Preparation method of tulobuterol and intermediate thereof

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to tulobuterol and a preparation method of an intermediate thereof. According to the preparation method, o-chlorobenzaldehyde is taken as a raw material, and a product is generated through epoxidation, ring-opening amination and alkalization dissociation. The preparation method provided by the invention has relatively simplified steps, does not need a concentration process of an epoxide intermediate, can realize continuous feeding and direct next-step reaction, shortens the production period, can significantly improve the production safety, improves the purity and yield of the obtained intermediate and the final product, and is beneficial to industrial production of tulobuterol. In addition, a single solvent is used in the salt forming reaction and recrystallization, so that the solvent can be recycled, and the production cost and the chemical pollution are reduced.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of tulobuterol and an intermediate thereof. Background Art

[0002] The chemical name of Tulobuterol is (1RS)-1-(2-chlorophenyl)-2-(1,1-dimethylethyl)aminoethanol, and its chemical structure is as follows:

[0003]

[0004] Tulobuterol is a white crystal or crystalline powder with one chiral center. It is a racemic form and was developed by Abbott Laboratories and approved for marketing in Japan in 1981 as an asthma drug. As a β2 receptor agonist, Tulobuterol can promote bronchial smooth muscle relaxation and has a very good application prospect in the pharmaceutical market.

[0005] According to the research, the existing synthesis technologies of tulobuterol commonly reported in the literature are as follows:

[0006] Route 1 (original research route JP1979151935A and reference 1 "Ge Xinyue, Pan Li, Wu Yongqi, et al. Improvement of the synthesis process of tulobuterol [J]. Chinese Journal of Medicinal Chemistry, 2015, 25(02): 112-114. DOI: 10.14142 / j.cnki.cn21-1313 / r.2015.02.005.")

[0007]

[0008] Taking o-chloroacetophenone as the starting material, tulobuterol is obtained through carbonyl α-bromination, carbonyl reduction and amination. This synthetic route uses highly irritating and corrosive liquid bromine and may use highly toxic benzene as the reaction solvent. Not only is it very inconvenient to use bromine in large quantities in industry and easily cause safety accidents, but also the α-brominated intermediate is easily hydrolyzed when exposed to water vapor in the air when placed during bromination and is extremely unstable. The bromination site selectivity is poor and there are many brominated impurities. Even if later generations optimized the route and used brominating agents such as N-bromosuccinimide, the explosive reducing agents potassium borohydride or sodium borohydride are still used in the carbonyl reduction reaction, which poses a great safety hazard and is not suitable for industrial scale-up production.

[0009] Route 2 (JP, 52-8818, B; Document 2 "KoshinakaE, KurataS, YamagishiK, etal.Synthesis and bronchodilating activity of o-chloro-alpha-(tert-butylaminomethyl)-benzylalcoholhydrochloride(C-78) and relatedcompounds(author'stransl)[J].Yakugakuzasshi:Journalofthe PharmaceuticalSocietyofJapan,1978,98(9):1198-1207.")

[0010]

[0011] Taking o-chloroacetophenone as the starting material, tulobuterol was obtained by oxidation with selenium dioxide and reduction by amination, with a total yield of 71%. Compared with the route of researchers such as Kato, the yield is indeed improved, but this synthetic route not only uses the expensive and highly toxic reagent selenium dioxide, but also uses the explosive compound potassium borohydride in the reduction reaction, which also poses a major safety hazard. In addition, under the action of potassium borohydride, tert-butylamine can undergo reductive amination with aldehydes and ketones, producing more impurities.

[0012] Route 3 (CN105439875B)

[0013]

[0014] Using 1-(2-chlorophenyl)-1-ethanol as the starting material, tulobuterol was obtained through dehydration, epoxidation and ring-opening reaction with a yield of 54%. This synthetic route not only requires heating at 180-210°C for 3-4 hours for dehydration reaction, which increases energy consumption, but also uses explosive meta-chloroperbenzoic acid (m-CPBA) as an oxidant in the epoxidation reaction, which poses a major safety hazard.

[0015] Route 4 (CN110172028A)

[0016]

[0017] Using o-chloroacetophenone as the starting material, tulobuterol is obtained by reacting elemental iodine and dimethyl sulfoxide (DMSO) and then undergoing amination reduction. The intermediates in this synthetic route easily form hydrates, which is not conducive to quality control. In addition, the explosive compound sodium borohydride is also used in the amination reduction reaction, which poses a major safety hazard.

[0018] Route 5 (CN111205194A)

[0019]

[0020] Taking o-chlorostyrene as the starting material, tulobuterol is obtained through bromination and amination with dibromohydantoin (DBH). This synthetic route not only makes it difficult to study the impurities and does not conform to the ICH process route selection concept, but also requires the use of column chromatography, which increases the difficulty of operation and is not convenient for large-scale industrial production.

[0021] Route 6 (CN113717063B)

[0022]

[0023] Taking o-chlorobenzaldehyde as the starting material, tulobuterol is obtained through epoxidation, ring-opening amination, and alkalization. Although this route has the advantages of high reaction site selectivity, green and environmentally friendly reagents compared to the above-mentioned bromination route, and no special reactions, the patent of this route uses a concentration process to treat the explosive and genotoxic carcinogen epoxy compound intermediates for the convenience of subsequent feeding. Safety accidents and carcinogenic substances are very likely to escape during scale-up production, which greatly endangers the health of operators and residents near the factory. A large amount of mixed solvents are used in the process for salt-forming reaction, so that during the scale-up production process, solvent recovery and application need to be distilled, separated and purified, and solvent reuse is difficult, resulting in a large amount of waste solvents, greatly increasing the cost of the later stage of production, and not easy for industrial production.

[0024] Therefore, there is still a desire for a new method for preparing tulobuterol, which is efficient, high-yield, simple and suitable for large-scale industrial production of tulobuterol. Summary of the invention

[0025] In order to solve the technical problems of safety hazards and complicated post-processing in the existing methods, the present invention aims to provide a preparation method for the commercial production of tulobuterol raw materials, which has the advantages of short production cycle, simple reagents, mild reaction conditions, cheap and readily available raw materials, simple and safe process operation, and easy post-processing, so as to realize efficient, high-yield, simple and large-scale industrial production of tulobuterol and meet the growing demand for tulobuterol in the pharmaceutical chemical industry.

[0026] Specifically, the present invention is achieved through the following technical solutions:

[0027] In one aspect, the present invention provides a method for preparing a tulobuterol intermediate, comprising: conducting an epoxidation reaction of o-chlorobenzaldehyde in a reaction solvent at a reaction temperature in the presence of a base, trimethylsulfoxide iodide, and a phase transfer catalyst, and after the reaction is complete, performing a post-treatment, wherein the post-treatment comprises: suction filtration, separating the filtrate, washing, and separating to obtain an organic phase of 2-(2-chlorophenyl)oxirane;

[0028]

[0029] Preferably, the washing liquid used for the washing comprises water and / or saturated saline solution, and the first washing is a water wash.

[0030] Preferably, in the reaction, trimethyl sulfoxide iodide and a phase transfer catalyst are first added to form sulfur ylide under alkaline conditions, and then o-chlorobenzaldehyde is added.

[0031] Preferably, the reaction temperature is 45-55° C., and / or the reaction solvent is one of N,N-dimethylformamide, tetrahydrofuran, toluene, and ethanol, and / or the phase transfer catalyst includes at least one of tetrabutylammonium bromide and tetrabutylammonium iodide, and / or the base includes at least one of sodium bicarbonate, sodium carbonate, triethylamine, DBU, potassium hydroxide, and sodium hydroxide.

[0032] Preferably, the molar ratio of o-chlorobenzaldehyde to trimethylsulfoxide iodide is 1:1.1-1:1.3, and / or the mass ratio of o-chlorobenzaldehyde to tetrabutylammonium bromide in the step is 1:0.1-1:0.4; and / or the molar ratio of o-chlorobenzaldehyde to base is 1:0.9-1:1.2.

[0033] In another aspect, the present invention provides a method for preparing tulobuterol, comprising the following steps:

[0034] Step 1: conducting an epoxidation reaction of o-chlorobenzaldehyde in a reaction solvent at a reaction temperature in the presence of a base, trimethylsulfoxide iodide, and a phase transfer catalyst. After the reaction is complete, post-treatment is performed, and the post-treatment includes: suction filtration, separation of the filtrate, washing, and separation to obtain an organic phase of 2-(2-chlorophenyl)oxirane;

[0035] Step 2: 2-(2-chlorophenyl)ethylene oxide organic phase undergoes a ring-opening reaction with tert-butylamine in a reaction solvent at a reaction temperature to generate a crude product of tulobuterol, compound A;

[0036] Step 3: The crude product of Tulobuterol, Compound A, reacts with an acid in a reaction solvent at a reaction temperature to form a salt to obtain Compound I;

[0037] Step 4: Compound I is recrystallized from an ethanol aqueous solution at the reaction temperature in the presence of a base to obtain a crude product of Tulobuterol. The crude product of Tulobuterol is dissolved in ethyl acetate, and further alkalized by adding a base. The liquids are separated, and the organic phase is washed with water and concentrated to obtain a white solid. The white solid is dissolved in a solvent and recrystallized to obtain Tulobuterol.

[0038]

[0039] Preferably, the washing liquid used for washing in step 1 includes water and / or saturated brine, and the first washing is water washing, and / or in the reaction in step 1, trimethyl sulfoxide iodide and a phase transfer catalyst are first added to form sulfur ylide under alkaline conditions, and then o-chlorobenzaldehyde is added, and / or the reaction temperature in step 1 is 45-55° C., and / or the reaction solvent in step 1 is one of N,N-dimethylformamide, tetrahydrofuran, toluene, and ethanol, and / or the phase transfer catalyst in step 1 includes at least one of tetrabutylammonium bromide and tetrabutylammonium iodide, and / or the base in step 1 includes sodium bicarbonate, sodium carbonate, triethylamine, 1,8-diazabicyclo At least one of undec-7-ene (DBU), potassium hydroxide, and sodium hydroxide, and / or the molar ratio of o-chlorobenzaldehyde to trimethylsulfoxide iodide in the step one is 1:1.1 to 1:1.3, and / or the mass ratio of o-chlorobenzaldehyde to tetrabutylammonium bromide in the step one is 1:0.1 to 1:0.4; and / or the molar ratio of o-chlorobenzaldehyde to the base is 1:0.9 to 1:1.2, more preferably 1:0.95 to 1:1.10, for example 1:0.98, 1:1.00, 1:1.06, and specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0040] Preferably, the reaction temperature in the step 2 is 70-80° C., the reaction solvent in the step 2 is one of N,N-dimethylformamide, tetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol or a mixed system of the aforementioned alcohol solvents, and / or the amount of tert-butylamine in the step 2 is based on o-chlorobenzaldehyde, and the molar ratio of o-chlorobenzaldehyde to tert-butylamine is 1:2-1:8, more preferably 1:4-1:6, for example, 1:4.5, 1:4.8, 1:5.2, 1:5.8, and specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0041] Preferably, the reaction temperature in the step three is 55 to 65 ° C, the reaction solvent in the step three is one of methanol, ethanol, ethyl acetate, and toluene, and / or the acid in the step three includes one of hydrochloric acid, oxalic acid, acetic acid, and citric acid. The mass ratio of the crude tulobuterol to oxalic acid is 1:0.4 to 1:0.8, for example, 1:0.42, 1:0.50, 1:0.79, and specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0042] Preferably, the reaction temperature in step 4 is 60-70° C., and / or the base comprises at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate, and / or the mass ratio of ethanol to water in the ethanol aqueous solution is 1:10, and / or the solvent in step 4 is one of n-heptane, n-hexane, and tertiary methyl ether, further preferably n-heptane.

[0043] Compared with the prior art, the present invention has the following beneficial effects:

[0044] 1. The preparation method of the tulobuterol intermediate 2-(2-chlorophenyl)ethylene oxide of the present invention does not use a concentration process, but adopts suction filtration, liquid separation, and washing to purify 2-(2-chlorophenyl)ethylene oxide. Since 2-(2-chlorophenyl)ethylene oxide is unstable, the method of the present invention avoids the escape of 2-(2-chlorophenyl)ethylene oxide caused by the concentration process, reduces the safety risk in the scale-up production, reduces the occurrence of safety accidents, and is conducive to reducing the content of impurities in the intermediates and products;

[0045] 2. The preparation method of tulobuterol described in the present invention can filter the 2-(2-chlorophenyl)ethylene oxide organic phase obtained in step 1, separate the liquid, wash and purify it, and then directly put it into the next step of reaction to achieve continuous reaction, which not only avoids the cumbersome concentration and drying process, greatly shortens the reaction time, but also solves the problem of the escape of the carcinogenic substance 2-(2-chlorophenyl)ethylene oxide, reduces the safety risk in the scale-up production, reduces the occurrence of safety accidents, and further reduces the content of impurities in the product;

[0046] 3. In the present invention, a single solvent is used for both the salt-forming reaction and the recrystallization, which can realize solvent recovery, reduce production costs and be beneficial to environmental protection;

[0047] 4. The present invention has obvious process advantages and simple post-processing, involving only simple operations of concentration, filtration, extraction and recrystallization. Moreover, the total yield of the obtained pure tulobuterol is as high as 87-88% and the purity is 100%. DETAILED DESCRIPTION

[0048] The present invention is further described in detail in conjunction with the following specific examples, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be thought of by those skilled in the art are included in the present invention, and the attached claims are the scope of protection. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and common common sense in the art, and the present invention does not particularly limit the content.

[0049] Example 1: Synthesis of 2-(2-chlorophenyl)oxirane

[0050] Add 2606.60g toluene, 746.60g trimethylsulfoxide iodide and 120.86g tetrabutylammonium bromide to a 10L reactor, stir and heat to 50±5°C, add 3398g 5% potassium hydroxide solution, continue stirring for 30min, then add 400.00g o-chlorobenzaldehyde, after the addition, maintain 50±5°C for 3h, and the remaining raw material is no more than 0.71% by HPLC. Stop heating, cool to 0-20°C, keep warm and stir for 1h, a large amount of white solid precipitates, filter and separate. Collect the toluene organic phase, add 1200.00g purified water, stir, separate, continue to add 1200.04g saturated salt water to the organic phase, stir, separate, collect the organic phase for temporary storage, and obtain 2831.70g 2-(2-chlorophenyl) oxirane toluene phase.

[0051] Example 2: Synthesis of 2-(2-chlorophenyl)oxirane

[0052] Add 5g of o-chlorobenzaldehyde, 32.5g of toluene, 9.42g of trimethylsulfoxide iodide and 1.52g of tetrabutylammonium bromide to a 250ml reaction bottle, stir and heat to 50±5℃, add 10g of 20% potassium hydroxide solution, and maintain 50±5℃ for 3h. The remaining raw material is not more than 0.26% as detected by HPLC. Stop heating, cool to 5±5℃, keep warm and stir for 1h, a large amount of white solid precipitates, filter, let the filtrate stand for 15min and then separate. Collect the toluene organic phase, add 15g of purified water, stir, separate, add 15g of purified water to the organic phase, stir, separate, collect the organic phase and store temporarily, and obtain 2-(2-chlorophenyl)ethylene oxide toluene phase.

[0053] Example 3: Synthesis of 2-(2-chlorophenyl)oxirane

[0054] Add 5g of o-chlorobenzaldehyde, 32.5g of toluene, 9.42g of trimethylsulfoxide iodide and 1.5g of tetrabutylammonium iodide to a 250ml reaction bottle, stir and heat to 50±5℃, add 7g of 20% sodium hydroxide solution, and maintain 50±5℃ for 3h. The remaining raw material is not more than 2.43% as detected by HPLC. Stop heating, cool to 5±5℃, keep warm and stir for 1h, a large amount of white solid precipitates, filter, let the filtrate stand for 15min and then separate. Collect the toluene organic phase, add 15g of purified water, stir, separate, add 15g of purified water to the organic phase, stir, separate, collect the organic phase and store temporarily, and obtain 2-(2-chlorophenyl)ethylene oxide toluene phase.

[0055] Example 4: Synthesis of 2-(2-chlorophenyl)oxirane

[0056] Add 325.00g toluene, 93.93g trimethylsulfoxide iodide and 15.00g tetrabutylammonium bromide to a 1L reactor, stir and heat to 50±5℃, add 400g 5% potassium hydroxide solution, continue stirring for 0.5-1h, then add 50.00g o-chlorobenzaldehyde, after the addition, maintain 50±5℃ for 3h, and the remaining raw material is no more than 3.89% by HPLC. Stop heating, cool to 0-10℃, keep stirring for 1h, a large amount of white solid precipitates, filter and separate. Collect the toluene organic phase, wash the organic phase with 150g purified water twice, and collect the 2-(2-chlorophenyl)ethylene oxide toluene phase.

[0057] Example 5: Synthesis of Tulobuterol Oxalate I

[0058] 1300 g of 2-(2-chlorophenyl)ethylene oxide toluene phase (from Example 1), 1300 g of ethanol and 461.5 g of tert-butylamine were added to a 5000 mL reaction bottle, and the mixture was stirred and heated to 75±5° C. for 15 h. The remaining raw material was not more than 0.95% as detected by HPLC. After stopping the reaction, the reaction solution was transferred to a rotary evaporator and concentrated under reduced pressure at 75° C. until no obvious droplets continued to drip out, to obtain 289.97 g of a white solid (crude tulobuterol).

[0059] In a 250 mL reaction bottle, 5 g of the above white solid and 40 g of ethanol were added respectively. After heating to 70±5°C and stirring to dissolve, 3.96 g of oxalic acid was added, and the mixture was stirred at 70±5°C for 0.5 h. The mixture was cooled to 35±5°C and stirred for 1 h. The mixture was cooled to 5±5°C and stirred for 1 h. The mixture was filtered with suction, and the filter cake was transferred to a forced air drying oven and dried at 55±5°C for 3 h to obtain 6.58 g of tulobuterol oxalate, with a yield of 91.92% based on o-chlorobenzaldehyde and a purity of 90.14% by HPLC.

[0060] Example 6: Synthesis of Tulobuterol Oxalate I

[0061] 296.3 g of 2-(2-chlorophenyl)ethylene oxide toluene phase (from Example 1), 315.1 g of ethanol and 113.0 g of tert-butylamine were added to a 2000 mL reaction bottle, and the mixture was stirred and heated to 75±5° C. for 15 h. The remaining raw material was not more than 0.91% as determined by HPLC. After stopping the reaction, the reaction solution was transferred to a rotary evaporator and concentrated under reduced pressure at 75° C. until no obvious droplets continued to drip out, to obtain 65.77 g of a white solid (crude tulobuterol).

[0062] To the above white solid, add 100-200 g of anhydrous ethanol, heat to 60±5°C and stir to dissolve, then add dropwise 132.9 g of oxalic acid solution (32.9 g of oxalic acid and 100.0 g of ethanol, control the temperature at 25±5°C and stir until dissolved), maintain stirring at 60±5°C for 1 h, cool to 35±5°C and stir for 1 h, cool to 5±5°C and stir for 1 h, filter with suction, transfer the filter cake to a forced air drying oven and dry at 55±5°C for 4 h to obtain 86.82 g of tulobuterol oxalate, based on o-chlorobenzaldehyde: yield 91.76%, HPLC purity 93.53%.

[0063] Example 7: Synthesis of Tulobuterol Oxalate I

[0064] 315 g of 2-(2-chlorophenyl)ethylene oxide toluene phase (from Example 1), 315 g of anhydrous ethanol and 112.5 g of tert-butylamine were added to a 1000 mL reaction bottle, and the mixture was stirred and heated to 75±5° C. for 15 h. The remaining raw material was not more than 0.90% as detected by HPLC. After stopping the reaction, the reaction solution was transferred to a rotary evaporator, concentrated under reduced pressure at 75° C., and concentrated until no liquid was dripped, and then 200 g of ethanol was added to concentrate until no liquid was dripped, to obtain 69.92 g of a white solid (crude tulobuterol).

[0065] To the above white solid, add 200 g of ethanol, heat to 60±5°C and stir until dissolved, then add 129.2 g of oxalic acid solution (29.2 g of oxalic acid and 100.0 g of ethanol, control the temperature at 25±5°C and stir until dissolved), keep stirring at 60±5°C for 1 h, cool to 35±5°C and stir for 1 h, cool to 5±5°C and stir for 1 h, filter with suction, transfer the filter cake to a forced air drying oven and dry at 55±5°C for 4 h to obtain 92.11 g of tulobuterol oxalate, based on o-chlorobenzaldehyde: yield 91.57%, HPLC purity 92.53%.

[0066] Example 8: Synthesis of pure Tulobuterol A

[0067] In a 2L reaction bottle, 54.50 g of tulobuterol oxalate (from Example 6), 1090.00 g of water and 109.00 g of anhydrous ethanol were added respectively, stirring and heating were started at a speed of 250 r / min, and 65±5°C was maintained until all the solids were dissolved. 2M sodium hydroxide solution was added dropwise to adjust the pH to 11-12, and the mixture was stirred at this temperature for 0.5-1 h. The pH was re-measured, and the pH was maintained at 11-12. The mixture was cooled to 40±5°C and maintained for 0.5-1 h for crystallization, cooled to 25±5°C and maintained for 0.5-1 h for crystallization, filtered, and the filter cake was washed with water. The filter cake was dried at 55±5°C by air blast to obtain 37.3 g of crude tulobuterol.

[0068] Add 37.3g of crude tulobuterol and 161.12g of ethyl acetate to the reaction flask, heat to dissolve at 45°C, add 64.40g of 2M sodium hydroxide aqueous solution, keep warm and stir for 0.5h and then separate the liquids. Collect the organic phase and add 64.8g of purified water, separate the liquids, concentrate the organic phase, and obtain 31.18g of white solid. Add 64.72g of n-hexane, start stirring and heating, the speed is 300r / min, and maintain 65±5°C until all the solids are dissolved. Cool to 40°C for crystallization for 2h, then cool to 0±5°C for crystallization for 2h, filter, rinse the filter cake with 9.52g of cold n-hexane, and drain the filter cake. The filter cake was vacuum dried at 55°C for 4h to obtain 34.75g of pure tulobuterol, with a yield of 95.13% and HPLC purity of 100%.

[0069] Example 9: Synthesis of Tulobuterol Pure Product A

[0070] In a 2L reaction bottle, 54.00 g of tulobuterol oxalate (from Example 7), 1080 g of water and 108 g of anhydrous ethanol were added respectively, and stirring and heating were started at a speed of 250 r / min, and 65±5° C. was maintained until all the solids were dissolved. A 2M sodium hydroxide solution was added dropwise within 10 min, and the pH was adjusted to 11-12. The mixture was stirred at this temperature for 0.5-1 h, the pH was re-measured, and the pH was maintained at 10-12. The mixture was cooled to 40±5° C. and maintained for 0.5-1 h for crystallization, cooled to 25±5° C. and maintained for 0.5-1 h for crystallization, filtered, and the filter cake was washed with water to obtain 41.8 g of a crude wet product of tulobuterol.

[0071] Add 41.8g of crude wet product of Tulobuterol and 208.3g of ethyl acetate to the reaction bottle, heat to dissolve at 45°C, add 83.6g of 2M sodium hydroxide aqueous solution, keep warm and stir for 0.5h and then separate. Collect the organic phase and add 90.2g of purified water, separate the liquid, concentrate the organic phase, and obtain 35.90g of white solid. Add 71.8g of n-heptane, start stirring and heating, the speed is 300r / min, and maintain 55±5°C until all the solids are dissolved. Cool to 40°C for crystallization for 2h, then cool to 0±5°C for crystallization for 2h, filter, rinse the filter cake with 11g of n-heptane, and drain to obtain the filter cake. The filter cake was vacuum dried at 55°C for 4h to obtain 34.43g of pure Tulobuterol, with a yield of 96.15% and a HPLC purity of 100%.

[0072] Example 10 Impurity Detection of Tulobuterol Intermediate (2-(2-chlorophenyl)oxirane)

[0073] Referring to Example 1, o-chlorobenzaldehyde was subjected to epoxidation reaction in toluene at 50°C in the presence of potassium hydroxide, trimethylsulfoxide iodide and tetrabutylammonium bromide, and the reaction solution was sampled at different reaction times, and different post-treatment methods were used to obtain the intermediate 2-(2-chlorophenyl)oxirane, and the impurity content was detected. The results are shown in Table 1, which show that after 3 hours of reaction, compared with the method of using a rotary evaporator to reduce pressure and concentrate the organic phase to precipitate solids after separation, the post-treatment method of separation and washing twice according to the present invention is more conducive to reducing the impurity content in 2-(2-chlorophenyl)oxirane.

[0074] Table 1 Impurity content test results

[0075]

[0076]

[0077] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. It should be pointed out that a person skilled in the art can make several improvements and modifications without departing from the technical principles of the present invention, and these improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for preparing a tulobuterol intermediate, characterized in that: include: o-Chlorobenzaldehyde is subjected to epoxidation reaction in a reaction solvent at a reaction temperature in the presence of a base, trimethylsulfoxide iodide and a phase transfer catalyst. After the reaction is complete, post-treatment is performed. The post-treatment comprises: suction filtration, separation of the filtrate, washing, and separation to obtain an organic phase of 2-(2-chlorophenyl)oxirane; 2. The method for preparing a tulobuterol intermediate according to claim 1, characterized in that: The washing liquid used for the washing includes water and / or saturated salt water, and the first washing is water washing.

3. The method for preparing a tulobuterol intermediate according to claim 1, characterized in that: In the reaction, trimethyl sulfoxide iodide and a phase transfer catalyst are first added to form sulfur ylide under alkaline conditions, and then o-chlorobenzaldehyde is added.

4. The method for preparing a tulobuterol intermediate according to claim 1, characterized in that: The reaction temperature is 45-55° C., and / or the reaction solvent is one of N,N-dimethylformamide, tetrahydrofuran, toluene, and ethanol, and / or the phase transfer catalyst includes at least one of tetrabutylammonium bromide and tetrabutylammonium iodide, and / or the base includes at least one of sodium bicarbonate, sodium carbonate, triethylamine, DBU, potassium hydroxide, and sodium hydroxide.

5. The method for preparing a tulobuterol intermediate according to claim 1, characterized in that: The molar ratio of o-chlorobenzaldehyde to trimethylsulfoxide iodide is 1:1.1-1:1.3, and / or the mass ratio of o-chlorobenzaldehyde to tetrabutylammonium bromide in the step is 1:0.1-1:0.4; and / or the molar ratio of o-chlorobenzaldehyde to alkali is 1:0.9-1:1.

2.

6. A method for preparing tulobuterol, characterized in that: The steps include: Step 1: conducting an epoxidation reaction of o-chlorobenzaldehyde in a reaction solvent at a reaction temperature in the presence of a base, trimethylsulfoxide iodide, and a phase transfer catalyst. After the reaction is complete, post-treatment is performed, and the post-treatment includes: suction filtration, separation of the filtrate, washing, and separation to obtain an organic phase of 2-(2-chlorophenyl)oxirane; Step 2: 2-(2-chlorophenyl)ethylene oxide organic phase undergoes a ring-opening reaction with tert-butylamine in a reaction solvent at a reaction temperature to generate a crude product of tulobuterol, compound A; Step 3: The crude product of Tulobuterol, Compound A, reacts with an acid in a reaction solvent at a reaction temperature to form a salt to obtain Compound I; Step 4: Compound I is recrystallized from an ethanol aqueous solution at the reaction temperature in the presence of a base to obtain a crude product of Tulobuterol. The crude product of Tulobuterol is dissolved in ethyl acetate, and further alkalized by adding a base. The liquids are separated, and the organic phase is washed with water and concentrated to obtain a white solid. The white solid is dissolved in a solvent and recrystallized to obtain Tulobuterol.

7. A method for preparing tulobuterol according to claim 6, characterized in that: The washing liquid used for washing in step 1 includes water and / or saturated brine, and the first washing is water washing, and / or in the reaction in step 1, trimethyl sulfoxide iodide and a phase transfer catalyst are first added under alkaline conditions to form sulfur ylide, and then o-chlorobenzaldehyde is added, and / or the reaction temperature in step 1 is 45-55° C., and / or the reaction solvent in step 1 is one of N,N-dimethylformamide, tetrahydrofuran, toluene, and ethanol, and / or the phase transfer catalyst in step 1 includes tetrabutyl sulfoxide. The method comprises: preparing the reaction mixture of at least one of trimethylolsulfoxide and o-chlorobenzaldehyde, and / or at least one of tetrabutylammonium bromide and tetrabutylammonium iodide, and / or the base in the step one comprises at least one of sodium bicarbonate, sodium carbonate, triethylamine, DBU, potassium hydroxide and sodium hydroxide, and / or the molar ratio of o-chlorobenzaldehyde to trimethylsulfoxide iodide in the step one is 1:1.1 to 1:1.3, and / or the mass ratio of o-chlorobenzaldehyde to tetrabutylammonium bromide in the step one is 1:0.1 to 1:0.4; and / or the molar ratio of o-chlorobenzaldehyde to the base is 1:0.9 to 1:1.

2.

8. The method for preparing tulobuterol according to claim 6, characterized in that: The reaction temperature in step 2 is 70-80° C., the reaction solvent in step 2 is one of N,N-dimethylformamide, tetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol or a mixed system of the aforementioned alcohol solvents, and / or the amount of tert-butylamine in step 2 is based on o-chlorobenzaldehyde, and the molar ratio of o-chlorobenzaldehyde to tert-butylamine is 1:2-1:

8.

9. The method for preparing tulobuterol according to claim 6, characterized in that: The reaction temperature in the step 3 is 55-65° C., the reaction solvent in the step 3 is one of methanol, ethanol, ethyl acetate, and toluene, and / or the acid in the step 3 includes one of hydrochloric acid, oxalic acid, acetic acid, and citric acid, and the mass ratio of the crude tulobuterol to oxalic acid is 1:0.4-1:0.

8.

10. The method for preparing tulobuterol according to claim 6, characterized in that: The reaction temperature in step 4 is 60-70° C., and / or the base includes at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate, and / or the mass ratio of ethanol to water in the ethanol aqueous solution is 1:10, and / or the solvent in step 4 is one of n-heptane, n-hexane, and tertiary methyl ether.

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