CN111499559B - Method for synthesizing donepezil in water - Google Patents
Method for synthesizing donepezil in water Download PDFInfo
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- CN111499559B CN111499559B CN201910094515.5A CN201910094515A CN111499559B CN 111499559 B CN111499559 B CN 111499559B CN 201910094515 A CN201910094515 A CN 201910094515A CN 111499559 B CN111499559 B CN 111499559B
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2282—Unsaturated compounds used as ligands
- B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
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Abstract
The invention discloses a method for synthesizing donepezil, which comprises the steps of adding 5, 6-dimethoxy indanone, 1-benzyl-4-piperidine methanol, a metal iridium catalyst and potassium hydroxide into a reaction container, heating for reacting for several hours, cooling to room temperature, spin-drying the solvent, and separating by a column to obtain a target compound. The method is characterized in that under the catalytic action of a metal iridium catalyst, 5, 6-dimethoxy indanone and 1-benzyl-4-piperidine methanol react to directly synthesize donepezil, raw materials used in the reaction are commercial reagents, and alcohol is an environment-friendly and low-toxicity chemical reagent; water produced by the reaction is a byproduct, so that the environment pollution is avoided; the atom economy of the reaction is high; the reaction is carried out in water, so the reaction meets the requirement of green chemistry and has wide development prospect.
Description
Technical Field
The invention belongs to the technical field of organic drug synthesis, and particularly relates to a method for synthesizing donepezil.
Background
Donepezil (donepezil) is a long-acting symptomatic treatment of Alzheimer's Disease (AD). AD is an acquired mental decline with impairment of other cognitive functions, primarily manifested as memory decline. Donepezil is a second-generation cholinesterase (ChE) inhibitor whose therapeutic effect is to reversibly inhibit acetylcholinesterase (AchE) induced hydrolysis of acetylcholinesterase to increase acetylcholine content at the receptor site. Donepezil may have other mechanisms including direct action on peptide disposition, neurotransmitter receptors, or Ca2+ channels. Donepezil is suitable for mild and moderate dementia of the alzheimer type. Although the synthesis of donepezil has been developed, the original reports that the synthesis method uses toxic chemical reagents, multiple organic reactions, low atom economy and environmental pollution.
Disclosure of Invention
The invention aims to provide a method for synthesizing donepezil (donepezil).
The invention is realized by the following technical scheme: synthesis of donepezil (formula I)
Is prepared from 5, 6-dimethoxyindanone (formula II)
With 1-benzyl-4-piperidinemethanol (III) in the presence of an iridium complex and a base
Alkylation reaction in water.
The reaction formula is
The synthesis of donepezil by the invention is realized by the following specific steps:
adding 5, 6-dimethoxy indanone (formula II), 1-benzyl-4-piperidine methanol (III), a metal iridium catalyst and potassium hydroxide into a reaction vessel, heating for reacting for several hours, cooling to room temperature, spin-drying the solvent, and separating by a column to obtain the target compound.
The catalyst used in the invention is water-soluble metallic iridium catalyst [ Cp Ir (6,6- (OH)2bpy)(H2O)][OTf]2Or [ (CpIrCl)2(thbpym)][Cl]2The structure is as follows:
the iridium catalyst was used in an amount of 1mol Ir% relative to 5, 6-dimethoxyindanone, 5, 6-dimethoxyindanone relative to 1-benzyl-4-piperidinemethanol relative to 1.3equiv., and the base was used in a molar amount relative to 1-benzyl-4-piperidinemethanol of 1equiv.
Compared with the prior art, the preparation method disclosed by the invention has the advantages that the 5, 6-dimethoxy indanone (formula II) and the 1-benzyl-4-piperidine methanol are reacted under the catalytic action of the metallic iridium catalyst in the synthesis of donepezil, and the reaction is directly synthesized, and the reaction shows remarkable advantages: 1) the raw materials used in the reaction are commercial reagents, and the alcohol is an environment-friendly and low-toxicity chemical reagent; 2) water produced by the reaction is a byproduct, so that the environment pollution is avoided; 3) the atom economy of the reaction is high; 4) therefore, the reaction meets the requirement of green chemistry and has wide development prospect.
Detailed Description
The following examples are shown to illustrate certain embodiments of the present invention and should not be construed as limiting the scope of the invention. Many modifications, variations and changes in materials, methods and reaction conditions may be made simultaneously with respect to the disclosure herein. All such modifications, variations and changes are intended to fall within the spirit and scope of the present invention.
Example 1:
mixing 1-benzyl-4-piperidinemethanol (103mg,0.5mmol), 5, 6-dimethoxy indenone (125mg,0.65mmol,1.3equiv), [ Cp X Ir (6,6- (OH)2bpy)(H2O)][OTf]2(2.5mg,0.0025mmol,0.5 mol%), potassium hydroxide (28mg,0.5mmol,1equiv) and water (1mL) were added in this order to a dry 25mL reaction mixture, reacted at 130 ℃ for 12 hours, and then cooled to room temperature. The solvent was removed by rotary evaporation and then purified by column chromatography (developing solvent: petroleum ether/ethyl acetate) to give the pure title compound in the following yields: 80 percent.1H NMR(500MHz,DMSO-d6)δ7.33-7.25(m,4H,ArH),7.25-7.19(m,1H,ArH),7.04(s,2H,ArH),3.84(s,3H,CH3),3.77(s,3H,CH3),3.41(s,2H,CH2),3.17(dd,J＝17.6Hz and 7.9Hz,1H,CH),2.77(t,J＝12.5Hz,2H,CH2),2.64-2.56(m,2H,CH2),1.92-1.83(m,2H,CH2),1.73-1.64(m,2H,CH2),1.57(d,J＝12.7Hz,1H,CH),1.46-1.33(m,1H,CH),1.24-1.16(m,2H,CH2),1.15-1.07(m,1H,CH)；13C NMR(125MHz,DMSO-d6)δ206.6,155.2,149.1,148.7,138.6,128.7,128.4,128.1,126.8,108.1,103.8,62.5,55.9,55.5,53.3,44.8,38.3,33.9,32.7,31.4.。
Example 2:
except using [ (CpIrCl)2(thbpym)][Cl]2(2.5mg,0.0025mmol,1mol Ir%) instead of [ Cp Ir (6,6- (OH)2bpy)(H2O)][OTf]2Other reaction raw materials, conditions and products are the same as example 1, yield: 82.
Claims (5)
1. a method for synthesizing donepezil I, which comprises
The synthesis of the compound is carried out by 5, 6-dimethoxy indanone II,
with 1-benzyl-4-piperidinemethanol III in the presence of an iridium complex catalyst and a base
A step of preparing a target product by alkylation reaction in water,
wherein, the iridium complex is a water-soluble metal-ligand bifunctional iridium catalyst, and has the following structure:
2. the process according to claim 1, wherein the iridium complex catalyst is used in an amount of 1mol Ir% relative to the 5, 6-dimethoxyindanone.
3. The method of claim 1, wherein the amount of 1-benzyl-4-piperidinemethanol is 1.3equiv. relative to 5, 6-dimethoxyindanone.
4. The process according to claim 1, wherein the molar amount of the base is 1equiv. relative to the molar amount of 5, 6-dimethoxyindanone.
5. The method of claim 1, wherein the base is potassium hydroxide.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910094515.5A CN111499559B (en) | 2019-01-31 | 2019-01-31 | Method for synthesizing donepezil in water |
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| CN201910094515.5A CN111499559B (en) | 2019-01-31 | 2019-01-31 | Method for synthesizing donepezil in water |
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| CN111499559B true CN111499559B (en) | 2022-03-15 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102702078A (en) * | 2012-05-29 | 2012-10-03 | 扬子江药业集团江苏海慈生物药业有限公司 | Method for preparing donepezil hydrochloride |
| CN107778217A (en) * | 2016-08-29 | 2018-03-09 | 南京理工大学 | Method for synthesizing donepezil |
| CN107903204A (en) * | 2017-12-05 | 2018-04-13 | 郑州大学 | A kind of synthetic method of donepezil |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102702078A (en) * | 2012-05-29 | 2012-10-03 | 扬子江药业集团江苏海慈生物药业有限公司 | Method for preparing donepezil hydrochloride |
| CN107778217A (en) * | 2016-08-29 | 2018-03-09 | 南京理工大学 | Method for synthesizing donepezil |
| CN107903204A (en) * | 2017-12-05 | 2018-04-13 | 郑州大学 | A kind of synthetic method of donepezil |
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