CN105418488A - Preparation method of donepezil hydrochloride - Google Patents
Preparation method of donepezil hydrochloride Download PDFInfo
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- CN105418488A CN105418488A CN201511030894.XA CN201511030894A CN105418488A CN 105418488 A CN105418488 A CN 105418488A CN 201511030894 A CN201511030894 A CN 201511030894A CN 105418488 A CN105418488 A CN 105418488A
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- ODUWQNYJVORKHM-UHFFFAOYSA-N CCC(C=C(CC1CC2CCNCC2)C(C2)C1=C)=C2OC Chemical compound CCC(C=C(CC1CC2CCNCC2)C(C2)C1=C)=C2OC ODUWQNYJVORKHM-UHFFFAOYSA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Cc1ccccc1 Chemical compound Cc1ccccc1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a preparation method of donepezil hydrochloride. The preparation method comprises the steps that 3-chlorine-1-(3, 4-dimethoxy phenyl) propane-1-ketone (II) is made to react with N-benzyl-4-formyl-piperidine (III) under the condition of a lewis acid ionic liquid catalyst, and 1-benzyl-4-(5, 6dimethoxy-1-indanone-2-methylene)-piperidine (IV) is obtained through a one-pot method, and then the donepezil hydrochloride (I) is obtained through reduction and salt formation. The preparation method of the donepezil hydrochloride has the advantages of being simple in process, low in production cost, environmentally friendly and suitable for industrialized production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, particularly a kind of preparation method of E 2020.
Background technology
E 2020 is the exploitation of Japanese Wei Cai company, the acetylcholinesterase depressant for the treatment of Alzheimer's dementia (AD).Have high selectivity, dosage is little, long half time, and untoward reaction is little, without advantages such as hepatotoxicities.Chemical name is: 1-benzyl-4-[(5,6-dimetlioxyindan ketone-2-base) methyl] piperidine hydrochlorate.E 2020 (I) structural formula is as follows:
Its existing operational path synthesis is as follows:
1) synthetic route of CN201010600277.X report, with N-benzyl-4-piperidine carboxylic acid for compound 4 prepared by raw material, compound 4 and compound 5 carry out Aldol condensation reaction under basic conditions, and then obtain E 2020 through reduction, salify, and synthetic route is as follows:
This route shortcoming is starting raw material 5,6-dimethoxy-1-indone need synthesize (with 3 through polystep reaction, 4-dimethylbenzaldehyde is starting raw material, obtain through condensation, reduction, ring closure reaction), or marketable material is expensive, and using highly basic NaH to carry out Aldol condensation reaction, aftertreatment bothers, and is unfavorable for suitability for industrialized production.
2) CN100436416 reports that synthetic route is as follows:
Take diethyl malonate as starting raw material, by condensation, reduction, replacement, finally close the obtained E 2020s of five step reactions such as ring decarboxylation, step is more, and yield is low.
Summary of the invention
The invention provides that a kind of E 2020 technique is simple, production cost is low, the preparation method of environmental protection.
The preparation method of a kind of E 2020 provided by the invention, comprises the following steps:
A, compound ii and compound III are reacted under Lewis acidic ionic liquid catalysts conditions, and one kettle way obtains compounds Ⅳ;
By adding in reactor by reactant under Lewis acidic ionic liquid catalyst action in the present invention, carry out condensation and pay gram alkylation one kettle way obtaining, reaction formula is as follows:
B, compounds Ⅳ obtain chemical compounds I through reduction, salify.
Lewis acidic ionic liquid catalyzer of the present invention is obtained by reacting by quaternary amine and Lewis acid, and wherein, quaternary amine is triethylamine hydrochloride, chlorination N-alkyl pyridine or chlorination 1,3-dialkylimidazolium; Lewis acid is aluminum trichloride (anhydrous), FERRIC CHLORIDE ANHYDROUS or Zinc Chloride Anhydrous.
Lewis acidic ionic liquid catalyst synthesis step of the present invention is: under nitrogen protection; 1:1 ~ 1:6 is by quaternary amine and Lewis acid batch mixing in molar ratio; control temperature 40 ~ 100 DEG C in mixing process, and keep reaction 3 hours in 40 ~ 100 DEG C, obtain Lewis acidic ionic liquid.
In the compounds of this invention II, compound III and ionic liquid, between Lewis acid, mol ratio is 1:1 ~ 1.1:2 ~ 3.
Aldol condensation reaction temperature of the present invention is 40 ~ 60 DEG C, preferably 55 ~ 60 DEG C, and the time is 4 ~ 5 hours, preferably 4.5 ~ 5 hours; Described pair gram of alkylating temperature of reaction is 145 ~ 175 DEG C, preferably 165 ~ 175 DEG C, and the reaction times is 5 ~ 6 hours, preferably 5.5 ~ 6 hours;
Beneficial effect of the present invention is as follows:
The chloro-1-(3 of 1.3-, 4-Dimethoxyphenyl) propane-1-ketone (II) starting raw material is easy to get, and directly use 5 than (patent CN201010600277.X) in regular course, 6-dimethoxy-1-indone participates in the more economical material benefit of Aldol condensation reaction, and this preparation method, by condensation, pair gram alkylated reaction two step one pot reaction, makes processing step shorten, operation is easy, decrease the purifying of intermediate, dry, reduce production cost.
2. use ionic-liquid catalyst as reaction medium and catalyzer, there is reaction conditions gentleness, product is easily separated with catalyst system, environmental friendliness, yield are high, feature that catalyzer can be recycled.
3. the shortcomings such as Aldol condensation reaction uses Lewis acidic ionic liquid to carry out catalysis, changes traditional inorganic acids or mineral alkali side reaction is many, and corrodibility is strong, and in reaction the complicated and contaminate environment of aftertreatment is serious.
4. carry out catalytic hydrogenation reaction with non-hydrogen Virahol, formic acid for hydrogen source, compared with using the hydrogenation process of hydrogen, have that security is high, reaction conditions is gentle, equipment requirements is low and selectivity advantages of higher.
Embodiment
Below by specific embodiment, summary of the invention of the present invention is described in further detail, but does not therefore limit content of the present invention.
Embodiment 1
Using chlorination 1-ethyl-3-methylimidazole-aluminum chloride as ionic liquid catalyst systems, concrete steps are as follows:
[Emim] Cl-AlCl
3preparation (Emim=1-ethyl-3-methylimidazole)
Device agitator on reactor; add 26.67g (0.2mol) aluminum trichloride (anhydrous) under nitrogen protection; add 29.3g (0.2mol) chlorination 1-ethyl 3-Methylimidazole in batches; remain on about 50 DEG C after adding to stir 3 hours; guarantee to react completely, [Emim] Cl-AlCl of obtained clear, yellowish
3ionic liquid.
The preparation of 1-benzyl-4-(5,6 dimethoxy-1-indone-2-methylene radical)-piperidines (IV)
Under nitrogen protection; the chloro-1-of 3-(3,4-Dimethoxyphenyl) propane-1-ketone (II) 22.9g (0.1mol), N-benzyl-4-piperidyl formaldehgde (III) 20.3g (0.1mol), [Emim] Cl-AlCl is added successively in there-necked flask
3(0.2mol), control temperature 40 ~ 45 DEG C is also held time 4.5 hours, be warmed up to 145 ~ 155 DEG C and maintain reaction 5.5 hours, TLC monitors reaction end, after reaction terminates, be down to room temperature, product and ionic liquid AUTOMATIC ZONING, product layer is poured in 5% hydrochloric acid frozen water, and suction filtration obtains crude product, by re-crystallizing in ethyl acetate, obtain 1-benzyl-4-(5,6 dimethoxy-1-indone-2-methylene radical)-piperidines (IV) 32.5g, yield 86%, purity 99.6%, ionic liquid layer dewater Posterior circle use.
The preparation method referenced patent CN201010600277.X of N-benzyl-4-piperidyl formaldehgde (III).
Embodiment 2
The preparation of ionic liquid
Device agitator on reactor, adds 27.3g (0.2mol) anhydrous ZnCl under nitrogen protection
2, add 34.9g (0.2mol) chlorination 1-butyl-3-Methylimidazole ([Bmim] Cl) in batches.Remain on about 40 DEG C after adding imidazole salts to stir 3 hours, guarantee to react completely, obtained water white [Bmim] Cl-ZnCl
2ionic liquid.
The preparation of 1-benzyl-4-(5,6 dimethoxy-1-indone-2-methylene radical)-piperidines (IV)
Under nitrogen protection; the chloro-1-of 3-(3,4-Dimethoxyphenyl) propane-1-ketone (II) 22.9g (0.1mol), N-benzyl-4-piperidyl formaldehgde (III) 20.3g (0.1mol), [Bmim] Cl-ZnCl is added successively in there-necked flask
2(0.2mol), control temperature 45 ~ 50 DEG C is also held time 4 hours, be warmed up to 155 ~ 165 DEG C and maintain reaction 5 hours, TLC monitors reaction end, after reaction terminates, be down to room temperature, product and ionic liquid AUTOMATIC ZONING, product layer is separated and pours in 5% hydrochloric acid frozen water, and suction filtration obtains crude product, by re-crystallizing in ethyl acetate, obtain 1-benzyl-4-(5,6 dimethoxy-1-indone-2-methylene radical)-piperidines (IV) 31.0g, yield 82%, purity 99.6%, ionic liquid layer dewater Posterior circle use.
Embodiment 3
The preparation of ionic liquid
Device agitator on reactor, adds 40.0g (0.3mol) anhydrous AlCl under nitrogen protection
3, add 27.5g (0.2mol) triethylamine hydrochloride ([Et in batches
3nH] Cl).Remain on about 60 DEG C after adding triethylamine hydrochloride to stir 3 hours, guarantee to react completely, obtained transparent [Et
3nH] Cl-AlCl
3ionic liquid.
The preparation of 1-benzyl-4-(5,6 dimethoxy-1-indone-2-methylene radical)-piperidines (IV)
Under nitrogen protection; the chloro-1-of 3-(3,4-Dimethoxyphenyl) propane-1-ketone (II) 22.9g (0.10mol), N-benzyl-4-piperidyl formaldehgde (III) 22.4g (0.11mol), [Et is added successively in there-necked flask
3nH] Cl-AlCl
3(2:3, by AlCl
3count 0.3mol), control temperature 55 ~ 60 DEG C is also held time 5 hours, be warmed up to 165 ~ 175 DEG C and maintain reaction 6 hours, TLC monitors reaction end, after reaction terminates, be down to room temperature, product and ionic liquid AUTOMATIC ZONING, product layer is poured in 5% hydrochloric acid frozen water, and suction filtration obtains crude product, by re-crystallizing in ethyl acetate, obtain 1-benzyl-4-(5,6 dimethoxy-1-indone-2-methylene radical)-piperidines (IV) 33.6g, yield 89%, purity 99.7%, ionic liquid layer dewater Posterior circle use.
Embodiment 4
The preparation of E 2020 (I)
By 25.8g (0.068mol) compound 1-benzyl-4-(5,6 dimethoxy-1-indone-2-methylene radical)-piperidines (IV) is dissolved in 150ml Virahol, add 2.5g10% palladium charcoal again, mixture reacts 4 hours under normal pressure, temperature 40 DEG C of conditions, Filtration of catalyst, boil off solvent again, the ethyl acetate solution of 10% hydrochloric acid is added in resistates, stirring heating dissolves rear evaporated under reduced pressure, residuum alcohol-ether (2:1) recrystallization obtains E 2020 (I) 25.5g, yield 90%, purity 99.8%.
Embodiment 5
The preparation of E 2020 (I)
By 25.8g (0.068mol) compound 1-benzyl-4-(5,6 dimethoxy-1-indone-2-methylene radical)-piperidines (IV) is dissolved in 150ml Virahol, add 2.5g10% palladium charcoal again, mixture reacts 4 hours under normal pressure, temperature 60 C condition, Filtration of catalyst, boil off solvent again, the ethyl acetate solution of 10% hydrochloric acid is added in resistates, stirring heating dissolves rear evaporated under reduced pressure, residuum alcohol-ether (2:1) recrystallization obtains E 2020 (I) 22.3g, yield 87%, purity 99.8%.
Embodiment 6
The preparation of E 2020 (I)
By 25.8g (0.068mol) compound 1-benzyl-4-(5,6 dimethoxy-1-indone-2-methylene radical)-piperidines (IV) is dissolved in 150ml formic acid, add 2.5g10% palladium charcoal again, mixture reacts 4 hours under normal pressure, temperature 40 DEG C of conditions, Filtration of catalyst, boil off solvent again, the ethyl acetate solution of 10% hydrochloric acid is added in resistates, stirring heating dissolves rear evaporated under reduced pressure, residuum alcohol-ether (2:1) recrystallization obtains E 2020 (I) 25.2g, yield 89%, purity 99.9%.
Claims (7)
1. a preparation method for E 2020, is characterized in that, described preparation method comprises the steps:
A, compound ii and compound III are reacted under Lewis acidic ionic liquid catalysts conditions, and one kettle way obtains compounds Ⅳ;
B, compounds Ⅳ obtain chemical compounds I through reduction, salify;
Synthetic route is as follows:
2. the preparation method of E 2020 according to claim 1, is characterized in that: described in step a, Lewis acidic ionic liquid catalyzer is obtained by reacting by quaternary amine and Lewis acid.
3. the preparation method of E 2020 according to claim 2, is characterized in that: described quaternary amine is triethylamine hydrochloride, chlorination N-alkyl pyridine or chlorination 1,3-dialkylimidazolium.
4. the preparation method of E 2020 according to claim 2, is characterized in that: described Lewis acid is aluminum trichloride (anhydrous), FERRIC CHLORIDE ANHYDROUS or Zinc Chloride Anhydrous.
5. the preparation method of E 2020 according to claim 2; it is characterized in that; Lewis acidic ionic liquid catalyst synthesis step is: under nitrogen protection, by quaternary amine and Lewis acid according to mol ratio 1:1 ~ 1:6 batch mixing, obtains Lewis acidic ionic liquid.
6. according to the preparation method of the E 2020 described in claim 1, it is characterized in that: in step a compound ii, compound III and ionic liquid, between Lewis acid, mol ratio is 1:1 ~ 1.1:2 ~ 3.
7. according to the preparation method of the E 2020 described in claim 1, it is characterized in that: step a concrete steps are: compound ii and compound III are under Lewis acidic ionic liquid catalysts conditions, control temperature of reaction 40 ~ 60 DEG C and hold time 4 ~ 5 hours, Aldol condensation reaction occurs; Be warmed up to 145 ~ 175 DEG C and maintain reaction 5 ~ 6 hours, occurring to pay gram alkylated reaction.
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|---|---|---|---|
| CN201511030894.XA CN105418488B (en) | 2015-12-31 | 2015-12-31 | A kind of preparation method of Doneppezil Hydrochloride |
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| CN201511030894.XA CN105418488B (en) | 2015-12-31 | 2015-12-31 | A kind of preparation method of Doneppezil Hydrochloride |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109354580A (en) * | 2018-11-21 | 2019-02-19 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of Doneppezil Hydrochloride |
| CN111100062A (en) * | 2019-12-30 | 2020-05-05 | 山东罗欣药业集团恒欣药业有限公司 | Synthesis method of donepezil hydrochloride |
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|---|---|---|---|---|
| US20070191610A1 (en) * | 2006-02-16 | 2007-08-16 | Mahesh Nagarimadugu | Process for the preparation of donepezil hydrochloride |
| WO2007108011A2 (en) * | 2006-03-20 | 2007-09-27 | Ind-Swift Laboratories Limited | Process for the preparation of highly pure donepezil |
| CN101671366A (en) * | 2008-09-09 | 2010-03-17 | 王忠卫 | Environmentally-friendly synthesis method for phenylphosphonic dichloride |
| CN102942591A (en) * | 2012-11-21 | 2013-02-27 | 山东科技大学 | Method for synthesizing diphenyl phosphonium chloride |
| CN103480412A (en) * | 2013-08-13 | 2014-01-01 | 滨海雅克化工有限公司 | Ionic liquid catalyst used in preparation of bisphenol A (phenyl polyphosphate) and preparation method thereof |
-
2015
- 2015-12-31 CN CN201511030894.XA patent/CN105418488B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070191610A1 (en) * | 2006-02-16 | 2007-08-16 | Mahesh Nagarimadugu | Process for the preparation of donepezil hydrochloride |
| WO2007108011A2 (en) * | 2006-03-20 | 2007-09-27 | Ind-Swift Laboratories Limited | Process for the preparation of highly pure donepezil |
| CN101671366A (en) * | 2008-09-09 | 2010-03-17 | 王忠卫 | Environmentally-friendly synthesis method for phenylphosphonic dichloride |
| CN102942591A (en) * | 2012-11-21 | 2013-02-27 | 山东科技大学 | Method for synthesizing diphenyl phosphonium chloride |
| CN103480412A (en) * | 2013-08-13 | 2014-01-01 | 滨海雅克化工有限公司 | Ionic liquid catalyst used in preparation of bisphenol A (phenyl polyphosphate) and preparation method thereof |
Non-Patent Citations (1)
| Title |
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| 韩波: "多奈哌齐的新型合成路线研究", 《四川大学硕士学位论文》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109354580A (en) * | 2018-11-21 | 2019-02-19 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of Doneppezil Hydrochloride |
| CN109354580B (en) * | 2018-11-21 | 2020-08-07 | 山东罗欣药业集团股份有限公司 | Preparation method of donepezil hydrochloride |
| CN111100062A (en) * | 2019-12-30 | 2020-05-05 | 山东罗欣药业集团恒欣药业有限公司 | Synthesis method of donepezil hydrochloride |
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