CN107266323B - A kind of side chain and its synthetic method, and the method using side chain synthesis hydroxychloroquine sulfate - Google Patents
A kind of side chain and its synthetic method, and the method using side chain synthesis hydroxychloroquine sulfate Download PDFInfo
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- CN107266323B CN107266323B CN201710584086.0A CN201710584086A CN107266323B CN 107266323 B CN107266323 B CN 107266323B CN 201710584086 A CN201710584086 A CN 201710584086A CN 107266323 B CN107266323 B CN 107266323B
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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
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Abstract
The invention discloses a kind of side chain and its synthetic methods, and using the method for side chain synthesis hydroxychloroquine sulfate, the synthesis step of side chain includes: that (1) N- ehtylethanolamine and the chloro- 2 pentanone of 5- are condensed to yield condensation product；(2) condensation product and acetoinices are esterified to obtain esterification products；(3) esterification products restore to obtain reduzate；(4) reduzate and halogenating agent react to obtain side chain.The synthesis step of hydroxychloroquine sulfate includes: that (A) 4- amino -7- chloroquinoline and paratoluensulfonyl chloride react to obtain 4-Tos amino -7- chloroquinoline；(B) side chain and 4-Tos amino -7- chloroquinoline react to obtain hydroxyl quinoline base；(C) hydroxyl quinoline base and sulfuric acid reaction obtain hydroxychloroquine sulfate.The present invention provides a kind of new side chain, synthesize no ammonification technique, without catalytic hydrogenation process, safety and environmental protection, and can low temperature be condensed hydroxychloroquine sulfate be 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 synthesized using the side chain
The method of hydroxychloroquine sulfate.
Background technique
Hydroxychloroquine sulfate, chemical name 2-4- (the chloro- 4- quinolyl of 7-) Aminopentyl ethylamino-alcohol sulfate salt, English
Name: Hydroxychloroquine Sulfate, chemical structural formula are as follows:
Hydroxychloroquine (Hydroxychloroquine, HCQ) is the antimalarial being made of 4- aminoquinoline compounds, sulfuric acid hydroxyl
Chloroquine is synthesized in nineteen forty-six by Surrey and Hammer.Clinically for treating lupus erythematosus discoides and systemic loupus erythematosus,
It is diseases related to be also widely used to rheumatism at present.
Lupus erythematosus discoides (DLE) is relatively common mucocutaneous property connective tissue disease, and 25%-35% has oral cavity damage
Evil, can single-shot nonjoinder skin lesion in oral cavity, mostly without obvious constitutional symptom.Its cause of disease and pathogenesis are still unclear at present
Chu, also relatively difficult, easy to recur and canceration in treatment.Tradition using chloroquine diphosphate (CQ) treatment DLE it is effective, but side effect compared with
Greatly.HCQ has anti-inflammatory, resistance amine and immunosuppressive action, declines lymphocyte transformation rate, inhibits vascular permeability, stablizes
Lysosome membrane, so targeted with HCQ treatment DLE.Up to the present, HCQ is considered than CQ safety.A large amount of clinical and documents
Report confirms, obtains satisfied effect 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, Dobois discovery for treating SLE
After the SLE patient of 75%-80% is treated with antimalarial, fash, fever, joint symptoms improve, especially skin lesion.Thereafter it grinds
Study carefully discovery, antimalarial can make SLE patient reduce or stop using cortin, and have anti-allergic effects.Canadian hydroxyl chlorine
Quinoline research group double blind control is studies have shown 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 treats the blood lipid level that can reduce Corticodependence patient, can obviously reduce the generation of thrombosis.Can be in view of HCQ
SLE brings beneficial effect, and most scholars advocate that HCQ for SLE patient mild to moderate, combines hormone, immunosuppressor is used
In the adjuvant treatment of severe SLE.
When treating SLE using antimalarial, foreign countries 90% select hydroxychloroquine, 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 permission is not needed only by antimalarial agent
When playing curative effect in a short time, hydroxychloroquine should be selected as far as possible.
With scientist, further study show that, hydroxychloroquine can play panimmunity adjustment effect in rheumatic disease,
Preferred hydroxychloroquine has significant anti-inflammatory effect, the activity that it can stablize lysosome, inhibit enzyme, and then inhibits swashing for inflammatory mediator
It is living, while can inhibit chemotactic and the infiltration of inflammatory cell such as neutrophil leucocyte, and substantially reduce proinflammatory cytokine such as TNF- ɑ,
The generation of IL-1 and IL-6；Secondly hydroxychloroquine can be by inhibiting the deposition of fibroblastic growth and connective tissue to inhibit
The hyperplasia of arthritic's synovial membrane；Hydroxychloroquine can inhibit the interaction of antigen-antibody and the synthesis of immune complex again, promote
Make the reduction of rheumatoid factor titre；Hydroxychloroquine can also be by influencing ultraviolet radiation absorption and stopping injury of the ultraviolet light to skin.With
Above various is all hydroxychloroquine in a large amount of foundations of clinical treatment rheumatic disease offer.Furthermore many center larger scale clinical researchs
Confirm that hydroxychloroquine plays significant therapeutic effect in the treatment of rheumatism.
Currently, generally taking following synthetic route in the synthesis of hydroxychloroquine sulfate:
The core of the route is, 5- (N- ethyl-N-2- ethylol amine) -2- amylamine (hereinafter referred to as hydroxychloroquine side chain) with
Hydroxychloroquine base is prepared in 100~140 DEG C of high temperature reactions in 4,7- dichloroquinolines, then with sulfuric acid at salt.US2546658 is public
A kind of hydroxychloroquine sulfate synthetic method is opened, reaction process is as follows:
The technique is older, uses phenol as solvent, phenol is toxic 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 relatively low, below 20%.
CA2561987 discloses a kind of method for synthesizing hydroxychloroquine sulfate, and reaction process is as follows:
This method establishes the basic item that hydroxychloroquine side chain synthesizes the raising yield of hydroxyl quinoline base with 4,7- dichloroquinoline
Part, i.e. pyroreaction, although product purity also 99.5% or more, 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, reaction process are as follows:
The method is still pyroreaction, and needs reaction under high pressure, and security risk is higher.
CN103724261A discloses a kind of new industrial process of hydroxychloroquine sulfate quinoline, and reaction process 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 not can avoid, and corresponding impurity still has, and the HPLC purity of patent report also only can guarantee≤99.2%.
Hydroxychloroquine side chain is the key intermediate for synthesizing hydroxychloroquine sulfate, and there are two types of synthetic methods reported in the literature:
Route one is the chloro- 2 pentanone of 5- to be first first prepared as ketal, then react with N- ehtylethanolamine, obtains 5- (N- ethyl-N-2-
Ethylol amine) -2 pentanone, then hydroxychloroquine side chain is made through ammonification, hydro-reduction；Route two, with the chloro- 2 pentanone of 5- and N- second
Ethylethanolamine reacts to obtain 5- (N- ethyl-N-2- ethylol amine) -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 generated, while imines needs high-pressure hydrogenation reduction to prepare amino, security risk is higher.2015, CN104803859A
A kind of synthetic method of 5- (N- ethyl-N-2- ethylol amine) -2- amylamine, the i.e. synthetic method of hydroxychloroquine side chain are disclosed,
Its synthetic route is as follows:
To sum up, the synthetic route of hydroxychloroquine sulfate is primarily present the unfavorable factor in terms of two at present: first is that hydroxy chloride
The preparation of quinoline side chain: need to use ammonia or high concentration liquefied ammonia, and smell weight generates baneful influence to environment, while imines needs height
Press hydro-reduction at amino, security risk is higher；Second is that prepared by hydroxychloroquine base: since 4 chlorine of 4,7- dichloroquinoline are living
Property it is relatively low, and the catalysis such as catalyst such as potassium bromide, potassium iodide can not be used only, 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, if you need to guarantee
Product quality is both needed to take relatively complicated aftertreatment technology and uses a large amount of organic solvent.In addition, existing synthetic route is also deposited
In the defect that the production cycle is long, impurity content is higher, yield is relatively low, cost of material is higher.Therefore, design a simple process,
The industrializing synthesis route that reaction condition is mild, safety and environmental protection, yield and quality height, manufacturing cost are low will be with great society
Meaning and significant economic value.
Summary of the invention
The purpose of the present invention is to provide a kind of side chain and its synthetic methods, and synthesize hydroxychloroquine sulfate 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 do not need high-pressure hydrogenation also
Original 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 lower reaction temperature, can avoid the end position-NH of hydroxychloroquine side chain2And-OH is in high temperature
Under the conditions of react, advantageously ensure that product quality, and do not need to carry out cumbersome aftertreatment technology.
The technical solution adopted by the invention is as follows:
A kind of side chain, structural formula are as follows:
Wherein, R Cl, Br or I.
A kind of synthetic method of side chain, comprising the following steps:
(1) condensation reaction: N- ehtylethanolamine, phase transfer catalyst, inorganic base, organic solvent are added to the water, control
Temperature is 20~30 DEG C, and the chloro- 2 pentanone of 5- is added dropwise and reacts 2~6 hours, is layered after the reaction was completed, obtains after taking organic layer dry
Condensation product organic phase, the chemical name of condensation product are as follows: 5- (N- ethyl-N-2- ethylol amine) -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 heat preservation
Hour, it after the reaction was completed, is layered, washing, obtains esterification products organic phase, the chemical name of esterification products after taking organic layer dry
Are as follows: 5- (N- ethyl-N-2- acetoxyl group amine) -2 pentanone；
(3) reduction reaction: being cooled to -5~0 DEG C for the esterification products organic phase, and reducing agent is added and reacts 1~4 hour,
Water is added, layering obtains reduzate organic phase, the chemical name of reduzate after taking organic layer dry are as follows: 5- (N- ethyl-
N-2- acetoxyl group amine) -2- methyl anyl alcohol；
(4) halogenating reaction: being added catalyst in reduzate organic phase, and controlled at 25~40 DEG C, heat preservation is added dropwise
Halogenating agent reacts 3~8 hours, is layered, washing, obtains side chain organic phase, the chemical name of side chain after taking organic layer dry are as follows:
5- (N- ethyl-N-2- acetoxyl group amine) -2- chloropentane.
Further, esterification and halogenating reaction need reaction system nothing is added before reaction is completed to be layered
It is reacted in machine aqueous alkali, is neutralized the acid generated during esterification and halogenating reaction, then layered, washing is protected
Demonstrate,prove without impurity, preferably 0~5 DEG C of inorganic base aqueous solution such as acid, alkali in the side chain organic phase that ultimately generates, can be to reaction after
System is tentatively cooled down, in favor of subsequent reactions.
Further, in step (1), the molar ratio of the chloro- 2 pentanone of 5- and N- ehtylethanolamine is 0.8~1.2, inorganic base
Molar ratio with the chloro- 2 pentanone of 5- is 1.2~1.8.
More preferably, the molar ratio of the chloro- 2 pentanone of 5- and N- ehtylethanolamine is 0.8~1.0, inorganic base and N- ethyl
The molar ratio of ethanol amine is 1.2~1.5.In the step molar ratio of the chloro- 2 pentanone of 5- and N- ehtylethanolamine be designed as 0.8~
1.0, be conducive to the chloro- 2 pentanone conversion of 5- thoroughly, 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 dosage of 5-, both ensures catalytic,
Auxiliary acid amount, and be unlikely to waste, it can also reduce three waste discharge.
Further, in step (1), phase transfer catalyst is tetrabutylammonium bromide, 4-butyl ammonium hydrogen sulfate, tetrabutyl chlorine
Change ammonium, tri-n-octyl methyl ammonium chloride, dodecyl trimethyl ammonium chloride or tetradecyl trimethyl ammonium chloride.In the step, N-
Ehtylethanolamine is dissolved in water, and the chloro- 2 pentanone of 5- is dissolved in organic solvent, therefore reaction system is water phase and organic phase mixed system,
Belong to outphasing system, phase transfer catalyst can in conjunction with the ion in water phase, and using itself compatibility to organic solvent,
N- ehtylethanolamine in water phase is transferred in organic phase, reaction is promoted, to accelerate outphasing system reaction rate.
More preferably, phase transfer catalyst is tetrabutylammonium bromide.
Further, in step (1), organic solvent is methylene chloride, chloroform or chlorobenzene.
More preferably, organic solvent is chloroform.
Further, in step (2), the molar 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
The reaction that acetyl group CH3CO- is introduced on-the OH of position has the characteristics that product yield is high, reaction condition is mild, environmental protection, commonly uses second
Acyl reagent is chloroacetic chloride or aceticanhydride.
More preferably, acetoinices are chloroacetic chloride, and reaction rate is most fast.
Further, in step (2), the mass concentration of inorganic base aqueous solution is 5~10%, and dosage is organic phase weight
0.5~2.0 times.
More preferably, the dosage of inorganic base aqueous solution is 1.0~2.0 times of organic phase weight.
Further, in step (3), the molar 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, alkalinity is strong, and has strong nucleophilicity, the ester group in esterification products can be reduced into hydroxyl.
More preferably, reducing agent is sodium borohydride, and reaction condition is mild, cheap, and use is relatively broad.
Further, in step (3), cooled down using ethyl alcohol.Ethyl alcohol is in addition to that can make esterification products organic phase drop rapidly
Outside temperature to required reaction temperature, with immiscible organic solvent, it may additionally facilitate reactant dissolution, accelerate reduction reaction rate.
Further, in step (3), the dosage of ethyl alcohol is the 15~40% of organic solvent weight, and the dosage of water is organic
0.5~2.0 times of weight of solvent.
More preferably, ethanol consumption is the 20~40% of organic solvent weight, and the dosage of water is organic solvent weight
0.5~1.5 times.
Further, in step (4), the molar 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- chlorosuccinimide, N- bromo-succinimide or N- N-iodosuccinimide.By halogenating reaction, make to restore
Hydroxyl in product is optionally substituted by halogen, and forms halides, the side chain as subsequent synthesis hydroxychloroquine sulfate.
More preferably, halogenating agent is thionyl chloride.
Further, in step (4), catalyst is n,N-Dimethylformamide, and dosage 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 dosage is organic phase weight
4.0~6.0 times.
Using the method for side chain synthesis hydroxychloroquine sulfate, comprising the following steps:
(A) N protection reaction: 4- amino -7- chloroquinoline, cosolvent being added in organic solvent, are warming up to 30~40 DEG C,
Paratoluensulfonyl chloride is added to react 2~6 hours, is layered, washing is concentrated, recrystallizes, dries to obtain 4-Tos amino -7- chloroquine
Quinoline；
(B) condensation reaction: in the side chain organic phase, catalyst and 4-Tos amino -7- chloroquinoline is added, is warming up to
60~80 DEG C of reactions are cooled to 5~20 DEG C after the reaction was completed, and layering obtains hydroxyl quinoline base crude product after organic layer is concentrated, weight
Hydroxyl quinoline base is obtained after crystallization, drying；
More preferably, after the reaction was completed, 5~10 DEG C are cooled to, layering.
(C) salt-forming reaction: the hydroxyl quinoline base is added in alcohols solvent, is warming up to 50~60 DEG C, after dissolution completely,
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, and needs that inorganic buck for reaction system is added
It is reacted in solution.
In step (A), using 0~10 DEG C of inorganic base aqueous solution.In step (B), after the reaction was completed, first by reaction system
It 20~30 DEG C are cooled to, are then added into 20~40 DEG C of inorganic base aqueous solution and react 3~8 hours, preferably 30~40 DEG C
Inorganic base aqueous solution.
Further, in step (A), the molar ratio of paratoluensulfonyl chloride and 4- amino -7- chloroquinoline is 1.0~1.2.
Further, in step (A), organic solvent is methylene chloride, chloroform or dichloroethanes, and dosage is 4- amino -7-
3~6 times of chloroquinoline weight.
More preferably, the organic solvent is chloroform.
Further, in step (A), cosolvent DMF, DMSO or dioxane, dosage are 4- amino -7- chloroquinoline weight
0.1~0.6 times of amount.
More preferably, the cosolvent is DMF.
More preferably, the dosage 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 dosage 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 molar ratio of side chain and 4-Tos amino -7- chloroquinoline is 1.0~1.5.
More preferably, the molar ratio of the side chain and 4-Tos amino -7- chloroquinoline is 1.0~1.2.
Further, in step (B), catalyst is potassium iodide, sodium iodide, tetrabutylammonium bromide, DMAP or pyridine, dosage
It is 0.02~0.1 times of side chain weight.
More preferably, catalyst is tetrabutylammonium bromide.
Further, in step (B), the mass concentration of inorganic base aqueous solution is 5~40%, and dosage is organic phase weight
1.0~3.0 times.
More preferably, 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 molar ratio of sulfuric acid and hydroxyl quinoline base is 1.0~1.1.
Further, in step (C), the alcohols solvent is 95% ethyl alcohol, methanol or ethanol solution, and dosage is hydroxyl
3~5 times of quinoline base weight.
More preferably, solvent is 95% ethyl alcohol.
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 bicarbonate or saleratus, wherein the preferred potassium hydroxide of inorganic base in step (1), step (2) and step
Suddenly the preferred sodium carbonate of inorganic base in (4), the preferred sodium hydroxide of inorganic base in step (A) and step (B).In step (1)
Inorganic base is added to the water together as catalyst and N- ehtylethanolamine, phase transfer catalyst, organic solvent, it is therefore an objective to
Promote the condensation reaction process of N- ehtylethanolamine and the chloro- 2 pentanone of 5-, accelerates reaction speed, preferably alkaline stronger hydroxide
Potassium.Inorganic base in subsequent step exists in the form of aqueous alkali, the acid for generating during neutralization reaction, and adjusts
PH, wherein the stability of the product generated in step (2) and step (4) is weaker, therefore, using the weaker sodium carbonate of alkalinity, and
Step (A) and the stability of (B) middle product generated are strong, preferably alkaline stronger sodium hydroxide.
In a kind of synthetic method of above-mentioned side chain, dry method are as follows: organic layer is at 10~20 DEG C in the work of desiccant
With lower drying 1~2 hour, desiccant was anhydrous sodium sulfate or anhydrous magnesium sulfate, and dosage is the 10~20% of organic solvent.
The reaction mechanism of synthetic route of the present invention are as follows:
Firstly, N- ehtylethanolamine and the chloro- 2 pentanone of 5- through condensation, esterification, reduction and it is halogenated after obtain side chain, reacted
Journey is as follows:
Then, 4- amino -7- chloroquinoline and paratoluensulfonyl chloride react to obtain 4-Tos amino -7- chloroquinoline, last 4-
Tos amino -7- chloroquinoline with side chain condensation, at salt, obtains hydroxychloroquine sulfate, reaction process is as follows again:
In conclusion by adopting the above-described technical solution, the beneficial effects of the present invention are:
1, the present invention is condensed using N- ehtylethanolamine and the chloro- 2 pentanone of 5- as raw material, is esterified, being restored and halogenating reaction
A kind of new side chain for being used to synthesize hydroxychloroquine sulfate is obtained afterwards, which 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；
2, side chain of the invention is instead of existing hydroxychloroquine side chain, and abandons tradition 4,7- dichloroquinoline, uses 4- ammonia instead
Base -7- chloroquinoline is reacted with paratoluensulfonyl chloride, after obtaining 4-Tos amino -7- chloroquinoline, is 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；
3, 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. synthetic route of the invention is simple, reaction condition is mild, safety and environmental protection, yield and quality are high, manufacturing cost is low,
Suitable for industrialized production hydroxychloroquine sulfate.
Detailed description of the invention
Fig. 1 is synthetic route schematic diagram of the present invention；
Fig. 2 is the HPLC map of hydroxychloroquine sulfate sample；
Fig. 3 is the HPLC map of hydroxychloroquine sulfate reference substance.
Specific embodiment
All features disclosed in this specification can be with any other than mutually exclusive feature and/or step
Mode combines.
It elaborates below with reference to Fig. 1, Fig. 2, Fig. 3 to the present invention.
The chloro- 2 pentanone of N- ehtylethanolamine, 5-, 4- amino -7- chloroquinoline used in the present invention and paratoluensulfonyl chloride, and
Used organic solvent, alcohols solvent are the raw material of industry that can be bought in the market, and " 95% ethyl alcohol " is industrial 95 ethyl alcohol.
Embodiment 1
The preparation of side chain:
(1) condensation reaction: by 30g N- ehtylethanolamine, 0.6g tetrabutylammonium bromide, 25g potassium hydroxide, 240g chloroform,
120g water is added in reaction flask, then controls 20~30 DEG C of temperature, and the chloro- 2 pentanone of 38g 5- is added dropwise, and after being added dropwise, stirring is anti-
It answers 3 hours, static layering, water phase discards, and organic layer adds 24g anhydrous sodium sulfate, controls 10~20 DEG C of temperature, stirring dry 1 is small
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: being cooled to 0~5 DEG C for condensation product organic phase (condensation product 50.2g) made from step (1),
24g chloroacetic chloride is added dropwise in heat preservation, and after being added dropwise, insulation reaction 2 hours, reaction solution was slowly added to be cooled in advance by end of reaction
(350g, sodium carbonate mass fraction are 6%), to stir 30 minutes, layering, organic addition 200g in 0~5 DEG C of aqueous sodium carbonate
Water washing, layering take organic layer to add 24g anhydrous sodium sulfate, control 10~20 DEG C of temperature, and stirring is 1 hour dry, and filtering obtains
Esterification products organic phase detects its content, esterification products 57.8g, molar yield 91.9%, GC Chun Du≤99.0%.
(3) reduction reaction: the esterification products organic phase made from the step (2) is added in (containing esterification products 57.8g)
40g ethyl alcohol is cooled to -5~0 DEG C, is slowly added to 12.0g sodium borohydride, adds rear insulation reaction 2.0 hours, and 180g water is added,
Stirring 30 minutes, stratification, then primary, the stratification with 100g water washing, organic layer add 24g anhydrous sodium sulfate, control temperature
10~20 DEG C of degree, stirring is 1 hour dry, and filtering obtains reduzate organic phase, detects its content, reduzate 54.6g rubs
That yield 93.6%, GC Chun Du≤99.0%.
(4) it halogenating reaction: in the reduzate organic phase made from the step (3) (containing reduzate 54.6g), is added
2.0g MDF, 25~40 DEG C of temperature control, 37.0g thionyl chloride is added dropwise in heat preservation, after being added dropwise to complete, reacts 4.0 hours, by reaction system
It is slowly added into 0~5 DEG C of aqueous sodium carbonate that (800g, sodium carbonate mass fraction are that 8%), layering, organic layer adds
200g water washing, after stratification, organic layer adds 24g anhydrous sodium sulfate, controls 10~20 DEG C of temperature, stirring is 1 hour dry, 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- ehtylethanolamine, 0.9g tetrabutylammonium bromide, 25g potassium hydroxide, 240g chloroform,
120g water is added in reaction flask, then controls 20~30 DEG C of temperature, and the chloro- 2 pentanone of 38g 5- is added dropwise, and after being added dropwise, stirring is anti-
It answers 3 hours, static layering, water phase discards, and organic layer adds 24g anhydrous sodium sulfate, controls 10~20 DEG C of temperature, stirring dry 1 is small
When, filtering, filtrate is condensation product organic phase, detects its content, condensation product 50.8g, molar yield 93.1% is (with 5-
Chloro- 2 pentanone meter), GC Chun Du≤98.5%.
(2) condensation product organic phase made from step (1) (containing condensation product 50.8g) esterification: is cooled to 0~5
DEG C, 24g chloroacetic chloride is added dropwise in heat preservation, and after being added dropwise, insulation reaction 2 hours, reaction solution was slowly added to drop in advance by end of reaction
(350g, sodium carbonate mass fraction are 6%), to stir 30 minutes, and layering, organic layer adds in the aqueous sodium carbonate of temperature to 0~5 DEG C
24g anhydrous sodium sulfate is added in 200g water washing, layering, organic layer, controls 10~20 DEG C of temperature, and stirring is 1 hour dry, filtering,
Esterification products organic phase is obtained, its content, esterification products 57.9g, molar yield 92.0%, GC Chun Du≤99.0% are detected.
(3) reduction reaction: 40g second is added in (containing esterification products 57.9g) in the esterification products organic phase made from step (2)
Alcohol is cooled to -5~0 DEG C, is slowly added to 12.0g sodium borohydride, and -5~0 DEG C is kept the temperature after adding and is reacted 2.0 hours, 180g is added
Water stirs 30 minutes, stratification, then primary, the stratification with 100g water washing, and 24g anhydrous sodium sulfate, control is added in organic layer
10~20 DEG C of temperature processed, stirring dry 1 hour, filtering obtained reduzate organic phase, detected its content, reduzate 53.8g,
Molar yield 92.1%, GC Chun Du≤99.0%.
(4) it halogenating reaction: in the reduzate organic phase made from step (3) (containing reduzate 53.8g), is added
2.0gMDF, 25~40 DEG C of temperature control, 36.0g thionyl chloride is added dropwise in heat preservation, after being added dropwise to complete, reacts 4.0 hours, by reaction system
It is slowly added into 0~5 DEG C of aqueous sodium carbonate that (800g, sodium carbonate mass fraction are that 8%), layering, organic layer adds
200g water washing, after stratification, 24g anhydrous sodium sulfate is added in organic layer, controls 10~20 DEG C of temperature, and stirring is 1 hour dry,
Filtering, 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- ehtylethanolamine, 1.2g tetrabutylammonium bromide, 25g potassium hydroxide, 240g chloroform,
120g water is added in reaction flask, then controls 20~30 DEG C of temperature, and the chloro- 2 pentanone of 38g 5- is added dropwise, and after being added dropwise, stirring is anti-
It answers 3 hours, static layering, water phase discards, and 24g anhydrous sodium sulfate is added in organic layer, controls 10~20 DEG C of temperature, stirring dry 1
Hour, filtering, filtrate is condensation product organic phase, detects its content, condensation product 51.7g, molar yield 94.7% is (with 5-
Chloro- 2 pentanone meter), GC Chun Du≤98.5%.
(2) esterification: being cooled to 0~5 DEG C for condensation product organic phase (condensation product 51.7g) made from step (1),
24g chloroacetic chloride is added dropwise in heat preservation, and after being added dropwise, insulation reaction 2 hours, reaction solution was slowly added to be cooled in advance by end of reaction
(350g, sodium carbonate mass fraction are 6%), to stir 30 minutes, and layering, organic layer adds 200g in 0~5 DEG C of aqueous sodium carbonate
Water washing, layering, organic layer add 24g anhydrous sodium sulfate, control 10~20 DEG C of temperature, and stirring is 1 hour dry, and filtering obtains
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 (containing esterification products 59.6g) in the esterification products organic phase made from step (2)
Alcohol is cooled to -5~0 DEG C, is slowly added to 12.0g sodium borohydride, adds rear insulation reaction 2.0 hours, and 180g water, stirring is added
30 minutes, 24g anhydrous sodium sulfate was added in stratification, then primary, the stratification with 100g water washing, organic layer, controlled temperature
10~20 DEG C, stirring dry 1 hour, filtering obtained reduzate organic phase, detected its content, reduzate 55.6g, mole
Yield 92.4%, GC Chun Du≤99.0%.
(4) it halogenating reaction: in the reduzate organic phase made from step (3) (containing reduzate 55.6g), is added
2.0gMDF, 25~40 DEG C of temperature control, 36.0g thionyl chloride is added dropwise in heat preservation, after being added dropwise to complete, reacts 4.0 hours, by reaction system
It is slowly added into 0~5 DEG C of aqueous sodium carbonate that (800g, sodium carbonate mass fraction are that 8%), layering, organic layer adds
200g water washing, after stratification, 24g anhydrous sodium sulfate is added in organic layer, controls 10~20 DEG C of temperature, and stirring is 1 hour dry,
Filtering, 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- ehtylethanolamine, 0.6g tetrabutylammonium bromide, 25g potassium hydroxide, 240g chloroform,
120g water is added in reaction flask, then controls 20~30 DEG C of temperature, and the chloro- 2 pentanone of 38g 5- is added dropwise, and after being added dropwise, stirring is anti-
It answers 3 hours, stratification, water phase discards, and organic layer adds 24g anhydrous sodium sulfate, controls 10~20 DEG C of temperature, stirring dry 1 is small
When, filtering, filtrate is condensation product organic phase, detects its content, condensation product 50.2g, molar yield 91.9% is (with 5-
Chloro- 2 pentanone meter), GC Chun Du≤98.5%.
(2) esterification: being cooled to 0~5 DEG C for condensation product organic phase (condensation product 50.2g) made from step (1),
24g chloroacetic chloride is added dropwise in heat preservation, and after being added dropwise, insulation reaction 2 hours, reaction solution was slowly added to be cooled in advance by end of reaction
(350g, sodium carbonate mass fraction are 6%), to stir 30 minutes, and layering, organic layer adds 200g water in 0~5 DEG C of aqueous sodium carbonate
24g anhydrous sodium sulfate is added in washing, layering, organic layer, controls 10~20 DEG C of temperature, and stirring is 1 hour dry, and filtering obtains ester
Change product organic phase, detects its content, esterification products 57.4g, molar yield 92.4%, GC Chun Du≤99.0%.
(3) reduction reaction: 40g second is added in (containing esterification products 57.4g) in the esterification products organic phase made from step (2)
Alcohol is cooled to -5~0 DEG C, is slowly added to 12.0g sodium borohydride, adds rear insulation reaction 2.0 hours, and 180g water, stirring is added
30 minutes, 24g anhydrous sodium sulfate was added in stratification, then primary, the stratification with 100g water washing, organic layer, controlled temperature
10~20 DEG C, stirring dry 1 hour, filtering obtained reduzate organic phase, detected its content, reduzate 54.4g, mole
Yield 93.8%, GC Chun Du≤99.0%.
(4) it halogenating reaction: in the reduzate organic phase made from step (3) (containing reduzate 54.4g), is added
2.0gMDF, 25~40 DEG C of temperature control, 39.0g thionyl chloride is added dropwise in heat preservation, after being added dropwise to complete, reacts 4.0 hours, by reaction system
It is slowly added into 0~5 DEG C of aqueous sodium carbonate that (800g, sodium carbonate mass fraction are that 8%), layering, organic layer adds
200g water washing, after stratification, 24g anhydrous sodium sulfate is added in organic layer, controls 10~20 DEG C of temperature, and stirring is 1 hour dry,
Filtering, 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 protection reaction: 45g 4- amino -7- chloroquinoline, 5g DMF are added in 180g chloroform, are warming up to 30~40
DEG C, 50.0g paratoluensulfonyl chloride is added, reacts 3 hours, after the reaction was completed, reaction system is added to 0~10 DEG C of sodium hydroxide
(200g, sodium hydroxide mass fraction are 8%) layering, and organic layer adds 100g washing, layering, and organic layer subtracts in aqueous solution
Concentration and recovery chloroform to be pressed, 100g methanol is added, 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 80g, mole 95.5%, Chun Du≤99.5%.
(B) condensation reaction: (contain side chain 56.8g) in the side chain organic phase made from embodiment 1 and 78.0g step (A) is added
4-Tos amino -7- chloroquinoline obtained, 3.0g tetrabutylammonium bromide are warming up to 65~70 DEG C of reactions, after reaction 6.0 hours, body
System is cooled to 20~30 DEG C, and into 30~40 DEG C of sodium hydrate aqueous solution, (300g, sodium hydroxide mass fraction are for addition
15%) 30~40 DEG C, are kept the temperature to react 6.0 hours, is cooled to 10~15 DEG C, stratification, after organic layer concentration and recovery chloroform
To hydroxyl quinoline base crude product, 95% ethyl alcohol of 260g is added, temperature rising reflux dissolved clarification is cooled to 0~10 DEG C, recrystallizes, filtering, 50
~60 DEG C dry to obtain hydroxyl quinoline base 110.4g, molar yield 96.1% (in terms of 4- amino -7- chloroquinoline), Chun Du≤99.5%.
(C) salt-forming reaction: hydroxyl quinoline base made from 70g step (B), 95% ethyl alcohol of 200g is taken to be added in reaction flask, heating
To 50~60 DEG C, dissolution is added dropwise the sulfuric acid that 18.8g mass fraction is 80%, rear insulation reaction is added dropwise 1 hour, is cooled to 0
~10 DEG C crystallize 2.0 hours, and filtering, 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 protection reaction: 45g 4- amino -7- chloroquinoline, 5g DMF are added in 180g chloroform, are warming up to 30~40
DEG C, 52.0g paratoluensulfonyl chloride is added, reacts 4 hours, after the reaction was completed, reaction system is added to 0~10 DEG C of sodium hydroxide
(200g, sodium hydroxide mass fraction are 8%) layering, and organic layer adds 100g washing, layering, and organic layer subtracts in aqueous solution
Concentration and recovery chloroform to be pressed, 100g methanol is added, 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 81.3g, mole 97.02%, Chun Du≤99.5%.
(B) condensation reaction: (contain side chain 53.8g) in the side chain organic phase made from embodiment 2 and 72.0g step (A) is added
4-Tos amino -7- chloroquinoline obtained, 2.5g tetrabutylammonium bromide are warming up to 65~70 DEG C of reactions, after reaction 6.0 hours, body
System is cooled to 20~30 DEG C, and into 30~40 DEG C of sodium hydrate aqueous solution, (300g, sodium hydroxide mass fraction are for addition
15%) 30~40 DEG C, are kept the temperature to react 6.0 hours, is cooled to 10~15 DEG C, stratification, after the concentrated recycling chloroform of organic layer
Obtain hydroxyl quinoline base crude product, then plus 95% ethyl alcohol of 260g, temperature rising reflux dissolved clarification, be cooled to 0~10 DEG C, recrystallize, filtering, 50
~60 DEG C dry to obtain hydroxyl quinoline base 101.9g, molar yield 95.3% (in terms of 4- amino -7- chloroquinoline), Chun Du≤99.5%.
(C) salt-forming reaction: hydroxyl quinoline base made from 70g step (B), 95% ethyl alcohol of 200g is taken to be added in reaction flask, heating
To 50~60 DEG C, dissolution is added dropwise the sulfuric acid that 18.8g mass fraction is 80%, rear insulation reaction is added dropwise 1 hour, is cooled to 0
~10 DEG C crystallize 2.0 hours, and filtering, 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 protection reaction: 45g 4- amino -7- chloroquinoline, 5g DMF are added in 180g chloroform, are warming up to 30~40
DEG C, 52.0g paratoluensulfonyl chloride is added, reacts 4 hours, after the reaction was completed, reaction system is added to 0~10 DEG C of sodium hydroxide
(200g, sodium hydroxide mass fraction are 8%) layering, and organic layer adds 100g washing, layering, and organic layer subtracts in aqueous solution
Concentration and recovery chloroform to be pressed, 100g methanol is added, 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 80.6g, mole 96.19%, Chun Du≤99.5%.
(B) condensation reaction: (contain side chain 57.0g) in the side chain organic phase made from embodiment 3 and 72.0g step (A) is added
4-Tos amino -7- chloroquinoline obtained, 2.5g tetrabutylammonium bromide are warming up to 65~70 DEG C of reactions, after reaction 6.0 hours, body
System is cooled to 20~30 DEG C, and into 30~40 DEG C of sodium hydrate aqueous solution, (300g, sodium hydroxide mass fraction are for addition
15%) 30~40 DEG C, are kept the temperature to react 6.0 hours, is cooled to 10~15 DEG C, stratification, after the concentrated recycling chloroform of organic layer
Obtain hydroxyl quinoline base crude product, then plus 95% ethyl alcohol of 260g, temperature rising reflux dissolved clarification, be cooled to 0~10 DEG C of recrystallization, filter, 50~
60 DEG C dry to obtain hydroxyl quinoline base 100.7g, molar yield 95.0% (in terms of 4- amino -7- chloroquinoline), Chun Du≤99.5%.
(C) salt-forming reaction: hydroxyl quinoline base made from 70g step (B), 95% ethyl alcohol of 200g is taken to be added in reaction flask, heating
To 50~60 DEG C, dissolution is added dropwise the sulfuric acid that 18.8g mass fraction is 80%, rear insulation reaction is added dropwise 1 hour, is cooled to 0
~10 DEG C crystallize 2.0 hours, and filtering, 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 protection reaction: 45g 4- amino -7- chloroquinoline, 5g DMF are added in 180g chloroform, are warming up to 30~40
DEG C, 52.0g paratoluensulfonyl chloride is added, reacts 4 hours, after the reaction was completed, reaction system is added to 0~10 DEG C of sodium hydroxide
(200g, sodium hydroxide mass fraction are 8%) layering, and organic layer adds 100g washing, layering, organic layer warp in aqueous solution
Recycling chloroform is concentrated under reduced pressure, adds 100g methanol, 30 minutes dissolved clarifications of temperature rising reflux are cooled to 0~5 DEG C of recrystallization, filtering, and 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 the side chain organic phase made from embodiment 4 and 75.0g step (A) is added
4-Tos amino -7- chloroquinoline obtained, 3.0g tetrabutylammonium bromide are warming up to 60~65 DEG C of reactions, after reaction 6.0 hours, body
System is cooled to 20~30 DEG C, and into 30~40 DEG C of sodium hydrate aqueous solution, (300g, sodium hydroxide mass fraction are for addition
15%) 30~40 DEG C, are kept the temperature to react 6.0 hours, is cooled to 10~15 DEG C, stratification, after the concentrated recycling chloroform of organic layer
Obtain hydroxyl quinoline base crude product, then plus 95% ethyl alcohol of 260g, temperature rising reflux dissolved clarification, be cooled to 0~10 DEG C of recrystallization, filter, 50~
60 DEG C dry to obtain hydroxyl quinoline base 103.4g, molar yield 93.6% (in terms of 4- amino -7- chloroquinoline), Chun Du≤99.5%.
(C) salt-forming reaction: hydroxyl quinoline base made from 70g step (B), 95% ethyl alcohol of 200g is taken to be added in reaction flask, heating
To 50~60 DEG C, dissolution is added dropwise the sulfuric acid that 18.8g mass fraction is 80%, rear insulation reaction is added dropwise 1 hour, is cooled to 0
~10 DEG C crystallize 2.0 hours, and filtering, 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), will be with opposed polarity using high pressure transfusion system using liquid as mobile phase
The mobile phases such as the mixed solvent of single solvent or different proportion, buffer are pumped into the chromatographic column equipped with stationary phase, in column respectively at
Divide after being separated, detected into detector, to realize the analysis to sample.Hydroxychloroquine sulfate made from embodiment 5
The HPLC map of sample is as shown in Fig. 2, the HPLC map of hydroxychloroquine sulfate reference substance is as shown in Figure 3.
Pass through the comparison of Fig. 2 and Fig. 3 it is clear that, hydroxychloroquine sulfate prepared by the present invention is compared to sulfuric acid hydroxyl
Chloroquine reference substance, dopant species are few, total purity is high, and largest single impurity purity is lower, are better than reference substance in quality.
It is as described above the embodiment of the present invention.The present invention is not limited to the above-described embodiments, anyone should learn that
The structure change made under the inspiration of the present invention, the technical schemes that are same or similar to the present invention each fall within this
Within the protection scope of invention.
Claims (7)
1. a kind of side chain, structural formula are as follows:
Wherein, R Cl, Br or I.
2. a kind of synthetic method of side chain described in claim 1, which comprises the following steps:
(1) condensation reaction: N- ehtylethanolamine, phase transfer catalyst, inorganic base, organic solvent are added to the water, and control temperature
It is 20~30 DEG C, the chloro- 2 pentanone of 5- is added dropwise and reacts 2~6 hours, is layered after the reaction was completed, is condensed after taking organic layer dry
Product organic phase；
(2) esterification: the condensation product organic phase is cooled to 0~10 DEG C, and heat preservation is added dropwise acetoinices and reacts 1~3 hour,
After the reaction was completed, it is layered, washing, obtains esterification products organic phase after taking organic layer dry；
(3) reduction reaction: being cooled to -5~0 DEG C for the esterification products organic phase, and reducing agent is added and reacts 1~4 hour, is added
Water, layering obtain reduzate organic phase after taking organic layer dry；Wherein, reducing agent is sodium borohydride, potassium borohydride or borine
Ether；
(4) halogenating reaction: being added catalyst in reduzate organic phase, and controlled at 25~40 DEG C, heat preservation is added dropwise halogenated
Reagent reacts 3~8 hours, is layered, washing, obtains side chain organic phase after taking organic layer dry；Wherein, halogenating agent is protochloride
Sulfone, phosphorus trichloride, thionyl bromide, phosphorus tribromide, phosphorus pentabromide, N- chlorosuccinimide, N- bromo-succinimide or N-
N-iodosuccinimide, catalyst are n,N-Dimethylformamide.
3. a kind of synthetic method of side chain according to claim 2, which is characterized in that the esterification and halogenating reaction are complete
Cheng Hou is needed for reaction system to be added in inorganic base aqueous solution and be reacted before being layered.
4. a kind of synthetic method of side chain according to claim 2, which is characterized in that in the step (1), phase transfer catalysis (PTC)
Agent is tetrabutylammonium bromide, 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, which is characterized in that in the step (2), acetoinices are
Chloroacetic chloride or aceticanhydride.
6. using the method for the side chain synthesis hydroxychloroquine sulfate as described in any one of claim 1-5, which is characterized in that packet
Include following steps:
(A) N protection reaction: 4- amino -7- chloroquinoline, cosolvent are added in organic solvent, are warming up to 30~40 DEG C, is added
Paratoluensulfonyl chloride reacts 2~6 hours, is layered, and washing is concentrated, recrystallizes, dries to obtain 4-Tos amino -7- chloroquinoline；Its
In, cosolvent DMF, DMSO or dioxane；
(B) condensation reaction: in side chain organic phase, catalyst and 4-Tos amino -7- chloroquinoline is added, is warming up to 60~80 DEG C
Reaction is cooled to 5~20 DEG C after the reaction was completed, and layering obtains hydroxyl quinoline base crude product, recrystallization, drying after organic layer is concentrated
After obtain hydroxyl quinoline base；Wherein, catalyst is potassium iodide, sodium iodide, tetrabutylammonium bromide, DMAP or pyridine；
(C) salt-forming reaction: the hydroxyl quinoline base is added in alcohols solvent, is warming up to 50~60 DEG C, after dissolution completely, is added dropwise
Sulfuric acid reacts 1 hour, is cooled to 0~10 DEG C of crystallization, obtains hydroxychloroquine sulfate after drying.
7. synthesizing the method for hydroxychloroquine sulfate according to claim 6, which is characterized in that in the step (A) and (B),
After the reaction was completed, it before being layered, needs for reaction system to be added in inorganic base aqueous solution and react.
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| CN108689929A (en) * | 2018-07-05 | 2018-10-23 | 上海中西三维药业有限公司 | A kind of preparation method of hydroxychloroquine and its sulfate |
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