The method of obtaining derivatives of propargylamine

 

(57) Abstract:

The invention relates to a method for producing L-isomers derived propargylamine General formula I

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where Y is hydrogen or fluorine atom, by decomposition of a D-tartrate-L-isomer amine of General formula II

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where Y is specified above, and interaction obtained L-isomer amine of General formula II in the presence of a base, with a halide of General formula V where X is halogen, followed by the interaction of the thus obtained L-isomer of General formula III

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with hydrogen chloride in an organic solvent. When this occurs, the release of the amine bases of D-tartrate-L-isomer amine of General formula II in aqueous suspension with ammonium hydroxide or salt of an alkali metal and/or ammonium salts and its interaction with 1-1,5 molar equivalents of a halide of General formula V at a temperature of 0-50oIn a buffer system with a pH of 8-12. After separation of the aqueous layer lead extraction mixture containing L-isomers of amines of the General formulas II and III in an organic solvent, water and a mixture of ammonium hydroxide and water and/or aqueous solution of a phosphate salt with a pH of 5.5 to 7.5. Next, dissolve the L-isomer amine of General formula III or its salts in aqueous layer I after distillation in the L-isomer salts of the General formula I. The method allows to obtain pure racemic form of the product. 2 C.p. f-crystals.

The present invention relates to environmentally safe way to obtain hydrochloride of 1-N-methyl-N-(2-phenyl-1 - methyl)-ethyl-N - propargylamine formula (Ia):

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referred to in this description of Selegiline. HCl (Selegilinee - HCl), and hydrochloride of 1-N-methyl-N-(2-(4-forfinal)-1 - methyl)-ethyl-N-propargylamine formula (Ib):

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referred to below p-fluoro-Selegiline-HCl - with good yield and without contaminants.

Thus, the invention relates to the derivatives of propargylamine having General formula (I):

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A method of obtaining the compound of formula (Ia), but without optical activity, (Hungarian patent application N 151090). The racemic form of the compound of formula (Ia) is prepared in several ways. In accordance with Examples 1 and 2 above works 1,3-dibromopropan added to N-(2-phenyl-1-methyl)-ethyl-N-methylamine and the reaction mixture was kept at 100oC for 7 hours. At the first station in response receive N-(2-phenyl-1-methyl)ethyl-N - methyl-N-(2-bromopropionyl)amine, after which the selection process liquor.

After distillation of the N-methyl-N-(2-phenyl-1-methyl)ethyl-N - propargylamine with vygodoi with Example 7 N-methyl-N-(2-phenyl-1-methyl)ethylamine interacts with propargylamine in alcoholic medium in the presence of aluminum metal. After adding to the reaction mixture liquor with the release of 48.6% get desired derived N-propargylamine.

Another known method is disclosed in the method of Example II Condensation of 2-phenyl-1-methylethylamine and N-methyl-N-propargylamine carried out under pressure. The reaction mass is treated with alkali and 35% receive the desired product.

In Example 5, the Hungarian patent application N 151090 reveals the way that from the point of view of starting materials similar to the proposed method. To 0.2 mmole of N-methyl-N-(2-phenyl-1-methyl)- ethyl-amine add 0.1 mol of propylbromide and the reaction mass is maintained at 100oC for 2 hours. Half of the initial amount of amine is binding forming hydrogen bromide. Although based on propylbromide output racemic product is 85%, from a practical point of view the whole process is not preferred due to the fact that (see Hungarian patent application N 187775) provide for the allocation of expensive amine, which is used as an agent that binds acid, by benzoylation, followed by the separation and hydrolysis, when this is not the product launch stage of the selection.

The known method polychemical-N-(2-phenyl-1-methyl)ethylamine interacts with paraformaldehyde, and then with acetylene in the presence as catalyst CuCl2. Optically active base of formula (IIIa)

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get with the release of approximately 20%. For compounds of formula Ia yield of the target product are not listed.

According to this method as the environment for the first time use water-insoluble solvent, and reaction with propylbromide is carried out at a temperature of 50-60oC. In this reaction, do not use the active binding agent and the released hydrogen bromide is associated with excess amine.

Thus, currently there is no way that industrial implementation can provide a good yield of compounds of formula (Ia).

New practical solution is not to use an excess of N-methyl-N-(2-phenyl-1-methyl)ethylamine for binding the acid, as the problem of efficient allocation of amine could not be solved. In accordance with the known method of the optically active base is released from L-N-methyl-N-(2-phenyl-1-methyl)ethyl-D - tartrate obtained in the fission process, referred to as L-methyl-Anara-D-tartrate. This method is carried out by adding water to the above tartrate (Sol) and strong his Podlachia osvobozhdalsya amine is extracted with water-immiscible solvent from the resulting aqueous solution. To ensure the most complete extraction of the amine aqueous layer was subjected to an additional extraction. As the water-immiscible solvent used aprotic solvents, such as benzene, toluene, ethylene dichloride, diisopropyl ether. The alkylation is carried out at the interaction of 1-N-methyl-N-(2-phenyl-1-methyl)ethylamine, 1-medianera dissolved in an organic solvent, with propylbromide at 55-60oC. the Reaction of alkylation is carried out in an organic solvent at a temperature of 50-60oC using propylbromide (first mentioned in Example 1 Hungarian patent application N 154655). The novelty of the method according to Hungarian patent application N 187775 is to use an aqueous alkali solution as an agent that binds acid to bind hydrogen bromide, forming in the process of alkylation, and used as a reaction medium water emulsion-solvent.

The reaction mixture alkylation process by separating the layer of organic solvent and washing the latter with water. Specified organic layer contains unreacted starting materials and side products that are close to the base of the formula (IIIa). Amine bases,aqueous acid. As the acid used inorganic acids with acidic exponent 1.0-2.12 or organic acids with acidic exponent 3.75-4.87, and in order to reduce the dissolution of the main product, use a method similar titration. Thus purified the basis of the formula (IIIa) are dissolved in a water-immiscible solvent, is treated with ethyl alcohol in hydrochloric acid, part of the mixture obtained solvent is evaporated and cooled the rest, then get the crystalline hydrochloride of the formula (I):

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The maximum yield is 65% (Example 1), while the yield of the target product according to an earlier proposal of Hungary is only 43%. It is also known that according to European patent application N 0344675 compound of formula (Ia) are obtained in an anhydrous solvent in the presence of potassium carbonate as acid binding agent by alkylation, the yield of the target product 56,6% after a difficult cleanup operations.

In accordance with European patent application N 0186680 the desired product is 1-p-fluoro-Selegiline-HCl. The alkylation reaction starting with racemic amine, optically active amine, respectively, with 1-p-fluoro-medianera-o-tartrate and who I associate acid or reaction medium in the form of emulsions of the water-solvent when used as an agent for binding the acid ammonium hydroxide. The maximum output is 47.1% (Example 5).

The method according to the present invention eliminates the above disadvantages.

Thus the present invention is to develop a possible method, compounds of General formula (I) in good yield and high purity, as well as the development of a simple and environmentally friendly way.

This method solves the problem lies in the fact that conduct the decomposition of the D-tartrate-L-isomer amine of General formula (II)

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with the Foundation of the subsequent interaction of the L-isomer amine of General formula (II) with a halide of General formula (V):

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In the presence of a base and interaction thus obtained L-isomer of General formula (III) with hydrogen chloride in an organic solvent, where

- X represents a halogen atom,

- Y represents a hydrogen atom or fluorine.

This method is characterized by the release of the amine bases of D-tartrate-L-isomer amine of General formula (II), where Y takes the values defined above, in an aqueous suspension with ammonium hydroxide or salt of an alkali metal and/or ammonium salt, and interaction in the buffer of the formula (V): where

- X takes the values defined above,

at a temperature of 0-50oC, and after separation of the aqueous layer, extracting a mixture containing Z-isomers of amines of the General formulas (II) and (III) in the organic layer, water, a mixture of ammonium hydroxide and water and/or aqueous solution of forstate with pH 5.5-7.5, and the dissolution of the L-isomer amine of General formula (II) or its salt in the water layer and the selective separating it from the L-isomer amine of General formula (III) and the transformation of the L-isomer amine of General formula (III) distillation residue in the L-isomer salts of General formula (I) by using method, which is in itself known.

Thus, the present method has the following advantages.

The selection of the optically active secondary amine is carried out in a reaction medium alkylation, resulting in no need for solvent extraction and the operation of separation of the organic layer, there is no loss in yield of product and no pollution (Hungarian patent application N 187775).

In response propargylamine do not use any dilution solvent or hydroxide of an alkali metal as an agent for binding the acid, and the reaction of alkylation is carried out in a buffer mixture on the basis of the wine to the amine base of General formula (III)

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practically does not contain any pollutants or source materials.

Purity amine bases of General formula (III), provided in accordance with this invention, provides the ability to remove a small amount of starting materials and side products prominent or water-ammonia extraction or by selective and simple double salt formation. For this purpose, use acid salt of General formula (IV)

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in aqueous solution. In this formula, A+represents ions of sodium, potassium or ammonium. Acid salt of General formula (IV) have a very low acidity, pKa= 7.21, which corresponds to the dissociation constant of the acid, and therefore, when using the cleaning method of the proposed method there is no problem of dissolution of the amine bases of General formula (III), because the basicity of the compounds is too small for salt formation. Inorganic acid, pKa = 1.0-2.12 (dissociation constant acid), and organic acid, pKa = 3.75-4.87 (dissociation constant acid), which is used for cleaning in the Hungarian patent application N 187775 are strong or moderate acids and their use leads to the dissolution of the primary product is of the need to use water-immiscible solvent, mainly benzene, toluene, to highlight the final product of General formula (I), and the use of such solvents is a big disadvantage from the point of view of industrial applicability, as well as from the point of view of ecology. In developed countries with strict guidelines for quality products, through the development of rigorous tests on the residual content of solvent, pharmaceutical materials, obtained using water-immiscible solvents may be used. When implementing this method instead of the undesirable mixture of solvents can be used to obtain compounds of General formula (I) is a water-soluble solvent, preferably acetone, isopropanol. The use of acetone as the reaction medium provides an additional advantage because of its selective solvent capacity and retention of contaminating materials present in a minimum amount, you can receive the product, the degree of purity which is far superior to the quality guidelines. Data HPLC indicate that the degree of purity is at least 99.9%, and the content of known and unknown impurities is less than 0.1%

Selegiline-CHL is listello 91%. The highest output of the known methods is 85%. (Example 5 Hungarian patent application N 151090),but this value is calculated on the alkylating agent is achieved by using a double excess methyl-Anara relatively Selegiline-base formula (IIIa) of unknown quality. In the known method (Hungarian patent application N 187775) in the allocation of the excess amine losses can be 40-50%, so this method is very uneconomical. In accordance with the Hungarian patent application N 187775 excess L-methyl-Anara-D-tartrate is no longer used, but the output is significantly reduced. The highest output is based on the original L-methyl-Anara-D-tartrate reaches 65% (Example 1). From the alkaline mother liquor and the wash liquids allocate additional 7.6-19% product, but the composition of this product is not given and it is impossible to determine which processing of this product needed to get the product that matches the first. In accordance with experiments of the applicant this output is only about 30%.

The maximum yield of Example 5, related to obtaining p-fluoro-Selegiline-hydrochloride, in European patent application N 0186680 is only 47.1% versus 85%, achieved by way n examples.

Example 1

Mix 149.7 g(0.5 mole) of L-methyl-Anara-D-tartrate and 210 g of concentrated ammonium hydroxide and the resulting mixture stirred at 20-25oC for 10 minutes Add 65.5 g (0.55 mole) of propargylamine and stirred for 3 hours at 30-35oC. Then add 210 ml of water and at a temperature of 20-25oC layers separated.

The oily layer is stirred with a mixture of 25 ml of water and 25 g of concentrated ammonium hydroxide, then add 50 ml of water and separated. The top layer (Selegiline-base) is distilled in a vacuum at a pressure of - 0.1-0.2 kPa. The distilled product is dissolved in 300 ml of acetone and by introducing gaseous hydrogen chloride bring the pH of the solution to 2-2.5 at a temperature of 20-30oC. the Suspension is crystallized for 2 h at -10oC, filtered, washed with acetone and dried. Get 101.8 g of L-N-methyl-N-(2-phenyl-1 - methyl)ethyl-N-propargylamine hydrochloride with a yield of 91%. According to HPLC the purity of the obtained product corresponds to 99.9%. The number of known and unknown impurities is less than 0.1%.

Example 2

Mix 149.7 g (0.5 mole) of L-methyl-Anara-D-tartrate, 210 ml of water and 210 g of concentrated ammonium hydroxide and stirred for 10 minutes Add 65.5 g (0.55 mole) disappear to the round 40-45oC another hour. After cooling to 20-25oC layers are separated and repeat the procedure described in Example 1.

Output: 100.7 g Selegilina. HCl, 90%.

The quality of the product matches the quality of the product obtained in Example 1.

Example 3

Repeat the procedure described in Example 2, and the resulting reaction mixture alkylation share at a temperature of 20-25oC. the Upper layer is shaken with water (2 x 25 ml) and then with 10% solution of sodium dihydrophosphate (2 x 30 g) and 25 ml of water. The mixture is separated. The top layer is distilled as in Example 1 and worked up. Yield: 98.5 g, 88%.

According to the HPLC purity of the product is at least 99.8%, and the content of known and unknown impurities is less than 0.05%.

Example 4

Mix 149.7 g (0.5 mole) of L-methyl-Anara-D-tartrate, 175 g of concentrated ammonium hydroxide and 175 ml of water. The resulting mixture was stirred for 10 min at 20-25oC and add 41.0 g (0.55 mole) of propargylamine. Then you can use the technique described in Examples 1 or 3.

Yield: 95 g, 85%.

The quality of the product is identical to the quality of the product obtained in Example 1.

Example 5

Mix 178.6 g (0.5 mole) of p-fluoro-L-methyl-Aut for 10 min at 20-25oC.

The mixture is cooled to 0oC and add 65.5 g (0.55 mole) of propargylamine. The mixture is stirred at 0-5oC, and then 1.5 hours at 20-25oC. the Layers are separated. The upper oily layer is shaken with a saturated solution of sodium chloride (2 x 30 g) and a solution of sodium dihydrophosphate (10% wt.) solution (2 x 30 g), and then with a solution (saturated) sodium chloride (2 x 30 g) and share. The top layer (p-fluoro-Selegiline-base) is distilled in a vacuum at a pressure of 0.1-0.2 kPa. The distilled product is dissolved in 300 ml of acetone and by introducing at 15-25oC gaseous hydrogen chloride bring the pH to 2.5. Suspension crystallized for 2 hours at 10oC, filtered, washed with acetone and dried. Get 102.3 g of p-fluoro-Selegiline-hydrochloride, yield 85%. According to the HPLC purity of the product is 99.9%.The content of known and unknown impurities is less than 0.1%

Example 6

Mix 149.7 g (0.5 mole) of L-methyl-Anara-D-tartrate, 750 ml of water and 414.6 g (3.0 mol) of potassium carbonate and the resulting mixture stirred for 10 min at a temperature of 30-35oC. Then add 65.5 g (0.55 mole) of propargylamine and stirred for one hour at a temperature of 35-40oC and one hour at a temperature of 40-45ml), separated and the upper layer is distilled and processed in accordance with the procedure described in Example 1.

Output: 101.8 g Selegiline-HCl, 91%.

According to HPLC the purity of the product corresponds to 99.9%. The content of known and unknown impurities is less than 0.1%.

Example 7

Mix 149.7 g (0.5 mole) of L-methyl-Anara-D-tartrate, 750 ml of water and 318.0 g (3 mol) of sodium carbonate and the resulting mixture stirred for 10 min at a temperature of 30-35oC. was Added 65.5 g (0.55 mole) of propargylamine and stirred for 1 hour at 35-40oC,and then for 0.5 hour at a temperature of 45-50oC. After cooling to 20-25oC lower layer separated. The upper oily layer is mixed with water (5 x 50 ml) and separated. Next, the top layer is distilled and treated with obtaining Selegiline-HCl according to the method of Example 1.

Output: 101.8 g, 91%

According to HPLC the purity of the product corresponds to 99.9%. The content of known and unknown impurities is less than 0.1%.

Example 8

The reaction mixture alkylation obtained by the method of Example 6 or 7, separated at a temperature of 20-25oC. the Upper layer is shaken with water (2 x 50 ml) and then with 10% solution of sodium dihydrophosphate (2

Output: 99.5 g,89%

According to HPLC the purity of the product corresponds to 99.9%. The content of known and unknown impurities is less than 0.05%.

Example 9

Mix 88.3 g (0.25 mole) of p-fluoro-methyl-Anara-D-tartrate (dihydrate), 375 ml of water and 138.2 g (1 mol) of potassium carbonate and stirred for 10 min at a temperature of 30-35oC. the Mixture is cooled to 10-15oC. Add 35.7 g (0.3 mole) of propargylamine and stirred at 15-20oC for 30 min, and then at 20-25oC for 2.5 hours. The layers are separated. The upper oily layer is shaken with 25 ml of water, 25 g of a saturated solution of sodium chloride, 10% solution of sodium dihydrophosphate (2 x 15 g) and a saturated solution of sodium chloride (2 x 25 g) and separated. The upper oily layer (p-fluoro-Selegiline-base) is distilled in a vacuum at a pressure of 0.1-0.2 kPa. The distilled product is dissolved in acetone and by introducing at a temperature of 15-25oC gaseous hydrogen chloride pH adjusted to 2.5-3.5. Suspension crystallized for 2 hours at -10oC, filtered and washed with acetone, and then dried. Get 45.3 g of p-fluoro-Selegiline-hydrochloride, yield 75%.

According to HPLC the purity of the product corresponds to 99.9%.

The content of the informed-Anara-D-tartrate (dihydrate), 375 ml of water and 159.0 g (1.5 mol) of sodium carbonate and the resulting mixture stirred for 10 min at a temperature of 30-36oC. Next, using the method of Example 9 and the mixture is processed.

Output: 45.3 g, 75%.

The quality of the product matches the quality of the product of Example 9.

Example 11

Mix 88.3 g (0.25 mole) of p-fluoro-L-methyl-Anara-D-tartrate (dihydrate), 105 g of concentrated ammonium hydroxide, 105 g of water and the resulting mixture stirred at 20-25oC for 10 minutes the Mixture is cooled to 5-10oC and added 32.8 g (0.275 mol) of propargylamine. The mixture is stirred for one hour at a temperature of 5-10oC for 1 hour at a temperature of 20-25oC and for 1 hour at 40-45oC. the Layers are separated, the upper oily layer is shaken with a mixture of water (2 x 25 ml) and 25 ml of concentrated ammonium hydroxide and with saturated sodium chloride solution (2 x 25 g), the layers separated. The mixture is treated in accordance with the method of Example 9.

Output: 48.3 g (80%).

The quality of the product matches the quality of the product obtained in Example 9.

Example 12

When 20-25oC in the doctrine stirred for 10 min 88.3 g (0.25 mole) of p-fluoro-L-methyl-Anara-D-tartrate is I) propylbromide. The mixture is stirred for one hour at 5-10oC for a further one hour at 25-30oC and separate the layers. The upper oily layer is shaken with 25 ml of water, 25 g of saturated salt solution, with 9% (wt.) a solution of sodium dihydrophosphate (2 x 15 g) and a 1% solution of sodium hydrogen phosphate (2 x 15 g) and 25 g of a saturated solution of sodium chloride and the layers separated. The mixture is treated in accordance with the method of Example 9.

Output: 48.3 g, 80%.

The quality of the product matches the quality of the product obtained in Example 9.

Example 13

Mix 88.3 g (0.25 mole) of p-fluoro-L-methyl-Anara-D-tartrate (dihydrate), 105 g of concentrated ammonium hydroxide and 105 g of water and the resulting mixture stirred for 10 min at 20-25oC. the mixture is cooled to 5oC and added 32.8 g (0.275 mol) of propargylamine. The mixture is stirred for 0.5 hours at 5-10oC, and then at 25-30oC for another 1.5 hours. The mixture is cooled to 20 to 25oC and the layers separated. The upper oily layer is shaken with 25 ml of water, 25 g of a saturated solution of sodium chloride, 2% aqueous solution of sodium hydrogen phosphate (2 x 15 g) and 8% solution of sodium dihydrophosphate (2 x 15 g) and 25 g of a saturated solution of sodium chloride and share. Ver Aut in 150 ml of isopropyl alcohol and adding hydrochloric acid at 15-25oC pH adjusted to 3.0-3.5. Suspension crystallized for 2 hours at -10oC, filtered, washed with isopropyl alcohol and dried.

Receive 48.3 g (80%) p-fluoro-Selegiline-hydrochloride. The quality of the product matches the quality of the product obtained in Example 9.

1. The method of obtaining L-isomer derived propargylamine General formula I

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where Y is hydrogen or fluorine atom,

by decomposition of the D-tartrate-L-isomer amine of General formula II

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where Y is specified above,

in aqueous-alkaline medium and the interaction of the obtained L-isomer amine of General formula II in the presence of a base with alogrithm General formula V

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where X is halogen,

with the subsequent interaction of the thus obtained L-isomer of General formula III

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with HCl in an organic solvent, characterized in that the release of the amine bases of D-tartrate-L-isomer amine of General formula II where Y takes the value defined above, is carried out in aqueous suspension with ammonium hydroxide, or salt of an alkali metal and/or ammonium salt, followed by interaction with 1 to 1.5 molar equivalents of halide of General formula V at a temperature of 0 - 50oIn a buffer system with a pH of 8 to 12, about reagirovanie mixture, containing L-isomers of amines of the General formulas II and III in an organic layer, water and a mixture of ammonium hydroxide and water and/or aqueous solution of phosphate (salt) pH 5.5 - 7.5 and the dissolution of the L-isomer amine of General formula II or its salts in the water layer and the selective separating it from the L-isomer amine of General formula III, and then the transformation of the L-isomer amine of General formula III after distillation in the L-isomer salts of the General formula I.

2. The method according to p. 1, characterized in that it includes the use as a phosphate salt monoosnoc phosphate salt of General formula IV

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where A+represents ions of sodium, potassium or ammonium.

3. The method according to p. 1, characterized in that it comprises using as the organic solvent is acetone or isopropanol to highlight salts of the General formula I.

 

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17 cl, 22 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 50-60% aqueous solution of quaternary ammonium salt of the formula: [(CH3)2-N-(CH2-CH=CHCl)2]+Cl- or [(CH3CH2)2-N-(CH2-CH=CHCl)2+Cl- and its using as an antistatic agent for fiber glass. Method involves interaction of a cleared waste in manufacturing allyl chloride containing 30-50 wt.-% of 1,3-dichloropropenes, 30-60 wt.-% of 1,2-dichloropropane and 3-5 wt.-% of 1,2,3-trichloropropane with dimethylamine at temperature 5°C or with diethylamine at temperature 50°C and in the mole ratio 1,3-dichloropropene to amine = 1.0:(1.0-1.1) followed by addition of stoichiometric amount of NaOH taken as 25-30% solution to reaction mass. Then tertiary amine chlorides-containing organic phase is separated and stoichiometric amount of 1,3-dichloropropene is added to organic phase followed by holding the prepared solution at temperature 70-80°C for 4-5 h and addition of desalted water to obtain 50-60% aqueous solution of the corresponding quaternary salt. This solution is settled and organic phase containing mainly 1,2-dichloropropane and 1,2,3-trichloropropane is separated. Method provides preparing a novel and relatively inexpensive antistatic agent and to utilize waste in manufacturing allyl chloride.

EFFECT: improved method of synthesis and preparing.

2 cl, 1 tbl, 3 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to improved method for production of 2-(1-aminoethyl)bicyclo[2.2.1]heptane hydrochloride useful as active ingredient in drug with high activity against A and B type influenza viruses as well as parainfluenza viruses. Claimed method includes interaction of 5-acetylbicyclo[2.2.1]hept-2-ene with hydroxylamine hydrochloride and sodium hydroxide in aqueous medium followed by hydration of obtained 5-acetylbicyclo[2.2.1]hept-2-ene oxime with hydrogen in presence of Raney nickel and treatment of obtained 2-(1-aminoethyl)bicyclo[2.2.1]heptane with hydrogen chloride or hydrochloric acid, wherein 5-acetylbicyclo[2.2.1]hept-2-ene oxime is hydrated in presence of alkali metal hydroxide or earth-alkali metal oxide or ammonia in lower saturated alcohols at 10-40°C and initial hydrogen pressure of 4.55-5.07 MPa.

EFFECT: Improved method for production of 2-(1-aminoethyl)bicyclo[2.2.1]heptane hydrochloride.

1 cl, 4 ex

FIELD: chemical technology, pharmacy.

SUBSTANCE: invention relates to an improved method for preparing sertraline hydrochloride form V that possesses the antidepressant effect. Method involves the following steps: (a) dissolving or suspending sertraline mandelate in a protonic solvent or a mixture of protonic solvents; (b) decreasing pH value of solution or suspension by addition of HCl aqueous solution of HCl solution in protonic solvent with addition of water to form a clear solution, and (c) isolation of the sertraline hydrochloride form V. At step (a) solvents from group comprising alcohol, water or their mixtures are chosen as solvents. For example, an alcoholic solvent used in step (a) can be chosen from group comprising methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, tert.-butyl alcohol and isobutyl alcohol or their mixtures but isopropyl alcohol is preferable. The dissolving or suspending step (a) is carried out at heating and/or stirring in solvent at temperature in the range 20-90oC usually. Decreasing the pH value in step (b) is carried out usually up to the range 1-3 preferably. Sertraline hydrochloride form V obtained at step (c) is isolated by cooling the mixture obtained at step (b). Cooling is carried out under natural conditions to room temperature or using mild cooling agents, such as cold water, water, alcohol or their mixtures wherein indicated alcohol is chosen from group comprising monohydric alcohol, dihydric alcohol or their mixtures. Also, invention relates to a method for preparing a pharmaceutical composition with immediate releasing the sertraline hydrochloride form V that involves mixing sertraline hydrochloride form V prepared by cl. 1 having particles size less 20 mcm and in the amount 90% of the total amount of particles, not less, with a pharmaceutically acceptable diluting agent, carrier or carrier. Proposed method provides simplifying the process for preparing the preparation based on decreasing the total amount of steps.

EFFECT: improved preparing method.

14 cl, 4 sch, 2 dwg, 1 tbl

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of didecyldimethyl ammonium bromide. Method involves interaction of decyl bromide with dimethylamine with addition of inorganic base aqueous solution. Decyl bromide is stirred with dimethylamine at room temperature for 45 min, not less, followed by heating the reaction mixture to temperature (92 ± 2.0)0C at the rate 1.50C/min, not above, and adding an inorganic alkaline reagent solution at the rate (0.85-1.0) dm3/min. Reaction is carried out in the mass ratio of reagents = 1:(0.1-0.12):(0.11-0.13), respectively to obtain organic layer that is separated and purified by treatment with an inorganic acid extractant. Stirring is carried out at room temperature for 60 min and reaction mixture is heated to 940C at the rate 0.80C/min by addition of an alkaline reagent solution at the rate 0.85 dm3/min. Decyl bromide, dimethylamine and inorganic alkaline reagent are taken preferably in the mass ratio = 1:0.11:0.12, respectively. In purification of didecyldimethyl ammonium bromide sulfuric acid aqueous solution is used as acid extractant.

EFFECT: improved method of synthesis.

5 cl, 5 tbl, 1 ex

FIELD: polymer precursor preparation methods.

SUBSTANCE: invention relates to improved method for preparing aqueous solution of dimethyldiallylammonium chloride, which can be then polymerized to produce high-efficiency polyelectrolytes applicable in chemical, petrochemical, and petroleum processing, paper-and-pulp, and other industries. Method comprises interaction of dimethylamine with allyl chloride at stirring and temperature 5-20°C for 3-4 h at dimethylamine-to-allyl chloride molar ratio 1.0:(1.01-1.05) followed by neutralization with 50% aqueous sodium chloride solution at 1:1 molar ratio, separation of water-alkali phase from organic phase to form 92-99% dimethyldiallylamine with boiling temperature 55-65°C, and mixing the latter for 4-6 h with allyl chloride at 1:1 molar ratio at 40-50°C, after which softened water is added at stirring and room temperature.

EFFECT: increased quality of target product and excluded presence of sodium chloride in aqueous solution of dimethyldiallylammonium chloride.

4 cl

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