CN107266323A - A kind of side chain and its synthetic method, and using the method for side chain synthesis hydroxychloroquine sulfate - Google Patents
A kind of side chain and its synthetic method, and using the method for side chain synthesis hydroxychloroquine sulfate Download PDFInfo
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- CN107266323A CN107266323A CN201710584086.0A CN201710584086A CN107266323A CN 107266323 A CN107266323 A CN 107266323A CN 201710584086 A CN201710584086 A CN 201710584086A CN 107266323 A CN107266323 A CN 107266323A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C219/06—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton
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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
Abstract
The invention discloses a kind of side chain and its synthetic method, and using the method for side chain synthesis hydroxychloroquine sulfate, the synthesis step of side chain includes：(1) N ehtylethanolamines and the pentanone of 5 chlorine 2 are condensed to yield condensation product；(2) condensation product and acetoinices esterification obtain esterification products；(3) esterification products reduction obtains reduzate；(4) reduzate and halogenating agent reaction obtain side chain.The synthesis step of hydroxychloroquine sulfate includes：(A) chloroquinoline of 4 amino 7 and paratoluensulfonyl chloride reaction obtain the chloroquinoline of 4 Tos amino 7；(B) side chain and the reaction of the chloroquinoline of 4 Tos amino 7 obtain hydroxyl quinoline base；(C) hydroxyl quinoline base and sulfuric acid reaction obtain hydroxychloroquine sulfate.The invention provides a kind of new side chain, it synthesizes no ammonification technique, without catalytic hydrogenation process, safety and environmental protection, and can low temperature condensation hydroxychloroquine sulfate is made, be obviously improved product quality, simplify production procedure.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of side chain and its synthetic method, and using side chain synthesis
The method of hydroxychloroquine sulfate.
Background technology
Hydroxychloroquine sulfate, chemical name 2-4- (the chloro- 4- quinolyls of 7-) Aminopentyl ethylamino-alcohol sulfate salt, English
Name：Hydroxychloroquine Sulfate, chemical structural formula is as follows：
HCQ (Hydroxychloroquine, HCQ) is the antimalarial being made up of 4- aminoquinoline compounds, sulfuric acid hydroxyl
Chloroquine is synthesized in nineteen forty-six by Surrey and Hammer.Clinically it is used to treat lupus erythematosus discoides and systemic loupus erythematosus,
Also it is widely used to rheumatism at present diseases related.
Lupus erythematosus discoides (DLE) is relatively common mucocutaneous property connective tissue disease, and 25%-35% has oral cavity damage
Evil, can single-shot in oral cavity and nonjoinder skin lesion, more without obvious constitutional symptom.Its cause of disease and pathogenesis are still unclear at present
It is also relatively difficult in Chu, treatment, easily recurrence and canceration.Tradition application chloroquine diphosphate (CQ) treatment DLE effectively, but side effect compared with
Greatly.HCQ has anti-inflammatory, resistance amine and immunosuppressive action, declines lymphocyte transformation rate, suppresses vascular permeability, stable
Lysosome membrane, so it is targeted to treat DLE with HCQ.Up to the present, HCQ is considered as than CQ safety.A large amount of clinical and documents
Report is confirmed, satisfied effect is obtained using hydroxychloroquine sulfate (HCQ) treatment DLE.
Systemic loupus erythematosus (Systemic Lupus Erythematosus, SLE) is that a kind of multisystem involvement is internal
Disease rich in Multiple Antibodies, the cause of disease is unclear, treats intractable.And antimalarial starts from nineteen fifty for treating SLE, Dobois has found
After 75%-80% SLE patient is treated with antimalarial, fash, heating, joint symptoms improve, especially skin lesion.Thereafter grind
Study carefully discovery, antimalarial can make SLE patient reduce or stop using cortin, and with anti-allergic effects.Canadian hydroxyl chlorine
The double blind control research of quinoline research group shows that HCQ can stablize the state of an illness of SLE patient, hence it is evident that reduce recurrence.The discovery such as Wallace,
HCQ treatments can reduce the blood lipid level of Corticodependence patient, can obviously reduce thrombotic generation.In view of HCQ can be
SLE brings beneficial effect, and most scholars advocate that HCQ is used for the SLE patient of mild to moderate, and joint hormone, immunodepressant are used
In severe SLE auxiliary treatment.
When treating SLE using antimalarial, foreign countries 90% select HCQ, and the country may by understanding and medicament sources etc. because
The influence of element, most of selection chloroquines.In fact for security standpoint, such as conditions of patients allows, need not only lean on antimalarial agent
When playing curative effect in a short time, should try one's best selection HCQ.
With scientist further study show that, HCQ can play panimmunity adjustment effect in rheumatic disease,
Preferred HCQ has significant anti-inflammatory effect, and it can stablize the activity of lysosome, inhibitory enzyme, and then suppress swashing for inflammatory mediator
It is living, while chemotactic and the infiltration of inflammatory cell such as neutrophil leucocyte can be suppressed, and substantially reduce proinflammatory cytokine such as TNF- ɑ,
IL-1 and IL-6 generation；Secondly HCQ can be by suppressing deposition and then suppression of fibroblastic growth with connective tissue
The hyperplasia of arthritic's synovial membrane；HCQ can suppress the interaction of antigen-antibody and the synthesis of immune complex again, promote
Make the reduction of rheumatoid factor titre；HCQ can also be by influenceing ultraviolet radiation absorption and stopping injury of the ultraviolet to skin.With
Above a variety of is all that HCQ provides a large amount of foundations in clinical treatment rheumatic disease.In addition many center larger scale clinical researchs
Confirm that HCQ plays significant therapeutic effect in the treatment of rheumatism.
At present, following synthetic route is typically taken in the synthesis of hydroxychloroquine sulfate：
The core of the route is, 5- (N- ethyl-N-2- ethylol amines) -2- amylamines (hereinafter referred to as hydroxychloroquine side chain) with
4,7- dichloroquinolines prepare hydroxychloroquine base in the reaction of 100~140 DEG C of high temperature, then with sulfuric acid into salt.US2546658 is public
A kind of hydroxychloroquine sulfate synthetic method is opened, course of reaction is as follows：
The technique is older, using phenol as solvent, and phenol is poisonous and has corrosivity, and environmental pollution is serious, and post processing is multiple
It is miscellaneous, it is not suitable for industrialized production, and yield is also than relatively low, below 20%.
CA2561987 discloses a kind of method for synthesizing hydroxychloroquine sulfate, and course of reaction is as follows:
This method establishes the basic bar that hydroxychloroquine side chain synthesizes the raising yield of hydroxyl quinoline base with 4,7- dichloroquinolines
Part, i.e. pyroreaction, although product purity is also more than 99.5%, but solvent for use methyl iso-butyl ketone (MIBK) and reagent lithium hydroxide
Price is high, and cost of material is high, and operating method is cumbersome, and the time is long, is unfavorable for industrialized production.
WO2010027150 also discloses that a kind of method for synthesizing hydroxychloroquine sulfate, and course of reaction is as follows:
The method is still pyroreaction, and need reaction under high pressure, and security risk is higher.
CN103724261A discloses a kind of new industrial process of hydroxychloroquine sulfate quinoline, and course of reaction is as follows：
This method uses inert gas shielding, reduces the risk of oxidation impurities generation, but still is pyroreaction, be dehydrated,
The side reactions such as condensation can not be avoided, and corresponding impurity still has, and the HPLC purity of its patent report also only can guarantee that≤99.2%.
Hydroxychloroquine side chain is the key intermediate for synthesizing hydroxychloroquine sulfate, and the synthetic method of document report has two kinds：
Route one, is that the chloro- 2 pentanones of 5- are first first prepared as into ketal, then is reacted with N- ehtylethanolamines, obtains 5- (N- ethyls-N-2-
Ethylol amine) -2 pentanone, then hydroxychloroquine side chain is made through ammonification, hydro-reduction；Route two, with the chloro- 2 pentanones of 5- and N- second
Ethylethanolamine reaction obtains 5- (N- ethyl-N-2- ethylol amines) -2 pentanone, then hydroxychloroquine is made through ammonification, hydro-reduction
Side chain.There is ammonification, step of hydrogenation in the case of two kinds of routes, ammonia or high concentration liquefied ammonia, smell weight, to environment need to be used
Baneful influence is produced, while imines needs high-pressure hydrogenation reduction to prepare amino, security risk is higher., CN104803859A in 2015
The synthetic method of the synthetic method, i.e. hydroxychloroquine side chain of a kind of 5- (N- ethyl-N-2- ethylol amines) -2- amylamines is disclosed,
Its synthetic route is as follows：
To sum up, the synthetic route of current hydroxychloroquine sulfate is primarily present the unfavorable factor of two aspects：One is hydroxy chloride
The preparation of quinoline side chain：Ammonia or high concentration liquefied ammonia need to be used, smell weight produces baneful influence, while imines needs height to environment
Press hydro-reduction into amino, security risk is higher；Two be prepared by hydroxychloroquine base：Because 4 chlorine of 4,7- dichloroquinolines are lived
Property it is relatively low, and can not be used only catalyst such as KBr, KI etc. catalysis, it is therefore desirable to react under the high temperature conditions,
In high-temperature reaction process, the end position-NH of hydroxychloroquine side chain2And-OH it is oxidizable, dehydration, condensation etc., therefore, such as need ensure
Product quality is both needed to take relatively complicated aftertreatment technology and uses substantial amounts of organic solvent.In addition, existing synthetic route is also deposited
In production cycle length, the defect that impurity content is higher, yield is relatively low, cost of material is higher.Therefore, design technique it is simple,
Reaction condition is gentle, safety and environmental protection, yield and the low industrializing synthesis route of quality height, manufacturing cost are by with great society
Meaning and significant economic value.
The content of the invention
Hydroxychloroquine sulfate is synthesized it is an object of the invention to provide a kind of side chain and its synthetic method, and using the side chain
Method, on the one hand the synthetic method of the side chain can avoid using ammonia or high concentration liquefied ammonia, and not need high-pressure hydrogenation also
Former so that the synthetic route safety and environmental protection, on the other hand, synthesized new side chain instead of existing hydroxychloroquine side chain,
Hydroxychloroquine sulfate can be synthesized under relatively low reaction temperature, the end position-NH of hydroxychloroquine side chain can be avoided2And-OH is in high temperature
Under the conditions of react, advantageously ensure that product quality, and cumbersome aftertreatment technology need not be carried out.
The technical solution adopted by the present invention is as follows：
A kind of side chain, its structural formula is as follows：
Wherein, R is Cl, Br or I.
A kind of synthetic method of side chain, comprises the following steps：
(1) condensation reaction：N- ehtylethanolamines, phase transfer catalyst, inorganic base, organic solvent are added to the water, controlled
Temperature is 20~30 DEG C, and the chloro- 2 pentanones of 5- are added dropwise and react 2~6 hours, are layered after the completion of reaction, take organic layer to be obtained after drying
Condensation product organic phase, the chemical name of condensation product is：5- (N- ethyl-N-2- ethylol amines) -2 pentanone；
(2) esterification：The condensation product organic phase is cooled to 0~10 DEG C, and acetoinices reaction 1~3 is added dropwise in insulation
Hour, after the completion of reaction, it is layered, washing, takes organic layer to obtain esterification products organic phase, the chemical name of esterification products after drying
For：5- (N- ethyl-N-2- acetoxyl groups amine) -2 pentanone；
(3) reduction reaction：The esterification products organic phase is cooled to -5~0 DEG C, reducing agent is added and reacts 1~4 hour,
Water is added, layering takes organic layer to obtain reduzate organic phase after drying, the chemical name of reduzate is：5- (N- ethyls-
N-2- acetoxyl groups amine) -2- methyl anyl alcohols；
(4) halogenating reaction：Catalyst is added in reduzate organic phase, it is 25~40 DEG C to control temperature, and insulation is added dropwise
Halogenating agent reacts 3~8 hours, is layered, washing, takes organic layer to obtain side chain organic phase after drying, the chemical name of side chain is：
5- (N- ethyl-N-2- acetoxyl groups amine) -2- chloropentanes.
Further, esterification and halogenating reaction are being reacted before completion is layered, it is necessary to which reaction system is added into nothing
Reacted in machine aqueous alkali, be neutralized the acid generated during esterification and halogenating reaction, then layered, washing is protected
The inorganic base aqueous solution without impurity, preferably 0~5 DEG C such as acid, alkali in the side chain organic phase ultimately generated is demonstrate,proved, can be to reacted
System is tentatively cooled, in favor of subsequent reactions.
Further, in step (1), the mol ratio of the chloro- 2 pentanones of 5- and N- ehtylethanolamines is 0.8~1.2, inorganic base
Mol ratio with the chloro- 2 pentanones of 5- is 1.2~1.8.
It is more highly preferred to, the mol ratio of the chloro- 2 pentanones of 5- and N- ehtylethanolamines is 0.8~1.0, inorganic base and N- ethyls
The mol ratio of monoethanolamine is 1.2~1.5.In the step mol ratio of the chloro- 2 pentanones of 5- and N- ehtylethanolamines be designed as 0.8~
1.0, be conducive to the chloro- 2 pentanone conversions of 5- thorough, reduce its residual in organic phase, improve the purity of condensation product and contain
Amount, reduces the generation of impurity, and the mole dosage of inorganic base is slightly more than the chloro- 2 pentanone mole dosages of 5-, both ensures catalytic,
Auxiliary acid amount, is unlikely to waste, can also reduce three waste discharge again.
Further, in step (1), phase transfer catalyst is TBAB, 4-butyl ammonium hydrogen sulfate, tetrabutyl chlorine
Change ammonium, tri-n-octyl methyl ammonium chloride, DTAC or tetradecyl trimethyl ammonium chloride.In the step, N-
Ehtylethanolamine is dissolved in water, and the chloro- 2 pentanones of 5- are dissolved in organic solvent, therefore reaction system is aqueous phase and organic phase mixed system,
Belong to outphasing system, phase transfer catalyst can be combined with the ion in aqueous phase, and using itself compatibility to organic solvent,
N- ehtylethanolamines in aqueous phase are transferred in organic phase, promote reaction, so as to accelerate outphasing system reaction rate.
It is more highly preferred to, phase transfer catalyst is TBAB.
Further, in step (1), organic solvent is dichloromethane, chloroform or chlorobenzene.
It is more highly preferred to, organic solvent is chloroform.
Further, in step (2), the mol ratio of acetoinices and the condensation product is 1.0~1.5.
Further, in step (2), acetoinices are chloroacetic chloride or aceticanhydride.Acetylation is exactly the end in condensation product
Acetyl group CH3CO- reaction is introduced on-the OH of position, with product yield is high, reaction condition is gentle, environmental protection the features such as, commonly use second
Acyl reagent is chloroacetic chloride or aceticanhydride.
It is more highly preferred to, acetoinices are chloroacetic chloride, its reaction rate is most fast.
Further, in step (2), the mass concentration of inorganic base aqueous solution is 5~10%, and consumption is organic phase weight
0.5~2.0 times.
It is more highly preferred to, the consumption of inorganic base aqueous solution is 1.0~2.0 times of organic phase weight.
Further, in step (3), the mol ratio of reducing agent and esterification products is 0.3~0.5.
Further, in step (3), reducing agent is sodium borohydride, potassium borohydride or borine ether.Borohydride reduction reagent
In hydride ion release after, alkalescence is strong, and with strong nucleophilicity, the ester group in esterification products can be reduced into hydroxyl.
It is more highly preferred to, reducing agent is sodium borohydride, its reaction condition is gentle, cheap, using relatively broad.
Further, in step (3), cooled using ethanol.Ethanol is except that can make esterification products organic phase drop rapidly
Temperature is to outside required reaction temperature, and itself and immiscible organic solvent may additionally facilitate reactant dissolving, accelerate reduction reaction rate.
Further, in step (3), the consumption of ethanol is the 15~40% of organic solvent weight, and the consumption of water is organic
0.5~2.0 times of weight of solvent.
It is more highly preferred to, ethanol consumption is the 20~40% of organic solvent weight, and the consumption of water is organic solvent weight
0.5~1.5 times.
Further, in step (4), the mol ratio of halogenating agent and reduzate is 1.2~1.5.
Further, in step (4), halogenating agent is thionyl chloride, phosphorus trichloride, thionyl bromide, phosphorus tribromide, pentabromo-
Change phosphorus, N- chlorosuccinimides, N- bromo-succinimides or N- N-iodosuccinimides.By halogenating reaction, make reduction
Hydroxyl in product is optionally substituted by halogen, and forms halides, is used as the side chain of follow-up synthesis hydroxychloroquine sulfate.
It is more highly preferred to, halogenating agent is thionyl chloride.
Further, in step (4), catalyst is DMF, and consumption is the 0.05 of halogenating agent weight
~0.2 times.
Further, in step (4), the mass concentration of inorganic base aqueous solution is 8~10%, and consumption is organic phase weight
4.0~6.0 times.
The method that hydroxychloroquine sulfate is synthesized using the side chain, is comprised the following steps：
(A) N protections reaction：4- amino -7- chloroquinolines, cosolvent are added in organic solvent, 30~40 DEG C are warming up to,
Add paratoluensulfonyl chloride to react 2~6 hours, be layered, washing is concentrated, recrystallizes, dries to obtain 4-Tos amino -7- chloroquines
Quinoline；
(B) condensation reaction：In the side chain organic phase, catalyst and 4-Tos amino -7- chloroquinolines are added, is warming up to
60~80 DEG C of reactions, after the completion of reaction, are cooled to 5~20 DEG C, layering obtains hydroxyl quinoline base crude product after organic layer is concentrated, weight
Hydroxyl quinoline base is obtained after crystallization, drying；
It is more highly preferred to, after the completion of reaction, is cooled to 5~10 DEG C, layering.
(C) salt-forming reaction：The hydroxyl quinoline base is added in alcohols solvent, 50~60 DEG C, after dissolving completely are warming up to,
Sulfuric acid is added dropwise, reacts 1 hour, is cooled to 0~10 DEG C of crystallization, obtains hydroxychloroquine sulfate.
Further, in step (A) and (B), reaction is completed before being layered, it is necessary to which reaction system is added into inorganic buck
Reacted in solution.
In step (A), using 0~10 DEG C of inorganic base aqueous solution.In step (B), after the completion of reaction, first by reaction system
20~30 DEG C are cooled to, reaction 3~8 hours is then added into 20~40 DEG C of inorganic base aqueous solution, preferably 30~40 DEG C
Inorganic base aqueous solution.
Further, in step (A), the mol ratio of paratoluensulfonyl chloride and 4- amino -7- chloroquinolines is 1.0~1.2.
Further, in step (A), organic solvent is dichloromethane, chloroform or dichloroethanes, and consumption is 4- amino -7-
3~6 times of chloroquinoline weight.
It is more highly preferred to, the organic solvent is chloroform.
Further, in step (A), cosolvent is DMF, DMSO or dioxane, and consumption is 4- amino -7- chloroquinoline weights
0.1~0.6 times of amount.
It is more highly preferred to, the cosolvent is DMF.
It is more highly preferred to, the consumption of the cosolvent is 0.1~0.4 times of 4- amino -7- chloroquinoline weight.
Further, in step (A), the mass concentration of inorganic base aqueous solution is 5~10%, and consumption is organic phase weight
1.0~2.0 times.
Further, in step (A), drying temperature is 40~70 DEG C.
Further, in step (B), the mol ratio of side chain and 4-Tos amino -7- chloroquinolines is 1.0~1.5.
It is more highly preferred to, the mol ratio of the side chain and 4-Tos amino -7- chloroquinolines is 1.0~1.2.
Further, in step (B), catalyst is KI, sodium iodide, TBAB, DMAP or pyridine, consumption
For 0.02~0.1 times of side chain weight.
It is more highly preferred to, catalyst is TBAB.
Further, in step (B), the mass concentration of inorganic base aqueous solution is 5~40%, and consumption is organic phase weight
1.0~3.0 times.
It is more highly preferred to, the mass concentration of the inorganic base aqueous solution is 10~40%.
Further, in step (B), drying temperature is 40~70 DEG C.
Further, in step (C), the mol ratio of sulfuric acid and hydroxyl quinoline base is 1.0~1.1.
Further, in step (C), the alcohols solvent is 95% ethanol, methanol or ethanol solution, and consumption is hydroxyl
3~5 times of quinoline base weight.
It is more highly preferred to, solvent is 95% ethanol.
Further, in step (C), crystallization time is 0.5~3 hour.
Further, in step (C), drying temperature is 40~70 DEG C.
In the synthetic method of above-mentioned side chain and hydroxychloroquine sulfate, the inorganic base used is sodium carbonate, potassium carbonate, hydroxide
Sodium, potassium hydroxide, sodium acid carbonate or saleratus, wherein, the preferred potassium hydroxide of inorganic base in step (1), step (2) and step
Suddenly the preferred sodium hydroxide of inorganic base in the preferred sodium carbonate of inorganic base in (4), step (A) and step (B).In step (1)
Inorganic base is added to the water together as catalyst, and N- ehtylethanolamines, phase transfer catalyst, organic solvent, it is therefore an objective to
Promote the condensation reaction process of N- ehtylethanolamines and the chloro- 2 pentanones of 5-, accelerate reaction speed, the preferably stronger hydroxide of alkalescence
Potassium.Inorganic base in subsequent step exists in the form of aqueous alkali, for the acid generated during neutralization reaction, and adjusts
PH, wherein, the stability of the product of generation is weaker in step (2) and step (4), therefore, using the weaker sodium carbonate of alkalescence, and
Step (A) and the stability of the product of (B) middle generation are strong, preferably the stronger sodium hydroxide of alkalescence.
In a kind of synthetic method of above-mentioned side chain, dry method is：Organic layer is in the work at 10~20 DEG C in drier
With lower drying 1~2 hour, drier was anhydrous sodium sulfate or anhydrous magnesium sulfate, and consumption is the 10~20% of organic solvent.
The reaction mechanism of synthetic route of the present invention is：
First, N- ehtylethanolamines and the chloro- 2 pentanones of 5- obtain side chain after condensation, esterification, reduction and halo, react
Journey is as follows：
Then, 4- amino -7- chloroquinolines and paratoluensulfonyl chloride reaction obtain 4-Tos amino -7- chloroquinolines, last 4-
Tos amino -7- chloroquinolines with side chain condensation, into salt, obtain hydroxychloroquine sulfate, course of reaction is as follows again：
(wherein R=Cl, Br, I, preferably -- Cl)
In summary, by adopting the above-described technical solution, the beneficial effects of the invention are as follows：
1st, the present invention is condensed as raw material using N- ehtylethanolamines and the chloro- 2 pentanones of 5-, is esterified, being reduced and halogenating reaction
Obtain a kind of new side chain for being used to synthesize hydroxychloroquine sulfate afterwards, the side chain synthesizes no ammonification technique, without catalytic hydrogenation
Technique, used solvent is easy to be recycled, safety and environmental protection, and easy to operate, reduces industrialized production difficulty；
2nd, side chain of the invention instead of existing hydroxychloroquine side chain, and abandon tradition 4,7- dichloroquinolines, use 4- ammonia instead
Base -7- chloroquinolines react with paratoluensulfonyl chloride, obtain after 4-Tos amino -7- chloroquinolines, are condensed with the new side chain low temperature
Hydroxychloroquine sulfate can be synthesized, the risk of high temperature secondary reaction impurities generation is reduced, improves the inherent quality of product, is simplified
Production procedure；
3rd, low temperature condensation process temperature of the invention is low, the time is short, advantageously reduces energy consumption, improves utilization rate of equipment and installations；
4. the synthetic route of the present invention is simple, reaction condition is gentle, safety and environmental protection, yield and quality height, manufacturing cost are low,
Suitable for industrialized production hydroxychloroquine sulfate.
Brief description of the drawings
Fig. 1 is synthetic route schematic diagram of the present invention；
Fig. 2 is the HPLC collection of illustrative plates of hydroxychloroquine sulfate sample；
Fig. 3 is the HPLC collection of illustrative plates of hydroxychloroquine sulfate reference substance.
Embodiment
All features disclosed in this specification, can be with any in addition to mutually exclusive feature and/or step
Mode is combined.
The present invention is elaborated with reference to Fig. 1, Fig. 2, Fig. 3.
N- ehtylethanolamines used of the invention, the chloro- 2 pentanones of 5-, 4- amino -7- chloroquinolines and paratoluensulfonyl chloride, and
Used organic solvent, alcohols solvent are can be in the raw material of industry bought on the market, and " 95% ethanol " is industrial 95 ethanol.
Embodiment 1
The preparation of side chain：
(1) condensation reaction：By 30g N- ehtylethanolamines, 0.6g TBABs, 25g potassium hydroxide, 240g chloroforms,
120g water is added in reaction bulb, then controls 20~30 DEG C of temperature, is added dropwise after the chloro- 2 pentanones of 38g 5-, completion of dropping, and stirring is anti-
Answer 3 hours, static layering, aqueous phase is discarded, organic layer adds 24g anhydrous sodium sulfates, control 10~20 DEG C of temperature, it is small that stirring dries 1
When, filtering, filtrate is condensation product organic phase, detects its content, and condensation product 50.2g, molar yield 92% is (chloro- with 5-
2 pentanone meter), GC Chun Du≤98.5%.
(2) esterification：Condensation product organic phase (condensation product 50.2g) made from step (1) is cooled to 0~5 DEG C,
Insulation is added dropwise after 24g chloroacetic chlorides, completion of dropping, insulation reaction 2 hours, and reaction, which is finished, to be slowly added to reaction solution to be cooled in advance
(350g, 6%) sodium carbonate mass fraction is, stirs 30 minutes, layering, organic addition 200g in 0~5 DEG C of aqueous sodium carbonate
Water washing, layering takes organic layer plus 24g anhydrous sodium sulfates, controls 10~20 DEG C of temperature, and stirring is dried 1 hour, and filtering is obtained
Esterification products organic phase, detects its content, esterification products 57.8g, molar yield 91.9%, GC Chun Du≤99.0%.
(3) reduction reaction：Added in esterification products organic phase made from the step (2) (containing esterification products 57.8g)
40g ethanol is cooled to -5~0 DEG C, is slowly added to 12.0g sodium borohydrides, adds rear insulation reaction 2.0 hours, adds 180g water,
Stirring 30 minutes, stratification, then with 100g water washings once, stratification, organic layer adds 24g anhydrous sodium sulfates, control temperature
10~20 DEG C of degree, stirring is dried 1 hour, filtering, is obtained reduzate organic phase, is detected its content, reduzate 54.6g rubs
That yield 93.6%, GC Chun Du≤99.0%.
(4) halogenating reaction：In reduzate organic phase made from the step (3) (containing reduzate 54.6g), add
37.0g thionyl chlorides are added dropwise in 2.0g MDF, 25~40 DEG C of temperature control, insulation, after being added dropwise to complete, and react 4.0 hours, by reaction system
It is slowly added into 0~5 DEG C of aqueous sodium carbonate that (800g, 8%) sodium carbonate mass fraction is, and layering, organic layer is added
After 200g water washings, stratification, organic layer adds 24g anhydrous sodium sulfates, controls 10~20 DEG C of temperature, and stirring is dried 1 hour, mistake
Filter, obtains side chain organic phase, detects its content, side chain 56.8g, molar yield 96%, GC Chun Du≤99.0%.
Embodiment 2
The preparation of side chain：
(1) condensation reaction：By 30g N- ehtylethanolamines, 0.9g TBABs, 25g potassium hydroxide, 240g chloroforms,
120g water is added in reaction bulb, then controls 20~30 DEG C of temperature, is added dropwise after the chloro- 2 pentanones of 38g 5-, completion of dropping, and stirring is anti-
Answer 3 hours, static layering, aqueous phase is discarded, organic layer adds 24g anhydrous sodium sulfates, control 10~20 DEG C of temperature, it is small that stirring dries 1
When, filtering, filtrate is condensation product organic phase, detects its content, condensation product 50.8g, and molar yield 93.1% is (with 5-
Chloro- 2 pentanone meter), GC Chun Du≤98.5%.
(2) esterification：Condensation product organic phase made from step (1) (containing condensation product 50.8g) is cooled to 0~5
DEG C, insulation is added dropwise after 24g chloroacetic chlorides, completion of dropping, insulation reaction 2 hours, and reaction is finished, and reaction solution is slowly added into advance drop
Into 0~5 DEG C of aqueous sodium carbonate, (350g, 6%) sodium carbonate mass fraction is, stirs 30 minutes to temperature, and layering, organic layer adds
200g water washings, layering, organic layer adds 24g anhydrous sodium sulfates, controls 10~20 DEG C of temperature, and stirring is dried 1 hour, filtering,
Esterification products organic phase is obtained, its content, esterification products 57.9g, molar yield 92.0%, GC Chun Du≤99.0% is detected.
(3) reduction reaction：40g second is added in esterification products organic phase made from step (2) (containing esterification products 57.9g)
Alcohol, is cooled to -5~0 DEG C, is slowly added to 12.0g sodium borohydrides, and -5~0 DEG C is incubated after adding and is reacted 2.0 hours, 180g is added
Water, is stirred 30 minutes, stratification, then with 100g water washings once, stratification, organic layer adds 24g anhydrous sodium sulfates, control
10~20 DEG C of temperature processed, stirring is dried 1 hour, filtering, is obtained reduzate organic phase, is detected its content, reduzate 53.8g,
Molar yield 92.1%, GC Chun Du≤99.0%.
(4) halogenating reaction：In reduzate organic phase made from step (3) (containing reduzate 53.8g), 2.0g is added
36.0g thionyl chlorides are added dropwise in MDF, 25~40 DEG C of temperature control, insulation, after being added dropwise to complete, and react 4.0 hours, and reaction system is slow
It is added in 0~5 DEG C of aqueous sodium carbonate that (800g, 8%) sodium carbonate mass fraction is, and layering, organic layer adds 200g
After water washing, stratification, organic layer adds 24g anhydrous sodium sulfates, controls 10~20 DEG C of temperature, and stirring is dried 1 hour, mistake
Filter, obtains side chain organic phase, detects its content, side chain 56.0g, molar yield 96%, GC Chun Du≤99.0%.
Embodiment 3
The preparation of side chain：
(1) condensation reaction：By 30g N- ehtylethanolamines, 1.2g TBABs, 25g potassium hydroxide, 240g chloroforms,
120g water is added in reaction bulb, then controls 20~30 DEG C of temperature, is added dropwise after the chloro- 2 pentanones of 38g 5-, completion of dropping, and stirring is anti-
Answer 3 hours, static layering, aqueous phase is discarded, organic layer adds 24g anhydrous sodium sulfates, control 10~20 DEG C of temperature, stirring dries 1
Hour, filtering, filtrate is condensation product organic phase, detects its content, condensation product 51.7g, and molar yield 94.7% is (with 5-
Chloro- 2 pentanone meter), GC Chun Du≤98.5%.
(2) esterification：Condensation product organic phase (condensation product 51.7g) made from step (1) is cooled to 0~5 DEG C,
Insulation is added dropwise after 24g chloroacetic chlorides, completion of dropping, insulation reaction 2 hours, and reaction, which is finished, to be slowly added to reaction solution to be cooled in advance
(350g, 6%) sodium carbonate mass fraction is, stirs 30 minutes, and layering, organic layer adds 200g in 0~5 DEG C of aqueous sodium carbonate
Water washing, layering, organic layer adds 24g anhydrous sodium sulfates, controls 10~20 DEG C of temperature, and stirring is dried 1 hour, and filtering is obtained
To esterification products organic phase, its content, esterification products 59.6g, molar yield 93.2%, GC Chun Du≤99.0% are detected.
(3) reduction reaction：40g second is added in esterification products organic phase made from step (2) (containing esterification products 59.6g)
Alcohol, is cooled to -5~0 DEG C, is slowly added to 12.0g sodium borohydrides, adds rear insulation reaction 2.0 hours, adds 180g water, stirring
30 minutes, stratification, then with 100g water washings once, stratification, organic layer adds 24g anhydrous sodium sulfates, controls temperature
10~20 DEG C, stirring is dried 1 hour, and filtering obtains reduzate organic phase, detects its content, reduzate 55.6g, mole
Yield 92.4%, GC Chun Du≤99.0%.
(4) halogenating reaction：In reduzate organic phase made from step (3) (containing reduzate 55.6g), 2.0g is added
36.0g thionyl chlorides are added dropwise in MDF, 25~40 DEG C of temperature control, insulation, after being added dropwise to complete, and react 4.0 hours, and reaction system is slow
It is added in 0~5 DEG C of aqueous sodium carbonate that (800g, 8%) sodium carbonate mass fraction is, and layering, organic layer adds 200g
After water washing, stratification, organic layer adds 24g anhydrous sodium sulfates, controls 10~20 DEG C of temperature, and stirring is dried 1 hour, mistake
Filter, obtains side chain organic phase, detects its content, side chain 57.0g, molar yield 94.5%, GC Chun Du≤99.0%.
Embodiment 4
The preparation of side chain：
(1) condensation reaction：By 30g N- ehtylethanolamines, 0.6g TBABs, 25g potassium hydroxide, 240g chloroforms,
120g water is added in reaction bulb, then controls 20~30 DEG C of temperature, is added dropwise after the chloro- 2 pentanones of 38g 5-, completion of dropping, and stirring is anti-
Answer 3 hours, stratification, aqueous phase is discarded, organic layer adds 24g anhydrous sodium sulfates, control 10~20 DEG C of temperature, it is small that stirring dries 1
When, filtering, filtrate is condensation product organic phase, detects its content, condensation product 50.2g, and molar yield 91.9% is (with 5-
Chloro- 2 pentanone meter), GC Chun Du≤98.5%.
(2) esterification：Condensation product organic phase (condensation product 50.2g) made from step (1) is cooled to 0~5 DEG C,
Insulation is added dropwise after 24g chloroacetic chlorides, completion of dropping, insulation reaction 2 hours, and reaction, which is finished, to be slowly added to reaction solution to be cooled in advance
(350g, 6%) sodium carbonate mass fraction is, stirs 30 minutes, and layering, organic layer adds 200g water in 0~5 DEG C of aqueous sodium carbonate
Washing, layering, organic layer adds 24g anhydrous sodium sulfates, controls 10~20 DEG C of temperature, and stirring is dried 1 hour, and filtering obtains ester
Change product organic phase, detect its content, esterification products 57.4g, molar yield 92.4%, GC Chun Du≤99.0%.
(3) reduction reaction：40g second is added in esterification products organic phase made from step (2) (containing esterification products 57.4g)
Alcohol, is cooled to -5~0 DEG C, is slowly added to 12.0g sodium borohydrides, adds rear insulation reaction 2.0 hours, adds 180g water, stirring
30 minutes, stratification, then with 100g water washings once, stratification, organic layer adds 24g anhydrous sodium sulfates, controls temperature
10~20 DEG C, stirring is dried 1 hour, and filtering obtains reduzate organic phase, detects its content, reduzate 54.4g, mole
Yield 93.8%, GC Chun Du≤99.0%.
(4) halogenating reaction：In reduzate organic phase made from step (3) (containing reduzate 54.4g), 2.0g is added
39.0g thionyl chlorides are added dropwise in MDF, 25~40 DEG C of temperature control, insulation, after being added dropwise to complete, and react 4.0 hours, and reaction system is slow
It is added in 0~5 DEG C of aqueous sodium carbonate that (800g, 8%) sodium carbonate mass fraction is, and layering, organic layer adds 200g
After water washing, stratification, organic layer adds 24g anhydrous sodium sulfates, controls 10~20 DEG C of temperature, and stirring is dried 1 hour, mistake
Filter, obtains side chain organic phase, detects its content, side chain 56.7g, molar yield 96.1%, GC Chun Du≤99.0%.
Embodiment 5
The preparation of hydroxychloroquine sulfate：
(A) N protections reaction：45g 4- amino -7- chloroquinolines, 5g DMF are added in 180g chloroforms, 30~40 are warming up to
DEG C, 50.0g paratoluensulfonyl chlorides are added, are reacted 3 hours, after the completion of reaction, reaction system is added to 0~10 DEG C of sodium hydroxide
(200g, sodium hydroxide mass fraction is 8%), layering, organic layer adds 100g washings, and layering, organic layer subtracts in the aqueous solution
Concentration and recovery chloroform is pressed, 100g methanol is added, 30 minutes dissolved clarifications of temperature rising reflux are cooled to 0~5 DEG C of recrystallization, filtered, 50~
60 DEG C of drying, obtain 4-Tos amino -7- chloroquinoline 80g, mole 95.5%, Chun Du≤99.5%.
(B) condensation reaction：(contain side chain 56.8g) in side chain organic phase made from embodiment 1 and add 78.0g steps (A)
Obtained 4-Tos amino -7- chloroquinolines, 3.0g TBABs are warming up to 65~70 DEG C of reactions, after reacting 6.0 hours, body
System is cooled to 20~30 DEG C, adds into 30~40 DEG C of sodium hydrate aqueous solution that (300g, sodium hydroxide mass fraction is
15%) 30~40 DEG C, are incubated to react 6.0 hours, 10~15 DEG C are cooled to, stratification, after organic layer concentration and recovery chloroform
To hydroxyl quinoline base crude product, the ethanol of 260g 95% is added, temperature rising reflux dissolved clarification is cooled to 0~10 DEG C, recrystallized, filtering, 50
~60 DEG C dry to obtain hydroxyl quinoline base 110.4g, molar yield 96.1% (in terms of 4- amino -7- chloroquinolines), Chun Du≤99.5%.
(C) salt-forming reaction：Hydroxyl quinoline base made from 70g steps (B), the ethanol of 200g 95% is taken to add in reaction bulb, heating
To 50~60 DEG C, dissolving is added dropwise insulation reaction 1 hour after the sulfuric acid that 18.8g mass fractions are 80%, completion of dropping, is cooled to 0
~10 DEG C crystallize 2.0 hours, filtering, and 50~60 DEG C dry to obtain hydroxychloroquine sulfate 57.7g, molar yield 93.2%, and Chun Du≤
99.8%, Zong Za≤0.2%, maximum Dan Za≤0.1%, do not know Za Zhi≤0.1%, calcination Can Zha≤0.2%, Shui Fen≤
0.3%, Chong Jin Shu≤10ppm.
Embodiment 6
The preparation of hydroxychloroquine sulfate：
(A) N protections reaction：45g 4- amino -7- chloroquinolines, 5g DMF are added in 180g chloroforms, 30~40 are warming up to
DEG C, 52.0g paratoluensulfonyl chlorides are added, are reacted 4 hours, after the completion of reaction, reaction system is added to 0~10 DEG C of sodium hydroxide
(200g, sodium hydroxide mass fraction is 8%), layering, organic layer adds 100g washings, and layering, organic layer subtracts in the aqueous solution
Concentration and recovery chloroform is pressed, 100g methanol is added, 30 minutes dissolved clarifications of temperature rising reflux are cooled to 0~5 DEG C of recrystallization, filtered, 50~
60 DEG C of drying, obtain 4-Tos amino -7- chloroquinoline 81.3g, mole 97.02%, Chun Du≤99.5%.
(B) condensation reaction：(contain side chain 53.8g) in side chain organic phase made from embodiment 2 and add 72.0g steps (A)
Obtained 4-Tos amino -7- chloroquinolines, 2.5g TBABs are warming up to 65~70 DEG C of reactions, after reacting 6.0 hours, body
System is cooled to 20~30 DEG C, adds into 30~40 DEG C of sodium hydrate aqueous solution that (300g, sodium hydroxide mass fraction is
15%) 30~40 DEG C, are incubated to react 6.0 hours, 10~15 DEG C are cooled to, stratification, organic layer is concentrated to be reclaimed after chloroform
Hydroxyl quinoline base crude product is obtained, then adds the ethanol of 260g 95%, temperature rising reflux dissolved clarification is cooled to 0~10 DEG C, recrystallized, filtering, 50
~60 DEG C dry to obtain hydroxyl quinoline base 101.9g, molar yield 95.3% (in terms of 4- amino -7- chloroquinolines), Chun Du≤99.5%.
(C) salt-forming reaction：Hydroxyl quinoline base made from 70g steps (B), the ethanol of 200g 95% is taken to add in reaction bulb, heating
To 50~60 DEG C, dissolving is added dropwise insulation reaction 1 hour after the sulfuric acid that 18.8g mass fractions are 80%, completion of dropping, is cooled to 0
~10 DEG C crystallize 2.0 hours, filtering, and 50~60 DEG C dry to obtain hydroxychloroquine sulfate 58.1g, molar yield 93.8%, and Chun Du≤
99.8%, Zong Za≤0.2%, maximum Dan Za≤0.1%, do not know Za Zhi≤0.1%, calcination Can Zha≤0.2%, Shui Fen≤
0.3%, Chong Jin Shu≤10ppm.
Embodiment 7
The preparation of hydroxychloroquine sulfate：
(A) N protections reaction：45g 4- amino -7- chloroquinolines, 5g DMF are added in 180g chloroforms, 30~40 are warming up to
DEG C, 52.0g paratoluensulfonyl chlorides are added, are reacted 4 hours, after the completion of reaction, reaction system is added to 0~10 DEG C of sodium hydroxide
(200g, sodium hydroxide mass fraction is 8%), layering, organic layer adds 100g washings, and layering, organic layer subtracts in the aqueous solution
Concentration and recovery chloroform is pressed, 100g methanol is added, 30 minutes dissolved clarifications of temperature rising reflux are cooled to 0~5 DEG C of recrystallization, filtered, 50~
60 DEG C of drying, obtain 4-Tos amino -7- chloroquinoline 80.6g, mole 96.19%, Chun Du≤99.5%.
(B) condensation reaction：(contain side chain 57.0g) in side chain organic phase made from embodiment 3 and add 72.0g steps (A)
Obtained 4-Tos amino -7- chloroquinolines, 2.5g TBABs are warming up to 65~70 DEG C of reactions, after reacting 6.0 hours, body
System is cooled to 20~30 DEG C, adds into 30~40 DEG C of sodium hydrate aqueous solution that (300g, sodium hydroxide mass fraction is
15%) 30~40 DEG C, are incubated to react 6.0 hours, 10~15 DEG C are cooled to, stratification, organic layer is concentrated to be reclaimed after chloroform
Hydroxyl quinoline base crude product is obtained, then adds the ethanol of 260g 95%, temperature rising reflux dissolved clarification is cooled to 0~10 DEG C of recrystallization, is filtered, 50~
60 DEG C dry to obtain hydroxyl quinoline base 100.7g, molar yield 95.0% (in terms of 4- amino -7- chloroquinolines), Chun Du≤99.5%.
(C) salt-forming reaction：Hydroxyl quinoline base made from 70g steps (B), the ethanol of 200g 95% is taken to add in reaction bulb, heating
To 50~60 DEG C, dissolving is added dropwise insulation reaction 1 hour after the sulfuric acid that 18.8g mass fractions are 80%, completion of dropping, is cooled to 0
~10 DEG C crystallize 2.0 hours, filtering, and 50~60 DEG C dry to obtain hydroxychloroquine sulfate 58.7g, molar yield 94.8%, and Chun Du≤
99.8%, Zong Za≤0.2%, maximum Dan Za≤0.1%, do not know Za Zhi≤0.1%, calcination Can Zha≤0.2%, Shui Fen≤
0.3%, Chong Jin Shu≤10ppm.
Embodiment 8
The preparation of hydroxychloroquine sulfate：
(A) N protections reaction：45g 4- amino -7- chloroquinolines, 5g DMF are added in 180g chloroforms, 30~40 are warming up to
DEG C, 52.0g paratoluensulfonyl chlorides are added, are reacted 4 hours, after the completion of reaction, reaction system is added to 0~10 DEG C of sodium hydroxide
(200g, sodium hydroxide mass fraction is 8%), layering, organic layer adds 100g washings, layering, organic layer warp in the aqueous solution
Be concentrated under reduced pressure recovery chloroform, adds 100g methanol, and 30 minutes dissolved clarifications of temperature rising reflux are cooled to 0~5 DEG C of recrystallization, filtering, 50
~60 DEG C of drying, obtain 4-Tos amino -7- chloroquinoline 80.9g, mole 96.50%, Chun Du≤99.5%.
(B) condensation reaction：(contain side chain 56.7g) in side chain organic phase made from embodiment 4 and add 75.0g steps (A)
Obtained 4-Tos amino -7- chloroquinolines, 3.0g TBABs are warming up to 60~65 DEG C of reactions, after reacting 6.0 hours, body
System is cooled to 20~30 DEG C, adds into 30~40 DEG C of sodium hydrate aqueous solution that (300g, sodium hydroxide mass fraction is
15%) 30~40 DEG C, are incubated to react 6.0 hours, 10~15 DEG C are cooled to, stratification, organic layer is concentrated to be reclaimed after chloroform
Hydroxyl quinoline base crude product is obtained, then adds the ethanol of 260g 95%, temperature rising reflux dissolved clarification is cooled to 0~10 DEG C of recrystallization, is filtered, 50~
60 DEG C dry to obtain hydroxyl quinoline base 103.4g, molar yield 93.6% (in terms of 4- amino -7- chloroquinolines), Chun Du≤99.5%.
(C) salt-forming reaction：Hydroxyl quinoline base made from 70g steps (B), the ethanol of 200g 95% is taken to add in reaction bulb, heating
To 50~60 DEG C, dissolving is added dropwise insulation reaction 1 hour after the sulfuric acid that 18.8g mass fractions are 80%, completion of dropping, is cooled to 0
~10 DEG C crystallize 2.0 hours, filtering, and 50~60 DEG C dry to obtain hydroxychloroquine sulfate 57.8g, molar yield 93.6%, and Chun Du≤
99.8%, Zong Za≤0.2%, maximum Dan Za≤0.1%, do not know Za Zhi≤0.1%, calcination Can Zha≤0.2%, Shui Fen≤
0.3%, Chong Jin Shu≤10ppm.
Embodiment 9
High performance liquid chromatography (HPLC), using liquid as mobile phase, using high pressure transfusion system, by with opposed polarity
The mobile phases such as mixed solvent, the buffer solution of single solvent or different proportion are pumped into the chromatographic column equipped with stationary phase, in post it is each into
Divide after being separated, detected into detector, so as to realize the analysis to sample.Hydroxychloroquine sulfate made from embodiment 5
The HPLC collection of illustrative plates of sample is as shown in Fig. 2 the HPLC collection of illustrative plates of hydroxychloroquine sulfate reference substance is as shown in Figure 3.
Pass through Fig. 2 and Fig. 3 contrast it is clear that, hydroxychloroquine sulfate prepared by the present invention is compared to sulfuric acid hydroxyl
Chloroquine reference substance, its dopant species is few, total purity is high, and maximum single miscellaneous purity is lower, is better than reference substance in quality.
It is embodiments of the invention as described above.The present invention is not limited to the above-described embodiments, anyone should learn that
The structure change made under the enlightenment of the present invention, the technical schemes that are same or similar to the present invention each fall within this
Within the protection domain of invention.
Claims (10)
1. a kind of side chain, its structural formula is as follows：
Wherein, R is Cl, Br or I.
2. a kind of synthetic method of side chain described in claim 1, it is characterised in that comprise the following steps：
(1) condensation reaction：N- ehtylethanolamines, phase transfer catalyst, inorganic base, organic solvent are added to the water, temperature is controlled
For 20~30 DEG C, the chloro- 2 pentanones of 5- are added dropwise and react 2~6 hours, are layered after the completion of reaction, take organic layer to be condensed after drying
Product organic phase；
(2) esterification：The condensation product organic phase is cooled to 0~10 DEG C, and insulation is added dropwise acetoinices and reacted 1~3 hour,
After the completion of reaction, it is layered, washing, takes organic layer to obtain esterification products organic phase after drying；
(3) reduction reaction：The esterification products organic phase is cooled to -5~0 DEG C, reducing agent is added and reacts 1~4 hour, add
Water, layering takes organic layer to obtain reduzate organic phase after drying；
(4) halogenating reaction：Catalyst is added in reduzate organic phase, it is 25~40 DEG C to control temperature, and halo is added dropwise in insulation
Reagent reacting 3~8 hours, is layered, washing, takes organic layer to obtain side chain organic phase after drying.
3. a kind of synthetic method of side chain according to claim 2, it is characterised in that the esterification and halogenating reaction are complete
Cheng Hou, reacts before being layered, it is necessary to which reaction system is added in inorganic base aqueous solution.
4. a kind of synthetic method of side chain according to claim 2, it is characterised in that in the step (1), phase transfer catalysis (PTC)
Agent is TBAB, 4-butyl ammonium hydrogen sulfate, tetrabutylammonium chloride, tri-n-octyl methyl ammonium chloride, trimethyl
Ammonium chloride or tetradecyl trimethyl ammonium chloride.
5. a kind of synthetic method of side chain according to claim 2, it is characterised in that in the step (2), acetoinices are
Chloroacetic chloride or aceticanhydride.
6. a kind of synthetic method of side chain according to claim 2, it is characterised in that in the step (3), reducing agent is boron
Sodium hydride, potassium borohydride or borine ether.
7. a kind of synthetic method of side chain according to claim 2, it is characterised in that in the step (4), halogenating agent is
Thionyl chloride, phosphorus trichloride, thionyl bromide, phosphorus tribromide, phosphorus pentabromide, N- chlorosuccinimides, N- bromos succinyl are sub-
Amine or N- N-iodosuccinimides, catalyst is DMF.
8. the method that hydroxychloroquine sulfate is synthesized using the side chain as described in any one in claim 1-7, it is characterised in that bag
Include following steps：
(A) N protections reaction：4- amino -7- chloroquinolines, cosolvent are added in organic solvent, 30~40 DEG C, addition are warming up to
Paratoluensulfonyl chloride reacts 2~6 hours, is layered, and washing is concentrated, recrystallizes, dries to obtain 4-Tos amino -7- chloroquinolines；
(B) condensation reaction：In side chain organic phase, catalyst and 4-Tos amino -7- chloroquinolines are added, 60~80 DEG C are warming up to
Reaction, after the completion of reaction, is cooled to 5~20 DEG C, layering obtains hydroxyl quinoline base crude product, recrystallization, drying after organic layer is concentrated
After obtain hydroxyl quinoline base；
(C) salt-forming reaction：The hydroxyl quinoline base is added in alcohols solvent, 50~60 DEG C, after dissolving completely is warming up to, is added dropwise
Sulfuric acid, reacts 1 hour, is cooled to 0~10 DEG C of crystallization, hydroxychloroquine sulfate is obtained after drying.
9. the method for hydroxychloroquine sulfate is synthesized according to claim 8, it is characterised in that in the step (A) and (B),
After the completion of reaction, reacted before being layered, it is necessary to which reaction system is added in inorganic base aqueous solution.
10. according to claim 8 synthesize hydroxychloroquine sulfate method, it is characterised in that the cosolvent be DMF,
DMSO or dioxane, the catalyst are KI, sodium iodide, TBAB, DMAP or pyridine.
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| CN108727263A (en) * | 2018-07-05 | 2018-11-02 | 上海中西三维药业有限公司 | Hydroxychloroquine sulfate crystal form A and preparation method thereof |
| CN110790705A (en) * | 2018-08-01 | 2020-02-14 | 华东理工大学 | Hydroxychloroquine derivative and preparation method and application thereof |
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| CN111635358A (en) * | 2020-06-29 | 2020-09-08 | 北京成宇化工有限公司 | Preparation method of hydroxychloroquine |
| CN111635358B (en) * | 2020-06-29 | 2022-06-03 | 北京成宇化工有限公司 | Preparation method of hydroxychloroquine |
| CN111793026A (en) * | 2020-07-23 | 2020-10-20 | 珠海润都制药股份有限公司 | Hydroxychloroquine sulfate, crystal form of enantiomer thereof and preparation method of crystal form |
| CN112986413A (en) * | 2020-11-30 | 2021-06-18 | 珠海润都制药股份有限公司 | Method for detecting hydroxychloroquine side chain in hydroxychloroquine |
| CN112986413B (en) * | 2020-11-30 | 2023-03-03 | 珠海润都制药股份有限公司 | Method for detecting hydroxychloroquine side chain in hydroxychloroquine |
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