CN116162036A - Preparation method of epinephrine impurity - Google Patents
Preparation method of epinephrine impurity Download PDFInfo
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- CN116162036A CN116162036A CN202211572225.5A CN202211572225A CN116162036A CN 116162036 A CN116162036 A CN 116162036A CN 202211572225 A CN202211572225 A CN 202211572225A CN 116162036 A CN116162036 A CN 116162036A
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- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 title claims abstract description 31
- 229930182837 (R)-adrenaline Natural products 0.000 title claims abstract description 31
- 229960005139 epinephrine Drugs 0.000 title claims abstract description 31
- 239000012535 impurity Substances 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000001914 filtration Methods 0.000 claims abstract description 14
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 239000002841 Lewis acid Substances 0.000 claims abstract description 7
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 7
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- 238000010791 quenching Methods 0.000 claims abstract description 4
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
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- 239000000706 filtrate Substances 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- OUCSEDFVYPBLLF-KAYWLYCHSA-N 5-(4-fluorophenyl)-1-[2-[(2r,4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-n,4-diphenyl-2-propan-2-ylpyrrole-3-carboxamide Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@H]2OC(=O)C[C@H](O)C2)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 OUCSEDFVYPBLLF-KAYWLYCHSA-N 0.000 claims description 14
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- 238000004809 thin layer chromatography Methods 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 9
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- 238000001514 detection method Methods 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 238000009210 therapy by ultrasound Methods 0.000 claims description 3
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 229940079593 drug Drugs 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 7
- 239000012043 crude product Substances 0.000 abstract description 3
- 238000003908 quality control method Methods 0.000 abstract description 3
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- 238000003756 stirring Methods 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
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- 150000001875 compounds Chemical class 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- LWTJEJCZJFZKEL-UHFFFAOYSA-N 2-chloro-3',4'-dihydroxyacetophenone Chemical compound OC1=CC=C(C(=O)CCl)C=C1O LWTJEJCZJFZKEL-UHFFFAOYSA-N 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 102000004305 alpha Adrenergic Receptors Human genes 0.000 description 2
- 108090000861 alpha Adrenergic Receptors Proteins 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 2
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
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- 239000012362 glacial acetic acid Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- LVERDXLUFRHUKR-UHFFFAOYSA-N 2-[benzyl(methyl)amino]-1-(3,4-dihydroxyphenyl)ethanone Chemical compound C=1C=CC=CC=1CN(C)CC(=O)C1=CC=C(O)C(O)=C1 LVERDXLUFRHUKR-UHFFFAOYSA-N 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
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- 206010006482 Bronchospasm Diseases 0.000 description 1
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- 206010013975 Dyspnoeas Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 101001018064 Homo sapiens Lysosomal-trafficking regulator Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 102100033472 Lysosomal-trafficking regulator Human genes 0.000 description 1
- 235000010703 Modiola caroliniana Nutrition 0.000 description 1
- 244000038561 Modiola caroliniana Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000037656 Respiratory Sounds Diseases 0.000 description 1
- 206010047924 Wheezing Diseases 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 238000002680 cardiopulmonary resuscitation Methods 0.000 description 1
- -1 chloroacetyl catechol Chemical compound 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
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- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
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- 238000012544 monitoring process Methods 0.000 description 1
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- 108091006084 receptor activators Proteins 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
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- 238000006467 substitution reaction Methods 0.000 description 1
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- 230000002792 vascular Effects 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
-
- 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
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
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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 relates to the technical field of medicinal chemistry, and discloses a preparation method of epinephrine impurities, which comprises the following steps of: reacting catechol with chloroacetyl chloride in a solvent at 0-40 ℃ for a certain time under the catalysis of Lewis acid, detecting that no raw material remains by TLC, adding 1mol/L dilute hydrochloric acid to quench the reaction, and filtering to obtain an intermediate 1 crude product; recrystallizing the crude intermediate 1 in a solvent to obtain a fine intermediate 1; the preparation method of the epinephrine impurity solves the problems of complicated operation, low yield, high cost and the like in the prior art for preparing the impurity, provides an inexpensive and easily available impurity reference substance with high quality for the related research of the epinephrine quality control, and promotes the medication safety.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of epinephrine impurities.
Background
Epinephrine (adrenaline or epinephrine), which acts on alpha and beta adrenergic receptors, is the strongest alpha receptor activator. By acting on alpha-adrenergic receptors, epinephrine can minimize vasodilation and increase vascular permeability that occurs during allergic reactions, which can lead to reduced vascular content and hypotension. Epinephrine relaxes smooth muscle of bronchi and iris, a histamine antagonist useful for the treatment of allergic reactions and related diseases. Such drugs also increase blood glucose and increase glycogenolysis in the liver. By acting on the beta-adrenergic receptor, epinephrine causes bronchial smooth muscle relaxation, helping to relieve bronchospasm, wheezing, and dyspnea that may occur during allergic reactions. In addition to the above functions, epinephrine is the primary drug used to reverse cardiac arrest during cardiopulmonary resuscitation (CPR).
The target compound 2- (benzyl methyl amino) -3',4' -dihydroxyacetophenone is shown as a formula I, is an important intermediate in the synthesis process of epinephrine, is an important impurity of epinephrine, and is recorded in European pharmacopoeia and United states pharmacopoeia.
In performing drug quality testing, high purity impurities are required to be used as controls for controlling the quality of drugs that may contain the impurities. Therefore, known impurity compounds of high purity must be synthesized.
The synthesis and preparation method of the compound has few reports, and only documents [1,2] report at present.
Document one: USRE30241E, WO2009004593A2, DE2015573A1, US3904671A, US4138581A, FR2042295A1. The above six patents all report the preparation of impurity H using N, N-dimethylformamide as the reaction solvent, and the synthetic route is as follows:
and II, literature: DE524717C, dalgliesh, charles E.19.The synthesis of beta-phenyl series. Journal of the Chemical Society (Resumed), 1949,0,90-93.Doi:10.1039/JR9490000090. Both documents report a process for preparing impurity H using 2-chloro-3 ',4' -dihydroxyacetophenone as starting material, the synthetic route being as follows:
among them, in the first literature, chloroacetyl catechol is used as a starting material, and a high boiling point solvent N, N-dimethylformamide is used as a reaction solvent, so that the removal is not easy, and the yield is low.
Among them, 2-chloro-3 ',4' -dihydroxyacetophenone is used as the starting material, and the synthesis conditions are limited because the raw materials are expensive and not easy to purchase.
Therefore, the invention mainly solves the problems related to the synthesis of epinephrine USP impurity H, and therefore, a preparation method of epinephrine impurity is provided.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of epinephrine impurity, which comprises the following steps:
step one, catechol and chloroacetyl chloride react for a certain time in a solvent at the temperature of 0-40 ℃ under the catalysis of Lewis acid, TLC (thin layer chromatography) detection is carried out, no raw materials remain, dilute hydrochloric acid is added for quenching reaction, and the reaction is filtered to obtain a crude intermediate 1;
step two, recrystallizing the crude intermediate 1 in a solvent to obtain a fine intermediate 1;
dissolving the obtained intermediate 1 fine product in a solvent, heating and reacting with N-methylbenzylamine under the action of an acid binding agent for a certain time, detecting that no raw material basically remains by TLC, filtering, concentrating the filtrate under reduced pressure to remove the solvent, heating and dissolving the filtrate with ethyl acetate, filtering, regulating the pH value of the filtrate to about 1 by using a hydrochloric acid solution, washing the water phase obtained by separating the filtrate once by using ethyl acetate, regulating the pH value of the water phase to 8-9 by using ammonia water, and carrying out ultrasonic treatment for a period of time to obtain granular impurity H, wherein the purity of the granular impurity H is more than 97%.
Preferably, intermediate 1 has the structural formula:
preferably, the epinephrine impurity has the structural formula:
preferably, the lewis acid in the first step is any one of aluminum trichloride, ferric trichloride, titanium tetrachloride and zinc chloride, the solvent is one of dichloromethane and 1, 2-dichloroethane, the reaction time is 3-5 hours, and the concentration of the dilute hydrochloric acid is not less than 1mol/L.
Preferably, the solvent in the second step is one of water and dilute acetic acid.
Preferably, the solvent in the third step is one of methanol and ethanol, the acid binding agent is one of triethylamine and N-methylbenzylamine, the solvent is one of methanol and ethanol, the reaction temperature is 0-60 ℃, and the reaction time is 1-4h.
Compared with the prior art, the invention has the following beneficial effects: the preparation method of the epinephrine impurity solves the problems of complicated operation, low yield, high cost and the like in the prior art for preparing the impurity, provides an inexpensive and easily available impurity reference substance with high quality for the related research of the epinephrine quality control, and promotes the medication safety.
Drawings
Other features, objects and advantages of the present application will become more apparent upon reading of the detailed description of non-limiting embodiments, made with reference to the following drawings, in which:
FIG. 1 is a chart showing H nuclear magnetic resonance hydrogen spectrum of the impurity H of the product synthesized in example 7 of the present invention.
FIG. 2 is a first page of the HPLC chart of impurity H in the product synthesized in example 7 of the present invention.
FIG. 3 is a second page of the high performance liquid chromatography for impurity H, a product synthesized in example 7 of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. The drawings are for illustrative purposes only, are schematic representations and are not intended to be limiting of the present patent, and in order to better illustrate the embodiments of the present invention, certain elements of the drawings may be omitted, enlarged or reduced, and not represent the actual product size, it will be understood by those skilled in the art that certain well-known structures, elements and descriptions thereof may be omitted, and that all other embodiments obtained by those skilled in the art without making inventive efforts are within the scope of protection of the present invention based on the embodiments of the present invention.
Referring to fig. 1-3, a method for preparing an epinephrine impurity, the method comprising the steps of:
step one, catechol and chloroacetyl chloride react for a certain time in a solvent at the temperature of 0-40 ℃ under the catalysis of Lewis acid, TLC (thin layer chromatography) detection is carried out, no raw materials remain, dilute hydrochloric acid is added for quenching reaction, and the reaction is filtered to obtain a crude intermediate 1;
step two, recrystallizing the crude intermediate 1 in a solvent to obtain a fine intermediate 1;
dissolving the obtained intermediate 1 fine product in a solvent, heating and reacting with N-methylbenzylamine under the action of an acid binding agent for a certain time, detecting that no raw material basically remains by TLC, filtering, concentrating the filtrate under reduced pressure to remove the solvent, heating and dissolving the filtrate with ethyl acetate, filtering, regulating the pH value of the filtrate to about 1 by using a hydrochloric acid solution, washing the water phase obtained by separating the filtrate once by using ethyl acetate, regulating the pH value of the water phase to 8-9 by using ammonia water, and carrying out ultrasonic treatment for a period of time to obtain granular impurity H, wherein the purity of the granular impurity H is more than 97%.
Wherein, the structural formula of the intermediate 1 is:
wherein, the structural formula of the epinephrine impurity is:
wherein the Lewis acid in the first step is any one of aluminum trichloride, ferric trichloride, titanium tetrachloride and zinc chloride, the solvent is one of dichloromethane and 1, 2-dichloroethane, the reaction time is 3-5 hours, and the concentration of the dilute hydrochloric acid is not less than 1mol/L.
Wherein the solvent in the second step is one of water and dilute acetic acid.
Wherein the solvent in the third step is one of methanol and ethanol, the acid binding agent is one of triethylamine and N-methylbenzylamine, the solvent is one of methanol and ethanol, the reaction temperature is 0-60 ℃, and the reaction time is 1-4h.
It should be noted that: the preparation method of the epinephrine impurity solves the problems of complicated operation, low yield, high cost and the like in the prior art for preparing the impurity, provides an inexpensive and easily available impurity reference substance with high quality for the related research of the epinephrine quality control, and promotes the medication safety;
what is not described in detail in this specification is prior art known to those skilled in the art.
Example 1
Preparation method of intermediate 1 crude product
1500mL of 1, 2-dichloroethane was added to a 5L four-necked flask, cooled to 4℃and 457g of aluminum trichloride was added thereto, followed by addition of 150g of catechol in portions and stirring at 4℃for about 10 minutes. 166g of chloroacetyl chloride is added, the temperature is raised to 15 ℃, the mixture is stirred for 1h, the temperature is raised to 25 ℃ and the mixture is stirred for 1h, the temperature is raised to 40 and the mixture is stirred for 1h, TLC monitors that the reaction raw materials are not remained (developing agent: dichloromethane: methanol=15:1, ultraviolet 254nm is observed), the reaction is stopped, and the temperature is reduced to below 30 ℃. 3000ml of 1mol/L hydrochloric acid is added dropwise under the temperature of 30 ℃, the temperature is reduced to 5 ℃ after the dripping, and stirring is continued for 1h. The filter cake was rinsed with 3000ml of water to give 405g of grey filter cake.
Example 2
Preparation method of intermediate 1 crude product
1000mL of methylene chloride was added to a 3L three-necked flask, the temperature was lowered to 5℃and 303g of aluminum trichloride was added thereto, then 100g of catechol was added thereto in portions, and the mixture was stirred at 5℃for about 10 minutes. 110g of chloroacetyl chloride is added, the temperature is raised to 30 ℃, the mixture is stirred for 1h, the temperature is raised to 40 ℃ and the mixture is stirred for 3h, TLC monitors that the reaction raw materials are not remained (developing agent: dichloromethane: methanol=15:1, ultraviolet 254nm is observed), the reaction is stopped, and the temperature is reduced to below 30 ℃. 3000ml of 1mol/L hydrochloric acid is added dropwise under the temperature of 30 ℃, the temperature is reduced to 6 ℃, and stirring is continued for 1h. The mixture was filtered, and the cake was rinsed with 2000ml of water to give 341g of a mauve cake.
Example 3:
preparation method of intermediate 1 fine product
The crude intermediate 1 obtained in example 1 was added to a 3L three-necked flask, 97g of glacial acetic acid and 1500ml of water were added, the temperature was raised to 83℃with stirring, the material was completely dissolved, 30g of activated carbon was added, and decolorization was carried out for 0.5h. And (3) performing hot filtration, cooling the obtained filtrate to 4 ℃, and stirring and crystallizing for 1h. Filtering, leaching the filter cake with 1000ml of water to obtain a gray filter cake, and drying in vacuum to obtain 205g of off-white solid with the yield of 80.9%.
Example 4:
preparation method of intermediate 1 fine product
The crude intermediate 1 obtained in example 2 was added to a 3L three-necked flask, 400ml of glacial acetic acid and 1000ml of water were added, the temperature was raised to 84℃with stirring, the material was completely dissolved, 20g of activated carbon was added, and decolorization was carried out for 0.5h. And (3) performing hot filtration, cooling the obtained filtrate to 5 ℃, and stirring and crystallizing for 1h. Filtering, leaching the filter cake with 1000ml of water to obtain a gray brown filter cake, and drying in vacuum to obtain 96g of gray brown solid with the yield of 56.8%.
Example 5:
process for the preparation of impurity H
Intermediate 1 (20 g) and 100mL of methanol were added to a 250mL three-necked flask and stirred to obtain a black clear liquid. 13g of triethylamine and 15g of N-benzyl methylamine were further added, the mixture was stirred and heated to 45℃and stirred at 45℃for 2 hours, and the reaction was stopped by TLC monitoring a small amount of the remaining reaction material (developing solvent: dichloromethane: methanol: ammonia water=10:1:0.1, observation at ultraviolet 254 nm). Distilling the reaction solution at 60 ℃ under reduced pressure to obtain black sticky matter, adding 100ml of ethyl acetate, heating to reflux, filtering, adding the filtrate into a beaker, and adding 1mol/L of dilute hydrochloric acid until the pH of the water phase is=1; separating, collecting an aqueous phase, and washing the aqueous phase once with 100ml of ethyl acetate; the aqueous phase was adjusted to pH 9 with aqueous ammonia, the reaction solution was sonicated to give a granular solid, filtered, rinsed with water, and the filter cake was air-dried overnight to give 24g of a earthy yellow solid with a purity of 95.932% and a yield of 85%.
Example 6:
process for the preparation of impurity H
Intermediate 1 (30 g), ethanol 150mL and N-benzylmethylamine 58g were added to a 250mL three-necked flask and stirred to obtain a black clear liquid. Stirring and heating to 44 ℃ for reaction for 3h. The reaction solution was distilled under reduced pressure to obtain a black viscous material, 200ml of water was added, 150ml of n-hexane was continuously added, and after stirring, filtration was carried out, rinsing with water, and air-blast drying of the cake was carried out overnight, to obtain 32g of a yellowish green solid with a purity of 86.881% and a yield of 73%.
Example 7:
process for the preparation of impurity H
Intermediate 1 (20 g) and 100mL of ethanol were added to a 250mL three-necked flask and stirred to obtain a black clear solution. 13g of triethylamine and 11g of N-benzyl methylamine were continuously added, the mixture was stirred and heated to 46℃and stirred at 46℃for 1 hour, TLC was used to monitor the absence of residual reaction materials (developing solvent: dichloromethane: methanol: ammonia water=10:1:0.1, observation at UV 254 nm) and the reaction was stopped. Distilling the reaction solution at 60 ℃ under reduced pressure to obtain black sticky matter, adding 100ml of ethyl acetate, heating to reflux, filtering, adding the filtrate into a beaker, and adding 1mol/L of dilute hydrochloric acid until the pH of the water phase is=1; separating, collecting an aqueous phase, and washing the aqueous phase once with 100ml of ethyl acetate; the aqueous phase was adjusted to pH 9 with aqueous ammonia, the reaction solution was sonicated to give a granular solid, filtered, rinsed with water, and the filter cake was air-dried overnight to give 21g of a yellowish green solid with a purity of 98.208% and a yield of 75%.
It is noted that relational terms such as first and second, and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Moreover, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (6)
1. A method for preparing an epinephrine impurity, comprising the steps of:
step one, catechol and chloroacetyl chloride react for a certain time in a solvent at the temperature of 0-40 ℃ under the catalysis of Lewis acid, TLC (thin layer chromatography) detection is carried out, no raw materials remain, dilute hydrochloric acid is added for quenching reaction, and the reaction is filtered to obtain a crude intermediate 1;
step two, recrystallizing the crude intermediate 1 in a solvent to obtain a fine intermediate 1;
dissolving the obtained intermediate 1 fine product in a solvent, heating and reacting with N-methylbenzylamine under the action of an acid binding agent for a certain time, detecting that no raw material basically remains by TLC, filtering, concentrating the filtrate under reduced pressure to remove the solvent, heating and dissolving the filtrate with ethyl acetate, filtering, regulating the pH value of the filtrate to about 1 by using a 1mol/L hydrochloric acid solution, washing the water phase obtained by separating the filtrate once by using ethyl acetate, regulating the pH value of the water phase to 8-9 by using ammonia water, and carrying out ultrasonic treatment for a certain time to obtain granular impurity H with the purity of more than 97%.
2. The method for preparing epinephrine impurity according to claim 1, wherein: the structural formula of the intermediate 1 is as follows:
3. the method for preparing epinephrine impurity according to claim 1, wherein: the structural formula of the epinephrine impurity is as follows:
4. the method for preparing epinephrine impurity according to claim 1, wherein: the Lewis acid in the first step is any one of aluminum trichloride, ferric trichloride, titanium tetrachloride and zinc chloride, the solvent is one of dichloromethane and 1, 2-dichloroethane, the reaction time is 3-5 hours, and the concentration of the dilute hydrochloric acid is not lower than 1mol/L.
5. The method for preparing epinephrine impurity according to claim 1, wherein: the solvent in the second step is one of water and dilute acetic acid.
6. The method for preparing epinephrine impurity according to claim 1, wherein: the solvent in the third step is one of methanol and ethanol, the acid binding agent is one of triethylamine and N-methylbenzylamine, the solvent is one of methanol and ethanol, the reaction temperature is 0-60 ℃, and the reaction time is 1-4h.
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