CN117466821A - Technological preparation method of clemizole hydrochloride - Google Patents
Technological preparation method of clemizole hydrochloride Download PDFInfo
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- alkali
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- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 229950002020 clemizole Drugs 0.000 title claims abstract description 24
- CJXAEXPPLWQRFR-UHFFFAOYSA-N clemizole Chemical compound C1=CC(Cl)=CC=C1CN1C2=CC=CC=C2N=C1CN1CCCC1 CJXAEXPPLWQRFR-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 35
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000003513 alkali Substances 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000002904 solvent Substances 0.000 claims abstract description 14
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 150000007529 inorganic bases Chemical class 0.000 claims 1
- 150000007530 organic bases Chemical class 0.000 claims 1
- 235000011118 potassium hydroxide Nutrition 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 abstract description 18
- SPMLMLQATWNZEE-UHFFFAOYSA-N 2-(chloromethyl)-1h-benzimidazole Chemical compound C1=CC=C2NC(CCl)=NC2=C1 SPMLMLQATWNZEE-UHFFFAOYSA-N 0.000 abstract description 6
- JQZAEUFPPSRDOP-UHFFFAOYSA-N 1-chloro-4-(chloromethyl)benzene Chemical compound ClCC1=CC=C(Cl)C=C1 JQZAEUFPPSRDOP-UHFFFAOYSA-N 0.000 abstract description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 5
- 238000005516 engineering process Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000012535 impurity Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000008034 disappearance Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 125000001033 ether group Chemical group 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229960001340 histamine Drugs 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 230000001387 anti-histamine Effects 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000938 histamine H1 antagonist Substances 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 208000028185 Angioedema Diseases 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 102000003834 Histamine H1 Receptors Human genes 0.000 description 1
- 108090000110 Histamine H1 Receptors Proteins 0.000 description 1
- 102000000543 Histamine Receptors Human genes 0.000 description 1
- 108010002059 Histamine Receptors Proteins 0.000 description 1
- 208000025047 Non-histaminic angioedema Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000001746 atrial effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/14—Radicals substituted by nitrogen atoms
Abstract
The application relates to the technical field of pharmaceutical technology preparation methods, in particular to a technology preparation method of clemizole hydrochloride. The method comprises the following steps: 2-chloromethyl benzimidazole (compound II) is taken as a raw material, after being dissolved in a solvent, alkali is added to enable the compound II to react with excessive tetrahydropyrrole (compound III) at the temperature of 70-120 ℃ to prepare a compound IV; dissolving the compound IV in a solvent, adding alkali to enable the compound II to react with 4-chlorobenzyl chloride (compound V) at the temperature of 80-100 ℃ to prepare a compound VI; and finally, the compound VI reacts with hydrochloric acid to prepare the clemizole hydrochloride (compound I).
Description
Technical Field
The application relates to the technical field of pharmaceutical technology preparation methods, in particular to a technology preparation method of clemizole hydrochloride.
Background
Clemizole hydrochloride is a propylamine antihistamine and is a strong H1 receptor antagonist. When the H1 receptor is excited, the contraction of smooth muscle of bronchus and gastrointestinal tract, the relaxation of smooth muscle of blood vessel, the reinforcement of the contraction of atrial muscle, the slowing of the conduction of atrioventricular, etc. can be caused. The H1 receptor antagonist replaces histamine in organisms, competitively antagonizes the action thereof, and does not inactivate histamine or inhibit synthesis and release thereof. The drug reversibly occupies the histamine receptor and competitively blocks histamine binding to the receptor, thereby exhibiting antihistaminic effects. Therefore, the traditional Chinese medicine composition is mainly used for relieving symptoms of anaphylactic reaction, such as urticaria, angioneurotic edema, rhinitis and conjunctivitis, and also can relieve itching caused by skin diseases. The main formulation of the clemizole hydrochloride is tablets and injection. Is clinically used for treating various allergic diseases, arrhythmia and the like.
The preparation method of the clemizole hydrochloride mainly comprises the following steps:
first kind:
second kind:
the preparation of the raw materials in the first route is difficult, and the reaction is not easy to operate; the second drying method causes cross reaction, which results in reduced reaction yield and purification, and is not suitable for scale-up.
Disclosure of Invention
The technical problems that in the existing method for preparing the clemizole hydrochloride, quaternary ammonium salt is converted into a product at high temperature and is decomposed into other impurities, different solvents can cause different decomposed impurities, different alkali influences on reaction impurities and yield, influences on reaction impurities and time in a temperature range, raw materials are difficult to prepare, the reaction is difficult to operate, the purity is low, the yield is low, large-scale production cannot be achieved and the like are mainly solved.
The technological method for preparing the clemizole hydrochloride comprises the following steps:
in the step of preparing the compound IV from the compound II and the compound III, the molar ratio of the compound II to the compound III is 1:1.5-1:8; the alkali 1 used in the reaction is one or more of organic alkali or inorganic alkali; the solvent 1 is one or more of 1, 4-dioxane, N-dimethylformamide, ethanol, N-propanol, isobutanol, toluene, tetrahydrofuran, dimethyl sulfoxide and ethyl acetate; the reaction temperature is 70-120 ℃.
In the step of preparing the compound VI from the compound IV and the compound V, the alkali 2 is sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide or sodium ethoxide; the solvent 2 is one or more of 1, 4-dioxane, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, ethanol and acetonitrile; the reaction temperature is 80-100 ℃.
The beneficial effects of this application: 2-chloromethylbenzimidazole (compound II) is taken as a raw material, dissolved in a proper solvent, and then added with proper alkali to enable the compound II to react with excessive tetrahydropyrrole (compound III) at proper temperature to prepare a compound IV; dissolving the compound IV in a proper solvent, adding a proper base, and reacting the compound II with 4-chlorobenzyl chloride (compound V) at a proper temperature to prepare a compound VI; and finally, the compound VI reacts with hydrochloric acid to prepare the clemizole hydrochloride (compound I). The experiment can realize the rapid preparation and large-scale production of the clemizole hydrochloride in the process.
The invention solves the problem that quaternary ammonium salt can be converted into a product and can be decomposed into other impurities at high temperature in the existing method for preparing the clemizole hydrochloride by excessive compound III in the reaction; the problem that different solvents can cause different decomposed impurities is solved by selecting a proper solvent 1 and a proper solvent 2; by selecting proper alkali 1 and alkali 2, the production of reaction impurities is reduced, and the total yield is improved; the impurity generation of the reaction is reduced by selecting a proper temperature range, and the technical problems of reaction time and the like are solved; the final technical effect can lead the purity of the product to reach 99 percent and the total yield to reach 85 percent.
Detailed Description
So that those skilled in the art can appreciate the features and effects of the present invention, a general description and definition of the terms and expressions set forth in the specification and claims follows. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, and in the event of a conflict, the present specification shall control.
The theory or mechanism described and disclosed herein, whether right or wrong, is not meant to limit the scope of the invention in any way, i.e., the present disclosure may be practiced without limitation to any particular theory or mechanism.
All features such as values, amounts, and concentrations that are defined herein in the numerical or percent ranges are for brevity and convenience only. Accordingly, the description of a numerical range or percentage range should be considered to cover and specifically disclose all possible sub-ranges and individual values (including integers and fractions) within the range.
In this context, not all possible combinations of the individual technical features in the individual embodiments or examples are described in order to simplify the description. Accordingly, as long as there is no contradiction between the combinations of these technical features, any combination of the technical features in the respective embodiments or examples is possible, and all possible combinations should be considered as being within the scope of the present specification.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. Further, it is understood that various changes and modifications may be made by those skilled in the art after reading the teachings of the present invention, and such equivalents are intended to fall within the scope of the claims appended hereto.
The following examples use instrumentation conventional in the art. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. The following examples used various starting materials, unless otherwise indicated, were conventional commercial products, the specifications of which are conventional in the art. In the description of the present invention and the following examples, "%" means weight percent, and "parts" means parts by weight, and ratios means weight, unless otherwise specified.
The following describes a preparation method of clemizole hydrochloride provided in the present application with reference to specific examples.
Example 1
Preparation of Compound IV:
2-chloromethylbenzimidazole (Compound II) (2.0 kg,12.0mol,1 e.q.) was added to the reaction vessel, N-dimethylformamide (10L) was added to dissolve the compound, potassium carbonate (3.3 kg,24.0mol,2 e.q.) was added after dissolving, and after heating to 100℃compound III tetrahydropyrrole (1.7 kg,24.0mol,2 e.q.) was added, and stirring was carried out at 100℃for 4 hours. After HPLC analysis of substrate disappearance and quaternary peak less than 0.5%, the reaction was cooled to room temperature. The mother liquor obtained is filtered, decompressed and dried to obtain the compound IV with the purity of 98 percent.
Preparation of Compound VI:
compound IV (12.0 mol,1 e.q.) was dissolved in N, N-dimethylformamide (10L), and potassium tert-butoxide (2.0 kg,18.0mol,1.5 e.q.) was added thereto at room temperature, followed by stirring for 0.5 hours. After this time, the temperature was raised to 80℃and 4-chlorobenzyl chloride (1.9 kg,12.0mol,1 e.q.) was added thereto, followed by stirring at 80℃for 1 hour. After HPLC detection of compound IV less than 2%, it was cooled to room temperature. Water (40L) was added to the reaction mixture, followed by extraction with methyl tertiary ether (5L) three times, and the organic phases were combined and distilled under reduced pressure to give Compound VI.
Preparation of Compound I:
to compound VI was added ethanol (4L), and then the ethanol solution of hydrochloride was added dropwise to ph=4-5. Cooling to 0 ℃, stirring for 2 hours, and filtering to obtain the white crystal compound I, wherein the purity is 99 percent and the total yield is 85 percent.
Example 2
Preparation of Compound IV:
2-chloromethylbenzimidazole (Compound II) (2.0 kg,12.0mol,1 e.q.) was added to the reaction vessel, 1, 4-dioxane (20L) was added to dissolve, potassium t-butoxide (2.0 kg,18.0mol,1.5 e.q.) was added after dissolution, and after heating to 110℃compound III tetrahydropyrrole (1.7 kg,24.0mol,2.0 e.q.) was added and stirred at 110℃for 4 hours. After HPLC analysis of substrate disappearance and quaternary peak less than 0.5%, the reaction was cooled to room temperature. The mother liquor obtained was filtered and spin-dried under reduced pressure to give compound IV, which had a purity of 95%.
The preparation of compound VI and compound I was carried out according to the procedure of example 1, with a purity of 96% and a total yield of 77%.
Example 3
The preparation of compound IV was carried out according to the procedure of example 1.
Compound IV (12.0 mol,1 e.q.) was dissolved in N, N-dimethylformamide (16L), sodium tert-butoxide (1.3 kg,13.2mol,1.1 e.q.) was added at room temperature, and the mixture was stirred for 0.5 hours at a temperature of 70 ℃. Thereafter, 4-chlorobenzyl chloride (1.9 kg,12.0mol,1.0 e.q.) was added at 70℃and stirred at 70℃for 1 hour. After HPLC detection of compound IV less than 2%, it was cooled to room temperature. Water (40L) was added to the reaction mixture, and after three times of extraction with methyl tertiary ether (5L), the organic phases were combined and distilled under reduced pressure to give compound VI, which was 98% pure and 63% yield.
The preparation of compound I was carried out according to the procedure of example 1.
Example 4
Preparation of Compound IV:
2-chloromethylbenzimidazole (Compound II) (2.0 kg,12.0mol,1 e.q.) was added to the reaction vessel, n-propanol (10L) was added to dissolve the compound, potassium hydrogencarbonate (2.4 kg,24.0mol,2.0 e.q.) was added after dissolving the compound, and after heating to 70℃compound III tetrahydropyrrole (1.7 kg,24.0mol,2.0 e.q.) was added, and the mixture was stirred at 70℃for 4 hours. After HPLC analysis of substrate disappearance and quaternary peak less than 0.5%, the reaction was cooled to room temperature. The mother liquor obtained was filtered and dried under reduced pressure to give compound IV, which had a purity of 91%.
The preparation of compound VI and compound I was carried out according to the procedure of example 1, with a purity of 93% and a total yield of 76%.
Example 5
Preparation of Compound IV:
2-chloromethylbenzimidazole (Compound II) (2.0 kg,12.0mol,1 e.q.) was added to the reaction vessel, toluene (20L) was added to dissolve the compound, potassium hydroxide (0.8 kg,12.0mol,1.0 e.q.) was added after dissolving, and after heating to 120℃compound III tetrahydropyrrole (1.7 kg,24.0mol,2.0 e.q.) was added and stirred at 120℃for 4 hours. After HPLC analysis of substrate disappearance and quaternary peak less than 0.5%, the reaction was cooled to room temperature. The mother liquor obtained was filtered and dried under reduced pressure to give compound IV, which had a purity of 95% and a yield of 71%.
The preparation of compound VI and compound I was carried out according to the protocol of example 1.
Example 6
The preparation of compound IV was carried out according to the procedure of example 1.
Compound IV (12.0 mol,1 e.q.) was dissolved in acetonitrile (20L), sodium tert-butoxide (1.7 kg,18mol,1.5 e.q.) was added at room temperature, and the mixture was stirred at 85℃for 0.5 hours. Thereafter, 4-chlorobenzyl chloride (1.9 kg,12.0mol,1.0 e.q.) was added at 85℃and stirred at 70℃for 1 hour. After HPLC detection of compound IV less than 2%, it was cooled to room temperature. Water (40L) was added to the reaction mixture, followed by extraction with methyl tertiary ether (5L) three times, and the organic phases were combined and distilled under reduced pressure to give Compound VI, 97% pure and 73% yield.
The preparation of compound I was carried out according to the procedure of example 1.
While the invention has been described with reference to the preferred embodiments, it is not limited thereto, and various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (10)
1. The technological preparation method of the clemizole hydrochloride is characterized by comprising the following steps:
wherein: in the step of preparing the compound IV from the compound II and the compound III, the mol ratio of the compound II to the compound III is 1:1.5-1:8; the alkali 1 used in the reaction is one or more of organic alkali or inorganic alkali; the solvent 1 is one or more of 1, 4-dioxane, N-dimethylformamide, N-propanol, isobutanol, toluene, dimethyl sulfoxide and ethyl acetate; the reaction temperature is 70-120 ℃;
in the step of preparing the compound VI from the compound IV and the compound V, the alkali 2 is sodium tert-butoxide, potassium tert-butoxide, sodium methoxide or sodium ethoxide; the solvent 2 is one or more of 1, 4-dioxane, N-dimethylformamide and acetonitrile; the reaction temperature is 80-100 ℃.
2. The process preparation method of clemizole hydrochloride according to claim 1, wherein: in the step of preparing the compound IV from the compound II and the compound III, the organic base is triethylamine or pyridine; the inorganic base is potassium carbonate, sodium bicarbonate, potassium bicarbonate or potassium hydroxide.
3. The process preparation method of clemizole hydrochloride according to claim 1 or 2, characterized in that: compound II and compound III in the step of preparing compound IV, compound II: compound iii: the molar ratio of the alkali 1 is 1:2-4:1-5.
4. A process for the preparation of clemizole hydrochloride according to claim 1 or 3, characterized in that: compound II and compound III in the step of preparing compound IV, compound II: compound iii: the molar ratio of the alkali 1 is 1:2:2.
5. The process preparation method of clemizole hydrochloride according to claim 1, wherein: in the step of preparing the compound IV from the compound II and the compound III, the solvent 1 is one or more of N-propanol, isobutanol, toluene, 1, 4-dioxane and N, N-dimethylformamide.
6. The process preparation method of clemizole hydrochloride according to claim 1, wherein: in the step of preparing the compound IV from the compound II and the compound III, the reaction temperature is 80-110 ℃.
7. The process preparation method of clemizole hydrochloride according to claim 1, wherein: in the step of preparing the compound VI from the compound IV and the compound V, the alkali 2 is sodium tert-butoxide or potassium tert-butoxide; the molar ratio of the compound IV to the alkali 2 is 1:1-3.
8. The process for preparing clemizole hydrochloride according to claim 1 or 7, characterized in that: in the step of preparing the compound VI from the compound IV and the compound V, the alkali 2 is potassium tert-butoxide; the molar ratio of the compound IV to the potassium tert-butoxide is 1:1.5.
9. The process preparation method of clemizole hydrochloride according to claim 1, wherein: in the step of preparing the compound VI from the compound IV and the compound V, the solvent 2 is N, N-dimethylformamide.
10. The process preparation method of clemizole hydrochloride according to claim 1, wherein: in the step of preparing the compound VI from the compound IV and the compound V, the reaction temperature is 90-100 ℃.
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