CN110963929A - Preparation method of salbutamol hydrochloride suitable for industrial production - Google Patents
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Abstract
The invention discloses a preparation method of salbutamol hydrochloride suitable for industrial production, which takes 4-hydroxy-3-hydroxymethyl acetophenone as a starting material and prepares the salbutamol hydrochloride through epoxy protection, oxidation, reductive amination and deprotection to form salt. The reaction process of the invention has no bromination process, avoids using high-risk reagents, has small environmental pollution, low equipment requirement, simple and convenient operation, mild reaction condition, simple steps and low production cost, and is suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of salbutamol, in particular to a preparation method of salbutamol hydrochloride, which is suitable for industrial production.
Background
Bronchial asthma (bronchialathhma) is a heterogeneous disease characterized by chronic inflammation of the airways involving various cells (e.g., eosinophils, mast cells, T lymphocytes, neutrophils, airway epithelial cells, etc.) and cellular components, and is one of the common diseases that seriously jeopardize human health. In recent years, with the deepening of the cognition on the pathogenesis of bronchial asthma, the drug treatment and research of asthma have made an important progress.
Salbutamol (salbutamol) as a short-acting β 2 adrenergic receptor agonist can effectively inhibit the release of allergic substances such as histamine, prevent bronchospasm, and is suitable for bronchial asthma, asthmatic bronchitis, bronchospasm, emphysema, etc.
Salbutamol was first discovered by the british in 1962 and was developed by the glatiramer co, uk, to come into the market; it was registered and produced in 1988 in China and used for treating reversible bronchial obstruction. In recent years, salbutamol is listed in the first 20 sales of the world drug market with good drug effect, has become the first choice drug for treating asthma and Chronic Obstructive Pulmonary Disease (COPD), and has multiple new applications in clinic.
The synthesis method of salbutamol (CAS: 18559-94-9) is more, and the synthesis route mainly comprises the following types:
1. salicylaldehyde compounds as starting materials
The synthetic route has a simple reaction structure, but has the following defects that the aldehyde group in ⑴ salicylaldehyde has a passivation effect, so that a Friedel-crafts acylation reaction is hindered to a certain extent, ⑵ raw material bromoacetyl chloride is not easy to obtain and is expensive, ⑶ second step amino nucleophilic substitution uses primary amine tert-butylamine, so that tertiary amine compounds are easy to generate, the yield of the step is reduced, process impurities are increased, and ⑷ phenolic hydroxyl in the starting material is not protected and is easy to oxidize by an oxidant, so that the process impurities are generated.
2. Using p-hydroxybenzaldehyde compounds as starting materials
The synthetic route has complicated reaction steps and longer route, and reduces the overall yield; meanwhile, primary alcohol process impurities are easily generated in the process of carrying out amino nucleophilic substitution on the intermediate epoxide.
3. Using p-hydroxyacetophenone compound as starting material
The synthesis route (a) has simple reaction structure and short operation route, and Schiff base and aldehyde group can be well reduced by safer sodium borohydride at the same time, thereby avoiding heavy metal pollution; but the phenolic hydroxyl group is not protected, so that oxidation impurities are easily generated, and the reduction of the ester group into alcohol also uses the borane thioether which is highly toxic and explosive.
Although benzyl is used for protecting phenolic hydroxyl in the synthetic route (b), borane thioether which is extremely toxic and explosive is still used, ester groups can only be reduced, and benzyloxy needs to be reduced additionally, so that a deprotection process is added, the risk of heavy metal pollution is increased, and the production cost is increased.
The synthesis route (c) uses highly toxic liquid bromine, has serious environmental pollution and high corrosion to equipment, and easily generates multi-bromine substitute process impurities in the bromination process; benzyl group must be reduced in addition, which increases the process of deprotection, increases the risk of heavy metal pollution and increases the production cost.
Disclosure of Invention
Aiming at the problems, the invention provides the salbutamol hydrochloride preparation method suitable for industrial production, which avoids the use of high-risk virulent reagents, has simple steps, low requirement on equipment, simple operation and less environmental pollution.
A preparation method of salbutamol hydrochloride suitable for industrial production comprises the following steps:
1. epoxy protection: cyclizing 4-hydroxy-3-hydroxymethyl acetophenone of the compound shown in the formula 1 and 2, 2-dimethoxypropane under the action of a catalyst to obtain 1- (2, 2-dimethyl-4H-benzo [ d ] [ l,3] dioxane-6-yl) ethanone of the compound shown in the formula 2;
2. and (3) oxidation: oxidizing the compound 1- (2, 2-dimethyl-4H-benzo [ d ] [ l,3] dioxane-6-yl) ethanone in the formula 2 with dimethyl sulfoxide under the action of a catalyst to obtain a compound 1- (2, 2-dimethyl-4H-benzo [ d ] [ l,3] dioxane-6-yl) ketoaldehyde in the formula 3;
3. reductive amination: the compound 1- (2, 2-dimethyl-4H-benzo [ d ] [ l,3] dioxane-6-yl) ketoaldehyde in the formula 3 is subjected to reductive amination with tert-butylamine and a reducing agent to prepare a compound 2- (tert-butylamino) -1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] dioxane-6-yl) ethanol in the formula 4;
4. deprotection to form salt: the compound 2- (tert-butylamino) -1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] dioxane-6-yl) ethanol of the formula 4 is added with hydrochloric acid to be deprotected to form salt, and salbutamol hydrochloride is prepared.
Further, the organic solvent selected in the step 1 is any one of dichloromethane, tetrahydrofuran, toluene, 1, 4-dioxane and N, N-dimethylformamide, and the volume dosage of the selected solvent is 2-5 times of the mass of the compound shown in the formula 1; the catalyst in the step 1 is any one of p-toluenesulfonic acid, acetic acid and sulfuric acid, and the dosage of the selected catalyst is 0.05-0.5 time of the mass of the compound in the formula 1; the reaction temperature is controlled at 20-120 ℃.
Further, the volume usage amount of the organic solvent dimethyl sulfoxide in the step 2 is 2-5 times of the mass of the compound of the formula 2; the catalyst in the step 2 is any one of hydrobromic acid, hydroiodic acid, iodine simple substance and hydrochloric acid, and the molar amount of the selected catalyst is 1-5 times of that of the compound shown in the formula 2; the reaction temperature is controlled at 20-90 ℃.
Further, the organic solvent selected in the step 3 is any one of methanol, ethanol, dichloromethane, toluene and tetrahydrofuran, and the volume dosage of the selected organic solvent is 2-5 times of the mass of the compound shown in the formula 3; the molar amount of the tert-butylamine in the step 3 is 1-1.5 times of that of the compound shown in the formula 3; the reducing agent is any one of sodium borohydride, potassium borohydride, lithium borohydride and sodium cyanoborohydride, and the molar amount of the reducing agent is 1-3 times of that of the compound shown in the formula 3; when tert-butylamine and a reducing agent are added, the temperature is controlled between 0 and 10 ℃, and then the reaction temperature is controlled between 20 and 120 ℃.
Further, the organic solvent selected in the step 4 is any one of methanol, ethanol, isopropanol and ethyl acetate, the volume dosage of the selected organic solvent is 5-8 times of the mass of the compound of the formula 4, the compound of the formula 4 is dispersed in the organic solvent, and then hydrogen chloride solution of the organic solvent is dropwise added; the molar content of hydrogen chloride in the hydrogen chloride solution is 1-5 times of the molar weight of the compound shown in the formula 4; when the hydrogen chloride solution of the organic solvent is dripped, the temperature is controlled to be 0-10 ℃, and then the reaction temperature is controlled to be 20-90 ℃.
The invention has the beneficial effects that: the whole reaction process has no bromination process, avoids using high-risk reagents, has small environmental pollution, low equipment requirement, simple and convenient operation, mild reaction conditions, simple steps and low production cost, and is suitable for industrial production.
Drawings
FIG. 1 is an HPLC purity analysis chart of salbutamol hydrochloride.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The embodiments of the present invention have been presented for purposes of illustration and description, and are not intended to be exhaustive or limited to the invention in the form disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art. The embodiment was chosen and described in order to best explain the principles of the invention and the practical application, and to enable others of ordinary skill in the art to understand the invention for various embodiments with various modifications as are suited to the particular use contemplated.
Example 1
A preparation method of salbutamol hydrochloride suitable for industrial production comprises the following steps:
1. synthesis of 1- (2, 2-dimethyl-4H-benzo [ d ] [ l,3] dioxan-6-yl) ethanone
⑴ 33.23g of 4-hydroxy-3-hydroxymethylacetophenone was charged into a 250mL three-necked flask together with a catalytic amount of p-toluenesulfonic acid (catalyst) of 3.23g, and then 100mL of methylene chloride (organic solvent) was added and dissolved with stirring to give a pale yellow reaction solution.
⑵ slowly adding mixed solution of 41.49g of 2, 2-dimethoxypropane and 60mL of dichloromethane (organic solvent) into the reaction solution at room temperature, continuously stirring until the reaction is completed, adding saturated sodium bicarbonate solution into the reaction solution to adjust the reaction system to be alkalescent, standing for layering, separating an organic layer, washing the organic phase with saturated sodium chloride aqueous solution and water respectively, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating, and drying in vacuum to obtain 38.34g of light yellow oily liquid with the yield of 93%.
1H-NMR(400Mz，CDCl3) δ: 1.49(s, 6H); 2.50(s, 3H); 4.62(s, 2H); 6.98-7.70 (m, 3H); ESI-HRMS shows that the molecular ion peak M/z is 207.1018[ M + H ]]+The corresponding molecular weights are consistent with the theoretical calculations (207.1021) for the formula provided, with absolute errors within the error range of the high resolution mass spectra.
2. Synthesis of 1- (2, 2-dimethyl-4H-benzo [ d ] [ l,3] dioxan-6-yl) ethanone aldehyde
Adding 30.00g of 1- (2, 2-dimethyl-4H-benzo [ d ] [ l,3] dioxane-6-yl) ethanone into a 250mL three-neck flask, adding 120mL of dimethyl sulfoxide (organic solvent) for dissolving, adding 22.15g of iodine simple substance (catalyst) at 20-30 ℃, heating to 60-70 ℃ for reacting for 4-5 hours till completion, cooling to room temperature, adding into ice water, extracting with organic solvents such as dichloromethane and the like, washing an organic phase with a saturated sodium carbonate solution, a sodium chloride solution and water, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating, and drying in vacuum to obtain 27.08g of a yellow oily liquid product, wherein the yield is 84.8%.
1H-NMR(400Mz，CDCl3) δ: 1.52(s, 6H); 4.53(s, 2H); 7.09-7.65 (m, 3H); 9.50(s, 1H); ESI-HRMS shows that the molecular ion peak M/z is 221.0808[ M + H ]]+The corresponding molecular weights are consistent with the theoretical calculations (221.0814) for the formula provided, with absolute errors within the error range of the high resolution mass spectra.
3. Synthesis of 2- (tert-butylamino) -1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] dioxan-6-yl) ethanol
Adding 25.00g of 1- (2, 2-dimethyl-4H-benzo [ d ] [ l,3] dioxane-6-yl) ketoaldehyde into a 250mL three-neck flask, adding 100mL of absolute ethyl alcohol (organic solvent) for dissolving, adding 10.10g of tert-butylamine (catalyst) at 0-10 ℃, enabling the system to be red clear liquid, heating to 70-80 ℃ for reflux reaction for 2-3 hours till the reaction is complete, cooling to room temperature, adding 8.59g of sodium borohydride (reducing agent) in batches at 0-10 ℃, after the addition is complete, reacting at room temperature for 1-2 hours till the reaction is complete, concentrating under reduced pressure to remove ethanol, extracting with solvents such as dichloromethane and the like, washing the organic phase with saturated sodium chloride solution, washing with water till the organic phase is neutral, drying with anhydrous sodium sulfate, filtering the sodium sulfate, concentrating, drying in vacuum to obtain 25.37g of a product yellow solid, the yield thereof was found to be 80.0%.
1H-NMR(400Mz，CDCl3) δ: 1.20(s, 9H); 1.49(s, 6H); 2.90-3.15 (m, 2H); 4.59(s, 2H); 4.87(m, 1H); 6.80-7.25 (m, 3H); ESI-HRMS shows that the molecular ion peak M/z is 280.1907[ M + H ]]+The corresponding molecular weights are consistent with the theoretical calculations (280.1913) for the formula provided, with absolute errors within the error range of the high resolution mass spectra.
4. Synthesis of salbutamol hydrochloride
Adding 25.00g of 2- (tert-butylamino) -1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] dioxane-6-yl) ethanol and 100mL of absolute ethanol (organic solvent) into a 250mL three-neck flask, stirring to form a yellow clear liquid, cooling the system to 0-10 ℃ under the protection of nitrogen, keeping the temperature, slowly dropwise adding 15mL of HCl/ethanol solution (33% by mass fraction) into the system (dropwise adding is finished for about 10 minutes), heating to reflux and stirring for 1-2 hours, cooling, crystallizing, filtering, washing a filter cake with 12mL of cold absolute ethanol, and drying in vacuum to obtain 17.27g of salbutamol hydrochloride, wherein the character of the salbutamol hydrochloride is white solid, and the yield of the salbutamol hydrochloride is 70.1%.
1H-NMR(400Mz，D2O) 6: 1.30(s, 9H); 3.15 to 3.23(m, 2H); 4.68(s, 2H); 4.85-4.91 (m, 1H); 6.85-7.32 (m, 3H); HPLC purity 99.879%, refer to fig. 1 and table 1.
Detector A Ch 1230 nm
| Peak # | Retention time | Area of | Height | Area% | Peak width of USP | Theoretical plate # | Degree of separation | Tailing factor |
| 1 | 7.674 | 144881460 | 11862741 | 99.879 | 0.557 | 3034 | 0.000 | 2.028 |
| 2 | 11.404 | 8104 | 424 | 0.006 | 0.518 | 7749 | 6.936 | 0.907 |
| 3 | 13.420 | 1660 | 84 | 0.001 | 0.511 | 11049 | 3.919 | 1.292 |
| 4 | 16.958 | 3263 | 133 | 0.002 | 1.406 | 2327 | 3.692 | 0.000 |
| 5 | 17.684 | 38062 | 1139 | 0.026 | 0.900 | 6183 | 0.629 | 0.000 |
| 6 | 18.866 | 124921 | 3786 | 0.086 | 0.885 | 7272 | 1.325 | 0.989 |
| Total of | 145057470 | 11868307 | 100.000 |
TABLE 1
It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by one of ordinary skill in the art and related arts based on the embodiments of the present invention without any creative effort, shall fall within the protection scope of the present invention.
Claims (10)
1. A preparation method of salbutamol hydrochloride suitable for industrial production is characterized by comprising the following steps:
step 1, cyclizing 4-hydroxy-3-hydroxymethyl acetophenone of a compound in a formula 1 and 2, 2-dimethoxypropane under the action of a catalyst to obtain 1- (2, 2-dimethyl-4H-benzo [ d ] [ l,3] dioxane-6-yl) ethanone of a compound in a formula 2;
step 2, oxidizing the compound 1- (2, 2-dimethyl-4H-benzo [ d ] [ l,3] dioxane-6-yl) ethanone in the formula 2 and dimethyl sulfoxide under the action of a catalyst to obtain a compound 1- (2, 2-dimethyl-4H-benzo [ d ] [ l,3] dioxane-6-yl) ketoaldehyde in the formula 3;
step 3, carrying out reductive amination on the compound 1- (2, 2-dimethyl-4H-benzo [ d ] [ l,3] dioxane-6-yl) ketoaldehyde in the formula 3, tert-butylamine and a reducing agent to obtain a compound 2- (tert-butylamino) -1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] dioxane-6-yl) ethanol in the formula 4;
and 4, adding hydrochloric acid into the compound 2- (tert-butylamino) -1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] dioxane-6-yl) ethanol in the formula 4, and carrying out deprotection to form salt so as to obtain salbutamol hydrochloride.
2. The method for preparing salbutamol hydrochloride according to claim 1, wherein the organic solvent used in step 1 is any one of dichloromethane, tetrahydrofuran, toluene, 1, 4-dioxane and N, N-dimethylformamide, and the volume of the selected solvent is 2-5 times of the mass of the compound of formula 1.
3. A method for preparing salbutamol hydrochloride according to claim 1 or 2, wherein the catalyst in step 1 is any one of p-toluenesulfonic acid, acetic acid and sulfuric acid, and the amount of the selected catalyst is 0.05-0.5 times of the mass of the compound of formula 1; the reaction temperature is controlled at 20-120 ℃.
4. A method for preparing salbutamol hydrochloride according to claim 1, wherein the volume of the organic solvent dimethyl sulfoxide used in step 2 is 2-5 times of the compound of formula 2.
5. The method for preparing salbutamol hydrochloride according to claim 1 or 4, wherein the catalyst in step 2 is any one of hydrobromic acid, hydroiodic acid, iodine and hydrochloric acid, and the molar amount of the selected catalyst is 1-5 times of the molar amount of the compound of formula 2; the reaction temperature is controlled at 20-90 ℃.
6. The method for preparing salbutamol hydrochloride according to claim 1, wherein the organic solvent used in step 3 is any one of methanol, ethanol, dichloromethane, toluene and tetrahydrofuran, and the volume amount of the selected organic solvent is 2-5 times of that of the compound of formula 3.
7. The method for preparing salbutamol hydrochloride according to claim 1 or 6, wherein the molar amount of tert-butylamine used in step 3 is 1-1.5 times the molar amount of the compound of formula 3; the reducing agent is any one of sodium borohydride, potassium borohydride, lithium borohydride and sodium cyanoborohydride, and the molar amount of the reducing agent is 1-3 times of that of the compound shown in the formula 3; when tert-butylamine and a reducing agent are added, the temperature is controlled between 0 and 10 ℃, and then the reaction temperature is controlled between 20 and 120 ℃.
8. The method for preparing salbutamol hydrochloride according to claim 1, wherein the organic solvent selected in step 4 is any one of methanol, ethanol, isopropanol and ethyl acetate, the volume usage amount of the selected organic solvent is 5-8 times of the mass amount of the compound of formula 4, the compound of formula 4 is dispersed therein, and then hydrogen chloride solution of the organic solvent is added dropwise.
9. A process for the preparation of salbutamol hydrochloride according to claim 8, wherein the molar amount of hydrogen chloride in the hydrogen chloride solution is 1 to 5 times the molar amount of the compound of formula 4.
10. The method for producing salbutamol hydrochloride according to claim 8 or 9, wherein the temperature is controlled to 0-10 ℃ and then the reaction temperature is controlled to 20-90 ℃ when the hydrogen chloride solution of the organic solvent is added dropwise.
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Cited By (2)
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| CN114539077A (en) * | 2022-04-07 | 2022-05-27 | 南京恒道医药科技有限公司 | Synthesis method of levalbuterol hydrochloride |
| CN114621103A (en) * | 2022-04-02 | 2022-06-14 | 河南普瑞制药有限公司 | Preparation method of salbutamol sulfate |
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