A process for the preparation of levosalbutamol hydrochloride

Abstract

The application belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of levosalbutamol hydrochloride. That is, asymmetric catalytic reduction is adopted, and a small amount of chiral catalyst can be used to obtain a chiral product with high purity. The product obtained through the preparation method meets the quality standard of the United States Pharmacopoeia USP43-NF, the purity of the product can reach more than 99.90%, and the maximum single impurity and isomer are both less than 0.05%.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of levalbuterol hydrochloride. BACKGROUND

[0002] Levalbuterol is (R)-a-[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol, and its chemical structural formula is as follows:

[0003]

[0004] Levalbuterol is a single optical isomer of albuterol, and is developed by Sepracor Company in the United States. It is an adrenergic beta2-receptor agonist, and is used for treating bronchial asthma. Levalbuterol aerosol was listed in the United States in 1999, and its trade name is Xopenex.

[0005] Compared with albuterol racemate, the levalbuterol has a better effect of relaxing bronchial smooth muscle, and the dextroisomer has no such effect, but the dextroisomer can produce adverse effects related to beta receptors, such as headache, dizziness, palpitation, finger tremor and the like. Compared with the racemate, the levalbuterol has a further improved curative effect, less adverse effects and less dosage.

[0006] There are many methods for synthesizing levalbuterol, and the most common method is to prepare the optical isomer by using racemic albuterol for resolution. These resolution methods are complex in steps, the resolution agent is very expensive, the cost is high, and the yield of the separated levalbuterol is less than 50%. The British patent document GB1298494A firstly discloses the synthesis of levalbuterol, and the process route is as follows: the levalbuterol is obtained by using D-(+)-dibenzoyl tartaric acid for crystallization resolution, then performing ester reduction reaction, and removing two benzyl protective groups.

[0007]

[0008] Similarly, the patent documents for chiral resolution by using D-(+)-dibenzoyl tartaric acid also include US6365756B1, CN1382685A, CN1927813A, CN1934067A and CN102260179A and the like.

[0009] In which, Chinese patent document CN1705634A, by hydrogenation reduction with rhodium and a chiral, bidentate phosphine ligand, chiral product is obtained, the process route is as follows:

[0010]

[0011] The process uses noble metal rhodium as catalyst, and needs high pressure hydrogen reaction, increases the danger and pollution, and the catalyst preparation requirement is higher, which is not conducive to industrial production.

[0012] Chinese Journal of Medicinal Chemistry, 2006, 16 (4): 222-225, reports that salicylaldehyde and bromoacetyl chloride are used as raw materials, 5-[[(1,1-dimethyl ethyl) amino] acetyl]-2-hydroxybenzaldehyde hydrochloride is synthesized by Friedel-Crafts acylation reaction, substitution reaction, and then asymmetric hydrogen transfer reaction catalyzed by chiral rhodium complex is used for cooperative reduction to obtain levosalbutamol, and finally, levosalbutamol hydrochloride is prepared by salting with hydrochloric acid, and the process route is as follows:

[0013]

[0014] The process uses toxic or dangerous substances such as aluminum chloride, azide acid, triphenylphosphine and rhodium chloride, and the preparation of catalyst [Rh (COD) Cl2] requires higher requirements.

[0015] Literature Tetrahedron Lett, 1994, 35 (31), 5551-5554, reports that chiral oxazaborolidine catalyst is used to reduce the precursor alpha-imine ketone or alpha-amino ketone under the action of borane to obtain levosalbutamol, and the process route is as follows:

[0016]

[0017] The method needs to specially prepare catalyst, and the imine precursor is not easy to store and cannot be mass produced, which brings difficulty to industrial batch production.

[0018] The present application overcomes the defects in the above process, and provides a new preparation method of levosalbutamol hydrochloride, which uses asymmetric catalytic reduction, and a small amount of chiral catalyst can obtain a large amount of chiral product, which is more scientific and economical than traditional chiral resolution process. In the preparation process, there is no heavy metal catalyst and dangerous reagent, no high pressure hydrogenation reaction, the operation is simple, the pollution is small, and the industrialization is easy to realize. And the product meets the quality standard of USP43-NF of the United States Pharmacopoeia, the purity is more than 99.90%, and the maximum single impurity and isomer are less than 0.05%. SUMMARY

[0019] The present application aims to provide a new preparation method of levosalbutamol hydrochloride.

[0020] The synthetic route is shown as follows:

[0021]

[0022] The preparation method is as follows:

[0023] (a) reacting compound VII and 2,2-dimethoxypropane under the catalysis of p-toluenesulfonic acid or camphorsulfonic acid in acetone, DMF or dichloromethane as a solvent to obtain compound VI;

[0024] (b) asymmetrically reducing compound VI and borane in tetrahydrofuran under the catalysis of (R)-2-methyl-CBS-oxazaborolidine or (1R,2S)-1-amino-2-indanol to obtain chiral compound V;

[0025] (c) reacting compound V and anhydrous potassium carbonate in isopropanol to obtain compound IV;

[0026] (d) reacting compound IV and tert-butylamine in anhydrous ethanol, and then salifying with D-(+)-dibenzoyltartaric acid to obtain compound III;

[0027] (e) alkaline hydrolysis of compound III with anhydrous sodium carbonate to obtain compound II;

[0028] (f) deprotection of compound II in hydrochloric acid and salification to obtain compound I.

[0029] Specifically,

[0030] In step (a), compound VII and 2,2-dimethoxypropane are reacted under the catalysis of p-toluenesulfonic acid in acetone at 20-60°C to obtain compound VI.

[0031] Preferably,

[0032] In step (a), when 1 mol of compound VII is used, the feeding amount of 2,2-dimethoxypropane is 2-4 mol, the feeding amount of p-toluenesulfonic acid is 0.01-0.05 mol, and the feeding amount of acetone is 1500-2000 ml;

[0033] In step (a), saturated sodium bicarbonate aqueous solution can also be added for crystallization, and the compound VI is dried at 30-50°C to obtain a pure product.

[0034] It is found through research that if water or other organic solvents are added, the product is an oil, and the product is melted when the drying temperature exceeds 50°C.

[0035] More preferably, in step (a), 1.0 mol of compound VII, 3.0 mol of 2,2-dimethoxypropane and 0.01 mol of p-toluenesulfonic acid are added to acetone, and the mixture is reacted at 40-45°C; TLC is used for monitoring the reaction; after the reaction is completed, the temperature is lowered to 20-25°C, 2.0-3.0 L of saturated aqueous sodium bicarbonate solution is added; the temperature is lowered to 0-5°C, and solid is precipitated; the mixture is stirred for 1-3 h; filtration is performed, the filter cake is washed with water, and the filter cake is dried at 35-40°C to obtain compound VI.

[0036] In step (b), compound VI and borane are subjected to asymmetric reduction in the presence of (R)-2-methyl-CBS-oxazaborolidine (R-CBS) as a catalyst in tetrahydrofuran at 0-40°C to obtain chiral compound V.

[0037] Preferably, in step (b), the moisture content of compound VI is controlled to be ≤0.3% and the moisture content of tetrahydrofuran is controlled to be ≤0.2%; the catalyst is R-CBS, and the amount of the catalyst is 0.05-0.15 mol.

[0038] Research shows that the moisture control has a great influence on the ee value of the chiral reduction reaction; after comparison of different catalysts, it is found that R-CBS has the best catalytic effect for step (b) of the present application.

[0039] More preferably, in step (b), tetrahydrofuran and 0.05 mol of R-CBS are mixed, 0.8 mol of borane dimethyl sulfide is slowly added to obtain solution 1; 1 mol of compound VI is dissolved in tetrahydrofuran, and the insoluble matter is filtered to obtain solution 2; solution 2 is added dropwise to solution 1, and the dropping is completed at 20±5°C for 1-1.5 h; TLC is used for monitoring the reaction; after the reaction is completed, anhydrous methanol is slowly added to quench the reaction, the temperature is controlled at 20-30°C, and stirring is performed for 20-40 min after the addition is completed; extraction is performed with ethyl acetate / water for 1-3 times, the organic phase is concentrated, ethanol / n-heptane is added, impurities are removed by filtration, the temperature is lowered to 0-5°C, and crystallization is performed; filtration is performed, and the filter cake is dried to obtain intermediate 2.

[0040] In step (c), compound V and anhydrous potassium carbonate are reacted in a solvent of isopropyl alcohol, anhydrous ethanol or anhydrous methanol at 20-80°C to obtain compound IV.

[0041] Preferably, in step (c), the amount of anhydrous potassium carbonate is 2-4 mol when 1 mol of compound V is used as the raw material.

[0042] In step (c), isopropyl alcohol is used as the solvent.

[0043] In step (c), isopropyl alcohol is used as the solvent.

[0044] In the step (d), the compound IV and the tert-butylamine are reacted in a solvent of anhydrous ethanol or anhydrous methanol at 20-80℃, and then the product is salted with D-(+)-dibenzoyl tartaric acid to obtain the compound III.

[0045] In the step (d), when the product is salted with hydrochloric acid, tartaric acid, fumaric acid or maleic acid, etc., no solid is obtained, and only the salt with D-(+)-dibenzoyl tartaric acid can realize solid crystallization. In this step, the salt crystallization with the organic acid can purify the compound III, and if the salt purification is not performed, the product is directly used in the next step, which will affect the next step and finally affect the quality of the compound I.

[0046] Preferably, in the step (d), when the compound IV is 1 mol, the amount of the solvent is 1700-2300 ml, and the amount of D-(+)-dibenzoyl tartaric acid is 0.5-0.6 mol.

[0047] More preferably, the steps (c) and (d) can be combined to prepare the compound III by one-pot method, so as to overcome the defect of instability of the compound IV.

[0048] Most preferably, in the steps (c) and (d), 1.0 mol of the compound V and 3.0 mol of anhydrous potassium carbonate are added to isopropyl alcohol, and stirred at 60±2℃ for 1.5-3h, and the reaction is monitored by thin layer chromatography. After the reaction is completed, the temperature is lowered to 0-5℃, and stirred for 1h. The filter cake is filtered, and 3.0 mol of tert-butylamine and anhydrous ethanol are added, and stirred at 75±2℃ for 3-4h. The reaction is monitored by thin layer chromatography, and the reaction is completed. The filtrate is filtered, and the temperature is controlled to be ≤45℃. The filtrate is concentrated under vacuum and reduced pressure. The concentrate is added to anhydrous methanol, and stirred to dissolve at 60-65℃. 0.5 mol of D-DBTA is dissolved in anhydrous methanol, and added to the above reaction solution. The reaction is stirred at 60-65℃ for 20-30min, and the solid is precipitated. The temperature is lowered to 0-5℃, and stirred for 1h. The filter cake is filtered, and washed with anhydrous methanol. The filter cake is dried to obtain the compound III.

[0049] In the step (e), the compound III is alkaline hydrolyzed with anhydrous sodium carbonate, sodium bicarbonate or sodium hydroxide to obtain the compound II.

[0050] Preferably, in the step (e), when the amount of the compound III is 1 mol, the amount of the alkali is 4-8 mol.

[0051] More preferably, in step (e), 1.0 mol of compound III is added to a system of ethyl acetate and water, stirred at 30±5°C for 20 min until completely dissolved; the organic phase is collected and concentrated under reduced pressure to 1.5-2.0 V of ethyl acetate; n-heptane is added and stirred at 40-45°C until completely dissolved; the temperature is lowered to 0-5°C, and solid is precipitated, and stirred for 1 h; filtered, and the filter cake is dried under vacuum to obtain compound II.

[0052] In step (f), compound II is added to a system of ethyl acetate and water, and 1.3-1.8 molar equivalents of hydrochloric acid is added, and the reaction is complete at 0-5°C, and anhydrous methanol or anhydrous ethanol is added to obtain compound I.

[0053] In step (f), when the reaction temperature is high, impurities increase; when the amount of hydrochloric acid is small, the reaction is incomplete, and when the amount is large, impurities significantly increase, so the amount of hydrochloric acid is preferably 1.3-1.8 eq; different reaction solvents are screened and compared, and it is found that when the reaction system of ethyl acetate and water is selected, the stability of the product is significantly better than that of ethanol or methanol as the reaction solvent, and the reason is that ethanol or methanol as the solvent residue reacts with compound I to generate degradation impurities.

[0054] Preferably, in step (f), when the amount of compound II is 1 mol, the amount of ethyl acetate is 6500-7500 ml, and the amount of water is 250-310 ml, and the amount of anhydrous ethanol or methanol is 1100-1700 ml.

[0055] More preferably, in step (f), 1.0 mol of compound II is added to ethyl acetate, stirred at 20±5°C until completely dissolved, and the temperature is lowered to 0-5°C; 1.5 mol of a solution of hydrochloric acid and water is added dropwise, and the temperature is controlled at 0-5°C, and the dropwise addition is completed in 10-15 min; after the dropwise addition is completed, the reaction is carried out at 0-5°C for about 2 h, and solid is precipitated, and thin layer chromatography is used for monitoring; after the reaction is complete, anhydrous methanol is added, and stirred at 0-5°C for 20-30 min; filtered, washed and dried to obtain compound I.

[0056] The following is an investigation of the reaction temperature, solvent system and amount of hydrochloric acid in step (f):

[0057] 1. Selection of water amount in the reaction system of ethyl acetate and water

[0058]

[0059] According to the above table, it can be seen that the amount of water added has no obvious effect on the quality of the product; but the more the amount of water, the lower the yield; and if the amount of water is too small, the precipitated product is easy to cake. Therefore, the amount of water is selected to be 1 V (note: 1 V is the ratio of the volume of water to the mass of compound II).

[0060] 2. Selection of the amount of methanol

[0061]

[0062] According to the above table, it can be seen that the amount of methanol has no obvious effect on product quality and yield; when the volume of methanol added is too small, the reaction solution cannot become homogeneous, and the product has poor precipitation properties and large viscosity. Therefore, the amount of methanol is selected to be 4V (note: the amount of methanol 4V is the ratio of the volume of methanol to the mass of compound II).

[0063] 3. Selection of the amount of hydrochloric acid

[0064]

[0065] According to the above table, it can be seen that when the amount of hydrochloric acid is too much, impurities 1 and 2 increase, and the pH and yield also decrease significantly; when the amount of hydrochloric acid is less, the reaction is slower, and the precipitated product is easy to cake. Therefore, the amount of hydrochloric acid is selected to be 1.5 eq.

[0066] 4. Selection of the reaction temperature

[0067]

[0068] According to the above table, it can be seen that when the reaction temperature is higher, impurities 1 and 2 increase, and in order to ensure the quality of API, the reaction temperature is selected to be 0-5℃.

[0069] Compared with the prior art, the present application has the following technical effects:

[0070] At present, the synthesis methods of levosalbutamol mainly include two types: one is to first synthesize racemic salbutamol, and then use chromatographic separation or chemical resolution to obtain chiral products; the other is to directly synthesize levosalbutamol by using asymmetric catalytic reaction. The disadvantage of the chemical resolution method is that multiple crystallizations are needed to achieve the required chiral purity, and the yield is low; and the amount of chiral acid used is large.

[0071] The new preparation method of hydrochloric acid levosalbutamol described in the present application uses asymmetric catalytic reduction, and a small amount of chiral catalyst can obtain a large amount of chiral product. The product obtained by the preparation method meets the quality standards of the United States Pharmacopoeia USP43-NF, the purity is more than 99.90%, and the maximum single impurity and isomer are both less than 0.05%. DETAILED DESCRIPTION

[0072] In order to better understand the present application, the following examples are provided, but they do not constitute a limitation on the scope of protection of the present application; if the specific conditions are not specified in the examples, they are carried out according to the conventional conditions or the conditions recommended by the manufacturer, and if the materials, reagents or instruments used are not specified by the manufacturer, they are all conventional products that can be purchased on the market.

[0073] Example 1, preparation of compound of formula VI

[0074] 200.0 g of compound VII, 254.99 g of 2,2-dimethoxypropane, 1.55 g of p-toluenesulfonic acid, 1200 ml of acetone, were added into a 5 L reaction flask in turn, and reacted at 40 °C for 2 h. 2400 ml of water was added, and a solid was precipitated. The temperature was lowered to 0-5 °C, and stirring was continued for 1 h. Filtration was performed. The filter cake was dried at 60 °C for 12 h to obtain 215.5 g of compound VI with a yield of 92.6%.

[0075] Mass spectrum: ESI-MS (m / z): 243.26 [M-H] — ; molecular formula: C 12 H 13 BrO3;

[0076] Nuclear magnetic resonance hydrogen spectrum: 1 HNMR (400 MHz, DMSO-d6) δ 7.79-7.88 (m, 2H), 6.93 (m, 1H), 4.94 (s, 2H), 4.82 (s, 2H), 1.51 (s, 6H).

[0077] Example 2, preparation of compound of formula V

[0078] 200 ml of tetrahydrofuran, 35 ml of R-CBS, 56 ml of borane dimethyl sulfide, were added into a 2 L reaction flask in turn. 200.0 g of compound VI was dissolved in 800 ml of tetrahydrofuran, and was added dropwise into the above reaction solution at room temperature. After the dropwise addition was completed, the reaction was continued at room temperature for 1 h. 200 ml of anhydrous methanol was slowly added into the reaction solution to quench the reaction. 1000 ml of ethyl acetate was added, and 4 L of purified water was used for extraction. The water phase was separated, and the ethyl acetate phase was concentrated under reduced pressure until no obvious liquid drops were observed. The concentrate was added into 200 ml of anhydrous ethanol and 2000 ml of n-heptane. Heating was performed at 75 °C until the solution was clear. The temperature was lowered to 0-5 °C, and a solid was precipitated. Stirring was continued for 1 h. Filtration was performed. The filter cake was dried at 60 °C for 6 h to obtain 159.8 g of compound V with a yield of 79.4%, a purity of 99.2%, and an isomer of 0.8%.

[0079] Mass spectrum: ESI-MS (m / z): 284.87 [M-H] — ; molecular formula: C 12 H 15 BrO3;

[0080] Nuclear magnetic resonance hydrogen spectrum: 1 HNMR (400 MHz, DMSO-d6) δ 7.170-7.187 (m, H),

[0081] 7.096-7.098 (m, 1H), 6.746-6.760 (d, H), 5.717-5.725 (d, H), 4.808 (s, 2H),

[0082] 4.699-4.712 (m, H), 3.513-3.632 (m, 2H), 1.462 (s, 6H).

[0083] Example 3, Preparation of compound of formula III

[0084] 130.0 g of compound V, 187.7 g of anhydrous potassium carbonate, 650 ml of isopropyl alcohol, 60 °C for 3 h, cooling to 0-5 °C, stirring for 1 h, filtration, to obtain compound IV, which is directly used in the next step.

[0085] The above compound IV, 99.3 g of tert-butylamine and 910 ml of anhydrous ethanol are sequentially added into a 2 L reaction flask, 75 °C for 3 h, filtration, filtration and concentration under reduced pressure until no obvious liquid drops out, the concentrate is added into 910 ml of anhydrous methanol and 81.1 g of D-DBTA, stirring at room temperature, precipitating solid, cooling to 0-5 °C, stirring for 1 h, filtration, the filter cake is dried at 60 °C for 6 h, to obtain 135.6 g of compound III, the yield of two-step reaction is 65.4%, the purity is 99.2%, and the isomer content is 0.02%.

[0086] Example 4, Preparation of compound of formula II

[0087] 55.0 g of compound III, 76.4 g of anhydrous sodium carbonate, 550 ml of ethyl acetate, 550 ml of purified water, are added into a 2 L reaction flask, stirring at room temperature until completely dissolved, separating the water phase, concentrating the ethyl acetate phase under reduced pressure until about 100 ml remains, adding 550 ml of n-heptane, cooling to 0-5 °C, precipitating solid, stirring for 1 h, filtration, the filter cake is dried at 60 °C for 6 h, to obtain 30.4 g of compound II, the yield is 90.7%, the purity is 99.8%, and the isomer content is 0.02%.

[0088] Mass spectrum: ESI-MS (m / z): 280.73 [M+H] + , 278.57 [M-H] - ; molecular formula: C 16 H 25 NO3;

[0089] Nuclear magnetic resonance hydrogen spectrum: 1 HNMR (400 MHz, DMSO-d6) δ 7.711-7.727 (m, H),

[0090] 7.037-7.040 (m, 1H), 6.718-6.731 (d, H), 5.109 (s, H), 4.804 (s, 2H), 4.423 (m, H), 2.546-2.559 (m, 2H), 1.456 (s, 6H), 1.012 (s, 9H).

[0091] Example 5, Preparation of the compound of formula I

[0092] 30.0 g of compound II, 900 ml of ethyl acetate were added into a 2 L reaction flask, cooled to 0-5 °C, and a solution of 13.4 ml of concentrated hydrochloric acid and 30 ml of water was added, and the reaction was maintained for 2 h. 120 ml of anhydrous methanol was added to the reaction solution, and a solid was precipitated. The stirring was maintained for 20 min, and then the solid was filtered and dried at below 40 °C for 6 h to obtain 24.6 g of compound I at a yield of 83.0% and a purity of 99.9% and an isomer content of 0.02%.

[0093] Mass spectrum: ESI-MS (m / z): 238.36 [M-H] — , 240.65 [M+H] + ; molecular formula: C 13 H 21 NO3;

[0094] Nuclear magnetic resonance hydrogen spectrum: 1 HNMR (400 MHz, DMSO-d6) δ 9.47 (s, H), 9.05-9.08 (d, H), 8.41 (s, H), 7.34 (s, H), 7.07-7.10 (dd, H), 6.77-6.79 (d, H), 6.01-6.02 (d, H), 5.04-5.07 (t, H), 4.82-4.86 (m, H), 4.47-4.49 (d, 2H), 2.80-2.96 (m, 2H), 1.30 (s, 9H).

[0095] Example 6, Preparation of the compound of formula VI

[0096] 700.0 g of compound VII, 740.85 g of 2,2-dimethoxypropane, 16.28 g of p-toluenesulfonic acid, and 4200 ml of acetone were sequentially added into a 20 L reaction kettle, and the reaction was maintained at 50 °C for 2 h. 8400 ml of water was added, and a solid was precipitated. The temperature was lowered to 0-5 °C, and the stirring was maintained for 1 h. The solid was filtered and dried at 60 °C for 12 h to obtain 737.8 g of compound VI at a yield of 90.6%.

[0097] Example 7, Preparation of the compound of formula V

[0098] 700 ml of tetrahydrofuran, 245 ml of R-CBS, 196 ml of borane dimethyl sulfide, were sequentially added into a 5 L reaction kettle, 700.0 g of compound VI was dissolved in 2800 ml of tetrahydrofuran, and the solution was added dropwise into the 5 L reaction kettle at room temperature. After the dropwise addition was completed, the reaction was carried out at 35-40 °C for 1 h. 700 ml of anhydrous methanol was slowly added into the reaction solution to quench the reaction. 3500 ml of ethyl acetate and 14000 ml of purified water were added for extraction. The water phase was separated, and the ethyl acetate phase was concentrated under reduced pressure until no obvious liquid drop was observed. The concentrate was added into 700 ml of anhydrous ethanol and 7000 ml of n-heptane. The mixture was heated to dissolve the solid at 75 °C, and then the temperature was lowered to 0-5 °C. The solid was precipitated and stirred for 1 h. The solid was filtered, and the filter cake was dried at 60 °C for 6 h to obtain 544.6 g of compound V with a yield of 77.3 %, a purity of 99.3 %, and an isomer content of 0.7 %.

[0099] Example 8, Preparation of a compound of formula III

[0100] 520.0 g of compound V, 625.2 g of anhydrous potassium carbonate, 2080 ml of isopropyl alcohol, were sequentially added into a 5 L reaction kettle, and the reaction was carried out at 70 °C for 3 h. The temperature was lowered to 0-5 °C, and the mixture was stirred for 1 h. The solid was filtered to obtain compound IV, which was directly used in the next step.

[0101] The above compound IV, 397.2 g of tert-butylamine, 3120 ml of anhydrous ethanol, were sequentially added into a 5 L reaction kettle, and the reaction was carried out at 75 °C for 3 h. The solid was filtered, and the filter cake was concentrated under reduced pressure until no obvious liquid drop was observed. The concentrate was added into 3120 ml of anhydrous methanol and 324.3 g of D-DBTA, and the mixture was stirred at room temperature until the solid was precipitated. The temperature was lowered to 0-5 °C, and the mixture was stirred for 1 h. The solid was filtered, and the filter cake was dried at 60 °C for 6 h to obtain 514.0 g of compound III with a yield of 61.2 % for two steps, a purity of 99.4 %, and an isomer content of 0.02 %.

[0102] Example 9, Preparation of a compound of formula II

[0103] 500.0 g of compound III, 809.9 g of anhydrous sodium carbonate, 5000 ml of ethyl acetate, 5000 ml of purified water, were sequentially added into a 20 L reaction kettle, and the mixture was stirred at room temperature until it was completely dissolved. The water phase was separated, and the ethyl acetate phase was concentrated under reduced pressure until about 900 ml of liquid was left. 5500 ml of n-heptane was added, and the temperature was lowered to 0-5 °C. The solid was precipitated and stirred for 1 h. The solid was filtered, and the filter cake was dried at 60 °C for 6 h to obtain 292.7 g of compound II with a yield of 96.1 %, a purity of 99.6 %, and an isomer content of 0.02 %.

[0104] Example 10, Preparation of a compound of formula I

[0105] 270.0 g of compound II, 6750 ml of ethyl acetate, 20 L of reaction kettle, cooling to 0-5 °C, adding 112.5 ml of concentrated hydrochloric acid and 297 ml of water solution, 0-5 °C for 2 h, adding 1600 ml of anhydrous methanol to the reaction solution, precipitating solid, 0-5 °C for 20 min, stirring and filtering, the filter cake is dried at 40 °C for 6 h, obtaining 204.3 g of compound I, the yield is 76.9%, the purity is 99.9%, and the isomer content is 0.02%.

[0106] Example 11, preparation of compound of formula VI

[0107] 1000.0 g of compound VII, 1481.65 g of 2,2-dimethoxypropane, 7.75 g of p-toluenesulfonic acid, 5000 ml of acetone, sequentially adding into 20 L of reaction kettle, 30 °C for 2 h, adding 12000 ml of water, precipitating solid, the temperature is reduced to 0-5 °C, stirring for 1 h, filtering; the filter cake is dried at 60 °C for 12 h, obtaining 1090.5 g of compound VI, the yield is 93.7%.

[0108] Example 12, preparation of compound of formula V

[0109] 1000 ml of tetrahydrofuran, 350 ml of R-CBS, 280 ml of borane dimethyl sulfide, sequentially adding into 10 L of reaction kettle, 1000.0 g of compound VI is dissolved in 4000 ml of tetrahydrofuran, adding dropwise into 10 L of reaction kettle at room temperature, after dropping, 5-10 °C for 1 h, 1000 ml of anhydrous methanol is slowly added into the reaction solution to quench the reaction, adding 5000 ml of ethyl acetate, 20000 ml of purified water for extraction, separating the water phase, reducing the pressure to concentrate the ethyl acetate phase until no obvious liquid drops, adding 1000 ml of anhydrous ethanol, 10000 ml of n-heptane to the concentrate, heating to dissolve at 75 °C, reducing the temperature to 0-5 °C, precipitating solid, stirring for 1 h, filtering, the filter cake is dried at 60 °C for 6 h, obtaining 805.0 g of compound V, the yield is 79.9%, the purity is 99.1%, and the isomer is 0.8%.

[0110] Example 13, preparation of compound of formula III

[0111] 780.0 g of compound V, 1500.0 g of anhydrous potassium carbonate, 4680 ml of isopropyl alcohol, 40 °C for 3 h, reducing the temperature to 0-5 °C, stirring for 1 h, filtering, obtaining compound IV, which is directly used in the next step.

[0112] The above compound IV, 595.8 g of tert-butylamine, 6240 ml of anhydrous ethanol, were added into a 10 L reaction kettle in turn, and reacted at 75 °C for 3 h. After filtration, the filtrate was concentrated under reduced pressure until no obvious liquid drops were dropped out. The concentrate was added into 6240 ml of anhydrous methanol and 486.5 g of D-DBTA, and stirred at room temperature. Solid was precipitated, and the temperature was lowered to 0-5 °C. After stirring for 1 h, filtration was performed. The filter cake was dried at 60 °C for 6 h to obtain 799.2 g of compound III, with a two-step reaction yield of 64.2% and a purity of 99.3% and an isomer content of 0.02%.

[0113] Example 14, Preparation of a compound of formula II

[0114] 770.0 g of compound III, 891.8 g of anhydrous sodium carbonate, 7700 ml of ethyl acetate, 7700 ml of purified water, were added into a 20 L reaction kettle, and stirred at room temperature until completely dissolved. The water phase was separated, and the ethyl acetate phase was concentrated under reduced pressure until about 1500 ml remained. 7000 ml of n-heptane was added, and the temperature was lowered to 0-5 °C. Solid was precipitated, and stirring was performed at room temperature for 1 h. Filtration was performed, and the filter cake was dried at 60 °C for 6 h to obtain 401.8 g of compound II, with a yield of 85.7% and a purity of 99.9% and an isomer content of 0.02%.

[0115] Example 15, Preparation of a compound of formula I

[0116] 390.0 g of compound II, 11700 ml of ethyl acetate were added into a 20 L reaction kettle, and the temperature was lowered to 0-5 °C. A solution of 185.9 ml of concentrated hydrochloric acid and 351 ml of water was added, and the reaction was performed at room temperature for 2 h. 1560 ml of anhydrous methanol was added into the reaction solution, and solid was precipitated. After stirring at room temperature for 20 min, filtration was performed. The filter cake was dried at below 40 °C for 6 h to obtain 340.6 g of compound I, with a yield of 88.8% and a purity of 99.9% and an isomer content of 0.02%.

Claims

1. A method for preparing levosalbutamol hydrochloride, characterized in that, (a) compound VII and 2,2-dimethoxypropane are reacted in the presence of p-toluenesulfonic acid or camphorsulfonic acid as catalyst in acetone, DMF or dichloromethane as solvent to obtain compound VI; (b) compound VI and borane are asymmetrically reduced in the presence of (R)-2-methyl-CBS-oxazaborolidine as catalyst in tetrahydrofuran as solvent to obtain chiral compound V; (c) compound V and anhydrous potassium carbonate are reacted in isopropanol to obtain compound IV; (d) compound IV and tert-butylamine are reacted in anhydrous ethanol, and then salified with D-(+)-dibenzoyltartaric acid to obtain compound III; (e) compound III is alkalized with anhydrous sodium carbonate to obtain compound II; (f) compound II is deprotected in hydrochloric acid and salified to obtain compound I; the synthetic route is as follows: wherein the step (b) needs to control the moisture of compound VI to be less than or equal to 0.3% and the moisture of tetrahydrofuran to be less than or equal to 0.2%; in the step (f), compound II is reacted in a system of ethyl acetate and water, 1.5 molar equivalents of hydrochloric acid is added, and the reaction is completed at 0-5°C, and then anhydrous methanol or anhydrous ethanol is added to obtain compound I.

2. The method according to claim 1, characterized in that, in the step (f), when the amount of compound II is 1 mol, the feeding amount of ethyl acetate is 6500-7500 ml, the feeding amount of water is 250-310 ml, and the feeding amount of anhydrous ethanol or methanol is 1100-1700 ml. in the step (f), 1.0 mol of compound II is added into ethyl acetate, stirred at 20±5°C until completely dissolved, cooled to 0-5°C, and then a solution of 1.5 mol of hydrochloric acid and water is added dropwise, and the temperature is controlled at 0-5°C, and the dropping is completed in 10-15 min; after dropping, the reaction is carried out at 0-5°C for 2 h, and then a solid is precipitated, and thin layer chromatography is used for monitoring; after the reaction is completed, anhydrous methanol is added, and stirred at 0-5°C for 20-30 min; filtered, washed and dried to obtain compound I.

4. The method according to claim 1, characterized in that, in the step (a), compound VII and 2,2-dimethoxypropane are reacted in the presence of p-toluenesulfonic acid as catalyst in acetone at 20-60°C to obtain compound VI. in the step (a), when compound VII is 1 mol, the feeding amount of 2,2-dimethoxypropane is 2-4 mol, the feeding amount of p-toluenesulfonic acid is 0.01-0.05 mol, and the feeding amount of acetone is 1500-2000 ml. in the step (a), saturated sodium bicarbonate aqueous solution can also be added for crystallization, and then dried at 30-50°C to obtain pure compound VI. ​ ​ ; ​ ​ ​ ​ 3. The preparation method according to claim 1, characterized in that, ​ ​ ​ 5. The preparation method according to claim 4, characterized in that, ​ 6. The preparation method according to claim 4, characterized in that, ​ 7. The preparation method according to claim 4, characterized in that, In step (a), 1.0 mol of compound VII, 3.0 mol of 2,2-dimethoxypropane and 0.01 mol of p-toluenesulfonic acid are added into acetone, and the mixture is reacted at 40-45°C; TLC is used for monitoring; after the reaction is completed, the temperature is lowered to 20-25°C, 2.0-3.0 L of saturated aqueous sodium bicarbonate solution is added; the temperature is lowered to 0-5°C, and solid is precipitated; the mixture is stirred for 1-3 h; filtration is performed, the filter cake is washed with water, and the filter cake is dried at 35-40°C to obtain compound VI.

8. The preparation method according to claim 1, characterized in that, In step (b), compound VI and borane are catalyzed by (R)-2-methyl-CBS-oxazaborolidine (R-CBS) to asymmetrically reduce chiral compound V in tetrahydrofuran at 0-40°C.

9. The production method according to claim 8, characterized by, In step (b), the moisture content of compound VI is controlled to be less than or equal to 0.3%, and the moisture content of tetrahydrofuran is controlled to be less than or equal to 0.2%; the catalyst is R-CBS, and the amount of R-CBS is 0.05-0.15 mol.

10. The preparation method according to claim 8, characterized in that, In step (b), tetrahydrofuran and 0.05 mol of R-CBS are mixed, 0.8 mol of borane dimethyl sulfide is slowly added to obtain solution 1; 1 mol of compound VI is dissolved in tetrahydrofuran, and insoluble substances are filtered to obtain solution 2; solution 2 is added dropwise to solution 1, and the dropping is completed at 20±5°C for 1-1.5 h; TLC is used for monitoring; after the reaction is completed, anhydrous methanol is slowly added to quench the reaction, the temperature is controlled at 20-30°C, and stirring is performed for 20-40 min after the addition is completed; ethyl acetate / water is used for extraction for 1-3 times, the organic phase is concentrated, ethanol / n-heptane is used for dissolution, impurities are removed by filtration, the temperature is lowered to 0-5°C, and crystals are precipitated; filtration is performed, and the filter cake is dried to obtain intermediate 2.

11. The preparation method according to claim 1, characterized in that, In step (c), compound V and anhydrous potassium carbonate are reacted in a solvent of isopropyl alcohol, anhydrous ethanol or anhydrous methanol at 20-80°C to obtain compound IV.

12. The method of claim 11, wherein, In step (c), when 1 mol of compound V is used, the amount of anhydrous potassium carbonate is 2-4 mol, and the amount of solvent is 1200-1700 ml.

13. The preparation method according to claim 11, characterized in that, In step (c), isopropyl alcohol is used as the solvent.

14. The preparation method according to claim 1, characterized in that, In step (d), compound IV and tert-butylamine are reacted in a solvent of anhydrous ethanol or anhydrous methanol at 20-80°C, and then D-(+)-dibenzoyltartaric acid is used for salt formation to obtain compound III.

15. The preparation method according to claim 14, characterized in that, In step (d), when 1 mol of compound IV is used, the amount of solvent is 1700-2300 ml, and the amount of D-(+)-dibenzoyltartaric acid is 0.5-0.6 mol.

16. The method of claim 1, wherein, Steps (c) and (d) are combined into one step, and a one-pot method is used to prepare compound III.

17. The preparation method according to claim 16, characterized in that, The one-pot method is: adding 1.0 mol of compound V and 3.0 mol of anhydrous potassium carbonate into isopropyl alcohol, stirring at 60±2℃ for 1.5-3h, monitoring by thin layer chromatography, after the reaction is completed, cooling to 0-5℃, stirring for 1h; filtering, adding anhydrous ethanol and 3.0 mol of tert-butylamine into the filter cake, stirring at 75±2℃ for 3-4h, monitoring by thin layer chromatography, after the reaction is completed, filtering, controlling the temperature of the filtrate to be ≤45℃, and concentrating under vacuum and reduced pressure; adding anhydrous methanol into the concentrate, dissolving by stirring at 60-65℃; dissolving 0.5 mol of D-DBTA in anhydrous methanol, adding into the above reaction solution, stirring at 60-65℃ for 20-30min, precipitating solid, cooling to 0-5℃, stirring for 1h; filtering, washing the filter cake with anhydrous methanol, and drying to obtain compound III.

18. The preparation method of claim 1, wherein, In the step (e), compound III is alkaline hydrolyzed with anhydrous sodium carbonate, sodium bicarbonate or sodium hydroxide to obtain compound II.

19. The method of claim 18, wherein, In the step (e), when the amount of compound III is 1 mol, the amount of alkali is 4-8 mol.

20. The method of claim 18, wherein, In the step (e), 1.0 mol of compound III and 6.0 mol of anhydrous sodium carbonate are added into a system of ethyl acetate and water, stirring at 30±5℃ for 20min until completely dissolved; collecting the organic phase, concentrating under reduced pressure until 1.5-2.0V of ethyl acetate remains; adding n-heptane, stirring at 40-45℃ until completely dissolved; cooling to 0-5℃, precipitating solid, stirring for 1h; filtering, vacuum drying the filter cake to obtain compound II.

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