Production method for 1-(4-chlorophenyl)-2-cyclopropylpropane-1-one and by-product therefor

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

The invention relates to a method for producing 1-(4-chlorophenyl)-2-cyclopropylamino-1-she (I), which is used as an intermediate product for the production of biologically active substances

A method of obtaining 1-(4-chlorophenyl)-2-cyclopropylamino-1-she (I), namely, that:

a) 4-chlorobenzaldehyde reacts with the Grignard reagent prepared from magnesium chloride and katila, which leads to the formation of 1-(4-chlorophenyl)-2-methyl-3-butene-1-ol;

b) the resulting product is subjected to interaction with dibromethane, zinc dust and odnoklasniki copper using ultrasound to activate the process;

b) obtained by reaction of 1-(4-chlorophenyl)-2-cyclopropylamino-1-ol oxidize a mixture of oxalicacid with dimethylsulfoxide solution of dry methylene chloride at a temperature of -78°C. Receive 1-(4-chlorophenyl)-2-cyclopropylamino-1-he (I) (patent USSR No. 1718722, publ. 07.03.1992).

The General reaction scheme:

The number of stages 3, total output, counting on the original 4-chlorobenzaldehyde, 48-50%.

The main disadvantage of this method is the need to use toxic oxalicacid and low temperatures (-78° (C) at the last stage of the process, and the identification of the reaction products at each stage of the process is and using column chromatography on SiO ₂that creates considerable difficulties during the implementation process in an industrial environment.

The present invention eliminates the stage of oxidation and greatly simplify and cheapen the process of obtaining ketone (I). The essence of the invention lies in the fact that 1-(4-chlorophenyl)-2-cyclopropylamino-1-he get cyclopropylamine corresponding unsaturated ketone, 1-(4-chlorophenyl)-2-methyl-3-butene-1-it (II), which, in turn, is obtained from 4-chlorobenzonitrile and chloride katila under the influence

zinc (Barbier reaction) in an organic solvent in the presence of aluminum chloride or without it.

The sequence of reactions may be represented by the following scheme:

A known method of producing arylketones by reacting NITRILES and allylbromide with zinc in the presence of aluminum chloride (Tetrahedron Letters 41, 2000, 8803-8806). Obtaining 1-(4-chlorophenyl)-2-methyl-3-butene-1-it (II), as well as the ketone (II), this work is not described.

There is a method of cyclopropylamine alkenes under the action of dibromethane, zinc dust and chloride monovalent copper in the air using acetyl chloride as a catalyst (J. Org. Chem., 1990, 55, 2491-2494). Obtaining 1-(4-chlorophenyl)-2-cyclopropylamino-1-she (I) in this work also does not describe the O.

Also known is a method of obtaining 1-(4-chlorophenyl)-2-methyl-3-butene-1-it (II), which consists in the interaction of 2-butenylamine (diethylamide) imidazolidine 4 chlorbenzoyl acid in tetrahydrofuran at very cold (-78°-25°). Duration of more than 12 hours. After completion of the reaction, the reaction mixture was hydrolized with hydrochloric acid. The target product is removed by extraction with ether and purified by distillation in high vacuum (Chemische Berichte, 118, 348-353, 1985). This method can be used in laboratory conditions, however, difficult to implement on an industrial scale. Other ways to obtain 1-(4-chlorophenyl)-2-methyl-3-butene-1-it (II) in the information sources were not found.

Thus, an object of the present invention is a new method to produce 1-(4-chlorophenyl)-2-cyclopropylamino-1-she (I)in which 4-chlorobenzonitrile subjected to interaction with chloride or bromide by Croteam and zinc and, optionally, in the presence of aluminum chloride in an organic solvent to obtain 1-(4-chlorophenyl)-2-methyl-3-butene-1-it. The obtained 1-(4-chlorophenyl)-2-methyl-3-butene-1-it is introduced into the reaction dibromethane, zinc and odnoklasniki copper in an organic solvent in an ultrasonic bath or in the presence of a catalyst.

As solvent in the first stage, you can use tetrahed furan, diethyl ether, dioxane or mixtures thereof. In the second stage can also be used methylene chloride, benzene, a mixture of toluene and dimethyl ether of ethylene glycol in the ratio 2:1, as well as other solvents.

As catalysts in the second stage using either acetyl chloride or trimethylchlorosilane and detribalized or sodium bis-(2-methoxyethoxy)-dehydroalanine.

Due to the fact that 1-(4-chlorophenyl)-2-methyl-3-butene-1-it decomposes when distilled in a vacuum, have been given the opportunity to conduct the second stage of cyclopropylamine, using separated from the precipitate of the reaction mixture formed after the reaction of 4-chlorobenzonitrile, zinc chloride and katila and containing non-hydrolyzed intermediate zinc salt (III) (Ukerewe "Practical work in organic chemistry. The issue I and II"., Moscow University publishing house, 1964., 274). That is, without isolating the 1-(4-chlorophenyl)-2-methyl-3-butene-1-it in its pure form. It turned out that thus you can obtain the target product with a yield of 86%, counting on the original 4-chlorobenzonitrile and purity according to GC to 84%.

Another object of the invention is a method of obtaining 1-(4-chlorophenyl)-2-methyl-3-butene-1-it consists in the fact that 4-chlorobenzonitrile subjected to interaction with bromide or chloride Croteam and zinc dust to dissolve the E. of tetrahydrofuran in the presence of aluminum chloride or without it, at a temperature of from 10°With up to 35-40°C. the Process of obtaining includes a step of isolation and purification, namely, that after adding to the resulting reaction mixture is not miscible with water, an organic solvent, for example hexane, it is treated with 2M hydrochloric acid, after which the target product isolated from the organic layer in a known manner. Compared with the known method (Chemische Berichte, 118, 348-353, 1985) the inventive method is much simpler and cheaper.

This is followed by examples illustrating, but not limiting the invention.

Example 1. Obtaining 1-(4-chlorophenyl)-2-methyl-3-butene-1-it.

To a solution of 6.78 g (0.05 mol) of 4-chlorobenzonitrile in 45 ml of THF added 13,0 g (0.2 mol) of zinc dust and cooled to 10°C. Then the reaction mass is added 2.67 g (0.02 mol) of aluminum chloride, the temperature rises to 15°C. To the resulting suspension is added dropwise a solution of 10,12 g (0,075 mol) of methyl Crotia in 50 ml of THF for 1 hour 30 minutes. Upon completion of addition, the reaction mass is stirred for 3.5 hours at a temperature of 35-40°C. Then the reaction mass is added 60 ml of hexane and cooled it to 0°C. At this temperature slowly added 36 ml of 2M hydrochloric acid and stirred for 10 minutes. The layers separated, the organic layer washed with 2M hydrochloric acid (2 x 35 ml), 5%solution of sodium carbonate (2 RosAPO 35 ml) and a saturated solution of sodium chloride (3 x 35 ml). Dried over sodium sulfate. The solvent is removed. The residue is distilled in vacuum. Get of 5.84 g of 1-(4-chlorophenyl)-2-methyl-3-butene-1-it. Yield 60%, T_Kip100-103°/0,83 mm Hg. GC purity of 82%. In the PMR spectrum recorded in d-DMSO along with the signals of aromatic protons observed in the field 7,45-of 7.95 ppm, attended doublet protons of a methyl group in the field of 1.25 ppm (d, 3H), in the field to 4.15 ppm (t, 1H) observed triplet vinyl proton in the area of 5.05-5,20 ppm (d.d., 2H) attended doublet of doublets methylene protons, and in the field 5,80-5,95 ppm (m, 1H) observed multiplet methine proton.

Example 2. In the conditions of example 1, without the addition of aluminum chloride. Got 5,94 g of 1-(4-chlorophenyl)-2-methyl-3-butene-1-it. Yield 61%. GC purity of 81.5%.

Example 3. Obtaining 1-(4-chlorophenyl)-2-methyl-3-butene-1-it.

To a solution of 27.5 g (0.2 mol) of 4-chlorobenzonitrile in 180 ml of THF, add 52,0 g (0.8 mol) of zinc dust and cooled the reaction mass to 10°C. Then the reaction mass is added for 10.68 g (0.08 mol) of aluminum chloride, the temperature of the reaction mixture rises to 25°C. To the resulting suspension is added dropwise 27,15 g (0.3 mol) of chloride Crotia in 135 ml of THF for 1 hour 30 minutes. The temperature of the reaction mixture rises to 30°C. Maintaining the temperature of the reaction mass 35-40°With, it is stirred for 4 hours. Then to the reaction mixture add 210 ml of Gex is on, cooled to 0°and slowly add 160 ml of 2M hydrochloric acid. The layers separated, the organic layer washed with 2M hydrochloric acid (2 x 100 ml), 5%solution of sodium carbonate (2 x 120 ml) and saturated sodium chloride solution (3 x 100 ml). Dried over anhydrous sodium sulfate. The solvent is removed, and the residue is distilled in vacuum. Get 33,84 g of 1-(4-chlorophenyl)-2-methyl-3-butene-1-it. Yield 87%, purity according to GC 76,7%.

Example 4. Obtaining 1-(4-chlorophenyl)-2-cyclopropylamino-1-it.

To a suspension of 7.8 g (0.12 mol) of zinc dust and 1.19 g (0.012 mol) odnoklasniki copper in 40 ml of dichloromethane added with 5.22 g (0.03 mol) of dibromomethane, and then to 0.19 g (0,0024 mol) acetyl chloride and stirred for 10 minutes. Then to the reaction mixture for 15 minutes add 5,74 g (0.03 mol) of 1-(4-chlorophenyl)-2-methyl-3-butene-1-she's in 15 ml of dichloromethane. Then to the reaction mass for 15 minutes and added dropwise 10,44 g (0.06 mol) of dibromomethane in 5 ml of dichloromethane. The reaction mass is heated to 40°C and stirred at a temperature of 40-45°5 hours. Then the reaction mass is cooled, add 40 ml of hexane and cooled to 0°C. then add 30 ml of 2M hydrochloric acid. The layers separated, the organic layer washed with 2M hydrochloric acid, 5%soda solution and saturated sodium chloride solution. Dried over anhydrous sodium sulfate, the solvent is removed in VA is uume. Get lower than the 5.37 g of 1-(4-chlorophenyl)-2-cyclopropylamino-1-it. Yield 86%, GC purity of 81%. Total yield, considering 4-chlorobenzonitrile is 70,4%.

Example 5. Obtaining 1-(4-chlorophenyl)-2-cyclopropylamino-1-it.

To a solution of 6.87 in g (0.05 mol) of 4-chlorobenzonitrile in 60 ml of a mixture of solvents, ether and THF (85:15 ratio), add 13 g (0.2 mol) of zinc dust and 2.67 g (0.02 mol) of aluminium chloride. Then at room temperature for 1 hour add 6,79 g (0,075 mol) of chloride Crotia in 10 ml of solvent mixture. The reaction mass is stirred for 3 hours at 34°C. Then the reaction mass is filtered, the filtrate is placed in another flask and add to it the 14.3 g (0.22 mol) of zinc dust, 4.35 g (0,044 mol) odnoklasniki copper and 26.1 g (0.15 mol) of dibromomethane. The reaction mass is stirred in an ultrasonic bath for 5 hours at a temperature of 36-42°C. Then cooled to 0°and carefully add 50 ml of 2M hydrochloric acid, stirred for 10 minutes and transferred into a separating funnel. The layers separated, the aqueous layer was extracted with ether (2 x 30 ml). The combined organic fractions washed with 2M hydrochloric acid (2 x 30 ml) and water (3 times 50 ml). The solvent is removed in vacuum. Get 8,93 g of 1-(4-chlorophenyl)-2-cyclopropylamino-1-it. The yield of 85.7%, GC purity of 84%.

Example 6. Obtaining 1-(4-chlorophenyl)-2-cyclopropylamino-1-it.

To a solution of 20,61 g (0.15 mol) of 4-chlorobenz the nitrile in 120 ml of a mixture of solvents, the ether and THF (ratio 85:15)to give 39 g (0.6 mol) of zinc dust and 8,01 g (0.06 mol) of aluminium chloride. Then at room temperature for 1 hour add 20,37 g (0,225 mol) of chloride Crotia in 60 ml of a mixture of solvents. The reaction mass is stirred for 3 hours at 34°C. Then the reaction mass is filtered and the filtrate is transferred into an addition funnel.

The flask 39 g (0.6 mol) of zinc dust, 5,94 g (0.06 mol) odnoklasniki copper, and 26.1 g (0.15 mol) of dibromomethane in 90 ml of ether. Then in the flask add 0,92 g (0.012 mol) of acetyl chloride. The flask is heated on a water bath temperature of 35°C, 5 minutes. Reaction mass of light gray becomes dark gray. Then 10 minutes add the reaction mass from the previous stage. Then added dropwise at 52.2 g (0.3 mol) of dibromomethane in 30 ml of ether. The reaction mass begins to boil, dibromethane added dropwise with such a rate as to maintain uniform boiling. After adding dibromethane the mixture is stirred for 5 hours at 45-50°C. Then the reaction mass is then cooled to 0°and slowly added 150 ml of 2M hydrochloric acid. Stirred for 10 minutes and transferred into a separating funnel. The layers separated, the aqueous layer washed with ether (2 times 50 ml). The organic fractions are combined and washed with 2M hydrochloric acid (2 x 50 ml) and water (3 times with 70 ml). Dried over anhydrous sodium sulfate. actuarial removed get 27,01 g of 1-(4-chlorophenyl)-2-cyclopropylamino-1-it. Yield 86%, GC purity of 78%.

Example 7. Obtaining 1-(4-chlorophenyl)-2-cyclopropylamino-1-it.

To a suspension of 26 g (0.4 mol) of zinc dust in 50 ml of a mixture of dioxane with THF (ratio 80:20) add 5.34 g (0.04 mol) of aluminium chloride. Then the flask was added dropwise over 15 minutes to a mixture of 13.7 g (0.1 mol) of 4-chlorobenzonitrile and 25 ml (0.15 mol) of chloride Crotia in 100 ml of solvent mixture. The reaction mass is stirred for 4 hours at 30-40°C. the Reaction mixture is filtered and the filtrate is transferred into an addition funnel.

The flask 26 g (0.4 mol) of zinc dust, 60 ml of benzene and 8 ml (0.1 mol) of dibromomethane, 4 g (0.04 mol) odnoklasniki copper and a few drops of trimethylchlorosilane. Heated to 40°C and stirred for 5 minutes. Then within 30 minutes, add the filtrate from the first stage. After adding the filtrate injected dropwise 16 ml (0.2 mol) of dibromomethane for 30 minutes. The reaction mass is stirred for 5 hours at 40-45°C. Then cooled to 0°and carefully add 250 ml of 2M hydrochloric acid, stirred for 5 minutes. Transferred into a separating funnel and separated layers. The organic phase is washed with 250 ml of 3%solution of sodium bicarbonate and 250 ml of saturated solution of sodium chloride. Dried over anhydrous sodium sulfate. The solvent is removed. Obtain 18 g of 1-(4-chlorophenyl)-2-cyclopropylamino-1-it. In the course of 86%. GC purity of 77%.

Example 8. Obtaining 1-(4-chlorophenyl)-2-cyclopropylamino-1-it.

To a solution of 6.87 in g (0.05 mol) of 4-chlorobenzonitrile in 40 ml of THF added 13,0 g (0.2 mol) of zinc dust and 2.67 g (0.02 mol) of aluminum chloride. Then at room temperature for 40 minutes add 6,79 g (0,075 mol) of chloride Crotia in 40 ml of THF. The reaction mass is stirred for 3.5 hours at a temperature of 34-37°C. Then, the THF removed in vacuo, and the residue is dissolved in 40 ml of methylene chloride.

A suspension of 13.0 g (0.2 mol) of zinc dust and 0.12 g (0.001 mol) odnoklasniki copper in 55 ml of methylene chloride is heated to 35°and at this temperature, add 3.0 ml (0,0015 mol) of a 0.5m solution of detribalized in diglyme and stirred for 15 minutes at this temperature. Then quickly add the solution from the previous stage. After that 45 minutes was added dropwise a solution of 26.1 g (0.15 mol) of dibromomethane in 10 ml of methylene chloride at a temperature of 35-37°C. Upon completion of addition, dibromethane in the reaction mass is added 0,074 g (0,0007 mol) odnoklasniki copper and stirred the reaction mass at 40-45°C for 5 hours.

Then the reaction mass is then cooled to 0°and add 50 ml of 2M hydrochloric acid. The layers are separated, the combined organic layers washed with 2M hydrochloric acid (2 x 50 ml), saturated sodium chloride solution (2 times 50 ml) and water (3 times the 50 ml) and dried over anhydrous sodium sulfate. The solvent is removed. Get 8,64 g of 1-(4-chlorophenyl)-2-cyclopropylamino-1-it. Yield 83%. GC purity of 78%.

Example 9. Obtaining 1-(4-chlorophenyl)-2-cyclopropylamino-1-it.

To a solution of 6.87 in g (0.05 mol) of 4-chlorobenzonitrile in 40 ml of THF added 13,0 g (0.2 mol) of zinc dust and 2.67 g (0.02 mol) of aluminum chloride. Then at room temperature for 40 minutes add 6,79 g (0,075 mol) of chloride Crotia in 40 ml of THF. The reaction mass is stirred for 3.5 hours at a temperature of 34-37°C. Then, the THF removed in vacuo, and the residue is dissolved in 40 ml of methylene chloride.

A suspension of 13.0 g (0.2 mol) of zinc dust and 0.12 g (0.001 mol) odnoklasniki copper in 55 ml of methylene chloride is heated to 35°and at this temperature, type of 0.43 g (0,0015 mol) of a 70%aqueous solution of sodium bis-(2-methoxyethoxy)-dehydroalanine in toluene and stirred for 15 minutes at this temperature. Then quickly add the solution from the previous stage. After that 45 minutes was added dropwise a solution of 26.1 g (0.15 mol) of dibromomethane in 10 ml of methylene chloride at a temperature of 35-37°C. Upon completion of addition, dibromethane in the reaction mass is added 0,074 g (0,0007 mol) odnoklasniki copper and stirred the reaction mass at 40-45°C for 5 hours.

Then the reaction mass is then cooled to 0°and add 50 ml of 2M hydrochloric acid. The layers are separated, the combined organic layers industry is with 2M hydrochloric acid (2 x 50 ml), a saturated solution of sodium chloride (2 times 50 ml) and water (3 times 50 ml) and dried over anhydrous sodium sulfate. The solvent is removed. Get a 8.34 g of 1-(4-chlorophenyl)-2-cyclopropylamino-1-it. Yield 80%. GC purity of 76%.

1. The way to obtain 1-(4-chlorophenyl)-2-cyclopropylamino-1-it (I)

namely, that

a) 4-chlorobenzonitrile subjected to interaction with chloride or bromide by Croteam and zinc in an organic solvent and, optionally, in the presence of aluminum chloride, to obtain, after hydrolysis of the reaction mixture of 2M hydrochloric acid, extraction and purification of 1-(4-chlorophenyl)-2-methyl-3-butene-1-it (II)

b) the obtained 1-(4-chlorophenyl)-2-methyl-3-butene-1-he (II) is subjected to interaction with dibromethane, zinc and odnoklasniki copper in an organic solvent in the presence of a catalyst or in an ultrasonic bath, followed by separation of the target product in a known manner.

2. The method of receiving according to claim 1, characterized in that the interaction with dibromethane, zinc and odnoklasniki copper (cyclopropanecarbonyl) were separated from the precipitate of the reaction mass formed after the reaction of 4-chlorobenzonitrile, zinc chloride and katila, with subsequent hydrolysis of 2M hydrochloric acid enjoyment of the operating mixture, formed after the reaction of cyclopropylamine.

3. The method of receiving according to claim 1 or 2, characterized in that as catalysts in the second stage of the process using acetyl chloride, or trimethylchlorosilane, or detribalized, or sodium bis-(2-methoxyethoxy)-dehydroalanine.

4. The way to obtain 1-(4-chlorophenyl)-2-methyl-3-butene-1-it

namely, that 4-chlorobenzonitrile subjected to interaction with chloride or bromide by Croteam and zinc dust to the solution tetragidrofurana, not necessarily in the presence of aluminum chloride at a temperature of 10-40°With the process of obtaining includes a step of isolation and purification, in which the reaction mass after adding to it is not miscible with water, an organic solvent is treated with 2M hydrochloric acid and produce the target product from the organic solvent by a known method.