CN108003097A - A kind of synthetic method of cinchocaine - Google Patents

A kind of synthetic method of cinchocaine Download PDF

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Publication number
CN108003097A
CN108003097A CN201711434689.9A CN201711434689A CN108003097A CN 108003097 A CN108003097 A CN 108003097A CN 201711434689 A CN201711434689 A CN 201711434689A CN 108003097 A CN108003097 A CN 108003097A
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CN
China
Prior art keywords
cinchocaine
synthetic method
chloro
diethylamino
ethyl
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Pending
Application number
CN201711434689.9A
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Chinese (zh)
Inventor
王庭见
杨彦军
王文新
胡俊峰
李春杰
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Shandong Yunjia Pharmaceutical Co Ltd
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Shandong Yunjia Pharmaceutical Co Ltd
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Priority to CN201711434689.9A priority Critical patent/CN108003097A/en
Publication of CN108003097A publication Critical patent/CN108003097A/en
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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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4

Abstract

The invention belongs to pharmaceutical chemistry technical field, and in particular to a kind of synthetic method of cinchocaine.This method has synthesized cinchocaine using 2 chlorine N [2 (diethylamino) ethyl] 4 quinoline formyl amine, n-butanol, sodium hydroxide as raw material.The synthetic method of the present invention has the advantages that molar yield is high, of low cost, safe and environment-friendly, is more suitable for industrializing.

Description

A kind of synthetic method of cinchocaine
Technical field
The invention belongs to pharmaceutical chemistry technical field, and in particular to a kind of synthetic method of cinchocaine, this method have The characteristics of safety and environmental protection.
Background technology
Cinchocaine Chinese nickname dibucaine, hundred cacaine of slave, cincaine, chemical name 2- butoxy-N- [2- (two Ethylamino) ethyl] -4- quinoline formyl amine, No. CAS：85-79-0, its structural formula are：
。
Cinchocaine is a kind of local anaesthesia medication, available for caudal anaesthesia and lumbar anesthesia, easily by mucous membrane, is also used for Surface anesthesia, but because its toxicity is larger, it is less to be used for infiltration anesthesia.When cinchocaine hydrochloride has anesthetic effect as anesthetic Between it is long the characteristics of, local anaesthesia effect is 22-25 times bigger than procaine.Cinchocaine hydrochloride is amide-type long effective local anesthetic, with nerve The temporary transient Percentage bound of tissue is more than totokaine, works short, action effective individual difference is big, may be with the blood vessel dilatation of cinchocaine Effect degree and absorption speed differ related.Cinchocaine has good permeability, nonirritant to local organization.
In the prior art the preparation method of cinchocaine be mainly seen in CN106496120, US1825623, US4839366 and J Labelled Comp Radiopharm.1985,V22 (2),117-125.These are adopted when being reported in synthesis cinchocaine Prepare n-butanol sodium with metallic sodium, then with the reaction synthesis of the chloro- N- of 2- [2- (diethylamino) ethyl] -4- quinoline formyls amine is pungent can Cacaine, the preparation method is there are great security risk because the chemical property of metallic sodium is very active, during room temperature just with oxygen, Water vigorous reaction, in last handling process easily and the serious consequences such as the inorganic matter vigorous reaction such as water, oxygen causes to explode, Er Qieding Sodium alkoxide alkalescence is strong, and the impurity produced in reaction process is more, and yield is relatively low, is unfavorable for industrialized production.
The content of the invention
In order to solve above-mentioned technical problem, the present invention provides a kind of synthetic method of cinchocaine, this method has The characteristics of safety and environmental protection.
The present invention is realized by following technical solutions：
A kind of synthetic method of cinchocaine, including following steps：
The chloro- N- of 2- [2- (diethylamino) ethyl] -4- quinoline formyls amine reacts to obtain cinchocaine with n-butanol, acid binding agent.
The acid binding agent for potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, triethylamine, one kind in diethylamine or It is a variety of.Preferably, the acid binding agent is sodium hydroxide.
The organic solvent is one in petroleum ether, n-hexane, normal heptane, normal octane, hexamethylene, toluene, dimethylbenzene Kind is a variety of.Preferably, the organic solvent is n-hexane.
The synthetic method of above-mentioned cinchocaine, includes the following steps：
The chloro- N- of 2- [2- (diethylamino) ethyl] -4- quinoline formyls amine, sodium hydroxide are added to n-butanol, n-hexane In solution, reflux water-dividing, reaction obtains cinchocaine.
Synthetic route is as follows：
Preferably, the synthetic method of above-mentioned cinchocaine, includes the following steps：
The chloro- N- of 2- [2- (diethylamino) ethyl] -4- quinoline formyls amine, sodium hydroxide are added to n-butanol, n-hexane In solution, reflux water-dividing, after reaction, cooling, adds deionized water and stirs, liquid separation removing water phase, organic phase low temperature crystallization, Filtering, obtains cinchocaine.
In the synthetic method of above-mentioned cinchocaine, the chloro- N- of 2- [2- (diethylamino) the ethyl] -4- quinoline formyls The weight ratio of amine and n-hexane is 1：2 ~ 10, the chloro- N- of 2- [2- (diethylamino) the ethyl] -4- quinoline formyls amine and positive fourth The weight ratio of alcohol is 1：0.25 ~ 1, the chloro- N- of 2- [2- (diethylamino) the ethyl] -4- quinoline formyls amine and sodium hydroxide Weight ratio is 1：0.13 ~ 0.33, the chloro- N- of 2- [2- (diethylamino) the ethyl] -4- quinoline formyls amine and deionized water Weight ratio is 1：1~5.
The synthetic method of above-mentioned cinchocaine, comprises the following steps that：
The chloro- N- of 2- [2- (diethylamino) ethyl] -4- quinoline formyls amine, sodium hydroxide are added to n-butanol, n-hexane In solution, reflux water-dividing is to slowly warm up to, after dividing water, is cooled to room temperature, adds deionized water stirring 1h, static layering 0.5h, liquid separation remove water phase, and organic phase adds deionized water stirring 0.5h, and static layering 0.5h, liquid separation removes water phase, organic 0 ~ 10 DEG C of stirring and crystallizing 8h of phase, gets rid of material, drying obtains cinchocaine fine work.
In the present invention, refered in particular to Ru non-, all amounts are unit of weight, and all raw material, equipment can be purchased from market .
The beneficial effects of the present invention are：
（1）When synthesizing cinchocaine, the present inventor uses sodium hydroxide substituted metal sodium, and reflux water-dividing synthesizes in n-hexane Cinchocaine, this method disposably put into all raw materials, enormously simplify operation, security significantly carries when post processing adds water Height, and reaction process accessory substance is reduced, and can obtain cinchocaine fine work without refined, yield greatly improves.
（2）Because metallic sodium chemical property is active, it is easy to sky gas and water and acutely chemical reaction occurs, there is the peaces such as catch fire, explode Full hidden danger, is unfavorable for industrializing, and the present invention uses sodium hydroxide substituted metal sodium, and post processing plus water extraction are gone out and will not be occurred when reacting The security risk such as catch fire, explode, building-up process is more environmentally-friendly, safety, more conducively industrializes.
（3）, it is necessary to first prepare n-butanol sodium with metallic sodium in previously reported synthetic method, then with the chloro- N- [2- of 2- (diethylamino) ethyl] reaction of -4- quinoline formyls amine, post processing needs extraction to go out metallic sodium or n-butanol sodium, and operation is relatively numb It is tired.Raw materials used disposable input, reflux water-dividing, reaction end are easily determined when the present invention feeds intake, divides to anhydrous and reacts Finish, operation is simple, clearly.
（4）In previously reported synthetic method, often using n-butanol as solvent, its dosage is generally the chloro- N- [2- of 2- (diethylamino) ethyl] 7 ~ 10 times of -4- quinoline formyl amine quality, and the metallic sodium market price is higher.The present invention is by positive fourth The dosage of alcohol is reduced to 0.25 ~ 1 times of the chloro- N- of 2- [2- (diethylamino) ethyl] -4- quinoline formyl amine quality, sodium hydroxide Price be far below metallic sodium, cost of material is greatly reduced.
（5）Yield greatly improved in gained cinchocaine of the invention, and without refined i.e. qualification, greatly reduces and be produced into This, more conducively industrializes.
Embodiment
The present invention is further described with reference to specific embodiment, so that those skilled in the art knows more about this hair It is bright, but be not intended to limit the present invention.
Embodiment 1
The sodium hydroxide of the chloro- N- of the 2- of 150g [2- (diethylamino) ethyl] -4- quinoline formyls amine, 39g are being added to 90g just Butanol, 600g n-hexane solution in, be to slowly warm up to reflux water-dividing, divide water to finish, be cooled to room temperature, add deionized water 1h, static layering 0.5h are stirred, liquid separation removes water phase, and organic phase adds deionized water stirring 0.5h, and liquid separation removes water phase, has 0 ~ 10 DEG C of stirring and crystallizing 8h of machine phase, filtering, drying obtain cinchocaine fine work 162.5g, molar yield 96.4%, liquid phase purity 99.9%。
Embodiment 2
The sodium hydroxide of the chloro- N- of the 2- of 150g [2- (diethylamino) ethyl] -4- quinoline formyls amine, 39g are being added to 90g just Butanol, 600g petroleum ether solution in, be to slowly warm up to reflux water-dividing, divide water to finish, be cooled to room temperature, add deionized water 1h, static layering 0.5h are stirred, liquid separation removes water phase, and organic phase adds deionized water stirring 0.5h, static layering 0.5h, point Liquid removes water phase, 0 ~ 10 DEG C of stirring and crystallizing 8h of organic phase, and filtering, drying obtain cinchocaine fine work 160.3g, molar yield 95.1%, liquid phase purity 99.9%.
Embodiment 3
The potassium carbonate of the chloro- N- of the 2- of 150kg [2- (diethylamino) ethyl] -4- quinoline formyls amine, 135kg are added to 90kg N-butanol, 600kg toluene solution in, be to slowly warm up to reflux water-dividing, divide water to finish, be cooled to room temperature, add deionization Water stirs 1h, static layering 2h, and liquid separation removes water phase, and organic phase adds deionized water stirring 0.5h, static layering 0.5h, point Liquid removes water phase, 0 ~ 10 DEG C of stirring and crystallizing 8h of organic phase, and filtering, drying obtain cinchocaine fine work 158.0g, molar yield 93.8%, liquid phase purity 99.8%.
Embodiment 4
The potassium carbonate of the chloro- N- of the 2- of 150g [2- (diethylamino) ethyl] -4- quinoline formyls amine, 135g are being added to 100g just Butanol, 600g normal heptane solution in, be to slowly warm up to reflux water-dividing, divide water to finish, be cooled to room temperature, add deionized water 1h, static layering 0.5h are stirred, liquid separation removes water phase, and organic phase adds deionized water stirring 0.5h, static layering 0.5h, point Liquid removes water phase, 0 ~ 10 DEG C of stirring and crystallizing 8h of organic phase, and filtering, drying obtain cinchocaine fine work 162.1g, molar yield 96.2%, liquid phase purity 99.8%.
Embodiment 5
The sodium hydroxide of the chloro- N- of the 2- of 150g [2- (diethylamino) ethyl] -4- quinoline formyls amine, 35g are being added to 90g just Butanol, 600g dimethylbenzene solution in, be to slowly warm up to reflux water-dividing, divide water to finish, be cooled to room temperature, add deionized water 1h, static layering 0.5h are stirred, liquid separation removes water phase, and organic phase adds deionized water stirring 0.5h, static layering 0.5h, point Liquid removes water phase, 0 ~ 10 DEG C of stirring and crystallizing 8h of organic phase, and filtering, drying obtain cinchocaine fine work 158.8g, molar yield 94.2%, liquid phase purity 99.9%.
Embodiment 6
The potassium hydroxide of the chloro- N- of the 2- of 150g [2- (diethylamino) ethyl] -4- quinoline formyls amine, 55g are being added to 90g just Butanol, 1000g hexamethylene solution in, be to slowly warm up to reflux water-dividing, divide water to finish, be cooled to room temperature, add deionization Water stirs 1h, static layering 0.5h, and liquid separation removes water phase, and organic phase adds deionized water stirring 0.5h, static layering 0.5h, Liquid separation removes water phase, 0 ~ 10 DEG C of stirring and crystallizing 8h of organic phase, and filtering, drying obtain cinchocaine fine work 153.2g, molar yield 90.9%, liquid phase purity 99.7%.
Embodiment 7
The sodium carbonate of the chloro- N- of the 2- of 150g [2- (diethylamino) ethyl] -4- quinoline formyls amine, 100g are being added to 100g just Butanol, 600g normal octane solution in, be to slowly warm up to reflux water-dividing, divide water reaction to finish, be cooled to room temperature, addition go from Sub- water stirs 1h, static layering 0.5h, and liquid separation removes water phase, and organic phase adds deionized water stirring 0.5h, static layering 0.5h, liquid separation remove water phase, 0 ~ 10 DEG C of stirring and crystallizing 8h of organic phase, and filtering, drying obtain cinchocaine fine work 158.8g, mole Yield 94.2%, liquid phase purity 99.8%.
Embodiment 8
The triethylamine of the chloro- N- of the 2- of 150g [2- (diethylamino) ethyl] -4- quinoline formyls amine, 100g are being added to 135g just Butanol, 800g dimethylbenzene solution in, be to slowly warm up to reflux water-dividing, divide water reaction to finish, be cooled to room temperature, addition go from Sub- water stirs 1h, static layering 0.5h, and liquid separation removes water phase, and organic phase adds deionized water stirring 0.5h, static layering 0.5h, liquid separation remove water phase, 0 ~ 10 DEG C of stirring and crystallizing 8h of organic phase, and filtering, drying obtain cinchocaine fine work 152.8g, mole Yield 90.7%, liquid phase purity 99.9%.
Embodiment 9
The diethylamine of the chloro- N- of the 2- of 150g [2- (diethylamino) ethyl] -4- quinoline formyls amine, 100g are being added to 150g just Butanol, 800g normal octane solution in, be to slowly warm up to reflux water-dividing, divide water reaction to finish, be cooled to room temperature, addition go from Sub- water stirs 1h, static layering 0.5h, and liquid separation removes water phase, and organic phase adds deionized water stirring 0.5h, static layering 0.5h, liquid separation remove water phase, 0 ~ 10 DEG C of stirring and crystallizing 8h of organic phase, and filtering, drying obtain cinchocaine fine work 156.9g, mole Yield 93.1%, liquid phase purity 99.7%.

Claims (9)

1. a kind of synthetic method of cinchocaine, including following steps：
The chloro- N- of 2- [2- (diethylamino) ethyl] -4- quinoline formyls amine reacts to obtain cinchocaine with n-butanol, acid binding agent.
2. the synthetic method of cinchocaine according to claim 1, it is characterised in that the acid binding agent is hydroxide One or more in potassium, sodium hydroxide, potassium carbonate, sodium carbonate, triethylamine, diethylamine.
3. the synthetic method of cinchocaine according to claim 2, it is characterised in that the acid binding agent is hydroxide Sodium.
4. the synthetic method of cinchocaine according to claim 1, it is characterised in that the organic solvent is oil One or more in ether, n-hexane, normal heptane, normal octane, hexamethylene, toluene, dimethylbenzene.
5. the synthetic method of cinchocaine according to claim 4, it is characterised in that the organic solvent for just oneself Alkane.
6. the synthetic method of cinchocaine according to claim 1, it is characterised in that include the following steps：
The chloro- N- of 2- [2- (diethylamino) ethyl] -4- quinoline formyls amine, sodium hydroxide are added to n-butanol, n-hexane In solution, reflux water-dividing, reaction obtains cinchocaine.
7. the synthetic method of cinchocaine according to claim 6, it is characterised in that include the following steps：
The chloro- N- of 2- [2- (diethylamino) ethyl] -4- quinoline formyls amine, sodium hydroxide are added to n-butanol, n-hexane In solution, reflux water-dividing, after reaction, cooling, adds deionized water and stirs, liquid separation removing water phase, organic phase low temperature crystallization, Filtering, obtains cinchocaine.
8. the synthetic method of cinchocaine according to claim 7, it is characterised in that the chloro- N- of the 2- [2- (diethyl Amino) ethyl] weight ratio of -4- quinoline formyls amine and n-hexane is 1：2 ~ 10, the described chloro- N- of 2- [2- (diethylamino) second Base] weight ratio of -4- quinoline formyls amine and n-butanol is 1：0.25 ~ 1, the chloro- N- of 2- [2- (diethylamino) the ethyl] -4- The weight ratio of quinoline formyl amine and sodium hydroxide is 1：0.13 ~ 0.33, the chloro- N- of 2- [2- (diethylamino) the ethyl] -4- The weight ratio of quinoline formyl amine and deionized water is 1：1~5.
9. the synthetic method of cinchocaine according to claim 7, it is characterised in that comprise the following steps that：
The chloro- N- of 2- [2- (diethylamino) ethyl] -4- quinoline formyls amine, sodium hydroxide are added to n-butanol, n-hexane In solution, reflux water-dividing is to slowly warm up to, after dividing water, is cooled to room temperature, adds deionized water stirring 1h, static layering 0.5h, liquid separation remove water phase, and organic phase adds deionized water stirring 0.5h, and static layering 0.5h, liquid separation removes water phase, organic Mutually in 0 ~ 10 DEG C of stirring and crystallizing 8h, material is got rid of, drying obtains cinchocaine fine work.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109456218A (en) * 2018-12-17 2019-03-12 山东诚汇双达药业有限公司 A kind of production method of trimecaine hydrochloride

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US1825623A (en) * 1931-09-29 Oonhohachzn
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CN106496120A (en) * 2016-10-14 2017-03-15 昆明源瑞制药有限公司 A kind of preparation method of cinchocaine hydrochloride
CN107586277A (en) * 2017-06-01 2018-01-16 合肥远志医药科技开发有限公司 A kind of preparation method of cinchocaine hydrochloride

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US1825623A (en) * 1931-09-29 Oonhohachzn
JPS58216159A (en) * 1982-06-11 1983-12-15 Yodogawa Seiyaku Kk Production of quinoline derivative
CN106496120A (en) * 2016-10-14 2017-03-15 昆明源瑞制药有限公司 A kind of preparation method of cinchocaine hydrochloride
CN107586277A (en) * 2017-06-01 2018-01-16 合肥远志医药科技开发有限公司 A kind of preparation method of cinchocaine hydrochloride

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109456218A (en) * 2018-12-17 2019-03-12 山东诚汇双达药业有限公司 A kind of production method of trimecaine hydrochloride

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