RU2332402C1 - Method of bis (4-alkylaminopyridine-1) alkanes production - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to production of bis(4-alkylaminopyridine-1) alkanes of formula I

where R¹ -s linear or branched alkyl, cycloalkyl or arylalkyl groups having from 4 to 18 carbons, preferably from 8 to 12 carbons, ideally - normal octyl, R² - linear or branched alkylene groups having from 4 to 18 carbons, preferably from 8 to 14 carbons, ideally - 1,10 decandyl, X¹, X² - halogenanions (identical or diverse): fluoride-, chloride-, bromide-, iodideanions, ideally - chlorideanions through interreacting of 4-alkylaminopyridine of formula II

with disubstituted alkylene of formula III X¹-R²-X² in a solvent at increased temperature with mole ratio of formula II compound to formula III compound equals 2:1, the process is carried out in anoxic environment, acetic acid or its mixture with water is used as a solvent, meanwhile the compound of formula II is treated with the compound of formula III in gradual and continuous way or portionwise, ensuring the reaction at temperature ranging from 90° to 130°C, ideally from 100 to 105°C.

EFFECT: preparation of bis(4-alkylaminopyridine-1) alkanes of high quality with higher yield at essential saving of expandable materials.

6 cl, 8 ex

Description

The invention relates to a method for producing bis (4-alkylaminopyridinium-1) alkanes of the formula I

where R ¹ - linear or branched alkyl, cycloalkyl or arylalkyl groups containing from 4 to 18 carbon atoms, preferably from 8 to 12 carbon atoms, and optimally normal octyl,

R ² - linear or branched alkylene groups containing from 4 to 18 carbon atoms, preferably from 8 to 14 carbon atoms, and optimally 1,10-decanediyl,

X ¹ , X ² - halogen anions (the same or different): fluoride, chloride, bromide, iodianion, and optimally, chloride anions.

Representatives of the class of compounds of formula I are known that exhibit antimicrobial properties with respect to a number of microorganisms, including gram-positive, gram-negative bacteria, fungi, and also exhibiting antiviral activity [1. German Patent 2708331, C07D 213/72, issued September 8, 1977. 2. DMBailey, CGDe Grazia, SJHoff, PLSchulenberg, JRO'Connor, DAParis, A. McKenzie Slee J. Med. Chem., 1984, v. 27, 11, p. 1457-1464. 3. Europatent EP 1 123927 A1 C07D 213/74, issued August 16, 2001]. At least one of the compounds of this class (the compound of formula I, R ¹ = nC ₈ H ₁₇ , R ² = (CH ₂ ) ₁₀ , X ¹ , X ² = 2Cl) under the trade name "octenidine dihydrochloride" is part of the skin -mucosal antiseptics manufactured by Schulke & Mayr (Octenimap, Octeniderm, Octenisept).

A known method of producing compounds of formula I, which consists in the interaction of 4-alkylaminopyridines of formula II

with disubstituted alkylene of formula III

The compounds of formula II and III are taken in a molar ratio of 2: 1. The process is carried out at elevated temperatures in the range from 80 to 150 ° C, usually from 100 to 120 ° C [1. The Federal Republic of Germany patent 2708331, С07D 213/72, issued on September 8, 1977. 3. European Patent EP 1123927 A1, C07D 213/74, issued on August 16, 2001].

The synthesis of compounds of formula I is carried out both without a solvent (in the melt of a mixture of the starting compounds) and in its presence. The solvent used is acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone-2, toluene, xylene, alcohols, glycols, polyols, polyethylene and polypropylene glycols, ethers, mono-and diesterified glycols, fully or partially esterified with polyethylene or polypropylene glycols, saturated hydrocarbons, acetone.

Presented in [1. German patent 2708331, C07D 213/72, issued September 8, 1977. D.M. Bailey, C.G. De Grazia, S.J. Hoff, P.L. Schulenberg, J.R. O'Connor, D.A. Paris, A.McKenzieslee. J. Med. Chem. 1984, v.27, No. 11, p.1457-1464] methods for the synthesis of compounds of formula I contain several disadvantages:

1. The use of toxic solvents (acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone) requires subsequent thorough cleaning of the target product from their traces, which increases the cost of the resulting compound of formula I.

2. The high reaction temperature in a number of proposed synthesis methods increases the proportion of by-products, the formation of which consumes the expensive starting compounds of formulas II and III. In addition, there are certain difficulties with the purification of the target product, which is painted with difficult to separate impurities.

3. In some of the proposed methods of synthesis, the product is obtained in the form of a finely dispersed, poorly filtered powder, or the yield of the product is small due to its high solubility in this solvent.

4. The use of solvents such as acetone, glycols gives very small yields of the target product.

The closest in technical essence and the achieved effect is a method for the synthesis of compounds of formula I, presented in [Europatent EP 1123927 A1, C07D 213/74, issued 16.08.2001,]. The method consists in the fact that the process is conducted in the presence of water. The advantages of water as a solvent are in its environmental friendliness, non-toxicity, fire safety, low cost. The target product is easily isolated in a sufficiently pure form and with a good yield. The essence of this method is that to the compounds of formulas II and III, taken in a molar ratio of 2: 1, water is taken, taken in an amount of from 25 to 100% of the total weight of the compounds of formulas II and III. Then the reaction mixture is heated at a temperature of 100 ° C for 5 to 7 hours. Upon completion of the process, the reaction mixture is diluted with acetone at the rate of 4-4.5 ml of acetone per 1 g of the total mass of the starting compounds of formulas II and III. Then, the desired product of formula I is filtered from a cooled acetone solution.

It should be noted some disadvantages of the known method for the synthesis of compounds of formula I:

1. In the known process, taken as a prototype, as well as in the previously mentioned methods, the reaction is carried out in the presence of atmospheric oxygen. The compound of formula II under the reaction conditions (elevated temperature, long flow time, the presence of atmospheric oxygen) will inevitably undergo oxidation, forming by-products that will contaminate the main reaction product.

2. Under the conditions of the prototype (hot aqueous medium with a basic pH, long reaction time), the compound of formula III will to some extent undergo hydrolysis and, possibly, elimination of the halogen atom. It also contributes to an increase in the proportion of by-products in the reaction mixture.

3. When isolating the target product from the water-acetone mixture, part of it inevitably remains in the mother liquor. This is due to the fact that the target product is better soluble in aqueous acetone than in anhydrous. The selection of the residual amount of the target product from the water-acetone mother liquor and its further purification requires additional material costs.

4. In the prototype method, as well as in all methods described in the literature for the synthesis of compounds of formula I, the entire amount of compounds of formulas II and III is immediately introduced into the reaction. This is permissible when carrying out the process with small amounts of the starting compounds of formulas II and III, since the thermal effect of the reaction in this case is small. When carrying out the process on a large scale (kilograms or tens of kilograms of the starting compounds), the problem arises of removing heat from the reaction medium during this exothermic reaction.

We offer a new solution to the problem of obtaining compounds of formula I, which allows to improve the quantitative and qualitative parameters of the target product, as claimed in the prototype synthesis method. According to the method proposed by us, a compound of formula II is treated with a compound of formula III at an elevated temperature in an oxygen-free atmosphere, acetic acid or its aqueous solutions are taken as a solvent, a compound of formula III is added to the compound of formula II gradually (in portions or continuously), the solvent is added to the reaction the mixture is not at the initial stage of synthesis. In this case, the target product is obtained in pure form with a yield that exceeds that during the reaction under the conditions of the prototype method, the reaction takes place in a shorter time, when the target product is isolated, less solvent (acetone) is consumed, and the target product is more completely recovered from the reaction mixture.

When carrying out the reaction under conditions identical to the prototype method [Europatent EP 1123927 A1, C07D 213/74, issued August 16, 2001], but in an argon atmosphere, a high-quality target product is isolated from a colorless reaction mixture (mp 216-217 ° C) with a yield of 81.2% (example 1). Comparative synthesis, carried out under conditions that completely repeat the conditions of the prototype method (in the presence of atmospheric oxygen, example 7), allowed to isolate the target product from a mixture of yellow-brown color with so pl. 214-215 ° C and a yield of 77.6%. In similar syntheses presented in the method [Europatent EP 1123927 A1, C07D 213/74, issued August 16, 2001], the yields of the target product vary from 75.5 to 85.7%, and its quality characteristics (melting points) from 214-217 ° C to 215-217 ° C.

When carrying out the reaction in an argon atmosphere and adding portionwise the compound of formula III to the compound of formula II (example 2), a high quality product (mp 216-217 ° C) is obtained with a yield of 81.8%, which is comparable with the results of example 1. This allows you to unlimitedly scale this synthesis without loss of yield and quality of the selected target product, since the gradual addition of the reagent allows you to control the heat dissipation resulting from the reaction, and to maintain the temperature of the reaction mixture within specified limits.

In example 3, the synthesis is carried out using acetic acid as a solvent. This eliminates the possible process of hydrolysis of the compounds of formula III in cases where water is used as a solvent. A lower yield of the selected target product (75.6%) is associated with its high solubility in acetic acid. In all the examples presented, the yield of only the first isolated fraction of the target product is given, while some of it remains in the filtrate contaminated with impurities. To isolate the total amount of the target product, more complex methods are used that increase its cost.

In example 4, the synthesis of compounds of formula I at the initial stage is carried out without solvent, in a melt, a mixture of compounds of formulas II and III. We found that treating the entire amount of the compound of formula II with half (or less) of the required amount of the compound of formula III gives the target product, which under the reaction conditions is still soluble in excess melt of the compound of formula II. The reaction is generally completed within 15-20 minutes. The following portions of the compound of formula III are added at 15 minute intervals simultaneously with the addition of the minimum amount of solvent (acetic acid) necessary to prevent crystallization of the target product. With this method, a minimal amount of acetic acid is consumed. The target product is isolated from a colorless reaction mass of good quality (mp 215-216 ° C) and with a higher yield (92.6%) than during synthesis under the conditions of the prototype methodology. To isolate the target product, less acetone is consumed (2.0 ml of acetone per 1 g of the total amount of starting reagents, whereas in the prototype synthesis the flow rate is 4.5 ml per 1 g, example 7). When all the necessary amount of the compound of formula III is added immediately to the compound of formula II, the reaction is carried out without solvent and in the presence of atmospheric oxygen (comparative example 8), then the target product of not very good quality is isolated from the tan reaction mixture (mp . 210-213 ° C) and with a lower yield (71.9%).

In examples 5 and 6, the synthesis is carried out under the conditions described in example 4, but water is used as a solvent. In these cases, a high-quality target product (mp 216-217 ° C) with high and comparable yields (88.9% and 91.1%, respectively) is isolated, despite the fact that under the conditions of Example 5, the reaction time is noticeably shorter than under the conditions of example 6 (4.5 hours and 6 hours, respectively).

The proposed solution to the problem of the synthesis of compounds of formula 1 allows to obtain the target product of high quality and with a larger output than with the presented prototype method with significant savings in consumables, i.e. contains clear signs of novelty and invention.

The following examples illustrate the essence of the present invention.

Example 1

A mixture of 20.60 g (0.1 M) of 4-octylaminopyridine and 10.50 g (0.05 M) of 1.10-dichlorodecane and 8 ml of water is heated at 100-105 ° C. with stirring under argon for 6 hours. Then the reaction mass (homogeneous colorless liquid) is cooled to 50 ° C and 135 ml of acetone are added to it with stirring. The solution is cooled to 5 ° C, the precipitate is filtered off, washed with 20 ml of acetone, cooled to 5 ° C, dried in vacuum over phosphorus pentoxide. Get 25.31 g of the target product with so pl. 216-217 ° C. Yield 81.2% of theoretical.

Example 2

A mixture of 24.72 g (0.12 M) of 4-octylaminopyridine and 10 ml of water is heated to boiling water with stirring in an argon atmosphere and 12.66 g (0.06 M) of 1,10-dichlorodecane divided into five are added to it approximately equal portions, at 10-minute time intervals, maintaining the temperature of the reaction mixture in the range of 100-105 ° C. After adding the entire amount of 1,10-dichlorodecane, the mixture was stirred at the same temperature for another 4 hours. Then the reaction mass is cooled to 50 ° C and 175 ml of acetone are added to it with stirring. The resulting colorless solution was cooled to 5 ° C, the precipitate was filtered off, washed with 20 ml of acetone cooled to 5 ° C, and dried in vacuo over phosphorus pentoxide. Obtain 30.57 g of the target product with so pl. 216-217 ° C. Yield 81.8% of theoretical.

Example 3

A mixture of 16.48 g (0.08 M) of 4-octylaminopyridine, 8.44 g (0.04 M) of 1,10-dichlorodecane and 6 ml of anhydrous acetic acid is heated to 100-105 ° C with stirring under argon atmosphere for 10 hours. Then the mixture is cooled to 50 ° C and 50 ml of acetone are added to it. The resulting solution was cooled to 10 ° C, the precipitate was filtered off, washed with 20 ml of acetone cooled to 10 ° C, dried in vacuum over phosphorus pentoxide. Obtain 18.83 g of the target product with so pl. 212-214 ° C. Yield 75.6% of theoretical.

Example 4

A mixture of 16.48 g (0.08 M) of 4-octylaminopyridine and 4.22 g (0.02 M) of 1,10-dichlorodecane is heated with stirring in an argon atmosphere, maintaining the temperature of the reaction mixture in the range of 100-105 ° C. After 15 minutes from the start of heating, 2.11 g (0.01 M) of 1,10-dichlorodecane and 1 ml of anhydrous acetic acid are added to the reaction mass. After the next 15-minute interval, another 2.11 g (0.01 M) of 1.10-dichlorodecane and 1.5 ml of acetic acid are added to the mixture (a total of 4.22 g (0.02 M) of 1.10- are added. dichlorodecane and 2.5 ml of acetic acid) and the reaction mixture is heated to 100-105 ° C with stirring for another 6 hours. After cooling to 50 ° C, 50 ml of acetone is added to the reaction mass, the mixture is stirred until a uniform precipitate is formed, it is cooled to 5 ° C and the precipitate is filtered off. It is washed with 20 ml of acetone, cooled to 5 ° C, dried in vacuum over phosphorus pentoxide. Obtain 22.98 g of the target product with so pl. 215-216 ° C. Yield 81.2% of theoretical.

Example 5

A mixture of 20.60 g (0.1 M) of 4-octylaminopyridine and 5.27 g (0.025 M) of 1,10-dichlorodecane is heated with stirring in an argon atmosphere, maintaining the temperature of the reaction mixture in the range of 100-105 ° C. 15 minutes after the start of heating, another 5.27 g (0.025 M) of 1,10-dichlorodecane and 1 ml of water are added to the reaction mass, and after another 15 minutes of heating, an additional 2 ml of water is added and the mixture is stirred at a temperature of 100 to 105 ° With another 4 hours. Then the reaction mass is cooled to 50 ° C, 70 ml of acetone are added, the resulting mixture is cooled to 5 ° C. A precipitate formed, which was filtered off, washed with 20 ml of acetone, cooled to 5 ° C, dried in vacuum over phosphorus pentoxide. Obtain 27.70 g of the target product with so pl. 216-217 ° C. Yield 88.9% of theoretical.

Example 6

A mixture of 16.48 g (0.08 M) of 4-octylaminopyridine and 4.22 g (0.02 M) of 1,10-dichlorodecane is heated with stirring in an argon atmosphere, maintaining the temperature of the reaction mixture in the range of 100-105 ° C. 15 minutes after the start of heating, 1.41 g of 1,10-dichlorodecane and 1 ml of water are added to the reaction mass. This process is repeated twice more at 15-minute intervals (a total of 4.22 g (0.02 M) of 1,10-dichlorodecane and 3 ml of water are added. Then the mixture is stirred at the same temperature (100-105 ° C) for another 5 hours. After cooling to 50 ° C, 60 ml of acetone are added to the reaction mass, the resulting mixture is cooled to 5 ° C. A precipitate formed, which was filtered off, washed with 20 ml of acetone, cooled to 5 ° C, dried in vacuum over phosphorus pentoxide. Receive 23.26 g of the target product with so pl. 216-217 ° C. Yield 91.1% of theoretical. Comparative examples.

Example 7

A mixture of 20.60 g (0.1 M) of 4-octylaminopyridine, 10.5 g (0.05 M) of 1.10-dichlorodecane and 8 ml of water is heated to 100-105 ° C with stirring in the presence of atmospheric oxygen for 6 hours. Then the reaction mass (tan) is cooled to 50 ° C and 140 ml of acetone are added to it with stirring. The solution is cooled to 5 ° C, the precipitate is filtered off, washed with 20 ml of acetone, cooled to 5 ° C, dried in vacuum over phosphorus pentoxide. Get 24,13 g of the target product with so pl. 214-215 ° C. Yield 77.6% of theoretical.

Example 8

A mixture of 20.60 g (0.1 M) of 4-octylaminopyridine and 10 g (0.05 M) of 1,10-dichlorodecane is heated with stirring in the presence of atmospheric oxygen. Within 15-20 minutes, the temperature of the reaction mixture is raised to 120 ° C, then it spontaneously, without external heating, rises to 155-160 ° C over the next 20 minutes. In this case, the initially molten reaction mass begins to crystallize rapidly. After another 40-45 minutes, the temperature drops to 115-120 ° C, and 60 ml of dimethylformamide are added to the reaction mass. The mixture is heated until the solid is completely dissolved. Then the brown colored solution is slowly cooled to 2 ° C, the precipitate is filtered off, washed with 50 ml of ether, dried in vacuum over phosphorus pentoxide. Obtain 22.36 g of the target product with so pl. 210-213 ° C. Yield 71.9% of theoretical.

Claims (6)

1. The method of obtaining bis (4-alkylaminopyridinium-1) alkanes of the formula I

where R ¹ - linear or branched alkyl, cycloalkyl or arylalkyl groups containing from 4 to 18 carbon atoms, preferably from 8 to 12 carbon atoms, and optimally normal octyl, R ² - linear or branched alkylene groups containing from 4 to 18 carbon atoms, preferably from 8 to 14 carbon atoms, and optimally 1,10-decanediyl, X ¹ , X ² - halogen anions (the same or different): fluoride, chloride, bromide, iodidanions, and optimally, chloride anions, by the interaction of 4-alkylaminopyridine formula II

with disubstituted alkylene of formula III

in a solvent at an elevated temperature at a molar ratio of the compound of formula II to the compound of formula III, which is 2: 1, respectively, characterized in that the process is carried out in an oxygen-free medium, and acetic acid or its mixture with water is taken as a solvent, while the compound of formula II treated with a compound of formula III gradually - continuously or in portions, ensuring the reaction in the temperature range from 90 to 130 ° C, and optimally from 100 to 105 ° C. 2. The production method according to claim 1, characterized in that the process is conducted in an atmosphere of nitrogen, or inert gases, or a mixture thereof, or pairs of inert hydrocarbons selected from the group: propane, butane, pentane, or pairs of fluorine-containing hydrocarbons, mainly freons. 3. The production method according to claim 1, characterized in that the process is carried out in an aqueous solution of acetic acid with its concentration in the solution in the range from 0 to 100% acetic acid. 4. The production method according to claim 1, characterized in that the process is carried out by adding to the compound of formula II a part of the required amount of a compound of formula III with or without a solvent, followed by further addition of the remaining amounts of a compound of formula III and a solvent. 5. The production method according to any one of claims 1, 4, characterized in that initially from 1 to 90%, and optimally from 1 to 50% of the required amount of the compound of formula III, is introduced into the reaction with the compound of formula II. 6. The production method according to any one of claims 1, 3, 4, characterized in that the solvent is taken in weight ratio to the total weight of compounds of formula II and III from 1:20 to 1: 1, respectively, and optimally from 1:10 to 1 : 4 respectively.