Preparation method of salbutamol and salbutamol sulfate

Abstract

The invention discloses a preparation method of salbutamol and salbutamol sulfate. According to the preparation method of the salbutamol, salbutamol is taken as a raw material, hydroxyl is protected under a specific catalyst, then Friedel-Crafts acylation is carried out, then the salbutamol reacts with tert-butylamine, then reduction is carried out to generate the salbutamol, reaction conditions are mild, reagent safety is high, imine intermediates cannot be generated in the synthesis process, the reaction yield is increased compared with a mainstream route, and the method is suitable for industrial production. A green and environment-friendly process route is provided for the preparation of the salbutamol sulfate.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical pharmaceuticals, and specifically to a preparation method of salbutamol and salbutamol sulfate. Background Art

[0002] Salbutamol sulfate is a short-acting β2-adrenergic receptor agonist, used as an anti-asthmatic drug, which can effectively inhibit the release of histamine and other allergenic substances and prevent bronchospasm. It is applicable to bronchial asthma, asthmatic bronchitis, bronchospasm, emphysema and other diseases.

[0003] The original research of salbutamol sulfate was developed and produced by GSK and approved by the FDA for listing in the United States in October 1996. This product is another blockbuster drug for obstructive tracheal diseases after salmeterol fluticasone.

[0004] The CAS number of salbutamol sulfate is 51022-70-9, which can be obtained by the salt formation reaction of salbutamol with sulfuric acid solution. Its chemical structural formula is:

[0005]

[0006] Literatures (SCHERING CORPORATION: EP0259159A2, Zheng Yumei, etc.) reported that the process mostly adopted by current domestic production enterprises is as follows:

[0007]

[0008]

[0009] Using salicylaldehyde as the raw material, DCM as the solvent, bromoacetyl chloride as the acylating agent, and aluminum chloride as the catalyst for the Friedel-Crafts acylation reaction; then reacting with tert-butylamine; next, reducing with sodium borohydride, and finally forming a salt with sulfuric acid to produce salbutamol sulfate. In the first step of this process, the Friedel-Crafts acylation reaction makes it difficult for the raw materials to be completely converted due to the presence of the aldehyde group, and the overall yield is not high, with a molar yield of only 35%; moreover, an imine structure will be formed during the reaction of the aldehyde group with tert-butylamine, and this structure is highly sensitizing to personnel and not environmentally friendly enough.

[0010] Chinese patent literature CN111620787A reported the following process route:

[0011]

[0012] This process uses salicyl alcohol as the raw material. After protecting the hydroxyl group, it is acylated with bromoacetyl chloride, then reacted with tert-butylamine, and then reduced with palladium on carbon to obtain salbutamol, and finally reacted with sulfuric acid to form a salt. This route uses benzyl chloride with strong irritation to protect the hydroxyl group and uses heavy metal palladium, which is not environmentally friendly enough.

[0013] Chinese patent document CN108863819A reported the following process:

[0014]

[0015]

[0016] In this process, the intermediate dihydroxy group was replaced with tert-butylamine to form an imine intermediate, which is highly irritating to personnel and not green enough. Summary of the Invention

[0017] The present invention provides a method for preparing salbutamol, which can improve the yield of salbutamol sulfate and overcome the environmental protection defects of the existing preparation methods.

[0018] In view of this, the solution of the present invention is as follows:

[0019] A method for preparing salbutamol, the steps comprising:

[0020] Adding salicyl alcohol to solvent I, adding catalyst I and acetone compound, and stirring and reacting to obtain intermediate I;

[0021] Adding catalyst II and acylating reagent to solvent II, dropping intermediate I, after stirring and reacting completely, adding dilute hydrochloric acid to quench the reaction to obtain intermediate II;

[0022] Adding intermediate II to solvent III, dropping tert-butylamine, after dropping, heating the reaction to completion and then cooling, adding a reducing agent to react to obtain salbutamol;

[0023] The reaction route of the said preparation method is as follows:

[0024]

[0025] Furthermore, in the preparation process of intermediate I:

[0026] The solvent I is selected from at least one of acetone, methyl tert-butyl ether, tetrahydrofuran, methanol or acetonitrile, and preferably its dosage is 5-10 times the mass of salicyl alcohol;

[0027] And / or, the catalyst I is selected from aluminum chloride, zinc chloride, iron chloride or p-toluenesulfonic acid, and preferably its dosage is 0.05-0.3 times the mass of salicyl alcohol;

[0028] And / or, the acetone compound is acetone or 2,2-dimethylpropane, and preferably its dosage is 0.5-2 times the mass of salicyl alcohol;

[0029] And / or, the reaction temperature is 30-60 °C.

[0030] Furthermore, in the preparation process of intermediate II:

[0031] The solvent two is selected from at least one of dichloromethane, chloroform, toluene, methyl tert-butyl ether, tetrahydrofuran or acetonitrile, and preferably the dosage thereof is 10 - 30 times the mass of the intermediate one;

[0032] And / or, the catalyst two is selected from aluminum chloride, iron chloride, zinc chloride or zirconium tetrachloride, and preferably the dosage thereof is 2 - 5 times the mass of the intermediate one;

[0033] And / or, the acylating agent is bromoacetyl chloride, bromoacetyl bromide, chloroacetyl chloride, chloroacetyl bromide, and preferably the dosage thereof is 0.5 - 2 times the mass of the intermediate one;

[0034] And / or, the reaction temperature is 30 - 60 °C.

[0035] Furthermore, in the process of preparing salbutamol from the intermediate two:

[0036] The solvent three is selected from methanol, ethanol, isopropanol, tetrahydrofuran or acetonitrile, and preferably the dosage thereof is 5 - 15 times the mass of the intermediate two;

[0037] And / or, the dosage of the tert-butylamine is 0.4 - 1 times the mass of the intermediate two;

[0038] And / or, the reaction temperature after adding the tert-butylamine is 40 - 80 °C;

[0039] And / or, the reducing agent is sodium borohydride, potassium borohydride or lithium aluminum hydride, and preferably the dosage thereof is 0.3 - 1 times the mass of the intermediate two;

[0040] And / or, the reaction temperature after adding the reducing agent is -10 - 20 °C.

[0041] Furthermore, the preparation method further includes a step of post-treating the intermediate one: filtering and concentrating the reaction product to obtain the intermediate one.

[0042] Furthermore, the preparation method further includes a step of post-treating the intermediate two: performing extraction and liquid separation on the reaction product, concentrating the organic phase to obtain a solid, and filtering and drying after slurrying with a solvent to obtain the intermediate two; preferably, the solvent used for slurrying is selected from one of dichloromethane, chloroform, toluene, methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, acetonitrile, etc., and preferably the dosage of the solvent is 4 - 8 times the mass of the intermediate one.

[0043] Another object of the present invention is to provide a preparation method of salbutamol sulfate, including preparing salbutamol by using the above-mentioned preparation method and a step of salifying salbutamol.

[0044] Further, the process of forming the salt of salbutamol is obtained by reacting the reaction product of salbutamol with an aqueous sulfuric acid solution, crystallizing, filtering, slurrying with Solvent Four, cooling and filtering, washing, and then drying.

[0045] Preferably, the concentration of the aqueous sulfuric acid solution is 30 - 60%.

[0046] Preferably, Solvent Four and the solvent used in the washing process are each independently selected from one of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, or acetonitrile; preferably, the amount of Solvent Four used is 0.5 - 4 times the mass of Intermediate Two.

[0047] Compared with the prior art, the present invention has the following beneficial effects:

[0048] The preparation method of salbutamol described in the present invention uses salicyl alcohol as a raw material, protects the hydroxyl group under a specific catalyst, then performs Friedel - Crafts acylation, and then reacts with tert - butylamine and reduces to generate salbutamol. The reaction conditions are mild, the reagents are highly safe, no imine intermediate is generated during the synthesis process, and the reaction yield is improved compared with the mainstream route.

[0049] The preparation method of salbutamol described in the present invention provides a new and more environmentally friendly process route for the preparation of salbutamol sulfate, providing a new reference for improving the industrial preparation of salbutamol sulfate. Specific Embodiments

[0050] The technical solutions of the present invention will be clearly and completely described below in conjunction with the preferred embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0051] In one embodiment, a method for synthesizing salbutamol sulfate is provided, including the following steps:

[0052] 1) Add salicylaldehyde to Solvent One, add Catalyst One, add an acetone compound, stir and react. After the reaction is complete, filter and concentrate to obtain a colorless transparent liquid Intermediate One;

[0053] 2) Add Catalyst Two to Solvent Two, then add an acylating reagent, dropwise add Intermediate One, stir and react. After the reaction is complete, add dilute hydrochloric acid to quench the reaction, extract and separate the layers. Concentrate the organic phase to obtain a pale yellow solid, slurry with Solvent Three, filter and dry to obtain Intermediate Two;

[0054] 3) Add intermediate two to solvent four, dropwise add tert-butylamine. After dropping, raise the temperature for reaction. After the reaction is complete, lower the temperature and add a reducing agent. After the reaction is completed, add aqueous sulfuric acid solution, lower the temperature for crystallization, filter, and slurry with solvent five to obtain salbutamol sulfate;

[0055] The reaction route of the above preparation process is as follows:

[0056]

[0057] The preparation method of the salbutamol sulfate uses salicyl alcohol as a raw material, protects the hydroxyl group under a specific catalyst, then carries out Friedel-Crafts acylation, and then reacts with tert-butylamine and reduces to generate salbutamol. The reaction conditions are mild, the reagents are highly safe, no imine intermediate is generated during the synthesis process, and compared with the mainstream route, the reaction yield is improved, and the molar yield can reach 65-70%, providing a new and more environmentally friendly process route for the preparation of salbutamol sulfate.

[0058] In a preferred embodiment, in step 1):

[0059] The solvent one is one or a mixture of two of acetone, methyl tert-butyl ether, tetrahydrofuran, methanol, acetonitrile, etc., and its dosage is 5-10 times the mass of salicyl alcohol; the catalyst one is one of aluminum chloride, zinc chloride, iron chloride, p-toluenesulfonic acid, etc., and its dosage is 0.05-0.3 times the mass of salicyl alcohol; the acetone compound is one of acetone, 2,2-dimethylpropane, etc., and its dosage is 0.5-2 times the mass of salicyl alcohol; the reaction temperature is 30-60 °C, and the reaction time is 4-5 h. The yield of intermediate one obtained in this process is greater than 97%, and the purity is greater than 99.5%.

[0060] In a preferred embodiment, in step 2):

[0061] The solvent two is selected from one of dichloromethane, chloroform, toluene, methyl tert-butyl ether, tetrahydrofuran, acetonitrile, etc., and its dosage is 10-30 times the mass of intermediate one; the catalyst two is selected from one of aluminum chloride, iron chloride, zinc chloride, zirconium tetrachloride, etc., and its dosage is 2-5 times the mass of intermediate one; the acylating agent is one of bromoacetyl chloride, bromoacetyl bromide, chloroacetyl chloride, chloroacetyl bromide, etc., and its dosage is 0.5-2 times the mass of intermediate 1; the solvent three is selected from one of dichloromethane, chloroform, toluene, methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, acetonitrile, etc., and its dosage is 4-8 times the mass of intermediate one; the reaction temperature in step 2) is 30-60 °C, and the reaction time is 18-24 h; the yield of intermediate two obtained in this process is greater than 87.5%, and the purity is greater than 99.6%.

[0062] In a preferred embodiment, in step 3):

[0063] The solvent 4 is one of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, etc., and its dosage is 5-15 times the mass of the intermediate 2; the tert-butylamine is 0.4-1 times the mass of the intermediate 2; the reaction temperature after adding tert-butylamine is 40-80°C, and the reaction is 3h; the reducing agent is one of sodium borohydride, potassium borohydride, lithium aluminum hydride, etc., and its dosage is 0.3-1 times the mass of the intermediate 2; the reaction temperature after adding the reducing agent is -10-20°C, and the reaction is 4h; the concentration of the sulfuric acid aqueous solution is 30%-60%; the solvent 5 is selected from one of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, etc., and its dosage is 0.5-4 times the mass of the intermediate 2. The yield is greater than 76.3% and the purity is greater than 99.8%.

[0064] The following are preferred implementation examples. Unless otherwise specified, the reagents used are commercially available standard products in the field, and the experimental methods are methods that are well-known to those skilled in the art.

[0065] Example 1

[0066] 1) Add 100 ml acetone, 10 g salicyl alcohol, and 2 g aluminum chloride to the reaction flask, stir at 50°C for 4 h, and take a sample for TLC detection to confirm that the reaction is complete. Filter through silica gel pad, rinse with a little acetone, and concentrate the filtrate under negative pressure to obtain 13.0 g colorless transparent oily liquid (intermediate 1). HPLC purity 99.5%.

[0067] 2) Add 200ml of dichloromethane, 15g of chloroacetyl chloride, 30g of aluminum chloride, and 10g of intermediate 1 to the reaction bottle, stir and heat to 35°C, react for 24 hours, and take a sample for TLC detection to confirm that the reaction is complete. Add 200ml of 5% dilute hydrochloric acid to quench the reaction, separate the liquids, extract the aqueous phase once with 100ml of dichloromethane, combine the organic phases and dry them with 20g of anhydrous sodium sulfate, filter, and concentrate the organic phase to obtain a yellow solid. Add 50ml of tertiary methyl ether, beat at 50°C for 1h, cool to 5°C and filter, rinse the filter cake with a small amount of tertiary methyl ether, and dry the filter cake at 60°C for 8h to obtain 10.7g of off-white solid (intermediate 2). HPLC purity 99.6%.

[0068] 3) Add 100ml of isopropanol and 10g of intermediate 2 to the reaction bottle, cool to 5°C, add 4.5g of tert-butylamine, heat to 80°C for 2 hours, and take a sample for TLC detection to confirm that the reaction is complete. Cool to 0°C, add 4g of sodium borohydride, keep warm for 4 hours, take a sample for TLC detection to confirm that the reaction is complete, add 30ml of 40% sulfuric acid aqueous solution, solid precipitates, cool to 20°C for crystallization for 2 hours, filter, rinse with a little isopropanol, add 20ml of acetone to the filter cake, beat at 50°C for 1h, cool to 5°C for filtration, rinse with a little acetone, and dry the filter cake at 50°C for 10h to obtain 11.1g of white solid (salbutamol sulfate). HPLC purity 99.8%.

[0069] Example 2

[0070] 1) Add 100 ml of tetrahydrofuran, 5 g of 2,2-dimethylpropane, 10 g of salicyl alcohol, and 2 g of aluminum chloride into a reaction flask, stir and react at 55 °C for 4 h. Take a sample for TLC detection to confirm that the reaction is complete. Filter through silica gel, wash with a little acetone, concentrate the filtrate under negative pressure to obtain 12.9 g of a colorless transparent oily liquid (Intermediate 1). HPLC purity is 99.6%.

[0071] 2) Add 200 ml of dichloromethane, 20 g of bromoacetyl chloride, 30 g of aluminum trichloride, and 10 g of Intermediate 1 into a reaction flask, stir and heat up to 45 °C, react for 20 hours. Take a sample for TLC detection to confirm that the reaction is complete. Add 200 ml of 5% dilute hydrochloric acid to quench the reaction, separate the layers, extract the aqueous phase with 100 ml of dichloromethane once, combine the organic phases, dry with 20 g of anhydrous sodium sulfate, filter, concentrate the organic phase to obtain a yellow solid. Add 50 ml of methyl tert-butyl ether, stir at 50 °C for 1 h, cool down to 10 °C and filter, wash the filter cake with a little methyl tert-butyl ether, dry the filter cake at 60 °C for 8 h to obtain 10.8 g of an off-white solid (Intermediate 2). HPLC purity is 99.6%.

[0072] 3) Add 100 ml of isopropanol and 10 g of Intermediate 2 into a reaction flask, cool down to 0 °C, dropwise add 5 g of tert-butylamine, heat up to 60 °C and react for 4 h. Take a sample for TLC detection to confirm that the reaction is complete. Cool down to 5 °C, add 4 g of potassium borohydride, keep the temperature for reaction for 4 h. Take a sample for TLC detection to confirm that the reaction is complete. Add 30 ml of 40% sulfuric acid aqueous solution, solid precipitates, cool down to 20 °C and crystallize for 2 h, filter, wash with a little isopropanol. Add 20 ml of isopropanol to the filter cake, stir at 45 °C for 1 h, cool down to 10 °C and filter, wash with a little isopropanol, dry the filter cake at 60 °C for 8 h to obtain 11.0 g of a white solid (Salbutamol Sulfate). HPLC purity is 99.8%.

[0073] Example 3

[0074] 1) Add 100 ml of methyl tert-butyl ether, 5 g of 2,2-dimethylpropane, 10 g of salicyl alcohol, and 1 g of aluminum chloride into a reaction flask, stir and react at 50 °C for 4 h. Take a sample for TLC detection to confirm that the reaction is complete. Filter through silica gel, wash with a little acetone, concentrate the filtrate under negative pressure to obtain 12.9 g of a colorless transparent oily liquid (Intermediate 1). HPLC purity is 99.6%.

[0075] 2) Add 200 ml of dichloromethane, 20 g of bromoacetyl chloride, 40 g of aluminum trichloride, and 10 g of Intermediate 1 into a reaction flask, stir and heat up to 40 °C, react for 22 hours, take a sample for TLC detection to confirm the completion of the reaction. Add 200 ml of 5% dilute hydrochloric acid to quench the reaction, separate the layers, extract the aqueous phase once with 100 ml of dichloromethane, combine the organic phases, dry with 20 g of anhydrous sodium sulfate, filter, concentrate the organic phase to obtain a yellow solid, add 50 ml of isopropyl ether, slurry at 50 °C for 1 h, cool down to 5 °C and filter, wash the filter cake with a small amount of isopropyl ether, and dry the filter cake at 60 °C for 6 h to obtain 11.0 g of a white solid (Intermediate 2). HPLC purity is 99.7%.

[0076] 3) Add 100 ml of ethanol and 10 g of Intermediate 2 into a reaction flask, cool down to 0 - 10 °C, dropwise add 5 g of tert-butylamine, heat up to 70 °C and react for 3 hours, take a sample for TLC detection to confirm the completion of the reaction. Cool down to 10 °C, add 4 g of sodium borohydride, keep the temperature for reaction for 4 hours, take a sample for TLC detection to confirm the completion of the reaction, add 30 ml of 40% sulfuric acid aqueous solution, solid precipitates, cool down to 20 °C and crystallize for 2 hours, filter, wash with a little ethanol, add the filter cake to 20 ml of isopropyl alcohol, slurry at 50 °C for 1 h, cool down to 5 °C and filter, wash with a little isopropyl alcohol, and dry the filter cake at 60 °C for 8 h to obtain 11.4 g of a white solid (Salbutamol Sulfate). HPLC purity is 99.9%.

[0077] Example 4

[0078] 1) Add 100 ml of methyl tert-butyl ether, 5 g of 2,2-dimethylpropane, 10 g of salicyl alcohol, and 1 g of ferric chloride into a reaction flask, stir and react at 50 °C for 4 h, take a sample for TLC detection to confirm the completion of the reaction. Filter through silica gel, wash with a little acetone, concentrate the filtrate under negative pressure to obtain 12.8 g of a colorless transparent oily liquid (Intermediate 1). HPLC purity is 99.5%.

[0079] 2) Add 200 ml of dichloromethane, 20 g of bromoacetyl chloride, 40 g of ferric chloride, and 10 g of Intermediate 1 into a reaction flask, stir and heat up to 45 °C, react for 20 hours, take a sample for TLC detection to confirm the completion of the reaction. Add 200 ml of 5% dilute hydrochloric acid to quench the reaction, separate the layers, extract the aqueous phase once with 100 ml of dichloromethane, combine the organic phases, dry with 20 g of anhydrous sodium sulfate, filter, concentrate the organic phase to obtain a yellow solid, add 50 ml of methyl tert-butyl ether, slurry at 45 °C for 1 h, cool down to 0 °C and filter, wash the filter cake with a small amount of methyl tert-butyl ether, and dry the filter cake at 50 °C for 10 h to obtain 10.8 g of a white solid (Intermediate 2). HPLC purity is 99.7%.

[0080] 3) Add 100 ml of isopropanol and 10 g of Intermediate II into a reaction flask, cool down to 5 °C, dropwise add 6 g of tert-butylamine, heat up to 70 °C and react for 3 hours. Take a sample for TLC detection to confirm the completion of the reaction. Cool down to 5 °C, add 3 g of sodium borohydride, keep the temperature for reaction for 4 hours, take a sample for TLC detection to confirm the completion of the reaction, add 30 ml of 40% sulfuric acid aqueous solution, precipitate solids, cool down to 20 °C for crystallization for 2 hours, filter, wash with a little isopropanol, add the filter cake to 20 ml of acetone, slurry at 50 °C for 1 h, cool down to 5 °C and filter, wash with a little acetone, dry the filter cake at 50 °C for 12 h to obtain 11.9 g of white solid (salbutamol sulfate). HPLC purity: 99.8%.

[0081] Example 5

[0082] 1) Add 100 ml of methyl tert-butyl ether, 5 g of 2,2-dimethylpropane, 10 g of salicyl alcohol and 1 g of zinc chloride into a reaction flask, stir and react at 50 °C for 4 h. Take a sample for TLC detection to confirm the completion of the reaction. Filter with silica gel as a pad, wash with a little acetone, concentrate the filtrate under negative pressure to obtain 12.8 g of colorless transparent oily liquid (Intermediate I). HPLC purity: 99.5%.

[0083] 2) Add 200 ml of dichloromethane, 20 g of bromoacetyl chloride, 40 g of zinc chloride and 10 g of Intermediate I into a reaction flask, stir and heat up to 38 °C, react for 23 hours. Take a sample for TLC detection to confirm the completion of the reaction. Add 200 ml of 5% dilute hydrochloric acid to quench the reaction, separate the layers, extract the aqueous phase with 100 ml of dichloromethane once, combine the organic phases, dry with 20 g of anhydrous sodium sulfate, filter, concentrate the organic phase to obtain a yellow solid, add 50 ml of methyl tert-butyl ether, slurry at 50 °C for 1 h, cool down to 5 °C and filter, wash the filter cake with a small amount of methyl tert-butyl ether, dry the filter cake at 60 °C for 6 h to obtain 10.7 g of off-white solid (Intermediate II). HPLC purity: 99.7%.

[0084] 3) Add 100 ml of isopropanol and 10 g of Intermediate II into a reaction flask, cool down to 5 °C, dropwise add 5 g of tert-butylamine, heat up to 75 °C and react for 3 hours. Take a sample for TLC detection to confirm the completion of the reaction. Cool down to 10 °C, add 4 g of potassium borohydride, keep the temperature for reaction for 4 hours, take a sample for TLC detection to confirm the completion of the reaction, add 30 ml of 40% sulfuric acid aqueous solution, precipitate solids, cool down to 20 °C for crystallization for 2 hours, filter, wash with a little isopropanol, add the filter cake to 20 ml of acetone, slurry at 50 °C for 1 h, cool down to 5 °C and filter, wash with a little acetone, dry the filter cake at 50 °C for 12 h to obtain 11.9 g of white solid (salbutamol sulfate). HPLC purity: 99.8%.

[0085] Example 6

[0086] 1) Add 100 ml of acetone, 5 g of 2,2-dimethylpropane, 10 g of salicyl alcohol, and 1 g of aluminum chloride to a reaction flask. Stir and react at 50 °C for 4 h. Take a sample for TLC detection to confirm the completion of the reaction. Filter with silica gel padding and wash with a little acetone. Concentrate the filtrate under negative pressure to obtain 12.8 g of a colorless transparent oily liquid (Intermediate 1). HPLC purity is 99.5%.

[0087] 2) Add 200 ml of dichloromethane, 20 g of chloroacetyl bromide, 30 g of aluminum chloride, and 10 g of Intermediate 1 to a reaction flask. Stir and heat up to 45 °C and react for 20 h. Take a sample for TLC detection to confirm the completion of the reaction. Add 200 ml of 5% dilute hydrochloric acid to quench the reaction. Separate the layers. Extract the aqueous phase with 100 ml of dichloromethane once. Combine the organic phases and dry with 20 g of anhydrous sodium sulfate. Filter and concentrate the organic phase to obtain a yellow solid. Add 50 ml of methyl tert-butyl ether and slurry at 40 °C for 1 h. Cool down to 10 °C and filter. Wash the filter cake with a little methyl tert-butyl ether. Dry the filter cake at 50 °C for 10 h to obtain 10.8 g of an off-white solid (Intermediate 2). HPLC purity is 99.7%.

[0088] 3) Add 100 ml of isopropyl alcohol and 10 g of Intermediate 2 to a reaction flask. Cool down to 5 °C and dropwise add 5 g of tert-butylamine. Heat up to 80 °C and react for 3 h. Take a sample for TLC detection to confirm the completion of the reaction. Cool down to 10 °C, add 5 g of sodium borohydride, and keep the temperature for reaction for 4 h. Take a sample for TLC detection to confirm the completion of the reaction. Add 30 ml of 50% sulfuric acid aqueous solution. A solid precipitates. Cool down to 20 °C and crystallize for 2 h. Filter and wash with a little isopropyl alcohol. Add 20 ml of acetone to the filter cake and slurry at 40 °C for 1 h. Cool down to 5 °C and filter. Wash the filter cake with a little acetone. Dry the filter cake at 55 °C for 10 h to obtain 11.9 g of a white solid (salbutamol sulfate). HPLC purity is 99.8%.

[0089] Comparative Example

[0090] Prepare salbutamol sulfate according to the method provided in Patent CN111620787A. However, due to the use of excessive benzyl chloride in the synthesis process, the post-treatment distillation has strong irritation, there is palladium residue in the subsequent reduction with palladium-carbon, and the atom utilization rate is low, the molar yield is 40%-45%, and there are more wastes.

[0091] It can be seen from Examples 1-6 that the molar yield of preparing salbutamol sulfate based on salicyl alcohol is 65-70%, and the purity is greater than 99.8%. It is thus inferred that the yield of preparing salbutamol is above this. This preparation process has mild reaction conditions, is green and environmentally friendly, has a higher yield compared with the prior art, is safer and more environmentally friendly, and is more conducive to industrial application.

[0092] Although embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing salbutamol, characterized in that the steps include: Add salicyl alcohol to solvent one, add catalyst one and acetone compound, stir and react to obtain intermediate one; Adding catalyst 2 and acylating agent into solvent 2, dropping intermediate 1, stirring and reacting completely, adding dilute hydrochloric acid to quench the reaction to obtain intermediate 2; The intermediate 2 is added to the solvent 3, and tert-butylamine is added dropwise. After the addition is complete, the temperature is lowered after the reaction is completed, and a reducing agent is added to react to obtain salbutamol; The reaction route of the preparation method is as follows:

2. The preparation method according to claim 1, characterized in that: During the preparation of the intermediate 1: The solvent is selected from at least one of acetone, methyl tert-ether, tetrahydrofuran, methanol or acetonitrile; and / or, the catalyst one is selected from aluminum chloride, zinc chloride, ferric chloride or p-toluenesulfonic acid; And / or, the acetone compound is acetone or 2,2-dimethylpropane; And / or, the reaction temperature is 30-60°C.

3. The preparation method according to claim 1, characterized in that: During the preparation of the intermediate 2: The second solvent is selected from at least one of dichloromethane, chloroform, toluene, tert-methyl ether, tetrahydrofuran or acetonitrile; and / or, the second catalyst is selected from aluminum chloride, ferric chloride, zinc chloride or zirconium tetrachloride; And / or, the acylating agent is bromoacetyl chloride, bromoacetyl bromide, chloroacetyl chloride, or chloroacetyl bromide; And / or, the reaction temperature is 30-60°C.

4. The preparation method according to claim 1, characterized in that: In the process of preparing salbutamol from the intermediate 2: The solvent three is selected from methanol, ethanol, isopropanol, tetrahydrofuran or acetonitrile; And / or, the amount of tert-butylamine used is 0.4-1 times the mass of the intermediate II; And / or, the reaction temperature after adding tert-butylamine is 40-80°C; and / or, the reducing agent is sodium borohydride, potassium borohydride or lithium aluminum hydride; And / or, the reaction temperature after adding the reducing agent is -10-20°C.

5. The preparation method according to claim 1, characterized in that: The method also includes a post-treatment step of the intermediate one: filtering and concentrating the reaction product to obtain the intermediate one.

6. The preparation method according to claim 1, characterized in that: The method also includes a step of post-processing the intermediate 2: extracting and separating the reaction product, concentrating the organic phase to obtain a solid, and then slurrying and filtering and drying to obtain the intermediate 2.

7. A method for preparing salbutamol sulfate, characterized in that: The method comprises the steps of preparing salbutamol by the preparation method according to any one of claims 1 to 6, and salifying the salbutamol.

8. The preparation method according to claim 7, characterized in that: The salbutamol salt-forming process comprises the following steps: reacting the salbutamol reaction product with a sulfuric acid aqueous solution, crystallizing, filtering, beating with a solvent, cooling and filtering, washing and drying.

9. The preparation method according to claim 8, characterized in that: The concentration of the aqueous sulfuric acid solution is 30-60%.

10. The preparation method according to claim 8, characterized in that: The solvent four and the solvent used in the washing process are each independently selected from one of methanol, ethanol, isopropanol, acetone, tetrahydrofuran or acetonitrile.

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