CN105503718A - Continuous preparing method for amodiaquine hydrochloride - Google Patents
Continuous preparing method for amodiaquine hydrochloride Download PDFInfo
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- CN105503718A CN105503718A CN201510949166.2A CN201510949166A CN105503718A CN 105503718 A CN105503718 A CN 105503718A CN 201510949166 A CN201510949166 A CN 201510949166A CN 105503718 A CN105503718 A CN 105503718A
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- 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
- C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a continuous preparing method for amodiaquine hydrochloride. The method is a continuous three-step reaction preparing method and has the advantages that an intermediate product prepared in the reaction step is not separated, and amodiaquine hydrochloride is directly prepared. The method is simple in technology, less equipment is occupied, operation is simple, water serves as reaction solvent, pollution of a system is small, and the method is suitable for industrial production.
Description
Technical field
The invention belongs to medicine and chemical technology field, be specifically related to a kind of continuous production method of Camoquin hydrochloride.
Background technology
Camoquin hydrochloride, English name: AmodiaquineHydrochloride, chemical name: 4-[(the chloro-4-quinolyl of 7-) is amino]-2-[(diethylin) methyl] phenol di-hydrochloride dihydrate, CAS:6398-98-7, chemical structural formula is as follows:
Camoquin hydrochloride (I).
Camoquin hydrochloride bulk drug " USP28 – NF23 " is included, preparation is included all at " USP28 – NF23 " and " Chinese Pharmacopoeia 2015 editions ", by suppressing schizont DNA replication dna and transcription, and present Antimalarial consumingly, the clinical malaria being mainly used in completed stroke, also it can be prevented to show effect, and can subtertian malaria be effected a radical cure, may be used for amebic liver abscess in addition, pulmonary distomiasis, rot and some autoimmune disorder, at present, Camoquin hydrochloride (AmodiaguineHydrochioride) and Artesunate (Artesunate) drug combination, it is the high-quality antimalarial drug that the World Health Organization (WHO) is recommended.
The preparation method of amodiaquine conventional is at present as follows:
Burckhalter in 1948, waits the method to Camoquin hydrochloride synthesis: paracetamol is raw material, carries out Mannich reaction and introduce monosubstituted N, N-diethyl methylene radical in alcohol system, after hydrolysis, generates amodiaquine with the effect of 4,7-dichloroquinoline; With p-NP be starting raw material after Mannich reaction, after hydrogenation, generate amodiaquine with the effect of 4,7-dichloroquinoline, its synthetic route is as follows:
Amodiaquine obtained by said synthesis route, be that starting raw material is when preparing with paracetamol, Mannich reaction, hydrolysis reaction, condensation reaction often walk and all will be separated, required production unit is many, process time is long, complex operation, total recovery is low, and Mannich reaction alcohol has certain harm as solvent to environment and human body; Take p-NP as the technique of starting raw material, will autoclave be used when hydro-reduction, and the limits of explosion of hydrogen is very low, has potential safety hazard.
US2474821 discloses a kind of preparation method of Camoquin hydrochloride, after adopting 4,7-dichloroquinoline and p-aminophenol condensation, then in dehydrated alcohol, carry out Mannich reaction under high temperature with paraformaldehyde and diethylamine, then acidifying obtains Camoquin hydrochloride, and its synthetic route is as follows:
The shortcoming that the method exists: 4-(4-hydroxybenzene the amido)-7-chloroquinoline in preparation process just carries out Mannich reaction after needing separation; Reaction is carried out in anhydrous conditions, wayward in process of production; React for a long time under hot conditions, easily produce impurity; There is most raw material 4, the 7-dichloroquinoline of economic worth can increase overall raw materials cost in the first step.
WO2008/062472A2 discloses a kind of preparation method of Camoquin hydrochloride, adopt 4,7-dichloroquinoline and p-aminophenol in glacial acetic acid after condensation, then add formaldehyde and diethylamine carries out Mannich reaction, then acidifying obtains Camoquin hydrochloride, and its synthetic route is as follows:
The shortcoming that the method exists: in preparation process, not exclusively, remaining p-aminophenol and formaldehyde carry out schiff base reaction and produces impurity for p-aminophenol and the reaction of 4,7-dichloroquinoline, to introduce in finished product and not easily to remove; P-aminophenol can carry out acylation reaction in acetic acid, thus the condensation difficulty of increase and 4,7-dichloroquinoline, and then yield is reduced; Glacial acetic acid has larger harm as solvent to environment and human body and not easily reclaims, has raw material 4, the 7-dichloroquinoline of economic worth can increase overall raw materials cost in the first step most.
Summary of the invention
Technical problem to be solved by this invention is a kind of continuous production method of Camoquin hydrochloride, solve the defects such as industrial production method ubiquity yield is low, complex operation, energy consumption are high, production efficiency of equipment is low, long reaction time, wastewater flow rate are large, organic residual solvent is high, the requirement that the Camoquin hydrochloride that present method obtains reaches " USP28 – NF23 ".
1. the present invention is achieved by the following technical solutions, and a kind of continuous production method of Camoquin hydrochloride, is characterized in that, comprise the following steps:
1), after paracetamol (formula II), paraformaldehyde and diethylamine being carried out Mannich reaction in aqueous systems, formula IV intermediate is obtained:
2) by formula IV intermediate, add hydrochloric acid water and solve formula V intermediate:
3) formula V intermediate alkali is regulated after pH, adds after 4,7-dichloroquinoline (formula III) carries out condensation reaction, be separated to obtain Camoquin hydrochloride:
2. method according to claim 1, is characterized in that: in described step, paracetamol: diethylamine: paraformaldehyde: the mol ratio of 4,7-dichloroquinoline is 1.00:(1.00 ~ 1.30): (1.00 ~ 1.30): (0.80 ~ 1.00).
3. according to method according to claim 1, it is characterized in that: described step 1) reaction solvent be water, wherein water is deionized water.
4. according to method according to claim 1, it is characterized in that: described step 1) in Mannich reaction temperature be 20 DEG C ~ 102 DEG C.
5. according to method according to claim 1, it is characterized in that: described step 1) in 30 minutes ~ 90 minutes Mannich reaction time.
6. according to method according to claim 1, it is characterized in that: described step 2) hydrolysising reacting temperature be 60 DEG C ~ 105 DEG C.
7. according to method according to claim 1, it is characterized in that: described step 3) alkali be sodium hydroxide solution, potassium hydroxide solution etc.
8. according to method according to claim 1, it is characterized in that: described step 3) pH be 1.0 ~ 6.0.
9. according to method according to claim 1, it is characterized in that: described step 3) setting-up point be 20 DEG C ~ 102 DEG C.
Advantage of the present invention is as follows:
1, the yield of the Camoquin hydrochloride of preparation method's gained of the present invention is high, and yield can up to 90%, and purity is good, by the area normalization method calculated purity of HPLC higher than 99.90%.
2, the continuous production method of Camoquin hydrochloride of the present invention is produced, and equipment capacity can improve 5 ~ 10 times, substantially increases output, and energy-conservation, consumption reduction, reduce production cost.
3, continuous production method of the present invention is short during reaction compared with method of the prior art, and the impurity of generation is few.
4, continuous production method of the present invention has the advantages such as operation is simpler, energy consumption is low, wastewater flow rate is few, organic residual solvent is few compared with method of the prior art.
5, use the harm of water as solvent to environment and human body few in continuous production method of the present invention, can industrialization scale operation.
6, main raw material paracetamol used in the present invention, 4,7-dichloroquinolines, diethylamine and formaldehyde are cheap and be easy to get, and wherein 4,7-dichloroquinolines are large medicine intermediate that market is easily buied.
Further illustrated by embodiment and explain Camoquin hydrochloride preparation method of the present invention, but not limiting the scope of the invention.Wherein temperature is degree Celsius, and yield is the molar yield calculated by paracetamol, and purity all calculates by the area normalization method of HPLC.
Embodiment
Embodiment 1
14.7g diethylamine is dropped in there-necked flask, 40.0g deionized water, 30.0g paracetamol and 6.0g paraformaldehyde, be heated to 80 DEG C, insulation reaction 30 minutes, be cooled to less than 40 DEG C, after adding 48g37% hydrochloric acid, be heated to 104 DEG C, insulation reaction 2 hours, after completion of the reaction, be cooled to 38 DEG C ~ 42 DEG C, drip NaOH solution, adjust pH to 3.0, add 4, 7-dichloroquinoline 35.4g, be heated to 100 DEG C, insulation reaction 1 hour, after completion of the reaction, be cooled to 3 DEG C ~ 7 DEG C, stirring and crystallizing 2 hours ~ 3 hours, suction filtration, control temperature is at 60 DEG C ~ 70 DEG C, vacuum tightness >=-0.080Mpa, within dry 8 hours, obtain Camoquin hydrochloride 85.23g, yield 92.39%, purity 99.96%.
Embodiment 2
17.4g diethylamine is dropped in there-necked flask, 40.0g deionized water, 30.0g paracetamol and 7.2g paraformaldehyde, be heated to 80 DEG C, insulation reaction 30 minutes, be cooled to less than 40 DEG C, after adding 48g37% hydrochloric acid, be heated to 104 DEG C, insulation reaction 2 hours, after completion of the reaction, be cooled to 38 DEG C ~ 42 DEG C, drip NaOH solution, adjust pH to 3.0, add 4, 7-dichloroquinoline 39.3g, be heated to 100 DEG C, insulation reaction 1 hour, after completion of the reaction, be cooled to 3 DEG C ~ 7 DEG C, stirring and crystallizing 2 hours ~ 3 hours, suction filtration, control temperature is at 60 DEG C ~ 70 DEG C, vacuum tightness >=-0.080Mpa, within dry 8 hours, obtain Camoquin hydrochloride 86.31g, yield 93.56%, purity 99.96%.
Embodiment 3
17.4g diethylamine is dropped in there-necked flask, 40.0g deionized water, 30.0g paracetamol and 6.7g paraformaldehyde, be heated to 80 DEG C, insulation reaction 30 minutes, be cooled to less than 40 DEG C, after adding 48g37% hydrochloric acid, be heated to 104 DEG C, insulation reaction 2 hours, after completion of the reaction, be cooled to 38 DEG C ~ 42 DEG C, drip NaOH solution, adjust pH to 3.0, add 4, 7-dichloroquinoline 37.3g, be heated to 100 DEG C, insulation reaction 1 hour, after completion of the reaction, be cooled to 3 DEG C ~ 7 DEG C, stirring and crystallizing 2 hours ~ 3 hours, suction filtration, control temperature is at 60 DEG C ~ 70 DEG C, vacuum tightness >=-0.080Mpa, within dry 8 hours, obtain Camoquin hydrochloride 85.21g, yield 92.37%, purity 99.96%.
Embodiment 4
16.0g diethylamine is dropped in there-necked flask, 40.0g deionized water, 30.0g paracetamol and 6.6g paraformaldehyde, be heated to 80 DEG C, insulation reaction 30 minutes, be cooled to less than 40 DEG C, after adding 48g37% hydrochloric acid, be heated to 104 DEG C, insulation reaction 2 hours, after completion of the reaction, be cooled to 38 DEG C ~ 42 DEG C, drip NaOH solution, adjust pH to 3.0, add 4, 7-dichloroquinoline 36.2g, be heated to 100 DEG C, insulation reaction 1 hour, after completion of the reaction, be cooled to 3 DEG C ~ 7 DEG C, stirring and crystallizing 2 hours ~ 3 hours, suction filtration, control temperature is at 60 DEG C ~ 70 DEG C, vacuum tightness >=-0.080Mpa, within dry 8 hours, obtain Camoquin hydrochloride 85.69g, yield 92.89%, purity 99.96%.
Embodiment 5 ~ 10
Based on embodiment 4, by changing the temperature and time of Mannich reaction, hydrolysising reacting temperature and time, setting-up point and time, other conditions constant (with "---", following table represents that this condition executes example 4 together), the result obtained is as following table:
| Sequence | Mannich reaction temperature | The Mannich reaction time | Hydrolysising reacting temperature | Setting-up point | Output | Yield | Purity |
| 5 | 40℃ | 90 minutes | —— | —— | 83.23g | 90.22% | 99.93% |
| 6 | 100℃ | 30 minutes | —— | —— | 84.12g | 91.19% | 99.95% |
| 7 | —— | —— | 60℃ | —— | 83.87g | 90.92% | 99.92% |
| 8 | —— | —— | 80℃ | 83.54g | 90.56% | 99.91% | |
| 9 | —— | —— | —— | 30℃ | 83.13g | 90.12% | 99.96% |
| 10 | —— | —— | —— | 80℃ | 85.29g | 92.46% | 99.95% |
Embodiment 11
16.0g diethylamine is dropped in there-necked flask, 40.0g deionized water, 30.0g paracetamol and 6.6g paraformaldehyde, be heated to 80 DEG C, insulation reaction 30 minutes, be cooled to less than 40 DEG C, after adding 48g37% hydrochloric acid, be heated to 104 DEG C, insulation reaction 2 hours, after completion of the reaction, be cooled to 38 DEG C ~ 42 DEG C, drip NaOH solution, adjust pH to 1.0, add 4, 7-dichloroquinoline 36.2g, be heated to 100 DEG C, insulation reaction 1 hour, after completion of the reaction, be cooled to 3 DEG C ~ 7 DEG C, stirring and crystallizing 2 hours ~ 3 hours, suction filtration, control temperature is at 60 DEG C ~ 70 DEG C, vacuum tightness >=-0.080Mpa, within dry 8 hours, obtain Camoquin hydrochloride 85.52g, yield 92.71%, purity 99.93%.
Embodiment 12
16.0g diethylamine is dropped in there-necked flask, 40.0g deionized water, 30.0g paracetamol and 6.6g paraformaldehyde, be heated to 80 DEG C, insulation reaction 30 minutes, be cooled to less than 40 DEG C, after adding 48g37% hydrochloric acid, be heated to 104 DEG C, insulation reaction 2 hours, after completion of the reaction, be cooled to 38 DEG C ~ 42 DEG C, drip KOH solution, adjust pH to 5.0, add 4, 7-dichloroquinoline 36.2g, be heated to 100 DEG C, insulation reaction 1 hour, after completion of the reaction, be cooled to 3 DEG C ~ 7 DEG C, stirring and crystallizing 2 hours ~ 3 hours, suction filtration, control temperature is at 60 DEG C ~ 70 DEG C, vacuum tightness >=-0.080Mpa, within dry 8 hours, obtain Camoquin hydrochloride 84.18g, yield 91.25%, purity 99.93%.
Detail the present invention above, comprise its preferred embodiment.But it should be understood that and consider content disclosed by the invention, those skilled in the art can change the present invention and/or improve in the scope of described claims, and these improvements and modifications also should be considered as protection scope of the present invention.
Claims (9)
1. a continuous production method for Camoquin hydrochloride, is characterized in that, comprise the following steps:
1), after paracetamol (formula II), paraformaldehyde and diethylamine being carried out Mannich reaction in aqueous systems, obtain formula IV intermediate, reaction formula is as follows,
2) by formula IV intermediate, add hydrochloric acid water and solve formula V intermediate, reaction formula is as follows,
3) regulated after pH by formula V intermediate alkali, add after 4,7-dichloroquinoline (formula III) carries out condensation reaction, be separated to obtain Camoquin hydrochloride, reaction formula is as follows,
2. method according to claim 1, is characterized in that: in described step, paracetamol: diethylamine: paraformaldehyde: the mol ratio of 4,7-dichloroquinoline is 1.00:(1.00 ~ 1.30): (1.00 ~ 1.30): (0.80 ~ 1.00).
3. according to method according to claim 1, it is characterized in that: described step 1) reaction solvent be deionized water.
4. according to method according to claim 1, it is characterized in that: described step 1) in Mannich reaction temperature be 20 DEG C ~ 102 DEG C.
5. according to method according to claim 1, it is characterized in that: described step 1) in 30 minutes ~ 90 minutes Mannich reaction time.
6. according to method according to claim 1, it is characterized in that: described step 2) hydrolysising reacting temperature be 60 DEG C ~ 105 DEG C.
7. according to method according to claim 1, it is characterized in that: described step 3) alkali be sodium hydroxide solution, potassium hydroxide solution etc.
8. according to method according to claim 1, it is characterized in that: described step 3) pH be 1.0 ~ 6.0.
9. according to method according to claim 1, it is characterized in that: described step 3) setting-up point be 20 DEG C ~ 102 DEG C.
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| CN201510949166.2A CN105503718A (en) | 2015-12-18 | 2015-12-18 | Continuous preparing method for amodiaquine hydrochloride |
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| CN201510949166.2A CN105503718A (en) | 2015-12-18 | 2015-12-18 | Continuous preparing method for amodiaquine hydrochloride |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2474821A (en) * | 1945-11-05 | 1949-07-05 | Parke Davis & Co | Quinoline compounds and process of making same |
| ES514870A0 (en) * | 1982-08-10 | 1983-05-01 | Cuatrecasas Labor M | PROCEDURE FOR OBTAINING SOLUBLE DERIVATIVES OF N- (4-HYDROXIFENIL) ACETAMIDE. |
| WO2008062472A2 (en) * | 2006-10-24 | 2008-05-29 | Cadila Healthcare Limited | Process for the preparation of memantine |
-
2015
- 2015-12-18 CN CN201510949166.2A patent/CN105503718A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2474821A (en) * | 1945-11-05 | 1949-07-05 | Parke Davis & Co | Quinoline compounds and process of making same |
| ES514870A0 (en) * | 1982-08-10 | 1983-05-01 | Cuatrecasas Labor M | PROCEDURE FOR OBTAINING SOLUBLE DERIVATIVES OF N- (4-HYDROXIFENIL) ACETAMIDE. |
| WO2008062472A2 (en) * | 2006-10-24 | 2008-05-29 | Cadila Healthcare Limited | Process for the preparation of memantine |
Non-Patent Citations (3)
| Title |
|---|
| J. H. BURCKHALTER, ET AL.: "Aminoalkylphenols as Antimalarials. Ⅱ. (Heterocyclic-amino)-α-amino-o-cresols. The Synthesis of Camoquin", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| TARIQ LATIF, ET AL.: "X-Ray Crystal Structure of N-[3-(Diethylaminomethyl)-4-hydroxyphenyl]acetamide and its Hydrochloride Salt. Two Forms of an Important Precursor in the Synthesis of Anti-Tuberculosis Drugs", 《AUST. J. CHEM.》 * |
| 罗代暄,等.: "《化学试剂与精细化学品合成基础（有机分册）》", 31 May 1991, 北京：高等教育出版社 * |
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