A kind of preparation method of salbutamol sulfate
Through a one-step reaction method and a palladium carbon catalyst, high-purity albutamol sulfate was directly prepared, which solved the complicated steps and impurities in the existing technology, and achieved an efficient and concise preparation process, which complied with the quality standards of the European Pharmacopoeia.
Patent Information
- Application Number
- CN202211731345.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2022-12-30
- Publication Date
- 2025-01-03
- Estimated Expiration
- 2042-12-30
AI Technical Summary
The existing preparation methods for albuterol sulfate are complicated and easy to introduce unknown impurities and inorganic salt solid waste, which is difficult to meet the high purity and low impurity requirements of the European Pharmacopoeia.
Using a one-step reaction method, compound I was mixed with saturated monohydric alcohol and dilute aqueous sulfuric acid solution, and hydrogen was pressurized using a palladium carbon catalyst. After filtration, the cooling and crystallization was eliminated, and the steps of synthesizing albuterol free base and sulfuric acid alone were reduced, thus reducing etherified impurities. The emergence of
The preparation of albuterol sulfate with high yield and high purity is achieved, reducing or avoiding the generation of etherified impurities, simplifying the operation process, avoiding the generation of inorganic salt solid waste, and improving the quality and environmental friendliness of the finished product.
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Figure CN115925562B_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of pharmaceutical chemical industry, and particularly relates to a method for preparing salbutamol sulfate. Background Art
[0002] Albuterol sulfate, chemically known as 1-(4-hydroxy-3-hydroxymethylphenyl)-2-(tert-butylamino)ethanol sulfate, is suitable for the treatment of chronic bronchospasm, severe acute asthma attacks and chronic obstructive pulmonary disease (COPD). It is a selective β2 receptor agonist. It can relax bronchial smooth muscle and has a strong selective effect on β2 receptors in bronchial smooth muscle. The drug was developed by Glaxo and first launched in 1968. It was registered in my country in 1988. Since its launch, it has been widely popular in the market for its good efficacy.
[0003] The structure of salbutamol sulfate is as follows:
[0004]
[0005] Although there are many methods for preparing salbutamol sulfate in the prior art, the existing methods have many reaction steps, cumbersome operations, long process cycles, and may introduce unknown impurities, resulting in transit losses. Some methods also use boron reducing agents, which not only easily produce a large amount of inorganic salt solid waste, which is difficult to handle; it is also easy for the difficult-to-remove boron element to remain in the finished product, affecting the quality of the finished product. In addition, the prior art usually prepares salbutamol free base first and then adds sulfuric acid to an alcohol solvent to form a salt, as shown below (R in the path is an alkyl group, such as methyl, ethyl, isopropyl), which easily generates a variety of etherified impurities,
[0006]
[0007] For example, when R-OH is methanol, the prior art preparation methods often generate impurity A listed in the European Pharmacopoeia. Impurity M Moreover, after a single purification, the concentration is often still greater than 0.1%, which is not easy to remove and difficult to meet the requirements of the European Pharmacopoeia. Therefore, there is still a need for a more concise and efficient preparation method that can not only stably ensure high yield and high purity of salbutamol sulfate, but also reduce or avoid the generation of etherified impurities, and further meet the quality standards of the European Pharmacopoeia. Summary of the invention
[0008] The present invention provides a method for preparing salbutamol sulfate. Specifically, the preparation is completed in one step using the following preparation route:
[0009] The method comprises the following steps,
[0010] 1) mixing compound I with a 5% to 30% aqueous sulfuric acid solution in a saturated monohydric alcohol i;
[0011] 2) Add palladium carbon, and filter after the hydrogen pressure reaction is completed;
[0012] 3) adding saturated monohydric alcohol ii, cooling and crystallizing to obtain the product;
[0013] Wherein, the saturated monohydric alcohol i and the saturated monohydric alcohol ii are each independently selected from saturated monohydric alcohols of C1 to C6;
[0014] The molar ratio of the compound I to sulfuric acid is less than 2:1.01, preferably the molar ratio of the compound I to sulfuric acid is 2:(1.03-1.15); in some more preferred embodiments of the present invention, the molar ratio of the compound I to sulfuric acid is 2:(1.03-1.06).
[0015] Furthermore, the concentration of the dilute sulfuric acid aqueous solution of the present invention is 5% to 30%, preferably the concentration of the sulfuric acid aqueous solution is 10% to 30%.
[0016] Furthermore, the palladium carbon described in the present invention is a wet-basis palladium carbon; the palladium content of the palladium carbon is 5% to 10%; preferably, the wet-basis content of the palladium carbon is 40% to 60%.
[0017] Furthermore, the saturated monohydric alcohol i and the saturated monohydric alcohol ii of the present invention are independently selected from methanol, ethanol, isopropanol and n-propanol; preferably, the saturated monohydric alcohol i is the same as the saturated monohydric alcohol ii; more preferably, the saturated monohydric alcohol i and the saturated monohydric alcohol ii are both selected from ethanol or isopropanol.
[0018] Furthermore, the filtration described in the present invention is precision filter filtration or diatomaceous earth filtration.
[0019] Furthermore, the pressure of the hydrogen pressurization in the present invention is above 0.3 MPa, preferably 0.3-0.4 MPa.
[0020] Furthermore, the hydrogen pressurization reaction time in step 2) of the present invention is preferably 6 to 12 hours.
[0021] Compared with the prior art, the preparation method of salbutamol sulfate of the present invention has the following beneficial technical effects: salbutamol sulfate is obtained by direct one-step reaction of compound I, without the need to separately synthesize salbutamol free base and then salt, the operation is convenient, the post-treatment is simple, and the technical effect can be achieved by using a safer wet-based palladium carbon, which overcomes the technical problem of the prior art that the anhydrous reaction system needs to be controlled. The finished product obtained by the preparation method of the present invention can effectively reduce or even avoid the generation of etherified impurities, including, for example, impurity A Impurity M And impurity 1 Impurity 2 Impurity 3 Impurity 4 etc.; at the same time, the finished product of the present invention has high overall HPLC purity and high yield, and does not generate additional inorganic salt solid waste. The solid catalyst used can also be regenerated or recycled, which is beneficial to cost saving and more environmentally friendly. In some preferred embodiments of the present invention, the purity of the finished product can be further improved, the heavy metal residue in the finished product can be reduced, the finished product can reach a higher quality, and the adverse effects of heavy metal residues can be avoided. BRIEF DESCRIPTION OF THE DRAWINGS
[0022] Figure 1 HPLC spectrum of salbutamol sulfate prepared in Example 1.
[0023] Figure 2 HPLC spectrum of salbutamol sulfate prepared in Example 2.
[0024] Figure 3 HPLC spectrum of salbutamol sulfate prepared in Example 4.
[0025] Figure 4 HPLC spectrum of salbutamol sulfate prepared in Comparative Example 2.
[0026] Figure 5 HPLC spectrum of salbutamol sulfate prepared in Comparative Example 5. DETAILED DESCRIPTION
[0027] The raw materials and reagents in the present invention are purchased from conventional commercial products or prepared according to conventional techniques in the art.
[0028] Example 1
[0029] At room temperature, 30.44g of compound I, 67g of 10% sulfuric acid aqueous solution, 210mL of isopropanol, and 3.0g of 10% wet basis (55%) palladium carbon were added to the reactor in sequence. The reactor was sealed, stirred, and nitrogen was introduced to replace the air in the reactor three times, and then hydrogen was introduced to replace the nitrogen. After the replacement, the hydrogen pressure in the reactor was maintained at 0.3-0.4Mpa, and the temperature was raised to 35-45°C to react for 8h. After the pressure was released, the solid was filtered with a precision filter after nitrogen replaced the hydrogen in the reactor, 150mL of isopropanol was added to the filtrate, the temperature was lowered to -10--5°C, stirred for 2-4h, filtered, and dried to obtain 32.3g of off-white salbutamol sulfate. The yield was 86.6%, the HPLC purity was 99.96%, the maximum single impurity was 0.01%, and no etherified impurities such as impurities 1-4, impurity A, and impurity M were detected.
[0030] Example 2
[0031] At room temperature, 100g of compound I, 215g of 10% aqueous sulfuric acid solution, 700ml of isopropanol, and 9.9g of 10% wet palladium carbon were added to the reactor in sequence. The reactor was sealed and stirred. Nitrogen was charged to replace the air in the reactor three times, and then hydrogen was charged to replace the nitrogen. After the replacement, the hydrogen pressure in the reactor was maintained at 0.3-0.4Mpa, and the temperature was raised to 35-45°C for reaction for 8h. The solid was filtered with a precision filter, 500mL of isopropanol was added, the temperature was lowered to -10--5°C, stirred for 2-4h, filtered, and dried to obtain 109.6g of off-white salbutamol sulfate. The yield was 89.4%, the HPLC purity was 99.91%, the maximum single impurity was 0.04%, and impurities 1-4, impurity A, and impurity M were not detected.
[0032] Example 3
[0033] At room temperature, 15.2 g of compound I was added to the reactor in sequence, and numbered 1 to 5, and sulfuric acid aqueous solution with concentration and dosage as shown in Table 1 was added thereto respectively, and then 100 ml of isopropanol was added respectively, stirred for 1 hour, and then 1.5 g of 10% wet basis palladium carbon was added, the reactor was sealed, stirring was started, nitrogen was filled into the reactor to replace the air three times, and then hydrogen was filled into the reactor to replace the nitrogen for 5 minutes. After the replacement, the hydrogen pressure in the reactor was maintained at 0.3 to 0.4 MPa, and the temperature was raised to 35 to 45°C to react for 8 hours. Filter the solid filtrate with a precision filter, add 100 mL of isopropanol, cool to -10 to -5°C, stir for 2 to 4 hours, filter, and dry to obtain off-white salbutamol sulfate. The results are shown in Table 1.
[0034] Table 1
[0035]
[0036] Example 4
[0037] At room temperature, 16.8g of compound I, 80g of 5% sulfuric acid aqueous solution, 110ml of isopropanol, and 2.5g of 10% wet palladium carbon were added to the reactor in sequence. The reactor was sealed and stirred. Nitrogen was charged to replace the air in the reactor three times, and then hydrogen was charged to replace the nitrogen for 5min. After the replacement, the hydrogen pressure in the reactor was maintained at 0.6-0.7Mpa, and the temperature was raised to 50-55°C to react for 16h. The reaction was complete. The solid was filtered with a precision filter, 110mL of isopropanol was added to the filtrate, the temperature was lowered to -10--5°C, stirred for 2-4h, filtered, and dried to obtain 16.8g of off-white salbutamol sulfate. The yield was 81.6%, the HPLC purity was 99.86%, the maximum single impurity was 0.03%, and impurities 1-4, impurity A, and impurity M were not detected.
[0038] The results of Examples 1 to 4 and Table 1 show that when the concentration of the aqueous sulfuric acid solution is 5% to 30%, salbutamol sulfate can be prepared with high purity and high yield using 5% or 10% palladium-carbon catalyst, with a yield of more than 80%, HPLC purity ≥ 99.6%, maximum single impurity < 0.1%, and no impurities 1 to 4, impurity A, or impurity M are detected. Among them, when the concentration of the aqueous sulfuric acid solution is 10% to 30%, the product yield can reach 85% or more, the reaction pressure required is smaller, the reaction time is less, it is more suitable for industrial production, and it is beneficial to energy saving.
[0039] Example 5
[0040] At room temperature, 15.2 g of compound I, 36 g of 10% aqueous sulfuric acid solution, and 100 mL of organic solvent X were added to four reaction kettles respectively, and stirred for 1 hour. Then 1.5 g of 10% wet palladium carbon was added, the reaction kettle was sealed, stirring was started, nitrogen was filled to replace the air in the kettle for 5 minutes, and then hydrogen was filled to replace the nitrogen for 5 minutes. After the replacement, the hydrogen pressure in the kettle was maintained at 0.3-0.4 MPa, and the temperature was raised to 35-40°C to react for 8 hours. The solids were filtered with precision filters respectively, the filtrate was refluxed for 3 hours, the filtrate was filtered, and 80 mL of organic solvent X was added, the temperature was lowered to -10--5°C, stirred for 3 hours, filtered, and dried to prepare salbutamol sulfate; wherein the organic solvent X and the corresponding results are shown in Table 2,
[0041] Table 2
[0042]
[0043] “——” indicates that no salbutamol sulfate solid was obtained.
[0044] According to Table 1 and Table 2, when the organic solvent X is selected from alcohols, such as methanol, ethanol, isopropanol, etc., high yield and high purity salbutamol sulfate can be obtained, and no etherified impurities are detected. When the organic solvent X is toluene, no solid precipitation is obtained; when the organic solvent X is ethyl acetate, the reaction system is turbid, and only a small amount of light yellow solid is precipitated.
[0045] Comparative Example 1
[0046] At room temperature, 16.8g of compound I, 35g of 10% aqueous sulfuric acid solution, 110ml of isopropanol, and 1.5g of 10% wet palladium carbon were added to the reactor in sequence. The reactor was sealed and stirred. Nitrogen was introduced to replace the air in the reactor three times, and then hydrogen was introduced to replace the nitrogen for 5 minutes. After the replacement, the hydrogen pressure in the reactor was maintained at 0.6-0.7Mpa, and the reactor was heated at 35-45°C for 48h. LCMS showed that a large amount of transition intermediates remained. The hydrogen pressure was increased to 1.2-1.3Mpa, and the reaction was continued for 10h. The impurities and products increased significantly, and the reaction was stopped.
[0047] Comparative Example 1 shows that when the molar ratio of Compound I to sulfuric acid is 2:1.00 or higher, a higher hydrogen pressure is required to promote the reaction, and more impurities are easily generated during the reaction.
[0048] Comparative Example 2
[0049] At room temperature, in a reactor, 16.8 g of compound I, 5.7 g of 70% sulfuric acid aqueous solution, 110 ml of isopropanol, and then 1.5 g of 10% wet-based palladium carbon were added. The reactor was sealed and stirred. Nitrogen was introduced to replace the air in the reactor three times, and then hydrogen was introduced to replace the nitrogen for 5 minutes. After the replacement, the hydrogen pressure in the reactor was maintained at 0.3-0.4 MPa, and the reaction was heated at 35-45°C for 8 hours. The solid was filtered through a precision filter, 110 mL of isopropanol was added to the filtrate, the temperature was lowered to -10--5°C, stirred for 2-4 hours, filtered, and dried to obtain 15.1 g of off-white salbutamol sulfate with a yield of 73.3%, an HPLC purity of 96.64%, and a maximum single impurity of 1.31%.
[0050] Comparative Example 3
[0051] At room temperature, 7.7 g of the hydrochloride of compound I was dissolved in 20 mL of anhydrous methanol in a reaction kettle, 1.54 g of sodium methoxide was added at 0°C and stirred for 5 min, 4.2 g of 5% wet palladium carbon was added, nitrogen was introduced to replace the air in the kettle three times, and then hydrogen was introduced, and the hydrogen pressure in the kettle was maintained at 0.4-0.5 MPa for 1 day. The raw materials were not completely reacted. The reaction was continued for 60 h, and the impurities increased, so the reaction was stopped.
[0052] Comparative Example 4
[0053] Add 800mL of methanol to a 1L three-necked flask, add 80g of the hydrochloride of compound I under stirring, cool the system to below 10°C, slowly add 27.8g of sodium borohydride in batches, and stir at room temperature for 16h. After the reaction is complete, filter with a Buchner funnel, concentrate the filtrate to dryness, add 400mL of acetone and 50g of anhydrous potassium carbonate, heat under reflux in an oil bath and stir for 1h, after the reaction is complete, stir at room temperature for 1h, filter with a Buchner funnel, and distill and concentrate the filtrate to dryness. Add 300mL of ethanol, stir and crystallize for 3h, filter with a Buchner funnel, wash the filter cake with a small amount of methanol, and vacuum dry at 60°C for 4h to obtain salbutamol solid.
[0054] Add 500mL of methanol and 50mL of purified water to a 1L three-necked flask, add 50g of salbutamol under stirring, heat in an oil bath, raise the temperature to 50°C, slowly drop 10.5g of concentrated sulfuric acid, cool to below 10°C, and keep warm for 3h for crystallization. After the reaction is completed, filter with a Buchner funnel, wash the filter cake with a small amount of methanol, and vacuum dry at 60°C for 4h to obtain 60.1g of salbutamol sulfate, with a yield of 70.8%, HPLC purity of 95.03%, maximum single impurity of 0.57%, etherified impurity A of 0.57%, impurity M of 0.50%, and boron content of 0.3%.
[0055] The description of the above embodiments is only used to help understand the method of the present invention and its core concept, and is not intended to limit the present invention. It should be pointed out that for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.
Claims
1. A method for preparing salbutamol sulfate, characterized in that: The preparation is completed in one step using the following route: The method comprises the following steps: 1) mixing compound I in saturated monohydric alcohol i with a dilute aqueous sulfuric acid solution; 2) Add palladium carbon, and filter after the hydrogen pressure reaction is completed; 3) adding saturated monohydric alcohol ii, cooling and crystallizing to obtain the product; Wherein, the saturated monohydric alcohol i and the saturated monohydric alcohol ii are each independently selected from saturated monohydric alcohols of C1 to C6; The molar ratio of the compound I to sulfuric acid is 2:(1.03-1.15); The concentration of the dilute sulfuric acid aqueous solution is 5% to 30%.
2. The preparation method according to claim 1, wherein the concentration of the dilute sulfuric acid aqueous solution is 10% to 30%.
3. The preparation method according to claim 1, wherein the molar ratio of compound I to sulfuric acid is 2:(1.03-1.06).
4. The preparation method according to any one of claims 1 to 3, characterized in that The palladium carbon is a wet-based palladium carbon.
5. The preparation method according to claim 4, characterized in that: The palladium content of the palladium carbon is 5% to 10%.
6. The preparation method according to any one of claims 1 to 3, characterized in that The saturated monohydric alcohol i and the saturated monohydric alcohol ii are each independently selected from methanol, ethanol, isopropanol and n-propanol.
7. The preparation method according to any one of claim 6, characterized in that The saturated monohydric alcohol i is the same as the saturated monohydric alcohol ii.
8. The preparation method according to any one of claims 1 to 3, characterized in that The pressure of the hydrogen pressurization is 0.3 MPa or more.