CN111018777B - Preparation method of dequalinium chloride - Google Patents
Preparation method of dequalinium chloride Download PDFInfo
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- CN111018777B CN111018777B CN201911162311.7A CN201911162311A CN111018777B CN 111018777 B CN111018777 B CN 111018777B CN 201911162311 A CN201911162311 A CN 201911162311A CN 111018777 B CN111018777 B CN 111018777B
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- 229960001378 dequalinium chloride Drugs 0.000 title claims abstract description 64
- LTNZEXKYNRNOGT-UHFFFAOYSA-N dequalinium chloride Chemical compound [Cl-].[Cl-].C1=CC=C2[N+](CCCCCCCCCC[N+]3=C4C=CC=CC4=C(N)C=C3C)=C(C)C=C(N)C2=C1 LTNZEXKYNRNOGT-UHFFFAOYSA-N 0.000 title claims abstract description 64
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- 238000000034 method Methods 0.000 claims abstract description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 13
- CKJCTZAIDVFHCX-UHFFFAOYSA-N 1,10-diiododecane Chemical compound ICCCCCCCCCCI CKJCTZAIDVFHCX-UHFFFAOYSA-N 0.000 claims abstract description 12
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 claims abstract description 11
- BTXPITUAZUILEM-UHFFFAOYSA-N 1-[10-(4-amino-2-methylquinolin-1-ium-1-yl)decyl]-2-methylquinolin-1-ium-4-amine;diiodide Chemical compound [I-].[I-].C1=CC=C2[N+](CCCCCCCCCC[N+]3=C4C=CC=CC4=C(N)C=C3C)=C(C)C=C(N)C2=C1 BTXPITUAZUILEM-UHFFFAOYSA-N 0.000 claims abstract description 11
- HQAIROMRVBVWSK-UHFFFAOYSA-N 4-chloro-2-methylquinoline Chemical compound C1=CC=CC2=NC(C)=CC(Cl)=C21 HQAIROMRVBVWSK-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000012046 mixed solvent Substances 0.000 claims abstract description 6
- 238000001816 cooling Methods 0.000 claims description 26
- 239000000047 product Substances 0.000 claims description 26
- 238000001035 drying Methods 0.000 claims description 25
- 238000005406 washing Methods 0.000 claims description 23
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 22
- 238000010438 heat treatment Methods 0.000 claims description 22
- COCFIBRMFPWUDW-UHFFFAOYSA-N 2-methylquinolin-4-amine Chemical compound C1=CC=CC2=NC(C)=CC(N)=C21 COCFIBRMFPWUDW-UHFFFAOYSA-N 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 10
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 8
- 150000003248 quinolines Chemical class 0.000 claims description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 235000019253 formic acid Nutrition 0.000 claims description 7
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 5
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 4
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims description 3
- -1 N-diethylformamide Chemical compound 0.000 claims description 2
- 229960000840 dequalinium Drugs 0.000 claims description 2
- PCSWXVJAIHCTMO-UHFFFAOYSA-P dequalinium Chemical compound C1=CC=C2[N+](CCCCCCCCCC[N+]3=C4C=CC=CC4=C(N)C=C3C)=C(C)C=C(N)C2=C1 PCSWXVJAIHCTMO-UHFFFAOYSA-P 0.000 claims description 2
- HXLVCCRPDYIRRX-UHFFFAOYSA-N iodoamine Chemical compound IN HXLVCCRPDYIRRX-UHFFFAOYSA-N 0.000 claims description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 4
- 238000001953 recrystallisation Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 238000005576 amination reaction Methods 0.000 abstract 2
- PCTDCXXLAPJUDC-UHFFFAOYSA-N 2,2-dimethyl-1H-quinolin-4-amine Chemical compound CC1(NC2=CC=CC=C2C(=C1)N)C PCTDCXXLAPJUDC-UHFFFAOYSA-N 0.000 abstract 1
- 238000006264 debenzylation reaction Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 239000012065 filter cake Substances 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
- 238000007710 freezing Methods 0.000 description 8
- 230000008014 freezing Effects 0.000 description 8
- 238000005352 clarification Methods 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 241000222122 Candida albicans Species 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 208000007117 Oral Ulcer Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 208000002399 aphthous stomatitis Diseases 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
- 229940046011 buccal tablet Drugs 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 208000007565 gingivitis Diseases 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of dequalinium chloride, which comprises the steps of reacting 2-methyl-4-chloroquinoline as a starting material with p-methoxybenzylamine to obtain an amination intermediate II, carrying out debenzylation reaction on the amination intermediate to obtain 2-methyl-4-aminoquinaldine, then reacting with 1, 10-diiododecane to obtain dequalinium iodide, continuing reacting with hydrochloric acid to obtain dequalinium chloride, and finally recrystallizing with a mixed solvent to obtain a refined dequalinium chloride. According to the preparation method of the dequalinium chloride, no nitrobenzene which is a highly toxic solvent is adopted, a nontoxic or low-toxic solvent is adopted, the reaction temperature is reduced in the reaction process, the method is environment-friendly, the reaction condition is simple, and a fine dequalinium chloride product is prepared by recrystallization of a mixed solvent, so that the impurity controllability of the dequalinium chloride process is realized, the yield and the purity of the prepared dequalinium chloride are high, the product quality is stable, and the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of chemical medicines, and particularly relates to a preparation method of dequalinium chloride.
Background
Dequalinium chloride, also known as clonidine, is a cationic surfactant with strong local antifungal, gram-positive, gram-negative, and Candida albicans effects, and can be used for treating acute and chronic pharyngolaryngitis, oral ulcer, gingivitis, etc. The dequalinium chloride buccal tablet is convenient to use, small in side effect, good in patient compliance and widely applied to clinic.
The dequalinium chloride has the characteristics of wide sterilization range, quick action, strong efficacy, almost no toxicity and irritation, no influence of saliva and serum on the activity, no absorption by blood and excretion from the body after being taken. From toxicity experiments, the product is a variety with extremely high safety and has little harm to pregnant women and lactating women.
The synthesis of the dequalinium chloride is mostly reported, and the detailed synthesis process of the dequalinium chloride is reported in the magazines of the Chinese pharmacist and the Hebei chemical industry in 2000, so that the reaction steps are long, and the yield is low. At present, 2-methyl-4-aminoquinoline is mostly used as a starting raw material to obtain a target product through two-step reaction, the method has short steps and simple operation, but the impurity source in the raw material medicine is difficult to control.
The present invention has been made in view of the above circumstances.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a preparation method of dequalinium chloride, which has the advantages of easily controllable raw material impurity sources, simple operation, avoidance of the use of a virulent solvent nitrobenzene, and high yield and purity of dequalinium chloride prepared by a mixed solvent recrystallization method.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of dequalinium chloride comprises the following steps:
(1) the 2-methyl-4-chloroquinoline and p-methoxybenzylamine are subjected to an ammoniation reaction to obtain the 2-methyl-4-aminated quinoline, and the reaction route is as follows:
(2) reacting 2-methyl-4-aminated quinoline with trifluoroacetic acid to obtain 2-methyl-4-aminoquinoline, wherein the reaction route is shown as follows:
(3) dissolving 2-methyl-4-aminoquinoline and 1, 10-diiododecane in a solvent for reaction to obtain dequalinium iodide, wherein the reaction route is shown as follows:
(4) under the action of hydrochloric acid, dequalinium iodoammonium obtains a dequalinium chloride crude product, and the reaction route is as follows:
(5) and dissolving the crude dequalinium chloride product in a mixed solvent of formic acid and ethyl acetate, heating to be clear, cooling, separating dequalinium chloride out, filtering, washing with water, and drying to obtain a refined dequalinium chloride product.
Further, the molar ratio of the 2-methyl-4-chloroquinoline to the p-methoxybenzylamine in the step (1) is 1: 0.7-100.
Further, the molar ratio of the 2-methyl-4-chloroquinoline to the p-methoxybenzylamine in the step (1) is 1: 4-75.
Further, the reaction temperature in the step (1) is 80-160 ℃.
Further, the reaction temperature is 100-160 ℃.
Further, the molar volume ratio of the 2-methyl-4-aminated quinoline to the trifluoroacetic acid in the step (2) is 1mol: 0.1-100L.
Further, the molar volume ratio of the 2-methyl-4-aminated quinoline to the trifluoroacetic acid in the step (2) is 1mol: 0.6-40L.
Further, the reaction temperature in the step (2) is 30-120 ℃.
Further, the reaction temperature is 75-90 ℃.
Further, the molar ratio of the 2-methyl-4-aminoquinoline to the 1, 10-diiododecane in the step (3) is 0.8-3: 1.
Further, the molar ratio of the 2-methyl-4-aminoquinoline to the 1, 10-diiododecane in the step (3) is 2-3: 1.
Further, the reaction temperature in the step (3) is 50-180 ℃.
Further, the reaction temperature was 80 ℃.
Further, the solvent in the step (3) is one or more of N, N-dimethylformamide, N-diethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, anisole and sulfolane.
Further, in the step (3), the molar volume ratio of the 2-methyl-4-aminoquinoline to the solvent is 1mol: 0.1-100L.
Further, in the step (3), the molar volume ratio of the 2-methyl-4-aminoquinoline to the solvent is 1mol: 0.32-3.33L.
Further, the reaction temperature in the step (4) is 80-100 ℃.
Compared with the prior art, the invention has the beneficial effects that:
according to the preparation method of the dequalinium chloride, no nitrobenzene which is a highly toxic solvent is adopted, a nontoxic or low-toxic solvent is adopted, the reaction temperature is reduced in the reaction process, the method is environment-friendly, the post-treatment of the product is simple, the complex operation is avoided, the fine dequalinium chloride product is prepared by recrystallization of the mixed solvent, the impurity controllability of the dequalinium chloride process is realized, the safety of the product is ensured, and the requirements of medical specifications are met; and the prepared dequalinium chloride has high yield and purity, simple reaction conditions and stable product quality, and is suitable for industrial production.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the examples given herein without any inventive step, are within the scope of the present invention.
The purity of the commercially available reagents such as 2-methyl-4-chloroquinoline, 4-methoxybenzylamine, and 1, 10-diiododecane used in the examples of the present invention was > 98%. Organic solvents trifluoroacetic acid, N-dimethylformamide, sulfolane, ethylene glycol dimethyl ether, hydrochloric acid, formic acid, methanol and the like were purchased from shanghai tatatake technologies ltd.
The route for synthesizing dequalinium chloride in the following examples is as follows:
example 1
The preparation method of dequalinium chloride of this embodiment includes the following steps:
(1) dissolving 2-methyl-4-chloroquinoline (7.10g, 0.04mol) in p-methoxybenzylamine (21.92g, 0.16mol), heating to 140 ℃ for reaction for 2h, cooling, pouring the reaction solution into water, separating out an off-white precipitate, performing suction filtration, washing a filter cake for three times, and drying the filter cake to obtain 9.53g of the product 2-methyl-4-N- (4-methoxy) benzylamine quinoline with the yield of 86.1% and the HPLC purity of 96.4%;
(2) dissolving 2-methyl-4-N- (4-methoxy) benzylamine quinoline (5.6g, 0.02mol) in 12mL trifluoroacetic acid, heating to 75 ℃, reacting for 3h, cooling, spin-drying, adding dichloromethane and water into the residue for extraction, extracting for three times, combining organic phases, drying, and desolventizing to obtain a product 2-methyl-4-aminoquinoline 2.82g, wherein the yield is 88.6%, and the HPLC purity is 99.5%;
(3) dissolving 2-methyl-4-aminoquinoline (3.16g, 0.02mol) in 6.4mL of ethylene glycol dimethyl ether, adding 1, 10-diiododecane (3.94g, 0.01mol), heating to 80 ℃, reacting for 6h, cooling, filtering, washing the filter cake twice, washing the filter cake once with methanol, and drying to obtain 8.66g of dequalinium iodide, wherein the yield is 61%, and the HPLC purity is 78.9%;
(4) dissolving dequalinium iodide (14.2g, 0.02mol) in hydrochloric acid, heating to 100 ℃, reacting for 1h, cooling to 50 ℃, slowly dropping 3.4mL of hydrogen peroxide, and stopping the reaction when the solution gradually becomes dark brown and light brown. Cooling and transferring the reaction solution, freezing and standing overnight, crystallizing and separating out dequalinium chloride, filtering, washing a filter cake with water, and drying to obtain 9.6g of a dequalinium chloride crude product, wherein the yield is 91% and the HPLC purity is 92.4%;
(5) dissolving 5g of crude dequalinium chloride in 150mL of mixed solution of formic acid and ethyl acetate according to the volume ratio of 1:3, heating to 60 ℃, cooling after complete clarification, freezing overnight, separating out a refined dequalinium chloride product, filtering, washing a filter cake with water, and drying to obtain 4.0g of refined dequalinium chloride product, wherein the HPLC purity is greater than 98%, and the yield is 80% (calculated based on the crude product).
Example 2
The preparation method of dequalinium chloride of this embodiment includes the following steps:
(1) dissolving 2-methyl-4-chloroquinoline (7.10g, 0.04mol) in p-methoxybenzylamine (274.1g, 2.0mol), heating to 160 ℃ for reaction for 1.5h, cooling, pouring the reaction solution into water, separating out an off-white precipitate, performing suction filtration, washing a filter cake for three times, and drying the filter cake to obtain 9.44g of the product 2-methyl-4-N- (4-methoxy) benzylamine quinoline with the yield of 85.9 percent and the HPLC purity of 97.1 percent;
(2) dissolving 2-methyl-4-N- (4-methoxy) benzylamine quinoline (5.6g, 0.02mol) in 60.0mL trifluoroacetic acid, heating to 85 ℃, reacting for 3h, cooling, spin-drying, adding dichloromethane and water into the residue, extracting for three times, combining organic phases, drying, desolventizing to obtain a product 2-methyl-4-aminoquinoline 2.79g, wherein the yield is 87.8%, and the HPLC purity is 99.6%;
(3) dissolving 2-methyl-4-aminoquinoline (3.16g, 0.02mol) in 6.7mL ethylene glycol diethyl ether, adding 1, 10-diiododecane (3.15g, 0.008mol), heating to 80 ℃, reacting for 6h, cooling, filtering, washing the filter cake twice, washing the filter cake once with methanol, and drying to obtain 8.73g of dequalinium iodide, wherein the yield is 61.5%, and the HPLC purity is 80.2%;
(4) dissolving dequalinium iodide (14.2g, 0.02mol) in hydrochloric acid, heating to 80 ℃, reacting for 1h, cooling to 50 ℃, slowly dropping 4.8mL of hydrogen peroxide, and stopping the reaction when the solution gradually becomes dark brown and light brown. Cooling and transferring the reaction solution, freezing and standing overnight, crystallizing and separating out dequalinium chloride, filtering, washing a filter cake with water, and drying to obtain a dequalinium chloride crude product 10.36g, wherein the yield is 98.2%, and the HPLC purity is 91.4%;
(5) dissolving 5g of crude dequalinium chloride in 200mL of mixed solution of formic acid and ethyl acetate according to the volume ratio of 1:3, heating to 60 ℃, cooling after complete clarification, freezing overnight, separating out a refined dequalinium chloride product, filtering, washing a filter cake with water, and drying to obtain 4.1g of the refined product, wherein the HPLC purity is more than 98%, and the yield is 82% (calculated based on the crude product).
Example 3
The preparation method of dequalinium chloride of this embodiment includes the following steps:
(1) dissolving 2-methyl-4-chloroquinoline (7.10g, 0.04mol) in p-methoxybenzylamine (411.1g, 3.0mol), heating to 100 ℃ for reaction for 2h, cooling, pouring the reaction solution into water, separating out a white-like precipitate, performing suction filtration, washing a filter cake for three times, and drying the filter cake to obtain 9.24g of the product 2-methyl-4-N- (4-methoxy) benzylamine quinoline with the yield of 84.8 percent and the HPLC purity of 97.3 percent;
(2) dissolving 2-methyl-4-N- (4-methoxy) benzylamine quinoline (5.6g, 0.02mol) in 80.0mL trifluoroacetic acid, heating to 90 ℃, reacting for 3h, cooling, spin-drying, adding dichloromethane and water into the residue, extracting for three times, combining organic phases, drying, desolventizing to obtain a product 2.79g, wherein the yield is 87.8%, and the HPLC purity is 99.6%;
(3) dissolving 2-methyl-4-aminoquinoline (4.75g, 0.03mol) in 40.5mL of sulfolane, adding 1, 10-diiododecane (3.94g, 0.01mol), heating to 80 ℃, reacting for 6h, cooling, filtering, washing the filter cake twice, washing the filter cake once with methanol, and drying 8.49g of dequalinium iodide, wherein the yield is 59.8%, and the HPLC purity is 80.5%;
(4) dissolving dequalinium iodide (14.2g, 0.02mol) in hydrochloric acid, heating to 100 ℃, reacting for 1h, cooling to 50 ℃, slowly dropping 4.8mL of hydrogen peroxide, and stopping the reaction when the solution gradually becomes dark brown and light brown. Cooling, transferring the reaction solution, freezing and standing overnight, crystallizing and separating out dequalinium chloride, filtering, washing a filter cake with water, and drying to obtain a dequalinium chloride crude product 10.36g, wherein the yield is 98.2%, and the HPLC purity is 91%;
(5) dissolving 5g of crude dequalinium chloride in 240mL of mixed solution of formic acid and ethyl acetate according to the volume ratio of 1:3, heating to 60 ℃, cooling after complete clarification, freezing overnight, separating out a refined dequalinium chloride product, filtering, washing a filter cake with water, and drying to obtain 3.8g of the refined product, wherein the HPLC purity is more than 98%, and the yield is 76% (calculated based on the crude product).
Example 4
The preparation method of dequalinium chloride of this embodiment includes the following steps:
(1) dissolving 2-methyl-4-chloroquinoline (7.10g, 0.04mol) in p-methoxybenzylamine (4.15g, 0.03mol), heating to 130 ℃ for reaction for 2h, cooling, pouring the reaction solution into water, separating out a white-like precipitate, performing suction filtration, washing a filter cake for three times, and drying the filter cake to obtain 7.48g of the product 2-methyl-4-N- (4-methoxy) benzylamine quinoline with the yield of 68.7 percent and the HPLC purity of 95.9 percent;
(2) dissolving 2-methyl-4-N- (4-methoxy) benzylamine quinoline (5.6g, 0.02mol) in 800.0mL trifluoroacetic acid, heating to 80 ℃, reacting for 2.5h, cooling, spin-drying, adding dichloromethane and water into the residue, extracting for three times, combining organic phases, drying, desolventizing to obtain a product 2.75g, the yield is 87.6%, and the HPLC purity is 99.6%;
(3) dissolving 2-methyl-4-aminoquinoline (4.75g, 0.03mol) in 100mL of sulfolane, adding 1, 10-diiododecane (3.94g, 0.01mol), heating to 80 ℃, reacting for 12h, cooling, filtering, washing the filter cake twice, washing the filter cake once with methanol, and washing 8g of dried dequalinium iodide, wherein the yield is 56.7%, and the HPLC purity is 81.5%;
(4) dissolving dequalinium iodide (14.2g, 0.02mol) in hydrochloric acid, heating to 100 ℃, reacting for 1h, cooling to 50 ℃, slowly dropping 6mL of hydrogen peroxide, and stopping the reaction when the solution gradually becomes dark brown and light brown. Cooling, transferring the reaction solution, freezing and standing overnight, crystallizing and separating out dequalinium chloride, filtering, washing a filter cake with water, and drying to obtain a dequalinium chloride crude product 10.3g, wherein the yield is 98% and the HPLC purity is 90.4%;
(5) dissolving 5g of crude dequalinium chloride in 300mL of mixed solution of formic acid and ethyl acetate according to the volume ratio of 1:5, heating to 60 ℃, cooling after complete clarification, freezing overnight, separating out a refined dequalinium chloride product, filtering, washing a filter cake with water, and drying to obtain 4.3g of the refined product, wherein the HPLC purity is more than 97%, and the yield is 85% (based on the crude product).
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.
Claims (12)
1. A preparation method of dequalinium chloride is characterized by comprising the following steps:
(1) the 2-methyl-4-chloroquinoline and p-methoxybenzylamine are subjected to an ammoniation reaction to obtain the 2-methyl-4-aminated quinoline, and the reaction route is as follows:
(2) reacting 2-methyl-4-aminated quinoline with trifluoroacetic acid to obtain 2-methyl-4-aminoquinoline, wherein the reaction route is shown as follows:
(3) dissolving 2-methyl-4-aminoquinoline and 1, 10-diiododecane in a solvent for reaction to obtain dequalinium iodide, wherein the solvent is one or more of N, N-dimethylformamide, N-diethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, anisole and sulfolane, and the reaction route is as follows:
(4) under the action of hydrochloric acid, dequalinium iodoammonium obtains a dequalinium chloride crude product, and the reaction route is as follows:
(5) dissolving the crude dequalinium chloride product in a mixed solvent of formic acid and ethyl acetate, heating to be clear, cooling, separating dequalinium chloride out, filtering, washing with water, and drying to obtain a refined dequalinium chloride product;
wherein the reaction temperature in the step (1) is 80-160 ℃;
the reaction temperature in the step (2) is 75-90 ℃.
2. The method for preparing dequalinium chloride according to claim 1, characterized in that the molar ratio of 2-methyl-4-chloroquinoline to p-methoxybenzylamine in step (1) is 1: 4-75.
3. The method for preparing dequalinium chloride according to claim 1, characterized in that the reaction temperature in step (1) is 100 ℃ to 160 ℃.
4. The method for preparing dequalinium chloride according to claim 1, characterized in that the molar volume ratio of 2-methyl-4-aminated quinoline to trifluoroacetic acid in step (2) is 1mol: 0.1-100L.
5. The method for preparing dequalinium chloride according to claim 4, characterized in that the molar volume ratio of 2-methyl-4-aminated quinoline to trifluoroacetic acid in step (2) is 1mol: 0.6-40L.
6. The method for preparing dequalinium chloride according to claim 1, wherein the molar ratio of 2-methyl-4-aminoquinoline to 1, 10-diiododecane in step (3) is 0.8-3: 1.
7. The method for preparing dequalinium chloride according to claim 6, characterized in that the molar ratio of 2-methyl-4-aminoquinoline to 1, 10-diiododecane in step (3) is 2-3: 1.
8. the method for preparing dequalinium chloride according to claim 1, characterized in that the reaction temperature in the step (3) is 50-180 ℃.
9. The method for preparing dequalinium chloride according to claim 8, characterized in that the reaction temperature in the step (3) is 80 ℃.
10. The method for preparing dequalinium chloride according to claim 1, characterized in that the molar volume ratio of 2-methyl-4-aminoquinoline to the solvent in step (3) is 1mol: 0.1-100L.
11. The method for preparing dequalinium chloride according to claim 1, characterized in that the molar volume ratio of 2-methyl-4-aminoquinoline to the solvent in the step (3) is 1mol: 0.32-3.33L.
12. The method for preparing dequalinium chloride according to claim 1, characterized in that the reaction temperature in the step (4) is 80-100 ℃.
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