CN113527199A - Preparation method of chloroquinate - Google Patents
Preparation method of chloroquinate Download PDFInfo
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- CN113527199A CN113527199A CN202110586303.6A CN202110586303A CN113527199A CN 113527199 A CN113527199 A CN 113527199A CN 202110586303 A CN202110586303 A CN 202110586303A CN 113527199 A CN113527199 A CN 113527199A
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- Prior art keywords
- reaction
- methylquinoline
- hydroxy
- dichlorohydantoin
- acid
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- GSBZYMWABSULDI-APVIKVHPSA-N (3S,5R)-2-chloro-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical compound ClC1[C@H](C([C@@H](CC1(C(=O)O)O)O)O)O GSBZYMWABSULDI-APVIKVHPSA-N 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- NBYLBWHHTUWMER-UHFFFAOYSA-N 2-Methylquinolin-8-ol Chemical compound C1=CC=C(O)C2=NC(C)=CC=C21 NBYLBWHHTUWMER-UHFFFAOYSA-N 0.000 claims abstract description 31
- ZKLFRQSZDUSMQE-UHFFFAOYSA-N 5,5-dichloroimidazolidine-2,4-dione Chemical compound ClC1(Cl)NC(=O)NC1=O ZKLFRQSZDUSMQE-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000000463 material Substances 0.000 claims abstract description 15
- 239000002841 Lewis acid Substances 0.000 claims abstract description 14
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 239000013067 intermediate product Substances 0.000 claims description 9
- 150000007529 inorganic bases Chemical class 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 238000012805 post-processing Methods 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 2
- 239000000460 chlorine Substances 0.000 abstract description 11
- 229910052801 chlorine Inorganic materials 0.000 abstract description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 7
- 239000007788 liquid Substances 0.000 abstract description 6
- 239000002699 waste material Substances 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000001914 filtration Methods 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 17
- 239000012043 crude product Substances 0.000 description 16
- 238000001816 cooling Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 230000001376 precipitating effect Effects 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical group [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000002386 leaching Methods 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- 239000012295 chemical reaction liquid Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000007670 refining Methods 0.000 description 6
- 238000005660 chlorination reaction Methods 0.000 description 5
- 244000052769 pathogen Species 0.000 description 4
- 230000001717 pathogenic effect Effects 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000005708 Sodium hypochlorite Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 241000220215 Moringa Species 0.000 description 1
- 235000011347 Moringa oleifera Nutrition 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 241001502500 Trichomonadida Species 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- GPTXWRGISTZRIO-UHFFFAOYSA-N chlorquinaldol Chemical compound ClC1=CC(Cl)=C(O)C2=NC(C)=CC=C21 GPTXWRGISTZRIO-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- CHNLPLHJUPMEOI-UHFFFAOYSA-N oxolane;trifluoroborane Chemical compound FB(F)F.C1CCOC1 CHNLPLHJUPMEOI-UHFFFAOYSA-N 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003643 water by type Substances 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
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
- C07D215/28—Alcohols; Ethers thereof with halogen atoms or nitro radicals in positions 5, 6 or 7
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of chloroquinate, which comprises the following steps: reacting the material I containing 8-hydroxy-2-methylquinoline and dichlorohydantoin in the presence of a catalyst Lewis acid to obtain the chloroquinadol. The invention uses dichlorohydantoin to replace chlorine as a reaction raw material, has good selectivity, few byproducts and strong reaction operability, does not need light shielding and gas protection, improves the quality yield, has the purity of more than 99.00 percent, and ensures the quality of the chloroquinalder. The method reduces the generation of waste liquid in the reaction process, avoids the pollution to the environment to the maximum extent, saves the cost, improves the quality, and is a green and environment-friendly process suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of cloquindol.
Background
The cloquindol is a broad-spectrum bacteriostatic agent and has the following structure:
the chemical name is: 5, 7-dichloro-8-hydroxy-2-methylquinoline, molecular weight 228.07, is a yellow needle-like crystal, has a slightly pungent odor, and has antimicrobial activity against fungi, trichomonads, bacteria (G + and G-), chlamydia, mycoplasma, etc. Because the medicine is slightly soluble in water, pathogenic microorganisms generally enter pathogen cells through endocytosis, the pH value of the pathogen cells is changed, the pathogen metabolism is inhibited, and the like, the pathogen death is finally caused, and human epithelial cells have no phagocytic function on the chloroquinalder, so that the medicine has small adverse reaction on a human body when being externally used.
The chloroquinalder is prepared by Moringa Theramex pharmaceutical factory, and the published production method is that 8-hydroxy-2-methylquinoline is used as raw material, hydrochloric acid is used as solvent, chlorine is used as chlorinated raw material, and the chloroquinalder is synthesized by one-step chlorination reaction. The equation is as follows:
the method has the disadvantages that chlorine is extremely toxic, has high requirements on safety production and is easy to cause environmental pollution. The reaction rate of the gas-liquid reaction is difficult to control, so that the dosage of the chlorine participating in the reaction is difficult to accurately control, the dosage of the chlorine is insufficient, the monochloro product is more, and the trichloro product and the polychlorinated product are increased due to excessive chlorine. The reaction also needs to be strictly protected from light, otherwise, the chlorination reaction is also easy to occur at the methyl position. The whole reaction has low conversion rate, more impurities and difficult purification.
The synthesis process of substituting chlorine with sodium hypochlorite as chloro material has the following reaction equation:
the process avoids the pollution of chlorine, but still uses hydrochloric acid with higher volatility, and the sodium hypochlorite solution has large dosage, can dissolve part of generated products in the reaction process, so that the yield is reduced, the generated waste liquid is more, and the cost for treating the waste liquid is increased.
Therefore, there is a need to develop a green and environment-friendly process for synthesizing chloroquinate.
Disclosure of Invention
In order to solve the technical problem, the invention provides a preparation method of chloroquinate, which takes 8-hydroxy-2-methylquinoline as a raw material to perform one-step chlorination reaction with dichlorohydantoin under the catalysis of Lewis acid to obtain the chloroquinate. The preparation method has the advantages of high reaction efficiency, good selectivity, less monochloro by-products, reaction time saving and simpler post-treatment. And has higher selectivity, and the purity of the prepared chloroquinate is over 99.00 percent.
According to one aspect of the present application, there is provided a preparation method of chloroquinate, the preparation method comprising: reacting the material I containing 8-hydroxy-2-methylquinoline and dichlorohydantoin in the presence of a catalyst Lewis acid to obtain the chloroquinadol.
The reaction equation for the above reaction is as follows:
optionally, the molar ratio of the 8-hydroxy-2-methylquinoline to the dichlorohydantoin is 1: 0.48-1.0.
Alternatively, the upper limit of the molar ratio of the 8-hydroxy-2-methylquinoline to the dichlorohydantoin is selected from 1: 0.49, 1: 0.50, 1: 0.51, 1: 0.52, 1: 0.53, 1: 0.54, 1:0.55, 1: 0.56, 1: 0.57, 1: 0.58, 1: 0.59, 1: 0.60, 1: 0.70, 1: 0.80, 1: 0.90 or 1: 1.00; the lower limit is selected from 1:0.48, 1: 0.49, 1: 0.50, 1: 0.51, 1: 0.52, 1: 0.53, 1: 0.54, 1:0.55, 1: 0.56, 1: 0.57, 1: 0.58, 1: 0.59, 1: 0.60, 1: 0.70, 1: 0.80 or 1: 0.90.
preferably, the molar ratio of the 8-hydroxy-2-methylquinoline to the dichlorohydantoin is 1: 0.55-0.75.
Alternatively, the molar ratio of 8-hydroxy-2-methylquinoline to lewis acid is 1: 0.02-0.08.
Alternatively, the upper limit of the molar ratio of the 8-hydroxy-2-methylquinoline to the lewis acid is selected from 1: 0.03, 1:0.04, 1: 0.05, 1: 0.06, 1: 0.07 or 1: 0.08; the lower limit is selected from 1: 0.02, 1: 0.03, 1:0.04, 1: 0.05, 1: 0.06 or 1: 0.07.
preferably, the molar ratio of the 8-hydroxy-2-methylquinoline to the Lewis acid is 1: 0.04-0.06.
Optionally, the lewis acid is selected from at least one of aluminum chloride, ferric trichloride, boron trifluoride, zinc chloride, and titanium tetrachloride.
Preferably, the lewis acid is selected from aluminium chloride.
Optionally, the conditions of reaction I are: the reaction temperature is 20-60 ℃, and the reaction time is 5-14 h.
Preferably, the reaction temperature is 32-41 ℃.
Preferably, the reaction time is 7-9 h.
Optionally, the material I containing 8-hydroxy-2-methylquinoline and dichlorohydantoin also comprises a solvent I; the solvent I is at least one selected from dichloromethane and chloroform.
Optionally, the mass-to-volume ratio of the 8-hydroxy-2-methylquinoline to the solvent is 1g (3-20) mL.
Alternatively, the upper limit of the mass to volume ratio of the 8-hydroxy-2-methylquinoline to the solvent is selected from 1g:4mL, 1g:5mL, 1g:6mL, 1g:7mL, 1g:8mL, 1g:9mL, 1g:10mL, 1g:11mL, 1g:12mL, 1g:13mL, 1g:14mL, 1g:15mL, 1g:16mL, 1g:17mL, 1g:18mL, 1g:19mL, or 1g:20 mL; the lower limit is selected from the group consisting of 1g:3mL, 1g:4mL, 1g:5mL, 1g:6mL, 1g:7mL, 1g:8mL, 1g:9mL, 1g:10mL, 1g:11mL, 1g:12mL, 1g:13mL, 1g:14mL, 1g:15mL, 1g:16mL, 1g:17mL, 1g:18mL, and 1g:19 mL.
Preferably, the mass-volume ratio of the 8-hydroxy-2-methylquinoline to the solvent is 1g (5-10) mL.
Optionally, the preparation method comprises:
A) mixing 8-hydroxy-2-methylquinoline, Lewis acid and a solvent to obtain an intermediate product A;
B) adding dichlorohydantoin into the intermediate product A, heating to the reaction temperature, and carrying out chlorination reaction to prepare the cloquindol.
Optionally, the preparation method further comprises a post-treatment step; the post-processing step comprises: (1) mixing the mixed system obtained after the reaction I with concentrated hydrochloric acid, and reacting II to obtain an intermediate product I; (2) and separating out a material II containing the intermediate product I and inorganic base to obtain a material III containing the chloroquinate.
Optionally, the acid is selected from hydrochloric acid with a mass fraction of 25% to 38%.
Preferably, the acid is selected from hydrochloric acid with the mass fraction of 30-38%.
Optionally, the mass to volume ratio of the 8-hydroxy-2-methylquinoline to the acid is 1g: (1-1.5) ml.
Alternatively, the upper limit of the mass to volume ratio of the 8-hydroxy-2-methylquinoline to the acid is selected from 1g: 1.01mL, 1g: 1.02mL, 1g: 1.03mL, 1g:1.04mL, 1g:1.05mL, 1g:1.06mL, 1g:1.07mL, 1g:1.08mL, 1g:1.09mL, 1g:1.10mL, 1g:1.11mL, 1g:1.12mL, 1g:1.13mL, 1g:1.14mL, 1g:1.15mL, 1g:1.16mL, 1g:1.17mL, 1g: 1.26: 1.18mL, 1g:1.19mL, 1g:1.20mL, 1g:1.21mL, 1g:1.22mL, 1g:1.23mL, 1g:1.24mL, 1g:1.25mL, 1g:1.26mL, 1g:1.27mL, 1g: 1.56: 1.28mL, 1g:1.29mL, 1g:1.30mL, 1g:1.24mL, 1g:1.35mL, 1g:1.35mL, 1g:1.44mL, 1g:1.35mL, 1.44mL, 1g:1.35mL, 1g:1.35mL, 1.44mL, 1g:1.35mL, 1.44mL, 1g:1.44mL, 1.35mL, 1g:1.35mL, 1.44mL, 1.35mL, 1g:1.44mL, 1.35mL, 1g:1.35mL, 1.44mL, 1g:1.35mL, 1.44mL, 1g:1.44mL, 1.35mL, 1.44mL, 1g:1.44mL, 1g:1.44mL, 1.35mL, 1.44mL, 1g:1.44mL, 1., 1g:1.49mL or 1g:1.50 mL; the lower limit is selected from 1g: 1.00mL, 1g: 1.01mL, 1g: 1.02mL, 1g: 1.03mL, 1g:1.04mL, 1g:1.05mL, 1g:1.06mL, 1g:1.07mL, 1g:1.08mL, 1g:1.09mL, 1g:1.10mL, 1g:1.11mL, 1g:1.12mL, 1g:1.13mL, 1g:1.14mL, 1g:1.15mL, 1g:1.16mL, 1g:1.17mL1g:1.18mL, 1g:1.19mL, 1g:1.20mL, 1g:1.21mL, 1g:1.22mL, 1g:1.23mL, 1g:1.24mL, 1g:1.25mL, 1g:1.26mL, 1g:1.27mL1g:1.28mL, 1g:1.29mL, 1g:1.30mL, 1g:1.31mL, 1g:1.32mL, 1g:1.33mL, 1g:1.34mL, 1g:1.35mL, 1g:1.36mL, 1g:1.37mL1g:1.38mL, 1g:1.39mL, 1g:1.40mL, 1g:1.41mL, 1g:1.42mL, 1g:1.43mL, 1g:1.44mL, 1g:1.45mL, 1g:1.46mL, 1g:1.47mL1g:1.48mL or 1g:1.49 mL.
Alternatively, the conditions of reaction II are: the temperature is 20-30 ℃.
Optionally, the reaction II is performed under normal temperature and pressure.
Optionally, the inorganic base is selected from at least one of ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and ammonium bicarbonate.
Preferably, the inorganic base is selected from aqueous ammonia.
Optionally, the pH of the material II containing the intermediate product I and the inorganic base is 2.5-5.0.
Optionally, the upper pH limit of the feed II containing the intermediate product I and an inorganic base is selected from 3.0, 3.5, 4.0, 4.5 or 5.0; the lower limit is selected from 2.5, 3.0, 3.5, 4.0 or 4.5.
Preferably, the pH of the material II containing the intermediate product I and the inorganic base is 3.0-3.5.
Optionally, the post-processing step further comprises: and mixing the material III containing the chloroquinate with the solution II, and refining to obtain the chloroquinate.
Optionally, the solvent II comprises an organic solvent and water; the organic solvent is at least one selected from methanol, ethanol and acetonitrile.
Preferably, the organic solvent is selected from ethanol.
Optionally, the volume ratio of the organic solvent to the water is 2-20: 1.
Preferably, the volume ratio of the organic solvent to the water is 6-9: 1.
Optionally, the mass-volume ratio of the material III containing the chloroquinate to the organic solvent is 1g (6-20) mL.
Preferably, the mass-volume ratio of the material III containing the chloroquinate to the organic solvent is 1g (7-12) mL.
Specifically, the post-processing includes: after the reaction is finished, cooling the reaction system to 20-30 ℃, filtering to remove the catalyst, dripping concentrated hydrochloric acid into the filtrate, precipitating, and filtering to obtain the cloquindol hydrochloride. And adding the solid into water, stirring to dissolve, slowly adding inorganic base, separating out the solid, filtering, leaching and drying to obtain a crude product. And refining the crude product by using a mixed solution of an organic solvent and water to obtain the chloroquinate.
Compared with the prior art, the invention has the following beneficial effects:
(1) the invention uses dichlorohydantoin to replace chlorine as the raw material of the chlorination reaction, has good selectivity, reduces side reaction, improves the quality yield, ensures the quality of the chloroquinate, and reduces the pollution to the environment, and the purity is over 99.00 percent.
(2) The invention uses dichloromethane or chloroform as solvent, which can be recycled, thus reducing the generation of waste liquid and the cost for treating the waste liquid; the catalyst Lewis acid is used, so that the generation of a mixture of a 4-chlorine product, a 2-chlorine product and a target product 2, 4-dichloro product can be avoided, and the problem that qualified chloroquinate cannot be obtained in the post-treatment stage is also avoided; in the post-treatment of the invention, the product is salified and separated out by dripping concentrated hydrochloric acid, thereby avoiding the generation and increase of impurities in the long-time concentration process, reducing the production energy consumption and reducing the production time.
(3) The method simplifies the process operation, has mild reaction temperature, does not need light protection and gas protection, has low requirement on reaction equipment, has strong reaction operability, ensures the production safety, and is a route suitable for industrial production.
Detailed Description
In order to further illustrate the present invention, the following examples are given to describe in detail the process for preparing chloroquinate provided by the present invention.
The raw materials in the examples of the present application were all purchased commercially, unless otherwise specified. If not stated, the test method adopts the conventional method, and the instrument setting adopts the setting recommended by the manufacturer.
The purity of chloroquinate was determined by HPLC.
HPLC：Waters 2998
The method for calculating the yield comprises the following steps: moles of product chloroquinadol/moles of 8-hydroxy-2-methylquinoline x 100%
Example 1
10g of 8-hydroxy-2-methylquinoline, 50mL of dichloromethane and 0.35g of aluminum chloride are put into a 250mL reaction bottle, stirred and cooled to 20-30 ℃, 7.8g of dichlorohydantoin is added, and the temperature is kept at 32-41 ℃ for reaction for 7 hours.
And cooling the reaction liquid to 20-30 ℃, filtering, dripping 15mL of concentrated hydrochloric acid into the filtrate, precipitating, filtering, adding 150mL of water, stirring to dissolve, slowly adding ammonia water until the pH value is 2.8, precipitating a solid, filtering, leaching, and drying to obtain a crude product.
The crude product is refined by 160mL of absolute ethyl alcohol and 20mL of water to obtain 8.7g of the pure product of the chloroquinader, the yield is 60.32 percent, and the HPLC purity is 99.23 percent.
Example 2
Adding 20g of 8-hydroxy-2-methylquinoline, 200mL of chloroform and 1.0g of aluminum chloride into a 500mL reaction bottle, stirring, cooling to 20-30 ℃, adding 15.3g of dichlorohydantoin, and carrying out heat preservation reaction at 32-41 ℃ for 8 hours.
And cooling the reaction liquid to 20-30 ℃, filtering, dripping 20mL of concentrated hydrochloric acid into the filtrate to precipitate, filtering, adding 200mL of water, stirring to dissolve, slowly adding ammonia water until the pH value is 3.5, precipitating a solid, filtering, leaching, and drying to obtain a crude product.
Refining the crude product with 280mL of absolute ethanol and 30mL of water to obtain 19.0g of the pure product of the chloroquinader, wherein the yield is 65.85% and the HPLC purity is 99.43%.
Example 3
10g of 8-hydroxy-2-methylquinoline, 80mL of dichloromethane and 0.5g of aluminum chloride are put into a 250mL reaction bottle, stirred and cooled to 20-30 ℃, 7.7g of dichlorohydantoin is added, and the temperature is kept at 32-41 ℃ for reaction for 9 hours.
And cooling the reaction liquid to 20-30 ℃, filtering, dripping 12mL of concentrated hydrochloric acid into the filtrate, precipitating, filtering, adding 100mL of water, stirring to dissolve, slowly adding ammonia water until the pH value is 4.0, precipitating a solid, filtering, leaching, and drying to obtain a crude product.
The crude product is refined by using 100mL of acetonitrile and 10mL of water to obtain 9.5g of the pure product of the chloroquinader, the yield is 66.05 percent, and the HPLC purity is 99.71 percent.
Example 4
50g of 8-hydroxy-2-methylquinoline, 750mL of dichloromethane and 2.5g of aluminum chloride are put into a 1L reaction bottle, stirred and cooled to 20-30 ℃, 37.3g of dichlorohydantoin is added, and the mixture is reacted for 9 hours at the temperature of 32-41 ℃.
And cooling the reaction liquid to 20-30 ℃, filtering, dripping 55mL of concentrated hydrochloric acid into the filtrate to precipitate, filtering, adding 600mL of water, stirring to dissolve, slowly adding ammonia water until the pH value is 5.0, precipitating a solid, filtering, leaching, and drying to obtain a crude product.
The crude product is refined by 1600mL of methanol and 200mL of water to obtain 43.5g of the pure product of the chloroquinader, the yield is 60.34 percent, and the HPLC purity is 99.45 percent.
Example 5
Putting 200g of 8-hydroxy-2-methylquinoline, 1800mL of dichloromethane and 9.5g of aluminum chloride into a 5L reaction bottle, stirring, cooling to 20-30 ℃, adding 156g of dichlorohydantoin, and carrying out heat preservation reaction for 10h at 32-41 ℃.
And cooling the reaction liquid to 20-30 ℃, filtering, dripping 250mL of concentrated hydrochloric acid into the filtrate, precipitating, filtering, adding 2200mL of water, stirring to dissolve, slowly adding ammonia water until the pH value is 4.5, precipitating a solid, filtering, leaching, and drying to obtain a crude product.
Refining the crude product with 280mL of absolute ethanol and 30mL of water to obtain 198.7g of the pure product of the chloroquinader, wherein the yield is 68.98% and the HPLC purity is 99.57%.
Example 6
Adding 20g of 8-hydroxy-2-methylquinoline, 200mL of chloroform and 1.2g of ferric chloride into a 500mL reaction bottle, stirring, cooling to 20-30 ℃, adding 15.2g of dichlorohydantoin, and carrying out heat preservation reaction at 32-41 ℃ for 8 hours.
And cooling the reaction liquid to 20-30 ℃, filtering, dripping 20mL of concentrated hydrochloric acid into the filtrate to precipitate, filtering, adding 200mL of water, stirring to dissolve, slowly adding ammonia water until the pH value is 3.5, precipitating a solid, filtering, leaching, and drying to obtain a crude product.
Refining the crude product with 280mL of absolute ethyl alcohol and 30mL of water to obtain 15.4g of the pure product of the chloroquinader, wherein the yield is 53.30 percent, and the HPLC purity is 99.27 percent.
Example 7
Putting 20g of 8-hydroxy-2-methylquinoline, 200mL of chloroform and 1.1g of boron trifluoride tetrahydrofuran solution into a 500mL reaction flask, stirring, cooling to 20-30 ℃, adding 15.5g of dichlorohydantoin, and carrying out heat preservation reaction at 32-41 ℃ for 8 hours.
And cooling the reaction liquid to 20-30 ℃, filtering, dripping 20mL of concentrated hydrochloric acid into the filtrate to precipitate, filtering, adding 200mL of water, stirring to dissolve, slowly adding ammonia water until the pH value is 3.8, precipitating a solid, filtering, leaching, and drying to obtain a crude product.
Refining the crude product with 280mL of absolute ethyl alcohol and 30mL of water to obtain 17.5g of a pure product of the chloroquinader, wherein the yield is 60.84 percent, and the HPLC purity is 99.70 percent.
As can be seen from the above examples, the method of the invention adopts Lewis acid as a catalyst and dichlorohydantoin as a chlorinated raw material, thereby greatly improving the yield and purity of the chloroquinate.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (10)
1. A preparation method of chloroquinate, which is characterized by comprising the following steps: reacting the material I containing 8-hydroxy-2-methylquinoline and dichlorohydantoin in the presence of a catalyst Lewis acid to obtain the chloroquinadol.
2. The method according to claim 1, wherein the molar ratio of the 8-hydroxy-2-methylquinoline to the dichlorohydantoin is 1:0.48 to 1.0.
3. The method according to claim 1, wherein the molar ratio of 8-hydroxy-2-methylquinoline to Lewis acid is 1: 0.02-0.08.
4. The production method according to claim 1, wherein the Lewis acid is at least one member selected from the group consisting of aluminum trichloride, ferric trichloride, boron trifluoride, zinc chloride, p-toluenesulfonic acid and titanium tetrachloride.
5. The method according to claim 1, wherein the conditions of reaction I are: the reaction temperature is 20-60 ℃, and the reaction time is 5-14 hours.
6. The process according to claim 1, wherein the material I containing 8-hydroxy-2-methylquinoline and dichlorohydantoin further comprises a solvent I; the solvent I is at least one selected from dichloromethane and chloroform.
7. The preparation method according to claim 6, wherein the mass-to-volume ratio of the 8-hydroxy-2-methylquinoline to the solvent I is 1g (3-20) mL.
8. The method of claim 1, further comprising a post-treatment step; the post-processing step comprises:
(1) mixing the mixed system obtained after the reaction I with acid, and reacting II to obtain an intermediate product I;
(2) and separating out a material II containing the intermediate product I and inorganic base to obtain a material III containing the chloroquinate.
9. The method according to claim 8, wherein the acid is hydrochloric acid with a mass fraction of 25 to 38%.
10. The method according to claim 8, wherein the mass-to-volume ratio of the 8-hydroxy-2-methylquinoline to the acid is 1g: (1-1.5) ml.
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