off, washed with hexane, and dried.

Obtain 1.3 g (61%) of 98.5% 1-phenyl-1-carbamide-5-N,N-diethylaminopentane (V) or 1.28 g (60,4%) in terms of 100% content of V, counting on IV.

To a solution of sodium methylate was obtained from 300 ml of methanol and 11.85 g (0,5153 g) of metallic sodium, under stirring and at room temperature add a solution 60,47 g 98% or 59,26 g (0,2259 mol) 100% 1-phenyl-1-carbamide-5-N,N-diethylaminopentane (V) in 300 ml of methanol. The reaction mixture was cooled to -1about-0aboutAnd slowly (over 1 h) was added dropwise 13 ml (40,42 g) (0,2526 mol) of bromine under vigorous stirring. Then the reaction mass is heated to boiling (65aboutC) and boiled for 10 min Control reactions carried out by TLC.

The reaction mixture is cooled to room temperature, poured 1200 ml of water, extracted with toluene (h) ml the combined toluene extract is washed with water (I ml) and dried over anhydrous sodium sulfate. The inorganic precipitate is filtered off, washed with 200 ml of toluene. Evaporated.

Get 59,2 g (90%) 96% 1-phenyl-1-carbomethoxyamino-5-N,N-diethyl - aminoindane (VI) in the form of an oily liquid light yellow or 56,83 g (86%) based on 100% table of contents VI, counting on V.

So Kip. 133aboutWhen 0,025 ml of RT.article.

2. Using bromosuccinimide, acetate of mercury in a mixture of DMF-methanol.

To a mixture of 5.0 g (0,0191 mol) 1-phenyl-1-carb is room temperature, add the 3.65 g (0,0200 mol) bromosuccinimide in 25 ml of DMF. The reaction mixture was stirred at room temperature (20-25aboutC) 6 hours.

The precipitate is filtered off, washed with 10 ml of DMF, and the filtrate evaporated to 2/3 of its volume, add 100 ml ethyl acetate and 100 ml of 0.5% aqueous soda solution. The organic layer is separated, the aqueous layer was extracted with ethyl acetate (CH ml). The combined organic extract was washed with 100 ml of water, dried over anhydrous sodium sulfate. The inorganic precipitate is filtered off, washed with 50 ml of ethyl acetate. Evaporated.

Obtain 4.5 g (80,7%) of 1-phenyl-1-carbomethoxyamino-5-N,N-diethylaminopentane (VI), counting on V.

Stage V. Obtain 1-phenyl-1-amino-5-N,N-diethylaminopentane (VII).

1. With ethanol and alkali.

A mixture of 12.0 g (0,3000 mol) sodium hydroxide, 20 ml of water, 20 ml of ethanol, and 8.2 g (0,0280 mol) 1-phenyl-1-carbomethoxyamino-5-N,N-diethylaminopentane (VI) is boiled under stirring for 24 h

The reaction mass is then cooled to room temperature, poured into 400 ml of water, add 100 ml of toluene and stirred. The organic layer is separated, the aqueous layer was extracted with toluene (g ml). The combined toluene extract is washed with water (I ml) and dried over anhydrous sodium sulfate. Inorganic sediment adfilternone (VII) in the form of an oily liquid light yellow or 5,12 g (77,9%) in terms of 100% contents VII counting on VI. When distilled in a vacuum, the obtained diamine VII (so Kip.117about/0,022 mm RT.CT.) get 5,2 g (79,1%) 92% VII in the form of a colorless oily liquid, counting on VI.

2. With ethanol, alkali and Kibaha.

The mixture 77,72 g (1,9430 mol) of sodium hydroxide, 3.7 g (0,0162 mol) Tabaha, 78 ml of water, 78 ml of ethanol, to 59.2 g of 96% or 56,83 g (0,1943 mol) 100% 1-phenyl-1-carbomethoxyamino-5-N,N-diethylamino - pentane (VI) is boiled under stirring for 6 hours Control reactions carried out by GLC.

The reaction mass is then cooled to room temperature, poured in 2800 ml of water, add 700 ml of toluene and stirred. The organic layer is separated, the aqueous layer was extracted with toluene (2 x 700 ml). The combined toluene extracts are washed with water (2 x 700 ml) and dried over anhydrous sodium sulfate. The inorganic precipitate is filtered off, washed with 300 ml of toluene. Evaporated.

Get 44.4 g (97,5%) 80% 1-phenyl-1-amino-5-N,N-diethylaminopentane (VII) in the form of an oily liquid light yellow or 35,52 g (78%) in terms of 100% contents VII, counting on VI. So Kip. 117aboutWhen 0,022 mm RT. Art.

3. Using n-butanol and lye.

A mixture of 7.6 g (0,1900 mol) of sodium hydroxide, 100 ml of n-butanol, CLASS="ptx2">

The reaction mass is then cooled to room temperature, poured into 50 ml water, the organic layer is separated, the aqueous layer was extracted with n-butanol (2 x 50 ml). n-Butanol is distilled off, the residue is treated with 100 ml of toluene and sued over anhydrous sodium sulfate. The inorganic precipitate is filtered off, washed with 50 ml of toluene. Evaporated.

Obtain 4.1 g (93,2%) 76% 1-phenyl-1-amino-5-N,N-diethylaminopentane (VII) in the form of an oily liquid light yellow or 3.12 g (71%) in terms of 100% contents VII, counting on VI.

4. Using n-butanol, alkali and Kibaha.

A mixture of 7.6 g (0,1900 mol) of sodium hydroxide, 0.5 g (0,0022 mol) Tabaha, 15 ml of water, 15 ml of n-butanol and 5.5 g (0,0188 mol) 1-phenyl-1-carbomethoxyamino-5-N,N-diethylaminopentane (VI) is boiled under stirring 4 h

The reaction mass is then cooled to room temperature, poured into 50 ml of water, add 30 ml of toluene and stirred. The organic layer is separated, the aqueous extracted with toluene (g ml). The combined toluene extract is washed with water (I ml) and dried over anhydrous sodium sulfate. The inorganic precipitate is filtered off, washed with 30 ml of toluene. Evaporated.

Get of 4.05 g (92%) 78% 1-phenyl-1-amino-5-N,N-diethylaminopentane the and VI.

The data of elemental analysis of the synthesized compounds correspond to the calculated.

P R I m e R 3. Obtain 1-phenyl-1-cyan-1-carbethoxy-5-bromopentane (II).

To 100 ml of toluene with vigorous stirring, 10 g (0,4350 g and sodium and heated to a temperature (955)aboutFor grinding of metallic sodium. Then slowly added dropwise a mixture of 25 ml of toluene and 50 ml of absolute ethanol and kept at boiling (95 5)aboutWith 40-60 min until gas evolution stops. The reaction mass is cooled to (555)aboutC, was added dropwise 54,89 ml (53,52 g) 99% or 52,98 g (0,4485 mol) 100% diethylmalonate and 52,95 ml (51,47 g) 99% or 50,96 g (0,4350 mol) 100% benzyl cyanide, heated to boiling and distilled azeotropic mixture of toluene and ethanol at atmospheric pressure. The temperature in the bath gradually, as the distillation, the temperature of the distillate in vapor rises from 78 to 103aboutC.

For complete removal of ethanol from the reaction mass after sedimentation and 95-100aboutWith in pairs added dropwise addition of 45 ml of toluene.

The reaction mass is then cooled to 10-15aboutC. the precipitation is filtered off and washed with toluene (g ml), dried. The reaction to produce 1-phenyl-1-cyan-1-LASS="ptx2">

Get 89 g (96.9% of the counting on benzyl cyanide) sodium salt of ethyl ether vanillaness acid, so pl. 221-225aboutC (decomp.).

Next, a mixture consisting of 87 g (0,4119 mol) of the obtained sodium salt of ethyl ether vanillaness acid, 464 g (256,64 ml) 95,86% or 444,79 g (2,0600 mol) of 100% of 1,4-dibromobutane and 250 ml of acetonitrile, stirred for 1.5 h at room temperature, then heated to 45-50aboutC and at this temperature, allowed to stand for 1 h and cooled to 15-20aboutC. Precipitated precipitated sodium bromide is filtered off, washed with acetonitrile (CH ml). From the mother liquor is distilled acetonitrile, 1,4-dibromobutan.

Get 123 g (92.1 per cent) 97% 1-phenyl-1-cyan-1-carbethoxy-5-bromopentane (II) in the form of an oily liquid yellow or 119,31 g (89.3%) in terms of 100% content II, counting on the sodium salt of the ethyl ester of phenylacetic acid.

So Kip. 135aboutWith 0.025 mm RT.article.

The data of elemental analysis of the synthesized compound (II) correspond to the calculated.

1. The WAY to OBTAIN HYDROCHLORIDE OF 1-PHENYL-1-P-NITROBENZOYL-AMINO-5-N,N-DIETHYLAMINOPENTANE AND 1-PHENYL-1-AMINO-5-N,N-DIETHYLAMINOPENTANE, characterized in that the p-nitrobenzoate in the medium of anhydrous aprotective 1-phenyl-1-cyan-1-carbethoxy-5-bromopentane with diethylamino boiling, by saponification and decarboxylation resulting 1-phenyl-1-cyan-1-carbethoxy-5-N, N-diethylaminopentane followed by acidic or alkaline hydrolysis of the resulting 1-phenyl-1-cyan-5-N,N-diethylaminopentane, processing the obtained 1-phenyl-1-carbamide-5-N,N-diethylaminopentane or bromine in the environment of methanol in the presence of sodium methylate at a temperature of from -1oC to the boiling temperature of the reaction mass, or bromosuccinimide in the presence of acetate of mercury in a mixture of dimethylformamide and methanol and boiling the obtained 1-phenyl-1-carbomethoxyamino-5-N,N-diethylaminopentane in spirit and alkaline environment.

2. The method according to p. 1, characterized in that the process of condensation of p-nitrobenzaldehyde with 1-phenyl-1-amino-5-N, N-diethyl-aminoethanol carried out in the temperature interval from 0oC to the boiling temperature of the reaction mass.

3. The method according to p. 1, characterized in that as an anhydrous aprotic solvent using an aromatic hydrocarbon, ether, ketone or nitrile.

4. The method according to p. 1, characterized in that as an anhydrous aprotic solvent used acetonitrile.

5. The way to obtain 1-phenyl-1-amino-5-N,N-diethylaminopentane, wherein the 1-phenyl-1-em and decarboxylation obtained 1-phenyl-1-cyan-1-carbethoxy-5-N, N-diethylaminopentane, acid or alkaline hydrolysis of the resulting 1-phenyl-1-cyan-5-N, N - diethylaminopentane, processing the obtained 1-phenyl-1-carbamide-5-N,N-diethylaminopentane or bromine in the environment of methanol in the presence of sodium methylate at a temperature of from -1oC to the boiling temperature of the reaction mass, or bromosuccinimide in the presence of acetate of mercury in a mixture of dimethylformamide and methanol and boiling the obtained 1-phenyl-1-carbomethoxyamino-5-N,N - diethylaminopentane in spirit and alkaline environment.

6. The method according to p. 5, characterized in that the saponification and decarboxylation of 1-phenyl-1-cyan-1-carbethoxy-5-N,N-diethylaminopentane carried out in an aqueous solution of caustic alkali in the presence of a phase transfer catalyst, such as triethylmethylammonium chloride, at a temperature from room temperature up to 50oC.

7. The method according to PP.1 and 6, characterized in that the saponification and decarboxylation of 1-phenyl-1-cyan-1-carbethoxy-5 - N,N-diethylaminopentane conducted in the environment of aromatic hydrocarbon.

8. The method according to p. 1, characterized in that the acid hydrolysis of 1-phenyl-1-cyan-5-N, N-diethylaminopentane carried out in the presence of hydrochloric acid at a temperature from room temperature up to 50oWith or in the presence of sulfuric acid at EnCana carried out in the presence of alkali and hydrogen peroxide in the environment of dimethyl sulfoxide at a temperature of from 5oWith up to a bedroom or in the presence of potassium tert-butylate while boiling.

10. The method according to p. 1, characterized in that the boiling of 1-phenyl-1-carbomethoxyamino-5-N, N-diethylaminopentane in spirit and alkaline medium is carried out in the presence of a phase transfer catalyst, such as triethylmethylammonium chloride.

 

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where Z - bond carbon-carbon (III) or 0 (IV)
The invention relates to methods of obtaining N,N-diethyl-meta-toluamide (DETA), which is one of the best repellents, and can be used in the chemical and pharmaceutical industries

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The invention relates to a method for producing complex organic esters or amides of certain organic esters
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The invention relates to chemistry, specifically to an improved method of obtaining benzamide

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein Ar represents phenyl substituted with a group taken among isobutyl, benzoyl, isopropyl, styryl, pentyl, (2,6-dichlorophenyl)-amino-group, α-hydroxyethyl, α-hydroxybenzyl, α-methylbenzyl and α-hydroxy-α-methylbenzyl; R represents hydrogen atom; X means linear (C1-C6)-alkylene, (C4-C6)-alkenylene, (C4-C6)-alkynylene optionally substituted with group -CO2R3 wherein R3 means hydrogen atom, group (CH2)m-B-(CH2)n wherein B means oxygen atom; m = 0; n means a whole number 2; or B means group -CONH; m means a whole number 1; n means a whole number 2 and so on; R1 and R2 are taken independently among group comprising hydrogen atom, linear (C1-C4)-alkyl, hydroxy-(C2-C3)-alkyl and so on. Invention proposes a method for preparing compounds of the formula (I). Invention proposes inhibitors of C5-induced hemotaxis of polymorphonuclear leukocytes and monocytes representing (R)-2-arylpropionic acid omega-aminoalkylamides of the formula (I). Also, invention relates to a pharmaceutical composition possessing inhibitory activity with respect to hemotaxis of polymorphonuclear leukocytes and monocytes and comprising compounds of the formula (I) in mixture with suitable carrier. Proposes (R)-2-arylpropionic acid omega-alkylamides are useful for inhibition of hemotaxic activation induced C5a and other hemotaxic proteins.

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

18 cl, 3 tbl, 23 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to methods for preparing N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine (nateglinide). Method for preparing nateglinide crystals of H-type is carried out by addition of inorganic acid to reaction mixture containing nateglinide to provide its acidification. The reaction mixture is prepared by interaction of trans-4-isopropylcyclohexylcarbonyl chloride with D-phenylalanine in a mixed solvent consisting of a ketone solvent and water in the presence of alkali. The ratio of water to ketone solvent is from 10:1 to 0.5:1. Temperature of the mixture is brought about to 58-72°C and concentration of ketone solvent - up to value above 8 wt.-% and less 22 wt.-% for carrying out precipitation of nateglinide crystals. Invention proposes variant for preparing nateglinide crystals of H-type. Also, invention proposes crystals of nateglinide of H-type showing average value of longitudinal axis from 1 to 5 mm and that for transverse axis from 0.1 to 0.5 mm. Invention provides enhancing effectiveness in isolation of nateglinide crystals.

EFFECT: improved preparing methods.

10 cl, 1 tbl, 13 ex

FIELD: industrial organic synthesis.

SUBSTANCE: invention provides a simple method for preparing high-purity acylphenylalanine useful as starting material for pharmaceutical products. Process comprises Schotten-Bauman reaction stage wherein acid chloride reacts with phenylalanine in mixed solvent consisting of water-miscible organic solvent and water, while maintaining alkali pH (>10) of solvent medium with the aid of potassium hydroxide.

EFFECT: prevented formation of impurities.

13 cl, 4 tbl, 12 ex

FIELD: organic chemistry, detergents.

SUBSTANCE: claimed method includes interaction of ethylene diamine with tetraacetic acid. Obtained reaction mixture is treated with acetic anhydride at elevated temperature and N,N,N',N'-tetraacetylethylene diamine is isolated from reaction mass by crystallization. Reagent interaction is carried out in system of two continuous reactors acting in mixing-displacement regime at continuous raw material feeding such as ethylene diamine into top of the first reactor and acetic anhydride into top of the second reactor. Molar ratio of fresh acetic anhydride to ethylene diamine is 2.05-2.1. Temperature difference between top and bottom parts is maintained from 20 to 30°C for the first reactor and from 20 to 40°C for the second one. Compound of present invention is useful in detergent compositions.

EFFECT: target product of increased yield and purity, simplified process.

1 dwg, 1 tbl, 8 ex

FIELD: industrial organic synthesis.

SUBSTANCE: process involves formic acid-methylamine reaction via intermediate methylammonium formate salt, which is dehydrated in presence of molybdenum trioxide catalyst dissolved in aqueous methylamine and added to formic acid in amount 2.0-4.0 wt % based on the latter. Reaction is carried out for 1-2 h in reactor filled with inert packing material having developed surface without cooling of reaction mixture, whereupon volatile products are distilled away at bottom temperature up to 190°C for 60-90 min. Bottom residue containing catalyst, after isolation of desired product, is returned to reactor.

EFFECT: reduced reaction time, reduced power consumption, improved quality of product obtained at increased yield, and diminished production waste.

5 cl, 8 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of aromatic carboxylic acid aminoanilides, such as 21-chloro-4,41-diaminobenzanilide or bis-(2-chloro-4-aminophenol)terephthalamide used in production of thermostable, refractory and highly strength fibers. Method is carried out by acylation of 2-chloro-4-nitroaniline with 4-nitrobenzoic acid chloroanhydride or terephthaloyl chloride, respectively, in organic solvent medium at heating followed by reduction of formed chloro-substituted nitroanilide of aromatic carboxylic acid in a solvent. The acylation process is carried out in the presence of ferric chloride as a catalyst, at chloroanhydride excess with respect to 2-chloro-4-nitroaniline at graduate increase of temperature up to boiling of reaction mass under atmosphere pressure. Ferric chloride is used as anhydrous FeCl3 or crystal hydrate FeCl3 x 6H2O or an aqueous solution. In the reduction process a mixture of water and dipolar aprotonic solvent is used, and mother solutions after isolation of chloro-substituted nitroanilide and chloro-substituted aminoanilide are recovered to recycle at corresponding step of process. Before recovering to recycle at acylation or reduction step, respectively, mother solutions are treated with activated carbon. Invention provides preparing end products of high quality and decreasing amount of waste.

EFFECT: improved method of synthesis.

6 cl, 1 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: method to manufacture benzyldimethyl[3-(myristoilamino)propyl]ammonium chloride monohydrate-С26Н47ClN2О·Н2О implies two stages, which are reacting myristic acid followed by the end product formation at the second stage. 3-dimethylaminopropylamide is obtained at the first stage by direct reaction of myristic acid with 3-dimethylaminopropylamine in aromatic hydrocarbons, while end product is obtained at the second stage by direct benzylation in alcohols or ketones.

EFFECT: improved purity of end product and process safety.

3 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the optically active compounds of bisoxazoline of the formula (1) and the method of their preparation, to the new intermediate products and methods of their preparation, it also refers to cooper asymmetric complex on the basis of the bisoxazoline optically active compound of the formula (1) and the method of preparation of cyclopropalcarbon acids using the asymmetric complex. In the compound of the formula (1) , R1 and R2 are equal and each time stand for C1-6 alkoxy group, C1-6 alkyl group substituted by unsubstituted phenyl group or phenyl group substituted by C1-6 alkyl or C1-6 alkoxy group, R1 and R2 with carbon atom of oxazoline ring, to which they are joined and form cykloalkyl ring which has 3-7 carbon atoms, R3 defines unsubstituted 1-naphthyl group or 2-naphthyl group, or 1-naphthyl group or 2-naphthyl group substituted by at least one C1-6 alkyl group or C1-6 alkoxy group; R4 and R5 are equal and each of them stands for hydrogen atom or C1-6 alkyl group or R4 and R5 with carbon atom, to which they are joined, form cykloalkyl ring which has 3-6 carbon atom and * mean asymmetrical center.

EFFECT: usage of the asymmetrical complex allows getting cyclopropanecarboxylic acid in high yields.

16 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to the method of making compounds with formula , involving reaction of but-2-enoic acid with chlorotrimethylsilane, bromination of the obtained trimethylsilylcrotonate with N-bromosuccinimide, reaction of the obtained trimethylsilyl-4-bromocrotonate or methyl or ethyl 4-bromocrotonate with dimethylamine so as to obtain 4-dimethylaminocrotonic acid, its separation in form of hydrochloride and chlorination with oxalyl chloride. The method allows for obtaining 4-dimethylamino-2-butenoylchloride, suitable for use as an intermediate compound in the synthesis of pharmaceutically active protein kinase inhibitors.

EFFECT: obtaining the agent, suitable for use as an intermediate compound in the synthesis of pharmaceutically active protein kinase inhibitors.

1 cl, 2 dwg, 3 ex

FIELD: chemistry; food products.

SUBSTANCE: present invention relates to use of N-isobutylamide 2E,4E-decadienoic acid (trans-pellitorine) as an aromatic substance, with a sialagogue but not burning effect in compositions used for food, oral hygiene or consumed for delectation, where trans-pellitorine is used in amounts of 20 parts/million in terms of the total mass of the composition. The invention also relates to the aromatic composition, with a sialagogue but not burning effect, containing trans-pellitorine in amounts of 20 parts/million in terms of the total mass of the composition, as well as to the method of obtaining trans-pellitorine. The invention also pertains to the method of obtaining N-isobutylamide 2E,4E-decadienoic acid.

EFFECT: obtaining a substance with sialagogue and/or irritant effect, as well as a wide neutral aromatic profile.

6 cl, 7 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention to a method for catalytic liquid-phase hydrogenation of 2',4',4-trinitrobenzanilide to yield aromatic polyamino-compounds. Method for liquid-phase hydrogenation of 2',4',4-trinitrobenzanilide is carried out at heating in water medium as a solvent in the presence of palladium-containing catalyst on a carrier. The process is carried out on block high-porous cellular catalyst with porosity value 70-95%, not less, and consisting of aluminum α-oxide-base carrier with active backing made of γ-Al2O3 palladium as an active component with the mass ratio = 0.45-0.85%. Invention provides simplifying technology of process with elimination of the separation step of catalyst from the hydrogenation catalyzate, prevention of the catalyst destruction, enhancing purity of the end product and increasing working life of the catalyst.

EFFECT: improved method of method.

8 ex

FIELD: industrial organic synthesis.

SUBSTANCE: title process resulting in production of aromatic polyamino compounds is carried out on heating in organic solvent (lower alcohols) medium in presence of supported palladium-containing catalyst, in particular, high-porosity (porosity 80-96%) cellular catalyst consisting of α-alumina-based support with active sulfated zirconium dioxide substrate and palladium as active component in amount 0.16-0.75 wt %.

EFFECT: simplified process, eliminated catalyst/hydrogenation catalysate separation stage, prevented destruction of catalyst, prolonged lifetime of catalyst, and increased purity of desired product.

1 tbl

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of aromatic carboxylic acid aminoanilides, such as 21-chloro-4,41-diaminobenzanilide or bis-(2-chloro-4-aminophenol)terephthalamide used in production of thermostable, refractory and highly strength fibers. Method is carried out by acylation of 2-chloro-4-nitroaniline with 4-nitrobenzoic acid chloroanhydride or terephthaloyl chloride, respectively, in organic solvent medium at heating followed by reduction of formed chloro-substituted nitroanilide of aromatic carboxylic acid in a solvent. The acylation process is carried out in the presence of ferric chloride as a catalyst, at chloroanhydride excess with respect to 2-chloro-4-nitroaniline at graduate increase of temperature up to boiling of reaction mass under atmosphere pressure. Ferric chloride is used as anhydrous FeCl3 or crystal hydrate FeCl3 x 6H2O or an aqueous solution. In the reduction process a mixture of water and dipolar aprotonic solvent is used, and mother solutions after isolation of chloro-substituted nitroanilide and chloro-substituted aminoanilide are recovered to recycle at corresponding step of process. Before recovering to recycle at acylation or reduction step, respectively, mother solutions are treated with activated carbon. Invention provides preparing end products of high quality and decreasing amount of waste.

EFFECT: improved method of synthesis.

6 cl, 1 tbl, 22 ex

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