Preparation method of imidazole ethanol

Abstract

The invention discloses a preparation method of imidazole ethanol in the technical field of medicine production, which comprises the following steps: adding a sodium hydroxide aqueous solution, tetrabutylammonium bromide and cis-benzoic acid-[2-bromomethyl-2-(2, 4-dichlorophenyl)-1, 3-dioxolane-4-yl] methyl ester into a reaction device, and carrying out hydrolysis reaction to obtain (2-(bromomethyl)-2-(2, 4-dichlorophenyl)-1, 3-dioxolane-4-yl) methyl ester; 2, 3-dioxolane-4-yl) methanol is used as a raw material; further mixing with hydrochloric acid for hydrolysis reaction to obtain 2, 2 ', 4'-trichloroacetophenone; according to the method, (S)-2-chloro-1-(2, 4-dichlorophenyl) ethanol is taken as a raw material, potassium borohydride and methanol are added, (S)-2-chloro-1-(2, 4-dichlorophenyl) ethanol is obtained through a reduction reaction, (S)-2-chloro-1-(2, 4-dichlorophenyl) ethanol and imidazole are subjected to a condensation reaction to obtain imidazole ethanol, impurities in the ketoconazole production process are taken as raw materials, the production cost is reduced, and the product is finally easy to separate and purify; the product can be used for further preparing antifungal drugs such as econazole, oconazole, tioconazole, miconazole nitrate and the like.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical production, and in particular to a method for producing alpha-(2,4-dichlorophenyl)-1H-imidazole-1-ethanol. Background Art

[0002] Imidazoleethanol, chemical name is alpha-(2,4-dichlorophenyl)-imidazole-1-ethanol, CAS: 61397-56-6; it is an important intermediate for antifungal drugs such as econazole, oconazole, tioconazole, and miconazole nitrate.

[0003] In the prior art, there is a method for preparing imidazole ethanol, which has a publication number of CN117486802A and a publication date of 20240202. The method for preparing imidazole ethanol comprises the following steps: (1) adding 2,4-dichloro-2-imidazole acetophenone and an ethanol solution into a hydrogenation reactor, and then adding a platinum-carbon catalyst for mixing; (2) replacing the gas in the hydrogenation reactor with a protective gas, and then introducing hydrogen into the hydrogenation reactor for reaction; (3) filtering the reaction material obtained in step (2), and then distilling the obtained filtrate to recover ethanol, cooling the liquid phase material remaining after the distillation, and collecting the solid phase material precipitated after cooling to obtain imidazole ethanol.

[0004] In the prior art, the synthesis and preparation of an imidazole aromatic alcohol derivative are also disclosed, with a publication number of CN102180835A and a publication date of 20110914. The imidazole aromatic alcohol derivative is 1-[2-(2,4-dichlorophenyl)-2-[(2,6-dichlorophenyl)methoxy]ethyl]-1H-imidazole nitrate, 1-[2-[(4-chlorophenyl)methoxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole, 1-[2-(4-chlorophenyl)-2-(2,6-dichlorobenzyloxy)ethyl ]-1H-imidazole nitrate, 1-[2-(2,4-dichlorophenyl)-2-[[4-phenylthio)phenyl]methoxy]ethyl}-1H-imidazole nitrate, 1-[2-[(2-chloro-3-thienylmethoxy)]-2-(2,4-dichlorophenyl)]ethylimidazole, 1-[2-(7-chlorobenzo[b]thien-3-yl)methoxy-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole nitrate, (2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]ethyl]-1H-imidazole nitrate. The synthesis route is to react halogenated acetophenone with imidazole in N-alkylation, reduce the carbonyl group to the corresponding alcohol, react with the corresponding benzyl halide in the presence of a phase transfer catalyst for O-alkylation, and finally react with an acid to form a salt to obtain the target compound.

[0005] The existing shortcomings are: since imidazole enters the reaction system first, there are many subsequent reverse reactions and it is difficult to purify the product. The existing condazole production process produces the impurity cis-benzoic acid-[2-bromomethyl-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl ester, which cannot be further utilized. Summary of the invention

[0006] The invention aims to provide a method for preparing imidazole ethanol, which utilizes impurities generated in the production process of condazole for production, obtains imidazole ethanol through the last step reaction of imidazole, reduces the reverse reaction in the previous reaction, makes the product easy to be finally separated and purified, and at the same time, makes more reasonable use of resources.

[0007] The object of the present invention is achieved in this way: a preparation method of imidazole ethanol comprises the steps:

[0008] S1, hydrolysis reaction 1

[0009] First, add sodium hydroxide aqueous solution, tetrabutylammonium bromide and cis-benzoic acid-[2-bromomethyl-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl ester into the reaction device, heat to 95-100°C and keep warm for reaction for 40-80 minutes, then cool to the reaction liquid temperature of 25-30°C, add dichloromethane for extraction, and concentrate the organic phase under reduced pressure to remove dichloromethane to obtain (2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methanol; the reaction formula is:

[0010]

[0011] In the formula, Y1 is cis-benzoic acid-[2-bromomethyl-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl ester; Y2 is sodium hydroxide; A1 is (2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methanol;

[0012] S2, hydrolysis reaction 2

[0013] The product (2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane-4-yl)methanol is mixed with hydrochloric acid and heated to 89-95°C. After the reaction is kept at this temperature for 180-300 minutes, the temperature is then lowered to 25-30°C for the reaction liquid, and the mixture is extracted with dichloromethane. The organic phase is concentrated under reduced pressure to remove dichloromethane to obtain 2,2',4'-trichloroacetophenone. The reaction formula is:

[0014] Wherein, Y3 is hydrochloric acid, A2 is 2,2',4'-trichloroacetophenone;

[0015] S3, reduction reaction

[0016] Potassium borohydride, 2,2',4'-trichloroacetophenone and methanol are reacted at -5-0°C for 20-40 minutes, and hydrochloric acid is added dropwise at -5-5°C. After the addition is complete, the temperature is raised to 25-30°C. The reaction solution is concentrated under reduced pressure at 45°C until the methanol weight residue is ≤8%. Tap water is added to the reaction liquid, and then dichloromethane is added for extraction. The organic phase is concentrated under reduced pressure to obtain (S)-2-chloro-1-(2,4-dichlorophenyl)ethanol. The reaction formula is:

[0017]

[0018] In the formula, Y4 is potassium borohydride, A3 is (S)-2-chloro-1-(2,4-dichlorophenyl)ethanol;

[0019] S4, condensation reaction

[0020] Imidazole and (S)-2-chloro-1-(2,4-dichlorophenyl)ethanol are mixed in N,N-dimethylformamide solvent at 100°C, heated to 150-160°C and kept for reaction for 30-50h, then cooled to 25-30°C, dichloromethane and water are added, and the organic phase is concentrated under reduced pressure to obtain a crude product alpha-(2,4-dichlorophenyl)-1H-imidazole-1-ethanol, which is the target product imidazoleethanol; its reaction formula is:

[0021]

[0022] In the formula, Y5 is imidazole; A4 is alpha-(2,4-dichlorophenyl)-1H-imidazole-1-ethanol; and DMF is N,N-dimethylformamide.

[0023] To further purify the target product, hydrochloric acid is added dropwise to the crude alpha-(2,4-dichlorophenyl)-1H-imidazole-1-ethanol obtained in step S4 at 0-10°C, and the mixture is filtered after stirring. The filter cake is discarded (the filter cake is an impurity, and the product is salted and dissolved in water). Dichloromethane and aqueous ammonia are added to the filtrate, and the reaction solution is filtered after stirring. The filter cake is reserved, the filtrate is separated, and the lower dichloromethane phase is concentrated under reduced pressure. After the concentration, the solid is mixed with the above-mentioned reserved filter cake, and methanol is added to the solid. The temperature is raised to 65-68°C and refluxed for 50-70 minutes, and then the temperature is lowered to 0-10°C for crystallization. The purpose of heating and reflux is to completely dissolve the crude product and to play a recrystallization role. The mixed solution is filtered to obtain alpha-(2,4-dichlorophenyl)-1H-imidazole-1-ethanol fine product.

[0024] Furthermore, the obtained pure product was washed with methanol to obtain a white solid with a purity of more than 99.5%, which was the pure product of alpha-(2,4-dichlorophenyl)-1H-imidazole-1-ethanol.

[0025] As a further improvement of the present invention, in steps S1-S4, the dichloromethane extraction temperature is 30°C, the reduced pressure concentration temperature is 45°C, and the reduced pressure is 0.07-0.09Mpa.

[0026] The beneficial effects of the present invention are:

[0027] 1. The production raw material cis-benzoic acid-[2-bromomethyl-2-(2,4-dichlorophenyl)-1,3-dioxolane-4-yl]methyl ester of the present invention is an impurity in the production process of ketoconazole, which can improve the utilization rate of raw materials in the ketoconazole process and reduce production costs.

[0028] 2. The present invention can be used as a ketoconazole production process to save costs, improve raw material utilization, and increase product output types.

[0029] 3. Imidazole and (S)-2-chloro-1-(2,4-dichlorophenyl)ethanol are reacted in the final step to obtain imidazole ethanol, which reduces the reverse reaction in the previous reaction and makes the product easy to be separated and purified.

[0030] The target product obtained by the invention can be used to further prepare antifungal drugs such as econazole, orconazole, tioconazole, miconazole nitrate and the like. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 It is the purity diagram of imidazole ethanol corresponding to Example 1.

[0032] Figure 2 It is the H NMR spectrum of imidazole ethanol corresponding to Example 1. DETAILED DESCRIPTION

[0033] Example 1

[0034] The first step (hydrolysis reaction):

[0035]

[0036] A clean and dry 2000mL three-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser was replaced with nitrogen, 423.4g (23.51moL) of water was added, the temperature was controlled at 25-35°C, 76.60g (1.915moL) of sodium hydroxide was added in batches, stirred to dissolve, 6g (0.0186moL) of tetrabutylammonium bromide was added at 25-45°C, 400g (0.896moL) of ((2R-CIS)-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)benzoic acid methyl ester was added at 25-45°C, the temperature was raised to 100°C and the reaction was kept for 1h. When the reaction liquid temperature was less than 30°C, dichloromethane was slowly added for extraction (50 g×3). The organic phases were combined and concentrated under reduced pressure at 45°C and a vacuum degree of -0.090 MPa to obtain 323.2 g of a crude product as an orange-yellow oil with a yield of about 99.92% and a purity of 94.917%.

[0037] Step 2 (hydrolysis reaction):

[0038]

[0039] Nitrogen replacement was performed in a clean and dry 1000mL three-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, and 94.6g (5.25moL) of water was added, the temperature was controlled at 25-45°C, 482.02g (4.89moL) of concentrated hydrochloric acid was added in batches, and 100g of A1 (0.292moL) was added at 25-45°C, and the temperature was raised to 92°C for 4h of insulation reaction. When the reaction liquid temperature was less than 30°C, dichloromethane was slowly added for extraction (30g×3), and the organic phases were combined and concentrated under reduced pressure at 45°C and a vacuum degree of -0.090Mpa to obtain 63.31g of crude product, which was an orange-yellow oil solid, with a yield of about 88.63% and a purity of 84.70% (-Cl) + 6.81% (-Br).

[0040] Step 3 (reduction reaction):

[0041]

[0042] A clean and dry 250mL three-necked flask equipped with a magnet and a thermometer was replaced with nitrogen, 48gA2 (0.215moL) and 114g (3.56moL) methanol were added, the temperature was controlled at -5-0℃, 5.8g (0.107moL) potassium borohydride was added in batches, the temperature was controlled at -5-0℃ and the reaction was kept for 0.5h. The temperature was controlled at -5-5°C, 108g 1M hydrochloric acid was added, and the temperature was raised to 25-30°C after the addition was completed. The reaction solution was concentrated under reduced pressure at 45°C and a vacuum degree of -0.090Mpa. The residual methanol was ≤8%. 100g tap water was added to the above reddish-brown liquid at a temperature of 25-30°C, and then dichloromethane was added for extraction (66g×3). The organic phases were combined and concentrated under reduced pressure at 45°C and a vacuum degree of -0.090Mpa to obtain 48.26g of a crude product, which was a reddish-brown solid with a purity of 87.729% (-Cl) + 6.130% (-Br) and a yield of 93.5%.

[0043] Step 4 (condensation reaction):

[0044]

[0045] A clean and dry 500mL three-necked flask equipped with a magnet and a thermometer was replaced with nitrogen, and 130.85g (1.922moL) imidazole was added, and the temperature was raised to 100°C. 123g (1.68moL) DMF was added at 100°C, and 61.48g (0.272moL) A3 was added at 100°C, and the temperature was raised to 154°C for 40h. 300g dichloromethane was slowly added when the reaction liquid temperature was less than 30°C, and then tap water was used for extraction (133g×3). The organic phase was concentrated under reduced pressure at 45°C and vacuum degree -0.090Mpa to obtain 73g crude product, which was a dark brown oily substance, with a yield of about 88.45% and a purity of 84.943%. Weigh 65g of A4 crude product, add 650g of tap water, cool to 10°C, add 253g of 1M hydrochloric acid dropwise, stir at 10°C for 1h after the addition, filter, discard the filter cake, the filter cake is an insoluble impurity, the product is salted and dissolved in water; then add 132.5g of dichloromethane to the filtrate, add 355g of 2.5% ammonia water dropwise at 10°C, stir at 10°C for 1h after the addition, filter, and the obtained filter cake is reserved for use. The filtrate is separated, and the lower dichloromethane phase is concentrated under reduced pressure at 45°C and vacuum degree -0.090Mpa, and mixed with the above-mentioned reserve filter cake to obtain 61.51g of khaki solid. Take 10g of the solid and add 15.82g of methanol thereto, heat to 65°C and reflux for 1h, then cool to 10°C, filter, add 1.58g of methanol to the filter cake to obtain 5g of white solid with a purity of 99.73% and a yield of 60%.

[0046] Embodiment 2:

[0047] The first step (hydrolysis reaction):

[0048]

[0049] Nitrogen replacement was performed in a clean and dry 1000mL three-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, and 211.7g (11.75moL) of water was added, the temperature was controlled at 25-35°C, 38.30g (0.957moL) of sodium hydroxide was added in batches, and stirred to dissolve, 3g (0.0093moL) of tetrabutylammonium bromide was added at 25-45°C, 200g (0.448moL) of Y1 was added at 25-45°C, and the temperature was raised to 100°C for 1h of insulation reaction. When the reaction liquid temperature was less than 30°C, dichloromethane was slowly added for extraction (25g×3), the organic phases were combined, and the organic phases were concentrated under reduced pressure at 45°C and vacuum degree -0.090Mpa to obtain 161.3g of crude product, which was an orange-yellow oily substance with a yield of about 99.9% and a purity of 94.92%.

[0050] Step 2 (hydrolysis reaction):

[0051]

[0052] Nitrogen replacement was performed in a clean and dry 500mL three-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, and 47.3g (2.63moL) of water was added, the temperature was controlled at 25-45°C, 241.01g (2.446moL) of concentrated hydrochloric acid was added in batches, and 50g (0.146moL) of A1 was added at 25-45°C, and the temperature was raised to 92°C for 4h of insulation reaction. When the reaction liquid temperature was less than 30°C, dichloromethane was slowly added for extraction (15g×3), and the organic phases were combined and concentrated under reduced pressure at 45°C and a vacuum degree of -0.090Mpa to obtain 31.62g of crude product, which was an orange-yellow oil solid, with a yield of about 88.6% and a purity of 84.74% (-Cl) + 6.79% (-Br).

[0053] Step 3 (reduction reaction):

[0054]

[0055] In a clean and dry 250mL three-necked flask equipped with a magnet and a thermometer, replace the atmosphere with nitrogen, add 24g (0.107moL) A2, 57g (1.78moL) methanol, control the temperature at -5-0℃, add 2.9g (0.054moL) potassium borohydride in batches, control the temperature at -5-0℃ and keep the reaction for 0.5h. Add 54g 1M hydrochloric acid at -5-5℃, raise the temperature to 25-30℃ after the addition is complete, concentrate the reaction solution at 45℃ under reduced pressure and vacuum degree -0.090Mpa, residual methanol ≤8%, add 50g tap water at 25-30℃ to the reddish brown liquid, then add dichloromethane for extraction (33g×3), combine the organic phases, concentrate the organic phases at 45℃ under reduced pressure and vacuum degree -0.090Mpa to obtain 24.10g crude product, which is a reddish brown solid with a purity of 87.732% (-Cl) + 6.128% (-Br) and a yield of 93.5%.

[0056] Step 4 (condensation reaction):

[0057]

[0058] A clean and dry 500mL three-necked flask equipped with a magnet and a thermometer was replaced with nitrogen, and 65.43g (0.96moL) imidazole was added, and the temperature was raised to 100°C. 62g (0.85moL) DMF was added at 100°C, and 30.8g (0.136moL) A3 was added at 100°C, and the temperature was raised to 154°C for 40h. 150g dichloromethane was slowly added when the reaction liquid temperature was less than 30°C, and then tap water (67g×3) was used for extraction. The organic phase was concentrated under reduced pressure at 45°C and vacuum degree -0.090Mpa to obtain 36.3g crude product, which was a dark brown oily substance, with a yield of about 88.4% and a purity of 84.941%. Weigh 32.5g of A4 crude product, add 325g of tap water, cool to 10°C, add 126.5g of 1M hydrochloric acid dropwise, stir at 10°C for 1h after the addition is complete, filter, discard the filter cake, add 67g of dichloromethane to the filtrate, add 177.5g of 2.5% ammonia water dropwise at 10°C, stir at 10°C for 1h after the addition is complete, filter the reaction liquid, use the filter cake for later use, separate the filtrate, concentrate the lower dichloromethane phase at 45°C and vacuum degree -0.090Mpa under reduced pressure, and mix with the above-mentioned spare filter cake to obtain 30.74g of khaki solid, take 20g of the solid, add 31.64g of methanol thereto, heat to 65°C and reflux for 1h, then cool to 10°C, filter, add 3.2g of methanol to the filter cake to obtain 10.12g of white solid with a purity of 99.78% and a yield of 60%.

[0059] The present invention is not limited to the above-mentioned embodiments. On the basis of the technical solution disclosed in the present invention, technicians in this field can make some substitutions and deformations to some technical features therein according to the disclosed technical content without creative labor, and these substitutions and deformations are all within the protection scope of the present invention.

Claims

1. A method for preparing imidazole ethanol, characterized in that, The steps include: S1, hydrolysis reaction 1 First, add sodium hydroxide aqueous solution, tetrabutylammonium bromide and cis-benzoic acid-[2-bromomethyl-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl ester into the reaction device, heat to 95-100°C and keep warm for reaction for 40-80 minutes, then cool to the reaction liquid temperature of 25-30°C, add dichloromethane for extraction, and concentrate the organic phase under reduced pressure to remove dichloromethane to obtain (2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methanol; the reaction formula is: In the formula, Y1 is cis-benzoic acid-[2-bromomethyl-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl ester; Y2 is sodium hydroxide; A1 is (2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methanol; S2, hydrolysis reaction 2 The product (2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane-4-yl)methanol is mixed with hydrochloric acid and heated to 89-95°C. After the reaction is kept at this temperature for 180-300 minutes, the temperature is then lowered to 25-30°C for the reaction liquid, and the mixture is extracted with dichloromethane. The organic phase is concentrated under reduced pressure to remove dichloromethane to obtain 2,2',4'-trichloroacetophenone. The reaction formula is: Wherein, Y3 is hydrochloric acid, A2 is 2,2',4'-trichloroacetophenone; S3, reduction reaction Potassium borohydride, 2,2',4'-trichloroacetophenone and methanol are reacted at -5-0°C for 20-40 minutes, and hydrochloric acid is added dropwise at -5-5°C. After the addition is complete, the temperature is raised to 25-30°C. The reaction solution is concentrated under reduced pressure at 45°C until the weight of the methanol residue is ≤8%. Tap water is added to the reaction liquid, and then dichloromethane is added for extraction. The organic phase is concentrated under reduced pressure to obtain (S)-2-chloro-1-(2,4-dichlorophenyl)ethanol; The reaction formula is: In the formula, Y4 is potassium borohydride, A3 is (S)-2-chloro-1-(2,4-dichlorophenyl)ethanol; S4, condensation reaction Imidazole and (S)-2-chloro-1-(2,4-dichlorophenyl)ethanol are mixed in N,N-dimethylformamide solvent at 100°C, heated to 150-160°C and kept for reaction for 30-50h, then cooled to 25-30°C, dichloromethane and water are added, and the organic phase is concentrated under reduced pressure to obtain a crude product alpha-(2,4-dichlorophenyl)-1H-imidazole-1-ethanol, which is the target product imidazoleethanol; its reaction formula is: In the formula, Y5 is imidazole; A4 is alpha-(2,4-dichlorophenyl)-1H-imidazole-1-ethanol; and DMF is N,N-dimethylformamide.

2. A method for preparing imidazole ethanol according to claim 1, characterized in that, The crude alpha-(2,4-dichlorophenyl)-1H-imidazole-1-ethanol obtained in step S4 is dropwise added with hydrochloric acid at 0-10°C, stirred and filtered, the filter cake is discarded, and then dichloromethane and ammonia water are added to the filtrate, the reaction solution is filtered after stirring, and the obtained filter cake is reserved for later use. The filtrate is separated, and the lower dichloromethane phase is concentrated under reduced pressure. After concentration, the solid is mixed with the above-mentioned reserve filter cake, and methanol is added to the solid. The temperature is raised to 65-68°C and refluxed for 50-70 minutes, and then the temperature is lowered to 0-10°C for crystallization. The mixed solution is filtered to obtain alpha-(2,4-dichlorophenyl)-1H-imidazole-1-ethanol fine product.

3. A method for preparing imidazole ethanol according to claim 2, characterized in that, The obtained pure product was washed with methanol to obtain a white solid with a purity of more than 99.5%, which was the pure product of alpha-(2,4-dichlorophenyl)-1H-imidazole-1-ethanol.

4. A method for preparing imidazole ethanol according to any one of claims 1 to 3, characterized in that: In steps S1-S4, the dichloromethane extraction temperature is 30°C, the reduced pressure concentration temperature is 45°C, and the reduced pressure is 0.07-0.09Mpa.

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