A process for the synthesis of levalbuterol hydrochloride

Abstract

The application provides a synthesis method of levalbuterol hydrochloride, which creatively takes raw material-1 (2-[benzyl(tert-butyl)amino]-1-(2,2-dimethyl-4 H -benzo[ d ][1,3]dioxin-6-yl)ethanone) as a starting material, and high-purity levalbuterol hydrochloride is prepared through reduction, separation, hydrolysis, hydrogenation debenzylization and salt formation reaction in sequence. The method has the advantages of mild reaction, simple operation, high yield, low cost and suitability for industrial production. The levalbuterol hydrochloride prepared by the method has single impurity less than 0.05% and total impurity less than 0.1%, which can effectively ensure the safety of patients in medication.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to a synthesis method of levalbuterol hydrochloride. BACKGROUND

[0002] Asthma is a common chronic respiratory disease in childhood, which has the characteristics of long course and easy recurrence. In recent years, with the deterioration of the ecological environment, the incidence of asthma is getting higher and higher. The prevalence of childhood asthma in China has increased from about 1% in 1990 to more than 3%, and shows a continuous growth trend, which seriously affects the health and quality of life of children. Through years of clinical observation, inhaled beta2 receptor agonists have gradually become the first-line drugs for the treatment of childhood asthma, among which the application of salbutamol is the most extensive. Salbutamol is a racemic body composed of equal amounts of left and right rotors, but only the left rotor has the effect of relaxing bronchial smooth muscle, and the right rotor will produce side effects such as headache, dizziness, palpitations, and finger tremor when combined with beta receptors. Therefore, levalbuterol has better safety and is more advantageous for the elderly and children.

[0003] Levalbuterol hydrochloride is the third generation of beta2 receptor agonists, and is the first optical active new drug listed in asthma treatment drugs. It has the advantages of long duration of action, fast onset, and small side effects, and can be used as a special drug for bronchospasm caused by reversible airway obstruction. Therefore, levalbuterol hydrochloride has high economic and social benefits, and has a broad application prospect.

[0004] Levalbuterol hydrochloride, with the chemical name of (R)-alpha1-[(tert-butyl amino) methyl]-4-hydroxy-1,3-benzene dimethanol hydrochloride, and the English name of Levalbuterol Hydrochloride, has the following structural formula:

[0005]

[0006] The existing literature reports the following methods for synthesizing levalbuterol hydrochloride:

[0007] Method one: Chinese patent CN104829468A discloses a synthesis method of levalbuterol hydrochloride. Salicylaldehyde is used as the starting material. First, Friedel-Crafts acylation reaction and amination reaction are carried out with bromoacetyl chloride to generate 5-[[(1,1-dimethyl ethyl) amino]-2-hydroxybenzaldehyde hydrochloride, then asymmetric hydrogen transfer reaction reduction is carried out with chiral borane catalyst to generate levalbuterol, and finally salt formation reaction is carried out to obtain levalbuterol hydrochloride. The process route is as follows:

[0008]

[0009] The above method applies a large amount of aluminum trichloride in the Friedel-Crafts reaction, which is seriously polluting and difficult to handle. In addition, a chiral borane catalyst is used in the chiral reduction process, which is toxic and has safety hazards in industrial production. In addition, the reaction requires anhydrous and oxygen-free environment, which is harsh and not suitable for large-scale production.

[0010] Method two: He Wei et al. (He Wei, Li Xiaoye, Liu Peng, et al. Synthesis of levosalbutamol hydrochloride [J]. Chinese Journal of Pharmaceuticals, 2006, 16(4): 222-225) and Chinese patent CN1705634A disclose a synthesis method of levosalbutamol hydrochloride, which is prepared from 4-acetyloxy-3-acetyloxymethyl benzophenone as starting material, through substitution reaction, catalytic hydrogenation reaction and reduction reaction to prepare levosalbutamol, and the process route is as follows:

[0011]

[0012] The optical purity of levosalbutamol prepared by the above method is only 70% e.e., which does not meet the quality standard of USP2023. Moreover, bromine is used in the first step of the reaction, which is highly toxic, corrosive and seriously polluting; the hydrogenation reduction step in the second step needs to be carried out under high pressure of 20 bar, which is dangerous; and a chiral rhodium complex is used in the chiral reduction process in the third step, which is a metal catalyst and is expensive, not suitable for large-scale industrial production.

[0013] Method three: Cheng Qingfang et al. (Cheng Qingfang et al. Asymmetric synthesis of (R)-salbutamol hydrochloride [J]. Organic Chemistry, 2007(12): 1558-1561) uses self-made chiral camphoryl β-diketone iron complex as catalyst to catalyze the high enantioselective epoxidation reaction of styrene compounds to synthesize levosalbutamol, and the process route is as follows:

[0014]

[0015] This method constructs chiral center to make the proportion of levosalbutamol much larger than that of dextroisomer, and then purifies through column chromatography to improve the purity of salbutamol. However, the starting material 3-acetyloxymethyl-4-acetyl styrene is a non-commercial product, which is a custom chemical and has high cost. In addition, this route uses expensive iron complex, and the reaction needs to be purified by column chromatography, which has high production cost and is not suitable for large-scale industrial production.

[0016] Method four: Chinese patent CN1934067A and Chinese patent CN100408549C are both prepared by salbutamol as starting material, in turn through resolution reaction, free reaction, hydrochloric acid transfer salt or hydrolysis reaction to prepare hydrochloric acid left salbutamol. Its process route is as follows:

[0017]

[0018] The starting material salbutamol of the above method is high in price, high in production cost, low in reaction yield and poor in economic benefit; and in the method described in Chinese patent CN1934067A, the phenolic hydroxyl group and benzyl alcohol of salbutamol are not protected, and multiple methyl etherization side reactions are easy to occur, resulting in poor product quality.

[0019] In view of various deficiencies in the existing synthesis method of hydrochloric acid left salbutamol, it is necessary to develop a green, simple, high-yield and low-cost process route. SUMMARY

[0020] In view of the problems of complex steps, difficult operation, high cost, low yield and low purity in the existing synthesis method of hydrochloric acid left salbutamol, the present application provides a new synthesis method of hydrochloric acid left salbutamol, which has the advantages of mild reaction, simple operation, high yield, low cost and suitability for industrial production.

[0021] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:

[0022] A synthesis method of hydrochloric acid left salbutamol, the synthesis route is as follows:

[0023]

[0024] Comprising the following steps:

[0025] a. Reduction reaction: the raw material-1 is dissolved in a solvent, then the reducing agent is added in batches, and the reaction is kept at 20-60 DEG C for 1-12h, after the reaction is completed, purified water is added to stir and crystallize, and after filtration, washing and drying, the intermediate-1 is obtained;

[0026] b. Resolution reaction: the intermediate-1 is dissolved in a solvent, then the resolution reagent is added, and the reaction is kept at 40-90 DEG C for 1-5h, after the reaction is completed, the temperature is lowered to 20-25 DEG C, and the filter cake is obtained by filtration; the filter cake is added to the refined solvent for crystallization, and after filtration, washing and drying, the intermediate-2 is obtained;

[0027] c. hydrolysis reaction: intermediate-2 and non-polar solvent are placed in a basic solution for free reaction, after the reaction is completed, standing, liquid separation; the organic phase is washed with purified water, and the organic phase is concentrated to dryness under reduced pressure; the concentrated residue is dissolved in a solvent, and dilute hydrochloric acid is added for hydrolysis deprotection reaction; a basic solution is added for free reaction, and intermediate-3 is obtained by filtration, washing and drying; wherein the non-polar solvent is dichloromethane, chloroform or 1,2-dichloroethane;

[0028] d. hydrogenation debenzyl reaction: a solution of intermediate-3 and hydrogen are reacted, after the reaction is completed, the reaction liquid is filtered and concentrated to dryness under reduced pressure to obtain intermediate-4 crude product; the intermediate-4 crude product is refined, and intermediate-4 pure product is obtained by filtration, washing and drying;

[0029] The preparation process of the solution of intermediate-3 is as follows: a solvent, intermediate-3 and triethylamine are added to a reaction bottle, 10% palladium-carbon is added under stirring, and the reaction is stirred at 20-30°C for 0.5-3h.

[0030] e. salt formation reaction: intermediate-4 pure product is dissolved in a salt formation solvent, and hydrochloric acid is slowly added for salt formation, and levosalbutamol hydrochloride is obtained by filtration, washing and drying.

[0031] Further, the reaction condition of the holding reaction in step a is preferably 40-50°C, and the reaction is carried out for 2h.

[0032] Further, the solvent in steps a, b, c and d is ethanol, methanol, isopropanol, n-butanol, acetonitrile, tetrahydrofuran or a mixed solvent thereof.

[0033] Further, the reducing agent in step a is sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride or lithium tetrahydroaluminate.

[0034] Further, the molar ratio of the reducing agent to raw material-1 in step a is (1.1-1.8):1, and preferably 1.3:1.

[0035] Further, the resolving agent in step b is L-(+)-tartaric acid, L-(+)-dibenzoyl tartaric acid, D-(+)-dibenzoyl tartaric acid or D-(+)-di-p-methylbenzoyl tartaric acid.

[0036] Further, the molar ratio of the resolving agent to intermediate-1 in step b is (1.0-1.8):1, and preferably 1.05:1.

[0037] Further, the reaction condition of the holding reaction in step b is preferably 65-70°C, and the reaction is carried out for 1h.

[0038] Further, the refining solvent in step b is ethanol, methanol, isopropanol, acetonitrile, tetrahydrofuran or a mixed solvent thereof.

[0039] Further, the hydrolytic deprotection reaction condition of step c is 5-35℃ for 0.5-5h; preferably 20-30℃ for 1h.

[0040] Further, the basic solution of step c is sodium carbonate solution, sodium hydroxide solution, sodium bicarbonate solution, potassium hydroxide solution, potassium carbonate solution or potassium bicarbonate solution.

[0041] Further, in the solution of intermediate-3 of step d, the mass ratio of solvent, triethylamine, 10% palladium carbon and intermediate-3 is (4-10):(0.02-0.2):(0.01-0.3):1; preferably 7:0.05:0.05:1.

[0042] Further, in the reaction of step e, the molar ratio of hydrochloric acid to intermediate-4 is (1.0-1.5):1, preferably 1.2:1.

[0043] Further, in the reaction of step e, the salt-forming solvent is ethanol, methanol, acetonitrile, ethanol / methyl tert-butyl ether, acetonitrile / water, ethanol / water, methanol / water or a mixed solvent of the above solvents.

[0044] Further, the reaction of intermediate-3 solution and hydrogen in step d is carried out in a micro-channel continuous flow reactor, and the steps are as follows: the intermediate-3 solution and hydrogen are pumped into the first mixing plate of the micro-channel continuous flow reactor through the feed pump of the micro-channel continuous flow reactor for reaction, after the reaction is completed, the micro-channel continuous flow reactor is cooled and depressurized, and the reaction liquid is discharged.

[0045] In the micro-channel continuous flow reactor, the flow rate of the intermediate-3 solution is 25-85g / min, preferably 50-55g / min; the flow rate of hydrogen is 510-550ml / min; the tail end back pressure of the micro-channel continuous flow reactor is 0.4-1.2Mpa, and the temperature of the circulating liquid in the reactor jacket is 80-150℃, preferably 0.7-0.8Mpa, 100-110℃.

[0046] The traditional hydrogenation debenzylization reaction usually uses a tank reactor, the gas-liquid heterogeneous mixing effect is poor, the reaction time is relatively long, the product yield is relatively low, the purity is relatively poor, and an excessive amount of hydrogen is required in the reaction process, the hydrogen has the characteristics of flammability and explosiveness, there is a great safety hazard in large-scale production, the operation is difficult, the amplification effect is obvious, and the risk of process quality control is high. In step d, the hydrogenation debenzylization reaction is performed by replacing the traditional high-pressure reaction kettle with a continuous flow microchannel reactor, which greatly reduces the content of by-products and energy consumption, effectively avoids the amplification effect existing in the traditional tank hydrogenation reaction, the hydrogen consumed in the reaction is equivalent, and basically no hydrogen is left after the reaction is completed, thereby eliminating the safety hazards of hydrogen leakage, combustion and explosion, making the operation of the whole process route more simple and safe, and realizing long-time stable and safe continuous flow production and post-processing, and reducing the production cost.

[0047] The beneficial effects of the present application are:

[0048] The present application provides a synthesis method of levalbuterol hydrochloride, which has the advantages of mild conditions and simple operation.

[0049] (1) The present application creatively uses raw material-1 (2-[benzyl (tert-butyl) amino]-1-(2,2-dimethyl-4H-benzo[d][1,3] dioxin-6-yl) ethanone) as a starting material, and sequentially performs reduction, separation, hydrolysis, hydrogenation debenzylization and salt formation reaction to prepare high-purity levalbuterol hydrochloride. The single impurity content of levalbuterol hydrochloride prepared by the method of the present application is less than 0.05%, and the total impurity is less than 0.1%, which can effectively ensure the safety of patients using the drug.

[0050] (2) In the preferred mode of step d, the present application uses a continuous flow microchannel reactor instead of a traditional high-pressure reaction kettle to perform hydrogenation debenzylization reaction, by adjusting the reaction temperature, material concentration and flow rate and other condition parameters, the preparation of levalbuterol hydrochloride is realized for the first time in a continuous flow reaction mode, the hydrogenation debenzylization time can be shortened from 2h to less than 1min, and the total yield and product purity are greatly improved.

[0051] (3) The intermediate-4 crude product prepared by hydrogenation debenzylization reaction can reduce the difficult-to-remove over-reduction impurities to less than 0.05% through refining operation, so that the single impurity of intermediate-4 is less than 0.05% and the total impurity is less than 0.1%, thereby better ensuring the quality of levalbuterol hydrochloride.

[0052] (4) In the synthesis method of the present application, the starting material of each step is 100g or more, which is more suitable for the industrialized production of levalbuterol hydrochloride drug. BRIEF DESCRIPTION OF DRAWINGS

[0053] Figure 1A mass spectrum of the levosalbutamol hydrochloride of the present application.

[0054] Figure 2 A nuclear magnetic resonance hydrogen spectrum of the levosalbutamol hydrochloride of the present application.

[0055] Figure 3 A nuclear magnetic resonance carbon spectrum of the levosalbutamol hydrochloride of the present application.

[0056] Figure 4 A liquid chromatogram of the levosalbutamol hydrochloride of the present application. DETAILED DESCRIPTION

[0057] In order to more clearly illustrate the present application, the specific embodiments of the present application are described in more detail by the following specific examples. However, it should be understood that the following specific examples are merely used to illustrate the present application, and are not intended to limit the present application in any manner.

[0058] Example 1

[0059] a. Into a 20 L glass reactor, 6.4 kg of ethanol and 1.0 kg of the raw material-1 were added, and stirring was started. Then, 133.8 g of sodium borohydride was added in portions, and after the addition, the reaction was allowed to proceed at 40-50 °C for 2 h. Then, 8.0 kg of purified water was added, and after the addition, stirring was performed at the same temperature for 1 h. The resulting mixture was filtered, and the filter cake was washed with purified water. The filter cake was dried at 60-70 °C under vacuum for 6 h to obtain 0.976 kg of the intermediate-1 at a yield of 97.1%.

[0060] b. Into a 20 L glass reactor, 12.2 kg of ethanol and 0.95 kg of the intermediate-1 were added, and stirring was started. Then, 405.2 g of L-tartaric acid was added, and the temperature was increased to 65-70 °C, and stirring was performed at the same temperature for 1 h. Then, the temperature was decreased to 20-25 °C, and the resulting mixture was filtered. The filter cake was added to 4.2 kg of ethanol, and the temperature was increased to 65-75 °C while stirring. Then, stirring was performed at the same temperature for 0.5 h. Then, the temperature was decreased to 0-10 °C, and stirring was performed at the same temperature for 2 h. Then, the resulting mixture was filtered, and the filter cake was washed with 0.6 kg of ethanol. The filter cake was dried at 40-50 °C under vacuum for 5 h to obtain 0.391 kg of the intermediate-2 at a yield of 29.3%.

[0061] c. Into a 20 L glass reactor, 4.6 kg of dichloromethane and 0.35 kg of intermediate-2 were added, and the pH was adjusted to 9-10 with a sodium carbonate solution (178.5 g of sodium carbonate / 3.5 kg of purified water) while controlling the temperature at 20-30 °C and stirring for 1 h. After standing and separation, the organic phase was washed with 3.5 kg of purified water, and concentrated under reduced pressure at 35-45 °C until no obvious fraction was left. Then, 1.1 kg of ethanol was added to the concentrated residue, and 1 M hydrochloric acid was added while stirring to adjust the pH to 1-2. After the addition, the temperature was controlled at 20-25 °C, and stirring was performed for 2 h. Then, 10% sodium hydroxide solution was added to adjust the pH to 8.8-9.5, and stirring was performed at 15-25 °C for 2 h. Filtration was performed, the filter cake was washed with 0.7 kg of purified water, and the filter cake was dried under vacuum at 45-55 °C for 5 h to obtain 0.200 kg of intermediate-3, with a yield of 90.1%.

[0062] d. Into a 2 L reaction bottle, 1.3 kg of ethanol, 0.19 kg of intermediate-3, and 9.5 g of triethylamine were added, and 9.5 g of 10% palladium-carbon was added while stirring, and stirring was performed at 20-30 °C for 0.5 h.

[0063] The back pressure at the tail end of the Corning G1 micro-channel continuous flow reactor was set to 0.7-0.8 MPa, the temperature of the circulating liquid in the reactor jacket was controlled at 100-110 °C, and the solution of intermediate-3 and hydrogen were pumped into the first mixing plate of the Corning G1 reactor through the feed pump, with the solution flow rate controlled at 50-55 g / min, and the flow rate controlled at 510-550 ml / min. After the reaction was completed, the reactor was cooled and depressurized. The reaction liquid was discharged, filtered, and the filtrate was concentrated under reduced pressure at 35-45 °C until dry. Then, 0.5 kg of ethanol was added to the concentrated residue, the temperature was increased to 20-30 °C while stirring, and hot filtration was performed, followed by 0.1 kg of ethanol washing. The filtrate was cooled to 0-10 °C, and stirring was performed for 3 h. Filtration was performed, the filter cake was washed with 0.2 kg of ethanol, and the filter cake was dried under vacuum at 40-50 °C for 6 h to obtain 0.126 kg of intermediate-4, with a yield of 91.3%.

[0064] e. Into a 5 L glass reaction bottle, 0.34 kg of ethanol, 0.12 kg of intermediate-4, and 0.17 kg of purified water were added, stirring was performed at 10-30 °C for 0.5 h, the temperature was slowly decreased to 0-10 °C, and 51.6 g of hydrochloric acid was added, and stirring was performed at the controlled temperature for 2 h. Filtration was performed, 0.17 kg of ethanol was used for washing, and the filter cake was dried under vacuum at 30-40 °C for 6 h to obtain 0.120 kg of levosalbutamol hydrochloride, with a yield of 87.0%, and an HPLC purity of 99.929%.

[0065] The levosalbutamol hydrochloride was identified by mass spectrometry and nuclear magnetic resonance hydrogen spectrum, the MS spectrum thereof is shown in Figure 1 , 1 the H-NMR spectrum thereof is shown in Figure 2 , 13 and the C-NMR spectrum thereof is shown in Figure 3The liquid chromatogram is shown as Figure 4 The liquid chromatogram is shown as

[0066] Example 2

[0067] a. Into a 20L glass reactor, 6.4kg of isopropyl alcohol and 1.0kg of raw material-1 were added, and stirring was started. Then, 634.4g of sodium triacetoxyborohydride was added in batches, and after the addition, the reaction was carried out at 20-30°C for 12h. Then, 8.0kg of purified water was added, and after the addition, stirring was carried out at 20-30°C for 1h. Filtration was carried out, and the filter cake was washed with purified water. The filter cake was dried at 60-70°C under vacuum for 6h to obtain 0.970kg of intermediate-1, and the yield was 96.5%.

[0068] b. Into a 20L glass reactor, 12.2kg of ethanol and 0.95kg of intermediate-1 were added, and stirring was started. Then, 557.0g of L-(+)-dibenzoyl tartaric acid was added, and the temperature was increased to 40-50°C, and stirring was carried out at 40-50°C for 5h. The temperature was decreased to 20-25°C, and filtration was carried out. The filter cake was added to 4.2kg of acetonitrile, and the temperature was increased to 40°C while stirring. Stirring was carried out at 40°C for 0.5h. The temperature was decreased to 0-10°C, and stirring was carried out at 0-10°C for 2h. Filtration was carried out, and the filter cake was washed with 0.6kg of ethanol. The filter cake was dried at 40-50°C under vacuum for 5h to obtain 0.379kg of intermediate-2, and the yield was 28.4%.

[0069] c. Into a 20L glass reactor, 4.6kg of dichloromethane and 0.35kg of intermediate-2 were added, and the pH was adjusted to 9-10 using a sodium carbonate solution (178.5g of sodium carbonate / 3.5kg of purified water) while controlling the temperature at 5-10°C, and stirring was carried out at 5-10°C for 5h. After standing, the liquid was separated, and the organic phase was washed with 3.5kg of purified water. The organic phase was concentrated under reduced pressure at 35-45°C until no obvious fraction was obtained. Then, 1.1kg of ethanol was added to the concentrated residue, and 1M diluted hydrochloric acid was added while stirring to adjust the pH to 1-2. After the addition, the temperature was controlled at 20-25°C, and stirring was carried out at 20-25°C for 2h. Then, 10% sodium hydroxide solution was added to adjust the pH to 8.8-9.5, and stirring was carried out at 15-25°C for 2h. Filtration was carried out, and the filter cake was washed with 0.7kg of purified water. The filter cake was dried at 45-55°C under vacuum for 5h to obtain 0.193kg of intermediate-3, and the yield was 86.8%.

[0070] d. Into a 2L reaction bottle, 0.76kg of ethanol, 0.19kg of intermediate-3, and 3.8g of triethylamine were added, and 57g of 10% palladium-carbon was added while stirring. Stirring was carried out at 20-30°C for 0.5h.

[0071] The back pressure of the tail end of the Corning G1 micro-channel continuous flow reactor was set to 0.4 MPa, the temperature of the circulating liquid in the reactor jacket was 80°C, the solution of intermediate-3 and hydrogen were pumped into the first mixing plate of the Corning G1 reactor by the feed pump, the flow rate of the solution was controlled to 25 g / min, and the flow rate was 510-550 ml / min. After the reaction was completed, the reactor was cooled and depressurized. The reaction liquid was discharged, filtered, and the filtrate was concentrated to dryness under reduced pressure at 35-45°C. Then 0.5 kg of ethanol was added to the concentrated residue, stirred and heated to 20-30°C, filtered while hot, and washed with 0.1 kg of ethanol. The filtrate was cooled to 0-10°C and stirred for 3 h. The filter cake was washed with 0.2 kg of ethanol, and the filter cake was vacuum dried at 40-50°C for 6 h to obtain 0.124 kg of intermediate-4, with a yield of 89.9%.

[0072] e. 0.34 kg of ethanol, 0.12 kg of intermediate-4 and 0.17 kg of purified water were added to a 5 L glass reaction flask, stirred at 10-30°C for 0.5 h, slowly added 43.0 g of hydrochloric acid at 0-10°C, and stirred for 2 h. Filtered, washed with 0.17 kg of ethanol, and the filter cake was vacuum dried at 30-40°C for 6 h to obtain 0.121 kg of levosalbutamol hydrochloride, with a yield of 87.7% and a HPLC purity of 99.922%. The spectral data of levosalbutamol hydrochloride were the same as those of Example 1.

[0073] Example 3

[0074] a. 6.4 kg of n-butanol and 1.0 kg of raw material-1 were added to a 20 L glass reaction kettle, and stirring was started. 185.9 g of lithium aluminum tetrahydride was added in batches, and after addition, the reaction was carried out at 50-60°C for 1 h. 8.0 kg of purified water was added, and after addition, the mixture was stirred at room temperature for 1 h. The mixture was filtered, washed with purified water, and the filter cake was vacuum dried at 60-70°C for 6 h to obtain 0.960 kg of intermediate-1, with a yield of 95.4%.

[0075] b. 12.2 kg of ethanol and 0.95 kg of intermediate-1 were added to a 20 L glass reaction kettle, and stirring was started. 1.74 kg of D-(+)-dibenzoyl tartaric acid was added, the temperature was raised to 80-90°C, and the mixture was stirred for 5 h. The temperature was lowered to 20-25°C, and the mixture was filtered. The filter cake was added to 4.2 kg of acetonitrile, the temperature was raised to 40°C while stirring, and the mixture was stirred for 0.5 h. The temperature was lowered to 0-10°C, and the mixture was stirred for 2 h. The mixture was filtered, the filter cake was washed with 0.6 kg of ethanol, and the filter cake was vacuum dried at 40-50°C for 5 h to obtain 0.384 kg of intermediate-2, with a yield of 28.7%.

[0076] c. Into a 20 L glass reactor, 4.6 kg of dichloromethane and 0.35 kg of intermediate-2 were added, and the pH was adjusted to 9-10 with a sodium carbonate solution (178.5 g of sodium carbonate / 3.5 kg of purified water) while the temperature was controlled at 30-35 °C and stirred for 1 h. After standing, the organic phase was separated and washed with 3.5 kg of purified water, and concentrated under reduced pressure at 35-45 °C until no obvious fraction was left. Then, 1.1 kg of ethanol was added to the concentrated residue, and 1 M dilute hydrochloric acid was added while stirring to adjust the pH to 1-2. After the addition was completed, the temperature was controlled at 20-25 °C and stirred for 2 h. Then, 10% sodium hydroxide solution was added to adjust the pH to 8.8-9.5, and the mixture was stirred at 15-25 °C for 2 h. The mixture was filtered, the filter cake was washed with 0.7 kg of purified water, and the filter cake was dried under vacuum at 45-55 °C for 5 h to obtain 0.194 kg of intermediate-3, with a yield of 87.4%.

[0077] d. Into a 2 L reaction bottle, 1.9 kg of ethanol, 0.19 kg of intermediate-3, and 38.0 g of triethylamine were added, and 57.0 g of 10% palladium-carbon was added while stirring, and the mixture was stirred at 20-30 °C for 0.5 h.

[0078] The back pressure at the tail end of the Corning G1 micro-channel continuous flow reactor was set to 1.2 MPa, and the temperature of the circulating liquid in the reactor jacket was 150 °C. The solution of intermediate-3 and hydrogen were pumped into the first mixing plate of the Corning G1 reactor through the feed pump, and the flow rate of the solution was controlled to 85 g / min, and the mass of hydrogen was 2.08 g. The flow rate was 510-550 ml / min. After the reaction was completed, the reactor was cooled and depressurized. The reaction liquid was discharged, filtered, and the filtrate was concentrated under reduced pressure at 35-45 °C until dry. Then, 0.5 kg of ethanol was added to the concentrated residue, the temperature was increased to 20-30 °C while stirring, and the mixture was filtered while hot, and washed with 0.1 kg of ethanol. The filtrate was cooled to 0-10 °C and stirred for 3 h. The mixture was filtered, and the filter cake was washed with 0.2 kg of ethanol, and the filter cake was dried under vacuum at 40-50 °C for 6 h to obtain 0.124 kg of intermediate-4, with a yield of 89.9%.

[0079] e. Into a 5 L glass reaction bottle, 0.34 kg of acetonitrile, 0.12 kg of intermediate-4, and 0.17 kg of purified water were added, and the mixture was stirred at 10-30 °C for 0.5 h, and then the temperature was lowered to 0-10 °C, and 64.5 g of hydrochloric acid was slowly added, and the mixture was stirred at 0-10 °C for 2 h. The mixture was filtered, and the filter cake was washed with 0.17 kg of ethanol, and the filter cake was dried under vacuum at 30-40 °C for 6 h to obtain 0.121 kg of levosalbutamol hydrochloride, with a yield of 87.7% and a HPLC purity of 99.912%. The spectral data of levosalbutamol hydrochloride were the same as in Example 1.

[0080] Example 4

[0081] a. Into a 20 L glass reactor, add 6.4 kg of ethanol and 1.0 kg of raw material-1, start stirring, and add 133.8 g of sodium borohydride in batches. After addition, keep the temperature at 40-50 °C for 2 h. Add 8.0 kg of purified water, and after addition, keep stirring for 1 h. Filter, wash with purified water, and dry the filter cake at 60-70 °C under vacuum for 6 h to obtain 0.990 kg of intermediate-1, with a yield of 98.5%.

[0082] b. Into a 20 L glass reactor, add 12.2 kg of ethanol and 0.95 kg of intermediate-1, start stirring, and add 405.2 g of L-tartaric acid. Warm to 65-70 °C and keep stirring for 1 h. Cool to 20-25 °C, filter, and add the filter cake to 4.2 kg of methanol. Warm to 65-75 °C while stirring, and stir for 0.5 h. Cool to 0-10 °C and stir for 2 h. Filter, wash the filter cake with 0.6 kg of methanol, and dry the filter cake at 40-50 °C under vacuum for 5 h to obtain 0.361 kg of intermediate-2, with a yield of 27.0%.

[0083] c. Into a 20 L glass reactor, add 4.6 kg of dichloromethane and 0.35 kg of intermediate-2. Adjust the pH to 9-10 with a sodium carbonate solution (178.5 g of sodium carbonate in 3.5 kg of purified water), and keep the temperature at 20-30 °C while stirring for 1 h. Stand still and separate the liquid. Wash the organic phase with 3.5 kg of purified water, and concentrate the organic phase under reduced pressure at 35-45 °C until no obvious fraction is left. Add 1.1 kg of ethanol to the concentrated residue, stir to dissolve, and adjust the pH to 1-2 with 1M dilute hydrochloric acid. Keep the temperature at 20-25 °C while stirring for 2 h. Then adjust the pH to 8.8-9.5 with 10% sodium hydroxide solution, and keep stirring at 15-25 °C for 2 h. Filter, wash the filter cake with 0.7 kg of purified water, and dry the filter cake at 45-55 °C under vacuum for 5 h to obtain 0.200 kg of intermediate-3, with a yield of 90.1%.

[0084] d. Add 1.3 kg of ethanol, 0.19 kg of intermediate-3, 9.5 g of triethylamine, and 9.5 g of 10% palladium-carbon to a 2 L hydrogenation reactor, set the rotation speed to 5-10 Hz, replace with nitrogen for 3 times, and then introduce hydrogen gas, controlling the pressure at 0.7-0.8 MPa. Keep the temperature at 60-70 °C for reaction. After the reaction is complete, cool and depressurize the reactor. Lead out the reaction liquid, filter, and concentrate the filtrate under reduced pressure at 35-45 °C until dry.

[0085] Then add 0.5 kg of ethanol to the concentrated residue, warm to 20-30 °C while stirring, filter while hot, and wash with 0.1 kg of ethanol. Cool the filtrate to 0-10 °C and stir for 3 h. Filter, wash the filter cake with 0.2 kg of ethanol, and dry the filter cake at 40-50 °C under vacuum for 6 h to obtain 0.099 kg of intermediate-4, with a yield of 71.7%.

[0086] e. Into a 5 L glass reactor flask, 0.22 kg of ethanol, 0.090 kg of intermediate-4 and 0.09 kg of methyl tert-butyl ether were added, stirred at 10-30 °C for 0.5 h, slowly added 38.7 g of hydrochloric acid at 0-10 °C, and stirred for 2 h, filtered, washed with 0.15 kg of ethanol, and the filter cake was dried at 30-40 °C under vacuum for 6 h to give 0.074 kg of levocetirizine hydrochloride, with a yield of 82.0% and a HPLC purity of 99.3%. The spectral data of levocetirizine hydrochloride were the same as in Example 1.

Claims

1. A process for the synthesis of levalbuterol hydrochloride, characterized in that, The synthetic route is as follows: ； The method comprises the following steps: a. Reduction reaction: the raw material-1 is dissolved in a solvent, and then a reducing agent is added in batches, and the reaction is kept at 40-60 DEG C for 1-12 h. After the reaction is completed, purified water is added to stir and crystallize, and then the filter cake is obtained by filtration, washing and drying to obtain the intermediate-1; wherein the reducing agent is sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride or lithium aluminum hydride; the molar ratio of the reducing agent to the raw material-1 is (1.1-1.8):1; b. Splitting reaction: the intermediate-1 is dissolved in a solvent, and then a splitting agent is added, and the reaction is kept at 40-90 DEG C for 1-5 h. After the reaction is completed, the temperature is lowered to 20-25 DEG C, and the filter cake is obtained by filtration. The filter cake is added to a refining solvent for crystallization, and then the filter cake is obtained by filtration, washing and drying to obtain the intermediate-2; the molar ratio of the splitting agent to the intermediate-1 is (1.0-1.8):1; c. Hydrolysis reaction: the intermediate-2 and a non-polar solvent are placed in an alkaline solution for free reaction, and then the reaction is completed. After standing and liquid separation, the organic phase is washed with purified water, and then the organic phase is concentrated to dryness under reduced pressure. The concentrated residue is dissolved in a solvent, and then dilute hydrochloric acid is added for hydrolysis and deprotection reaction. The free reaction is carried out by adding an alkaline solution, and then the intermediate-3 is obtained by filtration, washing and drying; wherein the non-polar solvent is dichloromethane, chloroform or 1,2-dichloroethane; d. Hydrogenation and debenzyl reaction: the solution of the intermediate-3 and hydrogen are reacted, and then the reaction liquid is filtered and concentrated to dryness under reduced pressure to obtain the intermediate-4 crude product. The intermediate-4 crude product is refined by filtration, washing and drying to obtain the intermediate-4 pure product; The preparation process of the solution of the intermediate-3 is as follows: the intermediate-3 and triethylamine are added to a solvent, and then 10% palladium-carbon is added under stirring. The reaction is carried out at 20-30 DEG C for 0.5-3 h. In the solution of the intermediate-3, the mass ratio of the solvent, triethylamine, 10% palladium-carbon and the intermediate-3 is (4-10):(0.02-0.2):(0.01-0.3):1; The reaction of the solution of the intermediate-3 and hydrogen in step d is carried out in a micro-channel continuous flow reactor. The steps are as follows: the solution of the intermediate-3 and hydrogen are pumped into the first mixing plate of the micro-channel continuous flow reactor through the feed pump of the micro-channel continuous flow reactor for reaction. After the reaction is completed, the micro-channel continuous flow reactor is cooled and depressurized, and the reaction liquid is discharged; The flow rate of the solution of the intermediate-3 into the micro-channel continuous flow reactor is 25-85 g / min, and the flow rate of hydrogen into the micro-channel continuous flow reactor is 510-550 ml / min. The tail end back pressure of the micro-channel continuous flow reactor is 0.4-1.2 MPa, and the temperature of the circulating liquid in the reactor jacket is 80-150 DEG C; e. Salting reaction: the intermediate-4 pure product is dissolved in a salting solvent, and then hydrochloric acid is slowly added for salting. The levo-salbutamol hydrochloride is obtained by filtration, washing and drying; the molar ratio of the hydrochloric acid to the intermediate-4 is (1.0-1.5):1; the salting solvent is ethanol, methanol, acetonitrile, ethanol / methyl tert-butyl ether, acetonitrile / water, ethanol / water, methanol / water or a mixed solvent of the above solvents; The solvent in steps a, b, c and d is ethanol, methanol, isopropyl alcohol, n-butanol, acetonitrile, tetrahydrofuran or a mixed solvent thereof.

2. The method of claim 1, wherein, The resolving reagent in step b is L-(+)-tartaric acid, L-(+)-dibenzoyl tartaric acid, D-(+)-dibenzoyl tartaric acid or D-(+)-di-p-toluoyl tartaric acid; and the refining solvent is ethanol, methanol, isopropyl alcohol, acetonitrile, tetrahydrofuran or a mixed solvent.

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