CN110963929B - Preparation method of salbutamol hydrochloride suitable for industrial production - Google Patents
Preparation method of salbutamol hydrochloride suitable for industrial production Download PDFInfo
- Publication number
- CN110963929B CN110963929B CN201911170139.XA CN201911170139A CN110963929B CN 110963929 B CN110963929 B CN 110963929B CN 201911170139 A CN201911170139 A CN 201911170139A CN 110963929 B CN110963929 B CN 110963929B
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- organic solvent
- dimethyl
- dioxane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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 whole 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 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 seriously harming 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 beta 2 adrenergic receptor agonist can effectively inhibit the release of allergic substances such as histamine and the like and prevent bronchospasm, and is suitable for diseases such as bronchial asthma, asthmatic bronchitis, bronchospasm, emphysema and the like.
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 classes:
1. salicylaldehyde compounds as starting materials
The synthetic route has simple reaction structure, but has the following disadvantages: the aldehyde group in the salicylaldehyde has a passivation effect, so that a Friedel-crafts acylation reaction is hindered to a certain extent; the raw material bromoacetyl chloride is not easy to obtain and has high price; the tertiary amine tert-butylamine is used for the nucleophilic substitution of the amino in the second step, so that tertiary amide is easily generated, the yield in the step is reduced, and process impurities are increased; the phenolic hydroxyl group in the starting material is not protected and is easily oxidized by an oxidizing agent, so that process impurities are generated.
2. Takes p-hydroxybenzaldehyde compounds as initial raw 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 and 2, 2-dimethoxypropane in the presence of catalyst to obtain 1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] dioxane-6-yl) ethanone of formula 2;
2. and (3) oxidation: oxidizing the compound 1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] 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 ] [1,3] dioxane-6-yl) ethanone aldehyde in the formula 3;
3. reductive amination: the compound 1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] dioxane-6-yl) ethanone aldehyde 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 and salified to prepare salbutamol hydrochloride.
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 and the dosage of the selected solvent are 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 shown 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 analytical chart of salbutamol hydrochloride.
Detailed Description
The present invention will be described in further detail with reference to the following drawings and 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 ] [1,3] dioxan-6-yl) ethanone
The preparation method comprises the steps of adding 33.23g of 4-hydroxy-3-hydroxymethylacetophenone and 3.23g of catalytic amount of p-toluenesulfonic acid (catalyst) into a 250mL three-neck flask, adding 100mL of dichloromethane (organic solvent), and stirring and dissolving to form light yellow reaction liquid.
And slowly dropwise adding a 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 complete, adding a 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 layer with a saturated sodium chloride aqueous solution and a saturated water solution respectively, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating, and drying in vacuum to obtain 38.34g of a light yellow oily liquid with the yield of 93%.
1 H-NMR(400Mz,CDCl 3 ) δ:1.49 (s, 6H); 2.50 (s, 3H); 4.62 (s, 2H); 6.98-7.70 (m, 3H); ESI-HRMS shows molecular ion peak m/z =207.1018 2 [ M + H ]] + The corresponding molecular weight is consistent with the theoretical calculation value (207.1021) of the provided structural formula, and the absolute error is within the error range of the high-resolution mass spectrum.
2. Synthesis of 1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] dioxan-6-yl) ethanolaminal
Adding 30.00g of 1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] 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%.
1 H-NMR(400Mz,CDCl 3 ) δ:1.52 (s, 6H); 4.53 (s, 2H); 7.09-7.65 (m, 3H); 9.50 (s, 1H); ESI-HRMS shows molecular ion peak m/z =221.0808[ M + H ]] + The corresponding molecular weight is consistent with the theoretical calculation value (221.0814) of the provided structural formula, and the absolute error is within the error range of the high-resolution mass spectrum.
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 ] [1,3] 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 ℃, carrying out reflux reaction for 2-3 hours till the reaction is complete, cooling to room temperature, then 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, evaporating ethanol, extracting with solvents such as dichloromethane and the like, washing the organic phase with saturated sodium chloride solution, washing to be neutral, drying with anhydrous sodium sulfate, filtering the sodium sulfate, concentrating, drying in vacuum to obtain 25.37g of product yellow solid, and obtaining the yield of 80.0%.
1 H-NMR(400Mz,CDCl 3 ) 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 molecular ion peak m/z =280.1907, [ 2 ] M + H] + The corresponding molecular weight is consistent with the theoretical calculation of the formula provided (280.1913), with absolute error within the error range of high resolution mass spectrometry.
4. Synthesis of salbutamol hydrochloride
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) are added into a 250mL three-neck flask, stirred to form a yellow clear liquid, the system is cooled to 0-10 ℃ under the protection of nitrogen, 15mL of HCl/ethanol solution (33% by mass fraction) is slowly dripped into the system (about 10 minutes is finished), after the addition is finished, the temperature is increased to reflux and stirred for 1-2 hours, the temperature is reduced, crystallization is carried out, filtration is carried out, a filter cake is washed by 12mL of cold absolute ethanol, and vacuum drying is carried out to obtain 17.27g of salbutamol hydrochloride, the character is white solid, and the yield is 70.1%.
1 H-NMR(400Mz,D 2 O) δ:1.30 (s, 9H); 3.15-3.23 (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 Ch1 230nm
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 should be apparent that the described embodiments are only some of the embodiments of the present invention, and not all of the 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 (7)
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 1 to prepare 1- (2, 2-dimethyl-4H-benzo [ d ] [ l,3] dioxane-6-yl) ethanone of a compound in a formula 2; the catalyst 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 shown in the formula 1; the reaction temperature is controlled at 20-120 ℃;
step 2, 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 2 to obtain the compound 1- (2, 2-dimethyl-4H-benzo [ d ] [ l,3] dioxane-6-yl) ethanone aldehyde in the formula 3; the catalyst 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 ℃;
step 3, 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 sequentially to prepare a compound 2- (tert-butylamino) -1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] dioxane-6-yl) ethanol in the formula 4; 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 to be 0-10 ℃, and then the reaction temperature is controlled to be 20-120 ℃;
and 4, adding hydrochloric acid into the compound 2- (tert-butylamino) -1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] dioxane-6-yl) ethanol of the formula 4, and carrying out deprotection and salt formation to obtain salbutamol hydrochloride, wherein the specific process comprises the steps of dispersing the compound of the formula 4 in an organic solvent, dropwise adding a hydrogen chloride solution of the organic solvent, controlling the temperature to be 0-10 ℃ when dropwise adding the hydrogen chloride solution of the organic solvent, and then controlling the reaction temperature to be 20-90 ℃.
2. The method for preparing salbutamol hydrochloride according to claim 1, wherein the step 1 is carried out in an organic solvent selected from 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 2, wherein the volume of the organic solvent dimethyl sulfoxide used in step 2 is 2-5 times of the compound of formula 2.
4. The method for preparing salbutamol hydrochloride according to claim 1, wherein the step 3 is performed in an organic solvent, the selected organic solvent is any one of methanol, ethanol, dichloromethane, toluene and tetrahydrofuran, and the volume of the selected organic solvent is 2-5 times of the mass of the compound of formula 3.
5. A method for preparing salbutamol hydrochloride according to claim 1 or 4, 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.
6. The method for preparing salbutamol hydrochloride according to claim 1, wherein the organic solvent used in step 4 is any one of methanol, ethanol, isopropanol and ethyl acetate, and the volume usage amount of the selected organic solvent is 5-8 times of the mass of the compound of formula 4.
7. The process for preparing salbutamol hydrochloride according to claim 6, wherein the molar content of hydrogen chloride in the hydrogen chloride solution is 1 to 5 times the molar amount of the compound of formula 4.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911170139.XA CN110963929B (en) | 2019-11-26 | 2019-11-26 | Preparation method of salbutamol hydrochloride suitable for industrial production |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911170139.XA CN110963929B (en) | 2019-11-26 | 2019-11-26 | Preparation method of salbutamol hydrochloride suitable for industrial production |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110963929A CN110963929A (en) | 2020-04-07 |
CN110963929B true CN110963929B (en) | 2022-10-21 |
Family
ID=70031655
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201911170139.XA Active CN110963929B (en) | 2019-11-26 | 2019-11-26 | Preparation method of salbutamol hydrochloride suitable for industrial production |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110963929B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114621103A (en) * | 2022-04-02 | 2022-06-14 | 河南普瑞制药有限公司 | Preparation method of salbutamol sulfate |
CN114539077B (en) * | 2022-04-07 | 2023-12-08 | 南京恒道医药科技股份有限公司 | Synthesis method of levosalbutamol hydrochloride |
Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS48103535A (en) * | 1972-04-13 | 1973-12-25 | ||
GB1458251A (en) * | 1973-03-01 | 1976-12-15 | Basf Ag | 1-phenyl-2-amino-ethanol derivatives |
CA1040658A (en) * | 1974-03-29 | 1978-10-17 | Jarkko Ruohonen | INDUSTRIAL METHOD FOR PRODUCING .alpha.1-TERT.-BUTYLAMINO-METHYL-4-HYDROXY-M-XYLENE-.alpha.1,.alpha.3-DIOLE |
US5399765A (en) * | 1994-05-23 | 1995-03-21 | Sepracor, Inc. | Enantioselective preparation of optically pure albuterol |
CN1705634A (en) * | 2002-10-24 | 2005-12-07 | 贝林格尔英格海姆法玛两合公司 | Process for preparing (R) salbutamol |
CN1733701A (en) * | 2005-08-17 | 2006-02-15 | 华东师范大学 | Method for asymmetrical hydrogen transfer of alpha-imino keton for synthesizing chirality salbutamol |
CN103951568A (en) * | 2014-05-19 | 2014-07-30 | 苏州弘森药业有限公司 | New process for synthesizing salbutamol and sulfate of salbutamol |
CN104557572A (en) * | 2014-12-30 | 2015-04-29 | 上海默学医药科技有限公司 | Levalbuterol intermediate and levalbuterol hydrochloride synthesis method |
CN105753721A (en) * | 2016-02-02 | 2016-07-13 | 浙江工业大学 | Synthesis method of levalbuterol |
CN106278910A (en) * | 2016-07-18 | 2017-01-04 | 浙江工业大学 | Preparation method of levalbuterol |
CN108863819A (en) * | 2018-06-26 | 2018-11-23 | 南京逐陆医药科技有限公司 | A kind of preparation method of free racemization salbutamol |
-
2019
- 2019-11-26 CN CN201911170139.XA patent/CN110963929B/en active Active
Patent Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS48103535A (en) * | 1972-04-13 | 1973-12-25 | ||
GB1458251A (en) * | 1973-03-01 | 1976-12-15 | Basf Ag | 1-phenyl-2-amino-ethanol derivatives |
CA1040658A (en) * | 1974-03-29 | 1978-10-17 | Jarkko Ruohonen | INDUSTRIAL METHOD FOR PRODUCING .alpha.1-TERT.-BUTYLAMINO-METHYL-4-HYDROXY-M-XYLENE-.alpha.1,.alpha.3-DIOLE |
US5399765A (en) * | 1994-05-23 | 1995-03-21 | Sepracor, Inc. | Enantioselective preparation of optically pure albuterol |
CN1705634A (en) * | 2002-10-24 | 2005-12-07 | 贝林格尔英格海姆法玛两合公司 | Process for preparing (R) salbutamol |
CN1733701A (en) * | 2005-08-17 | 2006-02-15 | 华东师范大学 | Method for asymmetrical hydrogen transfer of alpha-imino keton for synthesizing chirality salbutamol |
CN103951568A (en) * | 2014-05-19 | 2014-07-30 | 苏州弘森药业有限公司 | New process for synthesizing salbutamol and sulfate of salbutamol |
CN104557572A (en) * | 2014-12-30 | 2015-04-29 | 上海默学医药科技有限公司 | Levalbuterol intermediate and levalbuterol hydrochloride synthesis method |
CN105753721A (en) * | 2016-02-02 | 2016-07-13 | 浙江工业大学 | Synthesis method of levalbuterol |
CN106278910A (en) * | 2016-07-18 | 2017-01-04 | 浙江工业大学 | Preparation method of levalbuterol |
CN108863819A (en) * | 2018-06-26 | 2018-11-23 | 南京逐陆医药科技有限公司 | A kind of preparation method of free racemization salbutamol |
Also Published As
Publication number | Publication date |
---|---|
CN110963929A (en) | 2020-04-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110963929B (en) | Preparation method of salbutamol hydrochloride suitable for industrial production | |
EP1844039B1 (en) | 5-substituted quinoline and isoquinoline derivatives, a method for the production thereof and their use as antiphlogistics | |
US8575395B2 (en) | Method for the preparation of cinacalcet and intermediates and impurities thereof | |
Kanamori et al. | In vivo metabolism of 4-bromo-2, 5-dimethoxyphenethylamine (2C-B) in the rat: identification of urinary metabolites | |
AU2011200338A1 (en) | Purification process | |
CN111690947B (en) | Electrochemical synthesis method of trifluoromethylated aryl amide derivative | |
CN115108925A (en) | Salbutamol sulfate impurity and preparation method thereof | |
CN105001169B (en) | A kind of synthetic method of 3 aminoquinoxaline 2 (1H) ketone compounds | |
JP2009513578A (en) | New method | |
EP3201171B1 (en) | Method of preparing intermediate of salmeterol | |
CN108863753B (en) | Salbutamol impurity and synthetic method thereof | |
CN113185465B (en) | Preparation method of 4-ethyl-5-aminopyrimidine | |
WO2007144097A1 (en) | New chiral intermediate, process for producing the same and its use in the manufacture of tolterodine, fesoterodine, or the active metabolite thereof | |
CN109180588B (en) | Triptycene ionic liquid functional material, preparation and application thereof | |
US20100087545A1 (en) | Purification process | |
US7985323B2 (en) | Purification process | |
CN102924448A (en) | Alkaloid cryptolepine analogue quindoline acid compound and preparation method | |
CN114605241B (en) | Preparation method of esketamine hydrochloride intermediate and intermediate thereof | |
CN111217691A (en) | Compound 1- (2-benzyl-3, 5-bis (benzyloxy) phenyl) ethanone, preparation method and application thereof | |
CN101475491A (en) | N-substituted 1,2-diphenylethylamine compounds and synthesizing method thereof | |
CN114805200A (en) | Procaterol hydrochloride impurity, and preparation method and application thereof | |
FI58640B (en) | REFERENCE TO A THERAPEUTIC FRAME THERAPEUTIC SUBSTITUTE I (PHENYL-N-PHENYLETHYL-3-AMINOPROPYL) -THEOPHYLLINER | |
Miller et al. | Impurity profiling of an alternative pathway to ephedrine/pseudoephedrine and methamphetamine from the precursors benzaldehyde and nitroethane | |
EP1100767B1 (en) | Novel phenylethylamine derivatives, a method for the production thereof and their use as medicaments | |
WO2007096904A2 (en) | Improved process for the preparation of terbinafine hydrochloride and novel crystalline form of terbinafine |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |