CN111393311A - Environment-friendly and nontoxic synthesis method of clenbuterol hydrochloride - Google Patents
Environment-friendly and nontoxic synthesis method of clenbuterol hydrochloride Download PDFInfo
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- 229960001399 clenbuterol hydrochloride Drugs 0.000 title claims abstract description 38
- OPXKTCUYRHXSBK-UHFFFAOYSA-N clenbuterol hydrochloride Chemical compound Cl.CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(Cl)=C1 OPXKTCUYRHXSBK-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 231100000252 nontoxic Toxicity 0.000 title claims abstract description 22
- 230000003000 nontoxic effect Effects 0.000 title claims abstract description 22
- 238000001308 synthesis method Methods 0.000 title claims abstract description 22
- 229960001117 clenbuterol Drugs 0.000 claims abstract description 19
- STJMRWALKKWQGH-UHFFFAOYSA-N clenbuterol Chemical compound CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(Cl)=C1 STJMRWALKKWQGH-UHFFFAOYSA-N 0.000 claims abstract description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 48
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 34
- 239000000243 solution Substances 0.000 claims description 25
- 238000001914 filtration Methods 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000001035 drying Methods 0.000 claims description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 21
- 238000010438 heat treatment Methods 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 14
- 239000012065 filter cake Substances 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 11
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 11
- 239000012279 sodium borohydride Substances 0.000 claims description 11
- 229940125904 compound 1 Drugs 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 8
- 238000004537 pulping Methods 0.000 claims description 8
- 239000008213 purified water Substances 0.000 claims description 8
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- 238000001291 vacuum drying Methods 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 claims description 4
- 238000004321 preservation Methods 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 6
- 238000004519 manufacturing process Methods 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 description 3
- 206010036790 Productive cough Diseases 0.000 description 3
- 239000002262 Schiff base Substances 0.000 description 3
- 150000004753 Schiff bases Chemical class 0.000 description 3
- 229960000985 ambroxol hydrochloride Drugs 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 210000003802 sputum Anatomy 0.000 description 3
- 208000024794 sputum Diseases 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 210000000621 bronchi Anatomy 0.000 description 2
- 230000001886 ciliary effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 231100000024 genotoxic Toxicity 0.000 description 2
- 230000001738 genotoxic effect Effects 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 229940110515 cough out Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940066491 mucolytics Drugs 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 210000001533 respiratory mucosa Anatomy 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- 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
- 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
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides an environment-friendly and non-toxic synthesis method of clenbuterol hydrochloride, which comprises the following steps of 1) preparing an intermediate 1, 2) preparing an intermediate 2, 3) preparing clenbuterol, and 4) preparing clenbuterol hydrochloride.
Description
Technical Field
The invention belongs to the technical field of clenbuterol hydrochloride production, and particularly relates to an environment-friendly and non-toxic synthesis method of clenbuterol hydrochloride.
Background
The clenbuterol hydrochloride is a raw material medicine in the compound preparation of ambroxol hydrochloride oral liquid, and the compound preparation is formed by the clenbuterol hydrochloride and the ambroxol hydrochloride, wherein the ambroxol hydrochloride is a mucolytic agent, and can increase the secretion of serous glands of respiratory mucosa, reduce the secretion of mucous glands, reduce the viscosity of sputum, promote the secretion of lung surface active substances, increase the ciliary movement of bronchus and make the sputum easy to cough out, and the clenbuterol hydrochloride is a selective β receptor agonist and has the effects of relaxing the smooth muscle of the bronchus, enhancing the ciliary movement, dissolving mucus and promoting the discharge of the sputum.
The conventional production synthetic route of clenbuterol hydrochloride is as follows:
in the synthetic process, liquid bromine or other brominating agents are used for reacting to prepare an intermediate 1, the liquid bromine or the brominating agents are firstly used for polluting the environment and are harmful to occupational health of production operators, the intermediate is an α -bromo structure which is definitely considered as genotoxic impurities containing a warning structure by FDA and has obvious carcinogenic effect, and the intermediate is generated in the synthetic process, so that inevitable residues exist in a final finished product, and the raw material medicaments synthesized by the synthetic process have clinical use risks.
Disclosure of Invention
In order to solve the existing problems, the invention aims to provide an environment-friendly and non-toxic synthesis method of clenbuterol hydrochloride, the synthesis method adopts an oxidation method to synthesize an intermediate 1, then the intermediate 1 and tert-butylamine form a Schiff base intermediate 2, and clenbuterol is prepared through reduction, so that the preparation of an intermediate with a genotoxic α -bromo structure by using liquid bromine or other brominating agents in the traditional production process is avoided, the new synthesis method is environment-friendly and non-toxic, and the clinical use risk of the synthesized clenbuterol hydrochloride as a raw material medicine is effectively reduced.
In order to achieve the purpose, the technical scheme of the invention is as follows:
an environment-friendly and nontoxic synthesis method of clenbuterol hydrochloride comprises the following synthetic routes:
further, the synthesis method comprises the following steps:
1) preparation of intermediate 1
Adding the compound 1 into a reaction container, then adding tetrahydrofuran, adding an oxidant at normal temperature, heating to 45-50 ℃, reacting for 5-8 hours, filtering, concentrating, adding toluene, and stirring to dissolve clearly to obtain a solution;
2) preparation of intermediate 2
Taking another reaction vessel, adding the solution prepared in the step 1), heating to 40-45 ℃, dropwise adding a tetrahydrofuran solution dissolved with tert-butylamine, dropwise adding the tetrahydrofuran solution after 10-20 minutes, carrying out heat preservation reaction for 1-3 hours after dropwise adding, controlling the temperature to be 40-45 ℃ after the reaction is finished, distilling to remove the tetrahydrofuran solvent, adding a toluene solvent into distillation residues, pulping for 1-2 hours at normal temperature, filtering, washing a filter cake, and drying at 40-45 ℃ to obtain an intermediate 2;
3) preparation of clenbuterol
Taking another reaction container, adding the intermediate 2 and methanol prepared in the step 2), dropwise adding the aqueous solution of sodium borohydride, completing dropwise addition within 25-35 minutes, controlling the temperature of the reaction liquid to be 0-5 ℃ in the dropwise adding process, heating to 20-25 ℃ after completing dropwise addition, reacting for 2-3 hours, filtering after the reaction is finished, concentrating the filtrate to be viscous, then adding purified water, heating to 50-60 ℃, pulping for 1-2 hours, filtering, washing and drying the filter cake, wherein the drying temperature is 50-60 ℃, and thus obtaining clenbuterol; .
4) Preparation of clenbuterol hydrochloride
Taking another reaction container, adding the clenbuterol and the isopropanol obtained in the step 3), heating to 60-70 ℃, stirring to completely dissolve the solid, then filtering, transferring the filtrate into another reaction container, cooling to 30-40 ℃, dropwise adding 8-10 wt% of isopropanol hydrochloride solution, adjusting the pH value to 5-6, cooling to 10-15 ℃, stirring for crystallization for 2-3 hours, filtering, drying the filter cake, and drying at 40-45 ℃ to obtain the clenbuterol hydrochloride.
Further, in the step 1), the mass-to-volume ratio of the compound 1 to tetrahydrofuran is 1: 5-7 g/ml; the mass-to-volume ratio of the compound 1 to toluene is 1: 5-7 g/ml.
Further, the oxidant used in step 1) is selenium dioxide.
Further, in the tetrahydrofuran solution of tert-butylamine in step 2), the mass-to-volume ratio of tert-butylamine to tetrahydrofuran is 1: 2-4 g/ml.
Further, in the step 2), the volume ratio of the tetrahydrofuran solvent to the toluene is 1: 2-4 ml/ml.
Further, in the step 3), the weight-to-volume ratio of the intermediate 2 to the methanol is 1: 5-8 g/ml; the mass-volume ratio of the intermediate 2 to the purified water is 1: 2 to 3.
Further, the mass-to-volume ratio of the sodium borohydride to the water in the aqueous solution of the sodium borohydride in the step 3) is 1: 4-5 g/ml.
Further, the mass-to-volume ratio of clenbuterol to isopropanol in step 4) is 1: 9 to 11.
Further, the drying in the step 2), the step 3) and the step 4) is respectively carried out by adopting a vacuum drying oven.
The invention has the beneficial effects that:
the synthesis method adopts an oxidation method to synthesize the intermediate 1, then forms the Schiff base intermediate 2 with tert-butylamine, and then prepares clenbuterol through reduction, so that the problem that the intermediate with gene toxicity α -bromo structure is prepared by using liquid bromine or other brominating agents in the traditional production process is avoided, the new synthesis method is environment-friendly and nontoxic, and the clinical use risk of clenbuterol hydrochloride is effectively reduced.
Drawings
Fig. 1 is a schematic route of an environment-friendly and non-toxic synthetic method of clenbuterol hydrochloride provided by an embodiment of the present invention.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention.
Referring to fig. 1, the synthesis method of clenbuterol hydrochloride in an environment-friendly and non-toxic manner, provided by the invention, comprises the following steps:
further, the synthesis method comprises the following steps:
1) preparation of intermediate 1
Adding the compound 1 into a reaction container, then adding tetrahydrofuran, adding an oxidant at normal temperature, heating to 45-50 ℃, reacting for 5-8 hours, filtering, concentrating, adding toluene, and stirring to dissolve clearly to obtain a solution;
2) preparation of intermediate 2
Taking another reaction vessel, adding the solution prepared in the step 1), heating to 40-45 ℃, dropwise adding a tetrahydrofuran solution dissolved with tert-butylamine, dropwise adding the tetrahydrofuran solution after 10-20 minutes, carrying out heat preservation reaction for 1-3 hours after dropwise adding, controlling the temperature to be 40-45 ℃ after the reaction is finished, distilling to remove the tetrahydrofuran solvent, adding a toluene solvent into distillation residues, pulping for 1-2 hours at normal temperature, filtering, washing a filter cake, and drying at 40-45 ℃ to obtain an intermediate 2;
3) preparation of clenbuterol
Taking another reaction container, adding the intermediate 2 and methanol prepared in the step 2), dropwise adding the aqueous solution of sodium borohydride, completing dropwise addition within 25-35 minutes, controlling the temperature of the reaction liquid to be 0-5 ℃ in the dropwise adding process, heating to 20-25 ℃ after completing dropwise addition, reacting for 2-3 hours, filtering after the reaction is finished, concentrating the filtrate to be viscous, then adding purified water, heating to 50-60 ℃, pulping for 1-2 hours, filtering, washing and drying the filter cake, wherein the drying temperature is 50-60 ℃, and thus obtaining clenbuterol; .
4) Preparing clenbuterol hydrochloride:
taking another reaction container, adding the clenbuterol and the isopropanol obtained in the step 3), heating to 60-70 ℃, stirring to completely dissolve the solid, then filtering, transferring the filtrate into another reaction container, cooling to 30-40 ℃, dropwise adding 8-10 wt% of isopropanol hydrochloride solution, adjusting the pH value to 5-6, cooling to 10-15 ℃, stirring for crystallization for 2-3 hours, filtering, drying the filter cake, and drying at 40-45 ℃ to obtain the clenbuterol hydrochloride.
Further, in the step 1), the mass-to-volume ratio of the compound 1 to tetrahydrofuran is 1: 5-7 g/ml; the mass-to-volume ratio of the compound 1 to toluene is 1: 5-7 g/ml.
Further, the oxidant used in step 1) is selenium dioxide.
Further, in the tetrahydrofuran solution of tert-butylamine in step 2), the mass-to-volume ratio of tert-butylamine to tetrahydrofuran is 1: 2-4 g/ml.
Further, in the step 2), the volume ratio of the tetrahydrofuran solvent to the toluene is 1: 2-4 ml/ml.
Further, in the step 3), the weight-to-volume ratio of the intermediate 2 to the methanol is 1: 5-8 g/ml; the mass-volume ratio of the intermediate 2 to the purified water is 1: 2 to 3.
Further, the mass-to-volume ratio of the sodium borohydride to the water in the aqueous solution of the sodium borohydride in the step 3) is 1: 4-5 g/ml.
Further, the mass-to-volume ratio of clenbuterol to isopropanol in step 4) is 1: 9 to 11.
Further, the drying in the step 2), the step 3) and the step 4) is respectively carried out by adopting a vacuum drying oven.
Example 1
The specific synthesis method of clenbuterol hydrochloride in example 1 is as follows:
1) preparation of intermediate 1
Adding 50g of the compound 1 into a 500ml four-mouth bottle, then adding 300 g of tetrahydrofuran, adding 25g of selenium dioxide at normal temperature, then heating to 45-50 ℃ for reaction for 6 hours, filtering the reaction solution after the reaction is finished, concentrating the filtrate at 40-45 ℃ under reduced pressure until the filtrate is dried, adding 300ml of toluene, stirring to dissolve the filtrate clearly, and directly using the solution for the next reaction;
2) preparation of intermediate 2:
adding the toluene solution of the intermediate 1 in the previous step into a 500ml four-mouth bottle, heating to 40-45 ℃, dropwise adding a tetrahydrofuran solution of tert-butylamine (18g of tert-butylamine is dissolved in 50ml of tetrahydrofuran), dropwise adding for about 15 minutes, continuing to perform heat preservation reaction for 2 hours after the dropwise adding is finished, controlling the temperature to 40-45 ℃ after the reaction is finished, removing the solvent by reduced pressure evaporation, adding 150ml of toluene into distillation residues, pulping for 1 hour at normal temperature, filtering, washing a filter cake with a small amount of toluene, and then placing the filter cake in a 40-45 ℃ vacuum drying oven for drying to obtain about 35g of the intermediate 2.
3) Preparation of clenbuterol:
putting 35g of the intermediate 2 and 200ml of methanol into a 500ml four-mouth bottle, dropwise adding an aqueous solution of sodium borohydride (12g of sodium borohydride is dissolved in 50m of water), dropwise adding for about 30 minutes, controlling the temperature of the reaction solution to be 0-5 ℃ in the dropwise adding process, heating to 20-25 ℃ after dropwise adding, reacting for 2 hours, filtering after the reaction is finished, concentrating the filtrate to be viscous, then adding 60ml of purified water, heating to 50-60 ℃, pulping for 1 hour, filtering, washing the filter cake with a small amount of purified water, and drying in a vacuum drying oven at 50-60 ℃ to obtain 30g of clenbuterol. .
4) Preparation of clenbuterol hydrochloride:
putting 30g of clenbuterol and 300ml of isopropanol into a 500ml reaction bottle, heating to 65-70 ℃, stirring to completely dissolve solids, then adding 2g of activated carbon, filtering while hot, transferring the filtrate into another 500ml reaction bottle, cooling to 35-40 ℃, dropwise adding 8-10% isopropanol hydrochloride solution, adjusting the pH of the system to 5-6, cooling to 10-15 ℃, stirring for crystallization for 2 hours, filtering, and drying the filter cake in a vacuum drying oven at 40-45 ℃ to obtain about 28g of clenbuterol hydrochloride.
According to the environment-friendly and non-toxic synthesis method of clenbuterol hydrochloride, in the process of preparing the intermediate 1, the intermediate 1 is synthesized by adopting an oxidation method, then the Schiff base intermediate 2 is formed with tert-butylamine, and clenbuterol is prepared through reduction, so that the problem that an intermediate with a gene toxicity α -bromo structure is prepared by using liquid bromine or other brominating agents in the traditional production process is avoided, the new synthesis method is environment-friendly and non-toxic, and the clinical use risk of the clenbuterol hydrochloride obtained through synthesis as a raw material medicine is effectively reduced.
It should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and are not limited. Although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the present invention.
Claims (10)
1. The environment-friendly and nontoxic synthesis method of clenbuterol hydrochloride is characterized in that the synthesis route of the synthesis method is as follows:
2. the method for synthesizing clenbuterol hydrochloride in an environment-friendly and non-toxic manner according to claim 1, wherein the method for synthesizing clenbuterol hydrochloride comprises the following steps:
1) preparation of intermediate 1
Adding the compound 1 into a reaction container, then adding tetrahydrofuran, adding an oxidant at normal temperature, heating to 45-50 ℃, reacting for 5-8 hours, filtering, concentrating, adding toluene, and stirring to dissolve clearly to obtain a solution;
2) preparation of intermediate 2
Taking another reaction vessel, adding the solution prepared in the step 1), heating to 40-45 ℃, dropwise adding a tetrahydrofuran solution dissolved with tert-butylamine, dropwise adding the tetrahydrofuran solution after 10-20 minutes, carrying out heat preservation reaction for 1-3 hours after dropwise adding, controlling the temperature to be 40-45 ℃ after the reaction is finished, distilling to remove the tetrahydrofuran solvent, adding a toluene solvent into distillation residues, pulping for 1-2 hours at normal temperature, filtering, washing a filter cake, and drying at 40-45 ℃ to obtain an intermediate 2;
3) preparation of clenbuterol
Taking another reaction container, adding the intermediate 2 and methanol prepared in the step 2), dropwise adding the aqueous solution of sodium borohydride, completing dropwise addition within 25-35 minutes, controlling the temperature of the reaction liquid to be 0-5 ℃ in the dropwise adding process, heating to 20-25 ℃ after completing dropwise addition, reacting for 2-3 hours, filtering after the reaction is finished, concentrating the filtrate to be viscous, then adding purified water, heating to 50-60 ℃, pulping for 1-2 hours, filtering, washing and drying the filter cake, wherein the drying temperature is 50-60 ℃, and thus obtaining clenbuterol; .
4) Preparation of clenbuterol hydrochloride
Taking another reaction container, adding the clenbuterol and the isopropanol obtained in the step 3), heating to 60-70 ℃, stirring to completely dissolve the solid, then filtering, transferring the filtrate into another reaction container, cooling to 30-40 ℃, dropwise adding 8-10 wt% of isopropanol hydrochloride solution, adjusting the pH value to 5-6, cooling to 10-15 ℃, stirring for crystallization for 2-3 hours, filtering, drying the filter cake, and drying at 40-45 ℃ to obtain the clenbuterol hydrochloride.
3. The method for synthesizing clenbuterol hydrochloride in an environment-friendly and non-toxic manner according to claim 2, wherein in the step 1), the mass-to-volume ratio of the compound 1 to tetrahydrofuran is 1: 5-7 g/ml; the mass-to-volume ratio of the compound 1 to toluene is 1: 5-7 g/ml.
4. The method for synthesizing clenbuterol hydrochloride in an environment-friendly and non-toxic manner according to claim 2, wherein the oxidant used in step 1) is selenium dioxide.
5. The method for synthesizing clenbuterol hydrochloride in an environment-friendly and non-toxic manner according to claim 1, wherein in the tetrahydrofuran solution of tert-butylamine in step 2), the mass-to-volume ratio of tert-butylamine to tetrahydrofuran is 1: 2-4 g/ml.
6. The environment-friendly and non-toxic synthesis method of clenbuterol hydrochloride according to claim 5, wherein in the step 2), the volume ratio of the tetrahydrofuran solvent to the toluene is 1: 2-4 ml/ml.
7. The method for synthesizing clenbuterol hydrochloride in an environment-friendly and non-toxic manner according to claim 1, wherein in the step 3), the weight-to-volume ratio of the intermediate 2 to methanol is 1: 5-8 g/ml; the mass-volume ratio of the intermediate 2 to the purified water is 1: 2 to 3.
8. The environment-friendly and non-toxic synthesis method of clenbuterol hydrochloride according to claim 1, wherein the mass-to-volume ratio of sodium borohydride to water in the aqueous solution of sodium borohydride in step 3) is 1: 4-5 g/ml.
9. The environment-friendly and non-toxic synthesis method of clenbuterol hydrochloride according to claim 1, wherein the mass-to-volume ratio of clenbuterol to isopropanol in step 4) is 1: 9 to 11.
10. The environment-friendly and non-toxic synthesis method of clenbuterol hydrochloride according to claim 1, wherein the drying in step 2), step 3) and step 4) is performed by respectively adopting a vacuum drying oven.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1041545A (en) * | 1973-11-02 | 1978-10-31 | Johannes Keck | Process for the preparation of 4-amino-3,5-dihalogen-phenyl-ethanolamines |
| ES481178A1 (en) * | 1979-05-18 | 1980-02-16 | Ferrer Int | Procedure for obtaining aminoethanol derivatives. (Machine-translation by Google Translate, not legally binding) |
| US4407819A (en) * | 1980-08-25 | 1983-10-04 | American Cyanamid Company | Phenylethanolamine derivatives and acid addition salts thereof for the depression of fat deposition in warm blooded animals |
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| WO2017021982A1 (en) * | 2015-08-06 | 2017-02-09 | Vamsi Labs Ltd. | A PROCESS FOR PREPARING β AGONIST |
| CN109912434A (en) * | 2017-12-13 | 2019-06-21 | 上海安谱实验科技股份有限公司 | The synthetic method of phenyl ethyl amine beta receptor agonist |
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2020
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| CA1041545A (en) * | 1973-11-02 | 1978-10-31 | Johannes Keck | Process for the preparation of 4-amino-3,5-dihalogen-phenyl-ethanolamines |
| ES481178A1 (en) * | 1979-05-18 | 1980-02-16 | Ferrer Int | Procedure for obtaining aminoethanol derivatives. (Machine-translation by Google Translate, not legally binding) |
| US4407819A (en) * | 1980-08-25 | 1983-10-04 | American Cyanamid Company | Phenylethanolamine derivatives and acid addition salts thereof for the depression of fat deposition in warm blooded animals |
| DD280875A3 (en) * | 1987-10-14 | 1990-07-25 | Dresden Arzneimittel | PROCESS FOR PREPARING 1- (4-AMINO-3,5-DICHLOR-PHENYL) -2-TERT.-BUTYLAMINO-ETHANOL HYDROCHLORIDE |
| WO2017021982A1 (en) * | 2015-08-06 | 2017-02-09 | Vamsi Labs Ltd. | A PROCESS FOR PREPARING β AGONIST |
| CN109912434A (en) * | 2017-12-13 | 2019-06-21 | 上海安谱实验科技股份有限公司 | The synthetic method of phenyl ethyl amine beta receptor agonist |
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