CN110606830A - Method for producing piperaquine phosphate intermediate quinoline piperazine hydrochloride by applying piperazine - Google Patents
Method for producing piperaquine phosphate intermediate quinoline piperazine hydrochloride by applying piperazine Download PDFInfo
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- piperazine
- dichloroquinoline
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- quinoline
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- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title claims abstract description 95
- URFBJSKLANOEQM-UHFFFAOYSA-N piperazine quinoline hydrochloride Chemical compound N1=CC=CC2=CC=CC=C12.Cl.N1CCNCC1 URFBJSKLANOEQM-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 17
- UCRHFBCYFMIWHC-UHFFFAOYSA-N piperaquine Chemical compound ClC1=CC=C2C(N3CCN(CC3)CCCN3CCN(CC3)C=3C4=CC=C(C=C4N=CC=3)Cl)=CC=NC2=C1 UCRHFBCYFMIWHC-UHFFFAOYSA-N 0.000 title claims description 16
- 229950006717 piperaquine Drugs 0.000 title claims description 16
- 238000000034 method Methods 0.000 claims abstract description 33
- 239000012452 mother liquor Substances 0.000 claims abstract description 21
- HXEWMTXDBOQQKO-UHFFFAOYSA-N 4,7-dichloroquinoline Chemical compound ClC1=CC=NC2=CC(Cl)=CC=C21 HXEWMTXDBOQQKO-UHFFFAOYSA-N 0.000 claims description 70
- 238000006243 chemical reaction Methods 0.000 claims description 45
- 238000003756 stirring Methods 0.000 claims description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 36
- 238000002360 preparation method Methods 0.000 claims description 26
- 238000001914 filtration Methods 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 238000003912 environmental pollution Methods 0.000 abstract description 5
- 231100000331 toxic Toxicity 0.000 abstract description 4
- 230000002588 toxic effect Effects 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 3
- 229960005141 piperazine Drugs 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 238000010438 heat treatment Methods 0.000 description 21
- 239000000203 mixture Substances 0.000 description 18
- HJEYCIXFDZNPMJ-UHFFFAOYSA-N piperazine;quinoline Chemical compound C1CNCCN1.N1=CC=CC2=CC=CC=C21 HJEYCIXFDZNPMJ-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- -1 quinolyl piperazine Chemical compound 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 8
- 201000004792 malaria Diseases 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XRXDAJYKGWNHTQ-UHFFFAOYSA-N quipazine Chemical class C1CNCCN1C1=CC=C(C=CC=C2)C2=N1 XRXDAJYKGWNHTQ-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 230000007547 defect Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000003430 antimalarial agent Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 229960004191 artemisinin Drugs 0.000 description 2
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 2
- 229930101531 artemisinin Natural products 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229960003506 piperazine hexahydrate Drugs 0.000 description 2
- AVRVZRUEXIEGMP-UHFFFAOYSA-N piperazine;hexahydrate Chemical compound O.O.O.O.O.O.C1CNCCN1 AVRVZRUEXIEGMP-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- BWKBOZBYECIGSP-UHFFFAOYSA-N 2-piperazin-1-ylquinoline;hydrochloride Chemical compound Cl.C1CNCCN1C1=CC=C(C=CC=C2)C2=N1 BWKBOZBYECIGSP-UHFFFAOYSA-N 0.000 description 1
- DNXNPMDUDGUXOB-UHFFFAOYSA-N 7-chloro-4-piperazin-1-ylquinoline Chemical compound C=1C=NC2=CC(Cl)=CC=C2C=1N1CCNCC1 DNXNPMDUDGUXOB-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010048723 Multiple-drug resistance Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960002521 artenimol Drugs 0.000 description 1
- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 description 1
- NPLOXHOFYUTPAZ-GLWQFRTASA-N arterakine Chemical compound OP(O)(O)=O.OP(O)(O)=O.OP(O)(O)=O.OP(O)(O)=O.C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C.ClC1=CC=C2C(N3CCN(CC3)CCCN3CCN(CC3)C=3C4=CC=C(C=C4N=CC=3)Cl)=CC=NC2=C1 NPLOXHOFYUTPAZ-GLWQFRTASA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229930016266 dihydroartemisinin Natural products 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- VHBABGAFHUKREU-ICKLFXEKSA-N duo-cotecxin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C.ClC1=CC=C2C(N3CCN(CC3)CCCN3CCN(CC3)C=3C4=CC=C(C=C4N=CC=3)Cl)=CC=NC2=C1 VHBABGAFHUKREU-ICKLFXEKSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000004687 hexahydrates Chemical class 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006561 solvent free reaction Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 201000008827 tuberculosis Diseases 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 discloses a method for preparing high-purity quinoline piperazine hydrochloride, which has the advantages of simple process, easy purification of products, purity of more than or equal to 99.5 percent, avoidance of toxic reagents, little environmental pollution, low production cost and suitability for industrial production. The invention also discloses a method for producing quinoline piperazine hydrochloride by applying piperazine, which is used for directly applying mother liquor for the next production of quinoline piperazine hydrochloride without separating piperazine from the mother liquor.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and relates to a synthetic method of an antimalarial piperaquine phosphate intermediate 7-chloro-4- (1-piperazinyl) quinoline (quinoline piperazine for short) and a method for producing piperaquine phosphate intermediate quinoline piperazine hydrochloride by applying piperazine.
Background
Today, malaria remains as three catastrophic diseases in the world, alongside aids and tuberculosis, with over 90 countries and regions still at the medium and high prevalence level of malaria. According to the statistics of the World Health Organization (WHO), malaria infected people take 3-5 hundred million people every year in the world, the number of dead people exceeds 100 million, and most of the malaria infected people are children under five years of age. In order to enhance the therapeutic effect and slow the development of drug resistance, the WHO recommended the use of "artemisinin-based combination therapy" (ACT) for the treatment of malaria since 2001. Piperaquine phosphate belongs to a synthetic antimalarial drug and is mainly applied to the treatment of malaria with chloroquine resistance. In recent years, the combined application of the artemisinin and the derivatives thereof is increasingly emphasized. The compound preparation dihydroartemisinin piperaquine tablet composed of dihydroartemisinin and piperaquine phosphate not only overcomes the defect of long treatment course of dihydroartemisinin, but also makes up the defect of slow effect of piperaquine, has obvious synergistic effect, and is an excellent medicine for treating various malaria, especially multiple drug resistance malignant malaria.
Although various methods for synthesizing piperaquine have been disclosed in the literature, the synthetic route for preparing piperaquine phosphate by two condensations and then reacting with phosphoric acid has been studied more, and is specifically shown in scheme 1. 2015 latest edition of Chinese pharmacopoeia stipulates quality standards of piperaquine phosphate, but only 3 known impurities are confirmed in related substances stipulated by the quality standards, wherein a single impurity is stipulated to be not more than 0.5%, and the total impurities are stipulated to be not more than 2%. The international mainstream market generally requires that the related substances of the product are less than 0.1 percent, and the limit of the impurities can be determined only by performing pharmacological and toxicological tests on more than 0.1 percent of the impurities. Therefore, the national pharmacopoeia standard of piperaquine phosphate has a large difference with the advanced international standard, and a more advanced process is needed to prepare a high-purity product, so that the international advanced level is reached. In the route, the formula II, namely the quinoline piperazine, is a key intermediate, and the quality of the quinoline piperazine has great influence on the quality of a final product.
Scheme 1:
the main differences in the methods for preparing quinolyl piperazine disclosed in the prior art are the reaction conditions used (i.e., type of solvent, reaction temperature, whether acid-binding agent is added, post-treatment conditions, etc.) and the choice of the piperazine form of the reactant, either anhydrous or hexahydrate, which are not significantly different. Common to most of these syntheses is the difficulty in purifying the key intermediate quinoline piperazine from by-products or excess piperazine, resulting in low quality of the final piperaquine. In fact, the main by-product identified when reacting 4, 7-dichloroquinoline with piperazine is formula II-a, the bis-quinolinepiperazine, also known as acid-insoluble. This by-product has been reported to have some toxicity (singht, et al, j.med. hem, 1971,14,4, 283).
Furthermore, the synthesis of large amounts of the existing compounds of formula II requires elevated reaction mixture temperatures, and/or toxic solvents, and/or cumbersome extraction procedures, and/or highly diluted reaction conditions, and/or large excesses of piperazine.
The method for preparing quinoline piperazine by using the patent US20060270852 comprises the steps of refluxing 4, 7-dichloroquinoline and anhydrous piperazine (the molar ratio is 1: 3) at 84 ~ 85 ℃ for 36h in the presence of potassium carbonate and isopropanol, carrying out post-treatment by adopting reduced pressure distillation, extraction and concentration, adding n-hexane and stirring to obtain a target product, wherein the yield is about 95%, the purity is only 96.64%, and the method has long reaction time, complicated post-treatment and low purity.
Patent CN101440063 discloses a method for preparing quinoline piperazine, wherein 4, 7-dichloroquinoline and anhydrous piperazine (molar ratio is 1:8 ~ 1: 13) are refluxed for 36h in potassium carbonate, isopropanol/water/propanol and the like, and the target product is obtained by vacuum concentration, extraction, concentration and the like after the post-treatment.
Patent CN103360309 discloses a method for preparing quinoline piperazine, in which 4, 7-dichloroquinoline and anhydrous piperazine (molar ratio 1:1 ~ 4) are reacted in the presence of butanol, methanol or no solvent, after the reaction is finished, the mixture is added into water, concentrated hydrochloric acid is adjusted to acidity, filtration and extraction are performed, the pH of the water phase is adjusted to alkalinity, and the product is obtained by extracting and concentrating the organic phase, wherein the optimal purity is 99.5%.
Patent CN103596927 discloses a method for preparing quinoline piperazine, in which 4, 7-dichloroquinoline and anhydrous piperazine (molar ratio is about 1: 2.5) are reacted in methanol, after the reaction is finished, the mixture is filtered, decompressed and concentrated, and water is added for filtration to obtain the target product, which is a B crystal form, the yield is 86%, and the purity of HPLC test samples is not reported.
Patent CN102558048 discloses a method for preparing quinoline piperazine, which comprises the steps of carrying out solvent-free reaction on 4, 7-dichloroquinoline and piperazine hexahydrate (the molar ratio is about 1:3.9), adding water into lower-layer oily matter after the reflux reaction is finished, taking the oily matter by layers, washing the oily matter by water until the pH value is 7 ~ 8, adjusting the pH value of the oily matter to 2.5 ~ 3.5.5, filtering to remove insoluble substances, adjusting the pH value of filtrate to 9 ~ 10, taking the oily matter by layers after standing, adding purified water, stirring the oily matter into solid particles, and drying to obtain the target product.
The literature (Zhengqing four, synthesis and structural characterization of high-purity piperaquine phosphate, university of Guangxi science and technology, 2016,27(2): 107-.
Generally, a large amount of excess piperazine is used in the reaction, so that the recovery and reuse of piperazine also has an extremely important practical significance, and reports on the recovery and reuse of piperazine are few, as disclosed in the patent CN103360309, a method for recovering piperazine after the piperazine exists in an aqueous phase and is heated by the aqueous phase and water is evaporated is adopted, and the method for recovering piperazine by evaporating water is large in energy consumption, complex in operation process and high in cost due to the high boiling point of water. Therefore, the other invention of the invention adopts a mode of directly applying the piperazine rather than recycling the piperazine, thereby simplifying the operation and reducing the cost.
The method for preparing quinoline piperazine mainly has the defects of low purity of prepared products, low yield, complex operation, long production period, serious environmental pollution, high production cost and the like, so a new preparation method needs to be developed aiming at the defects, and the method has important significance for recycling or applying excessive reaction raw material piperazine.
Disclosure of Invention
The invention aims to provide a method for preparing high-purity quinoline piperazine hydrochloride, which has the advantages of simple process, no extraction and concentration procedures, easy purification of products, purity of more than or equal to 99.5 percent, no toxic reagent, little environmental pollution, low production cost and suitability for industrial production. The invention also aims to provide a method for producing piperaquine phosphate intermediate by using piperazine, which comprises the following steps: the method does not need to separate the piperazine from the mother liquor, and directly applies the mother liquor to the production of the next batch of quinoline piperazine, so that the yield of the intermediate quinoline piperazine hydrochloride can be improved, the environmental pollution is reduced, and the production cost is reduced.
The invention discloses a preparation method of high-purity quinoline piperazine hydrochloride, which comprises the following steps:
(1) adding water and anhydrous piperazine into a reactor, stirring, adjusting the pH value with acid, continuing stirring, adding 4, 7-dichloroquinoline, and continuing stirring for reaction after the addition is finished;
(2) cooling after the reaction is finished, and filtering (collecting mother liquor as a solvent for next use);
wherein the method further comprises the step (3) of drying.
Wherein the molar ratio of the 4, 7-dichloroquinoline to the anhydrous piperazine in the step (1) is 1:3 ~ 1:8, preferably 1:4 ~ 1: 6.
Wherein the weight ratio of the 4, 7-dichloroquinoline to the water in the step (1) is 1:1.5 ~ 1:3, preferably 1:2 ~ 1: 2.5.
Wherein the acid in the step (1) is hydrochloric acid, preferably concentrated hydrochloric acid.
Wherein the pH is adjusted in step (1) to a range of 6.0 ~ 8.0.0, preferably 6.5 ~ 7.0.0.
Wherein the pH is adjusted in step (1) and then heated to 60 ℃ ~ 100 ℃.
Wherein the reaction temperature after the 4, 7-dichloroquinoline is added in the step (1) is 80 ℃ ~ 100 ℃, and the preferred reaction temperature is 90 ℃ ~ 100 ℃.
Wherein the temperature of the step (2) is lowered to 45 deg.C ~ 65 deg.C, preferably 50 deg.C ~ 60 deg.C
The invention relates to a method for producing piperaquine phosphate intermediate quinoline piperazine hydrochloride by using piperazine, which comprises the following steps:
(1) adding anhydrous piperazine into all mother liquor of the previous batch, stirring, adjusting the pH value with acid, continuing stirring, adding 4, 7-dichloroquinoline, and continuing stirring for reaction after the addition is finished;
(2) cooling after the reaction is finished, and filtering (collecting mother liquor as a solvent for next use);
wherein the method further comprises the step (3) of drying.
Wherein the mother liquor in the step (1) is generated in the reaction process of anhydrous piperazine and 4, 7-dichloroquinoline, and is a filtrate obtained after cooling and filtering.
Wherein the molar ratio of the 4, 7-dichloroquinoline to the anhydrous piperazine in the step (1) is 1:1.5 ~ 1:4, preferably 1:2 ~ 1:3.
Wherein the weight ratio of 4, 7-dichloroquinoline to 4, 7-dichloroquinoline at the time of first preparation in step (1) is 0.9: 1 ~ 1.1.1: 1, preferably 1:1.
Wherein the acid in the step (1) is hydrochloric acid, preferably concentrated hydrochloric acid.
Wherein the pH is adjusted in step (1) to a range of 6.0 ~ 8.0.0, preferably 6.5 ~ 7.0.0.
Wherein the pH is adjusted in step (1) and then heated to 60 ℃ ~ 100 ℃.
Wherein the reaction temperature after the 4, 7-dichloroquinoline is added in the step (1) is 80 ℃ ~ 100 ℃, and the preferred reaction temperature is 90 ℃ ~ 100 ℃.
Wherein the temperature of the step (2) is lowered to 45 deg.C ~ 65 deg.C, preferably 50 deg.C ~ 60 deg.C
The application times are 4 times at most.
The preparation method adopts fresh solvent for the first time, the indiscriminate preparation is generated in the reaction process of the anhydrous piperazine and the 4, 7-dichloroquinoline, and the filtrate obtained after cooling and filtering is the solvent.
The preparation method of the high-purity quinoline piperazine hydrochloride provided by the invention has the advantages of simple process, easiness in product purification, purity of more than or equal to 99.5%, avoidance of toxic reagents, small environmental pollution and low production cost, and is suitable for industrial production. The method for producing the piperaquine phosphate intermediate by applying the piperazine provided by the invention has the advantages that the piperazine is not required to be separated from the mother liquor, and the mother liquor is directly applied to the production of the quinoline piperazine hydrochloride in the next batch.
Drawings
FIG. 1 is an HPLC chromatogram of the purity of quinolyl piperazine hydrochloride prepared in example 1.
FIG. 2 is an HPLC chromatogram of the purity of quinolyl piperazine hydrochloride prepared in example 2.
FIG. 3 is an HPLC chromatogram of the purity of quinolyl piperazine hydrochloride prepared in example 3.
FIG. 4 is an HPLC plot of the purity of quinolyl piperazine hydrochloride prepared in example 4.
FIG. 5 is an HPLC chromatogram of the purity of quinolyl piperazine hydrochloride prepared in example 5.
FIG. 6 is an HPLC chromatogram of the purity of quinolyl piperazine hydrochloride prepared in example 6.
Detailed Description
Example 1
Preparation of quinoline piperazine hydrochloride (first preparation)
Adding 40g of water and 36g of anhydrous piperazine into a three-necked bottle, stirring, adjusting the pH of a system to 6.0 by using concentrated hydrochloric acid, heating to 65 ℃, and stirring for reacting for 1 hour; continuously heating to 90 ℃, slowly adding 20g of 4, 7-dichloroquinoline, continuously heating to 95 ℃ after the addition is finished, stirring for reaction, and reacting for 5 hours; after the reaction is finished, the temperature is reduced to 45 ℃, the mixture is stirred for 1 hour, the mixture is filtered while the mixture is hot (mother liquor is collected and used as a solvent), and a filter cake is dried to obtain 26.1g of the quinolyl piperazine hydrochloride, wherein the yield is 91.0 percent, and the purity is 99.7 percent.
Example 2
Preparation of quinoline piperazine hydrochloride (first preparation)
Adding 60g of water and 52g of anhydrous piperazine into a three-necked bottle, stirring, adjusting the pH value of a system to 7.0 by using 30% hydrochloric acid, heating to 80 ℃, stirring for 30 minutes, slowly adding 20g of 4, 7-dichloroquinoline, continuing to stir for reaction after the addition is finished, and reacting for 5 hours; after the reaction is finished, the temperature is reduced to 60 ℃, the mixture is stirred for 30 minutes, the mixture is filtered while the mixture is hot (mother liquor is collected and used as a solvent), and a filter cake is dried to obtain 25.9g of the quinolyl piperazine hydrochloride, wherein the yield is 90.3 percent, and the purity is 99.6 percent.
Example 3
Preparation of quinoline piperazine hydrochloride (first preparation)
Adding 80kg of water and 150kg of piperazine into a 1000L reaction tank, stirring, adjusting the pH value of a system to 7.5 by using concentrated hydrochloric acid, heating to 75 +/-10 ℃, stirring for reaction for 1 hour, continuously heating to 95 +/-5 ℃, slowly adding 100kg of 4, 7-dichloroquinoline, controlling the temperature to 95 +/-5 ℃ after the addition, stirring for reaction for 4 ~ 5 hours, cooling to 60 +/-5 ℃ after the reaction is finished, stirring for 1 hour, centrifuging while hot (collecting mother liquor as a solvent for application), drying a filter cake to obtain 131kg of quinoline piperazine hydrochloride, wherein the yield is 91.3%, and the purity is 99.6%.
Example 4
Preparation of quinoline piperazine hydrochloride (first use preparation)
Adding 28g of anhydrous piperazine into the total amount of mother liquor in the embodiment 1, adjusting the pH value of a system to 8.0 by using 35% hydrochloric acid, heating to 60 ℃, stirring for 30 minutes, continuously heating to 80 ℃, stirring for 30 minutes, slowly adding 22g of 4, 7-dichloroquinoline, continuously stirring for reaction after the addition is finished, and reacting for 5 hours; after the reaction is finished, the temperature is reduced to 45 ℃, the mixture is stirred for 30 minutes, the mixture is filtered while the mixture is hot (mother liquor is collected and used as a solvent), and a filter cake is dried to obtain 30g of the quinolyl piperazine hydrochloride, wherein the yield is 95.0 percent, and the purity is 99.7 percent.
Example 5
Preparation of quinoline piperazine hydrochloride (first use preparation)
Adding 13.1g of anhydrous piperazine into the total amount of mother liquor in the embodiment 2, adjusting the pH value of a system to 6.5 by using concentrated hydrochloric acid, heating to 75 ℃, stirring for 30 minutes, continuously heating to 85 ℃, stirring for 30 minutes, slowly adding 20g of 4, 7-dichloroquinoline, heating to 95 ℃ after the addition is finished, continuously stirring for reaction, and reacting for 4 hours; after the reaction is finished, the temperature is reduced to 60 ℃, the mixture is stirred for 30 minutes, the mixture is filtered while the mixture is hot (mother liquor is collected and used as a solvent), and a filter cake is dried to obtain 26.9g of the quinolyl piperazine hydrochloride, wherein the yield is 93.7 percent, and the purity is 99.6 percent.
Example 6
Preparation of quinolinylpiperazine hydrochloride (fourth application preparation)
The amount of 4, 7-dichloroquinoline at the time of first preparation was 20 g. Adding 13.1g of anhydrous piperazine into the whole mother liquor of the previous batch, adjusting the pH value of the system to 7 by using concentrated hydrochloric acid, heating to 75 ℃, stirring for 30 minutes, continuously heating to 85 ℃, stirring for 30 minutes, slowly adding 20g of 4, 7-dichloroquinoline, heating to 95 ℃ after the addition is finished, continuously stirring for reaction, and reacting for 4 hours; after the reaction is finished, the temperature is reduced to 60 ℃, the mixture is stirred for 30 minutes, the mixture is filtered while the mixture is hot, and a filter cake is dried to obtain 27.0g of quinoline piperazine hydrochloride, wherein the yield is 94.1 percent, and the purity is 99.5 percent.
Comparative example 1
Preparation of quinolinylpiperazines
In a three-necked flask, 59.4g of 4, 7-dichloroquinoline and 103.2g of anhydrous piperazine were added, 50mL of butanol was added, the mixture was stirred, heated to 110 ℃ and reacted for 1 hour, and the progress of the reaction was followed by Thin Layer Chromatography (TLC). After the reaction is completed, transferring the reaction solution into 200mL of water, adjusting the solution to acidity by using concentrated hydrochloric acid, filtering, extracting by using dichloromethane (2X 100 mL), collecting and combining organic layers, concentrating and recovering the solvent; adjusting the water phase of the NaOH aqueous solution to be strong alkaline, separating an oil phase from a water phase, extracting the water phase twice by using dichloromethane (2X 100 mL), combining organic layers, washing by using a small amount of water, dehydrating, and concentrating to obtain 66g of quinoline piperazine with the purity of 99.3%; the yield is 88.8%.
Comparative example 2
Preparation of quinolinylpiperazines
Piperazine 54g was stirred in 150ml of anhydrous methanol to give a clear solution. Then 50g of 4, 7-dichloroquinoline were slowly added to the solution. The solution was refluxed for 8 hours and cooled to room temperature. Filtering, and concentrating under reduced pressure. The resulting oil was washed with water (150ml) to give a solid precipitate. Filtration, washing with water and drying gave 53g of quinolinylpiperazine in 84.7% yield and 95.8% purity.
Comparative example 3
Preparation of quinolinylpiperazines
Adding 112g of piperazine hexahydrate into a reaction bottle, heating until the solid is completely melted, keeping the temperature at 60 ℃, slowly adding 30g of 4, 7-dichloroquinoline while stirring, continuously heating to 100 ℃, and stirring and refluxing for 6 hours. Stopping heating and stirring, cooling to 90 ℃, preserving heat, standing and layering. Taking the lower oily substance, adding 50ml of purified water, heating to 80 ℃, stirring for 10 minutes, standing for layering, taking the lower oily substance, and repeatedly washing with water until the pH value is 7. Adding the oily substance into the reaction flask again, adding concentrated hydrochloric acid with concentration of 35.8% and 100g of purified water with temperature of 80 deg.C under stirring, acidifying to pH 3, stopping stirring, and filtering. Transferring the filtrate to a reaction bottle, cooling to 20 ℃, adding 25% sodium hydroxide solution with stirring, alkalifying to pH 10, and standing for layering. And (3) taking the lower oily substance, adding 50ml of water, stirring until the material becomes solid particles, filtering, washing a filter cake with water until the pH value of the filtrate is 7, and drying to obtain 29.8g of the quinoline piperazine, wherein the yield is 79.4% and the purity is 93.9%.
Comparative example 4
Preparation of quinolinylpiperazines
Adding 15g of water, 15g of methanol, 15g of 4, 7-dichloroquinoline and 30g of anhydrous piperazine into a reaction bottle, stirring and heating to 70 ℃, refluxing for 5 hours, cooling to room temperature after the reaction is finished, stirring for 1 hour, filtering, pouring the filtrate into the reaction bottle, adding 15g of water, adding hydrochloric acid to adjust the pH value to be 8, stirring for 1 hour after the pH value is measured again, and filtering. Adding 60g of water into the filter cake, stirring, adding hydrochloric acid solution to adjust the pH value to 4.5, adding 0.15g of activated carbon after the solid is dissolved, heating to 60 ℃ for decoloring for 30 minutes, filtering, neutralizing the filtrate with 30% sodium hydroxide, adjusting the pH value to 8, cooling to room temperature, stirring for 30 minutes, filtering, washing with water, and drying to obtain 15.2g of quinoline piperazine with the yield of 81% and the purity of 96.8%.
Comparative example 5
Preparation of quinolinylpiperazines
26.1g of piperazine is taken, 400g of purified water is added, stirring is carried out, concentrated hydrochloric acid is added to adjust the pH value to 6.5 after dissolution, 20g of 4, 7-dichloroquinoline is added, heating and stirring are carried out for 4 hours, filtering is carried out, cooling is carried out, sodium hydroxide is added to adjust the pH value to 10, standing is carried out for crystallization at 20 ℃, filtering and drying are carried out to obtain 23g of piperazine, the yield is 91.9%, and the purity is 97.3%.
Claims (10)
1. A method for producing quinoline piperazine hydrochloride serving as a piperaquine phosphate intermediate by using piperazine mechanically comprises the following steps:
(1) adding anhydrous piperazine into all mother liquor of the previous batch, stirring, adjusting the pH value with acid, continuing stirring, adding 4, 7-dichloroquinoline, and continuing stirring for reaction after the addition is finished;
(2) cooling after the reaction is finished, and filtering (collecting mother liquor as a solvent for next use);
wherein the mother liquor in the step (1) is generated in the reaction process of anhydrous piperazine and 4, 7-dichloroquinoline, and is a filtrate obtained after cooling and filtering.
2. The method of claim 1, further comprising the step of (3) drying.
3. The process according to claim 1, wherein the molar ratio of 4, 7-dichloroquinoline to anhydrous piperazine in step (1) is 1:1.5 ~ 1:4, preferably 1:2 ~ 1:3.
4. The process according to claim 1, wherein the weight ratio of 4, 7-dichloroquinoline to 4, 7-dichloroquinoline at the time of first preparation in step (1) is 0.9: 1 ~ 1.1: 1, preferably 1:1.
5. The process according to claim 1, wherein the acid in step (1) is hydrochloric acid, preferably concentrated hydrochloric acid.
6. The process according to claim 1, wherein the pH is adjusted in step (1) in the range of 6.0 ~ 8.0.0, preferably 6.5 ~ 7.0.0.
7. The method according to claim 1, wherein the pH is adjusted in step (1) and then heated to 60 ℃ ~ 100 ℃.
8. The process according to claim 1, wherein the reaction temperature after the addition of 4, 7-dichloroquinoline in step (1) is 80 ℃ ~ 100 ℃, preferably 90 ℃ ~ 100 ℃.
9. The process according to claim 1, wherein the reduced temperature in step (2) is 45 ℃ ~ 65 ℃, preferably 50 ℃ ~ 60 ℃.
10. The method of claim 1, wherein the number of applications is up to 4.
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|---|---|---|---|---|
| GB1047935A (en) * | 1963-04-04 | 1966-11-09 | American Cyanamid Co | Substituted piperazines and preparation thereof |
| WO2009050734A2 (en) * | 2007-10-15 | 2009-04-23 | Elder Pharmaceuticals Ltd. | An industrially feasible process for the manufacture of bisquinoline derivatives by using substantially pure n-monosubstituted piperazines |
| WO2010081851A1 (en) * | 2009-01-14 | 2010-07-22 | Genoscience Pharma | Piperidin-4-ylpiperazine compounds for the treatment of hcv infection |
| CN103058926A (en) * | 2012-12-14 | 2013-04-24 | 重庆康乐制药有限公司 | Preparation method of 7-chlorine-4-(piperazineyl-1-yl) quinoline |
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|---|---|---|---|---|
| GB1047935A (en) * | 1963-04-04 | 1966-11-09 | American Cyanamid Co | Substituted piperazines and preparation thereof |
| WO2009050734A2 (en) * | 2007-10-15 | 2009-04-23 | Elder Pharmaceuticals Ltd. | An industrially feasible process for the manufacture of bisquinoline derivatives by using substantially pure n-monosubstituted piperazines |
| WO2010081851A1 (en) * | 2009-01-14 | 2010-07-22 | Genoscience Pharma | Piperidin-4-ylpiperazine compounds for the treatment of hcv infection |
| CN103058926A (en) * | 2012-12-14 | 2013-04-24 | 重庆康乐制药有限公司 | Preparation method of 7-chlorine-4-(piperazineyl-1-yl) quinoline |
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