CN109354580A - A kind of preparation method of Doneppezil Hydrochloride - Google Patents
A kind of preparation method of Doneppezil Hydrochloride Download PDFInfo
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- CN109354580A CN109354580A CN201811389075.8A CN201811389075A CN109354580A CN 109354580 A CN109354580 A CN 109354580A CN 201811389075 A CN201811389075 A CN 201811389075A CN 109354580 A CN109354580 A CN 109354580A
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- doneppezil hydrochloride
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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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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Abstract
The invention belongs to pharmaceutical technology fields, disclose a kind of preparation method of Doneppezil Hydrochloride.It with 2- chloromethyl -4,5- dimethoxy benzaldehyde and (1- methoxy piperide -4- base) acetaldehyde for raw material, is reacted through Wittig, intramolecular asymmetry hydrogen acylation reaction, replaces, obtain Doneppezil Hydrochloride at salt.The present invention uses completely new raw material, and cheap and easy to get, reaction step is shorter, and product yield significantly improves.Using the intramolecular asymmetry hydrogen acylation reaction of precious metal catalyst, the selective problems of hydrogenation process in the prior art are overcome, and the recycling of catalyst is realized in post-processing.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of preparation method of Doneppezil Hydrochloride.
Background technique
Doneppezil Hydrochloride is a kind of high selectivity developed by Japanese Eisai Co., Ltd, long-acting, invertibity
The mild to moderate Alzheimer disease for the treatment of acetylcholinesterase inhibitor.Defend the synthetic route that material pharmacy is related to are as follows:
The route total recovery is less than 20%
At present synthetic hydrochloric acid donepezil method mainly include the following types:
Method one: German Bayer AG discloses following formulas in patent EP0711756A1:
That there are impurity is more (crude product contain 5%) for above-mentioned process, and yield is low and unstable, and catalyst, which is not easily recycled, etc. lacks
Point brings many difficulties to industrial production.
CN1030752 discloses one kind with boc-protected piperidyl formaldehgde and 5, and 6- dimethyl -1- indone is raw material, warp
Add hydrogen, de- Boc protection, then reacts the method for generating donepezil with benzyl chloride.The shortcomings that this synthesis technology, is in reduction α, β-
There are the selective problems of carbon-carbon double bond and carbonyl functional group when unsaturated carbonyl condensation product, product quality and yield are influenced.
Method two: US2004014321A1 is by 5,6- dimethoxy -2- [(4- pyridyl group) methylene] -1- indone first through urging
Change plus hydrogen obtains hydride, then reacts to obtain donepezil with cylite
The disadvantage is that the product donepezil after the technique final step is reacted with cylite can be further anti-with cylite
Impurity should be generated, need to refine could remove, and yield is also only 70-75%.
EP0711756A1 first reacts 5,6- dimethoxy -2- [(4- pyridyl group) methylene] -1- indone with cylite
Catalytic hydrogenation obtains donepezil, which is easy to take off in reduction process to generate more impurity, and product needs more
Secondary purification could be qualified, causes yield lower.
CN101723878A directly with hydride 5,6- dimethoxy -2- (4- piperidino methyl) -1- indone be raw material with
Substituted sulfonic acid benzyl ester is condensed to yield donepezil, and yield is higher, and purity is 97% or so, but the preparation process of hydride is still more multiple
It is miscellaneous.
In addition, the patent that notification number is CN100436416C discloses one kind with 1-Boc-4- piperidinealdehyde and malonic acid two
Ethyl ester is the method that raw material prepares Doneppezil Hydrochloride, and route is as follows:
The shortcomings that technique, is that operating procedure is more, causes yield lower.
Summary of the invention
In order to overcome the deficiencies in the prior art, the present invention provides a kind of preparation method of Doneppezil Hydrochloride, with
The prior art is compared, and method reaction step provided by the invention is shorter, and yield is higher, and product purity is higher.It is suitble to industry metaplasia
It produces.
The preparation method of Doneppezil Hydrochloride provided by the invention, sequentially includes the following steps:
(1) compound I and compound II occurs Wittig in the presence of alkali in aprotic solvent and reacts to obtain chemical combination
Object III；
(2) intramolecular asymmetry hydrogen acylation reaction occurs under the action of catalyst for compound III, and one is added after reaction
Kind acid stirring 30min, is then added a kind of aqueous solution of alkali, extracts liquid separation, organic phase is concentrated to get compound IV；
(3) compound IV, which reacts with benzyl chloride in the presence of alkali and hydrochloric acid is added, obtains Doneppezil Hydrochloride at salt；Reaction
Route is as follows:
Aprotic solvent is one of methylene chloride, tetrahydrofuran, N,N-dimethylformamide (DMF) in step (1).
Alkali used is sodium hydroxide, sodium carbonate, sodium ethoxide, one of sodium tert-butoxide in step (1)
Compound II is slowly dropped in compound I by step in (1), and time for adding is controlled in 30~60min.
Catalyst is Rh (dppe) ClO containing norbornadiene (NBD) ligand in step (2)4, Rh (dppp) ClO4, Rh
(dppb)ClO4One of.
The acid being added in step (2) is one of concentrated hydrochloric acid, formic acid, acetic acid, and alkali is potassium hydroxide, sodium hydroxide, carbon
One of sour sodium, potassium carbonate.
Alkali is one of triethylamine, sodium carbonate, sodium bicarbonate in step (3).
The molar ratio of compound IV in step (3), benzyl chloride and alkali is 1:1:1.1~1.5.
Compared with the existing technology, the present invention obtain it is following the utility model has the advantages that
(1) completely new raw material and route are used, cheap and easy to get, reaction step is shorter, and product yield significantly improves.
(2) the intramolecular asymmetry hydrogen acylation reaction for using metal catalytic, overcomes the choosing of hydrogenation process in the prior art
Selecting property problem, and the recycling of catalyst may be implemented in post-processing.
Specific embodiment:
Below with reference to embodiment, the present invention will be further described, but does not therefore limit the contents of the present invention.
Embodiment 1: the preparation of compound III
DMF100mL is added in 500mL there-necked flask, is cooled to 0-10 DEG C, 33.36g triphenylphosphine is added, 27.25g is added
Compound I is warming up to 50~60 DEG C of reactions, and TLC detection compound I fundamental reaction is complete after 4h, and nitrogen is replaced three times, and hydrogen is added
Sodium oxide molybdena 1.87g, is stirred to react 30min；Reaction solution is cooled to 0~10 DEG C, and the DMF solution of compound II is slowly added dropwise, and (10g is molten
In 20mL), 0~10 DEG C of temperature control is reacted, and HPLC detection fundamental reaction is complete after 1.5h, and water and each 50mL stirring of normal heptane is added
30min stands liquid separation, and 30mL*3 washing organic phase is added three times, filters after washing every time, organic to be added to anhydrous sodium sulfate
5.00g stirs 30min, filtering, and normal heptane is divided exactly in decompression, obtains compound III18.23g, yield 89.7%, and HPLC detects pure
Degree 99.0%.
Embodiment 2: the preparation of compound III
Tetrahydrofuran 100mL is added in 500mL there-necked flask, is cooled to 0-10 DEG C, 33.36g triphenylphosphine is added, is added
27.25g compound I is warming up to 50~60 DEG C of reactions, and TLC detection compound I fundamental reaction is complete after 4h, and nitrogen is replaced three times,
Sodium carbonate 4.95g is added, is stirred to react 30min；Reaction solution is cooled to 0~10 DEG C, and the tetrahydrofuran of compound II is slowly added dropwise
Solution (10g is dissolved in 20mL), 0~10 DEG C of temperature control is reacted, and HPLC detection fundamental reaction is complete after 1.5h, and water is added and normal heptane is each
50mL stir 30min, stand liquid separation, be added 30mL*3 washing organic phase three times, every time washing after filter, it is organic be added to it is anhydrous
Sodium sulphate 5.00g stirs 30min, filtering, and decompression divides exactly normal heptane, obtains compound III18.45g, yield 90.8%, HPLC
Detect purity 99.5%.
Embodiment 3: the preparation of compound III
100mL methylene chloride is added in 500mL there-necked flask, is cooled to 0-10 DEG C, 33.36g triphenylphosphine is added, is added
27.25g compound I is warming up to 50~60 DEG C of reactions, and TLC detection compound I fundamental reaction is complete after 4h, and nitrogen is replaced three times,
Sodium ethoxide 3.18g is added, is stirred to react 30min；Reaction solution is cooled to 0~10 DEG C, and the methylene chloride of compound II is slowly added dropwise
Solution (10g is dissolved in 20mL), 0~10 DEG C of temperature control is reacted, and HPLC detection fundamental reaction is complete after 1.5h, and water is added and normal heptane is each
50mL stir 30min, stand liquid separation, be added 30mL*3 washing organic phase three times, every time washing after filter, it is organic be added to it is anhydrous
Sodium sulphate 5.00g stirs 30min, filtering, and decompression divides exactly normal heptane, obtains compound III18.69g, yield 92.0%, HPLC
Detect purity 99.1%.
Embodiment 4: the preparation of compound IV
Methylene chloride 100mL is added in 500mL there-necked flask, 1.80g [Rh (dppe) (NBD)] ClO is added4, it is passed through hydrogen 5
Minute, then use nitrogen replacing hydrogen.The dichloromethane solution (18.0g is dissolved in 36mL methylene chloride) of compound III is added dropwise
Into above-mentioned catalyst solution.It is passed through nitrogen, 20~30 DEG C of temperature control reactions, HPLC detection reaction substantially completely, is added after 2 hours
Concentrated hydrochloric acid 3.60g stirs 20min, and 10%NaOH aqueous solution 50mL is added and stirs 30min, stands liquid separation, organic phase is concentrated to get
16.26g compound IV, yield 90.3%, HPLC detect purity 99.3%.
Embodiment 5: the preparation of compound IV
Methylene chloride 100mL is added in 500mL there-necked flask, 1.80g [Rh (dppb) (NBD)] ClO is added4, it is passed through hydrogen 5
Minute, then use nitrogen replacing hydrogen.The dichloromethane solution (18.0g is dissolved in 36mL methylene chloride) of compound III is added dropwise
Into above-mentioned catalyst solution.It is passed through nitrogen, 20~30 DEG C of temperature control reactions, HPLC detection reaction substantially completely, is added after 2 hours
Formic acid 3.60g stirs 20min, and 10%KOH aqueous solution 50mL is added and stirs 30min, stands liquid separation, organic phase is concentrated to get
15.91g compound IV, yield 88.4%, HPLC detect purity 99.2%.
Embodiment 6: the preparation of compound IV
Methylene chloride 100mL is added in 500mL there-necked flask, 1.80g [Rh (dppp) (NBD)] ClO is added4, it is passed through hydrogen 5
Minute, then use nitrogen replacing hydrogen.The dichloromethane solution (18.0g is dissolved in 36mL methylene chloride) of compound III is added dropwise
Into above-mentioned catalyst solution.It is passed through nitrogen, 20~30 DEG C of temperature control reactions, HPLC detection reaction substantially completely, is added after 2 hours
Acetic acid 3.60g stirs 20min, and 10%Na is added2CO3Aqueous solution 50mL stirs 30min, stands liquid separation, and organic phase is concentrated to get
15.48g compound IV, yield 86.0%, HPLC detect purity 99.3%.
Embodiment 7: the preparation of Doneppezil Hydrochloride
15.00g compound IV is added in dichloromethane solvent, triethylamine 5.23g is added dropwise after 20~30 DEG C of dissolutions, continues
Stirring 10 minutes, in 35 DEG C of dropwise addition 5.92g benzyl chlorides, 20~30 DEG C of temperature control reactions filter after reaction, and filtrate concentration is dense
Contracting object is dissolved with methanol, and 10% methanolic hydrogen chloride solution is added dropwise into salt, is cooled to 0~10 DEG C of crystallisation by cooling, is filtered, is used methanol
Filter cake is washed, 50~60 DEG C of dryings obtain Doneppezil Hydrochloride 17.23g, yield 88.3%, and HPLC detects purity 99.1%, maximum
Single miscellaneous 0.08%.
Embodiment 8: the preparation of Doneppezil Hydrochloride
15.00g compound IV is added in dichloromethane solvent, 6.48g sodium carbonate is added after 20~30 DEG C of dissolutions, continues
Stirring 10 minutes, in 35 DEG C of dropwise addition 5.92g benzyl chlorides, 20~30 DEG C of temperature control reactions filter after reaction, and filtrate concentration is dense
Contracting object is dissolved with methanol, and 10% methanolic hydrogen chloride solution is added dropwise into salt, is cooled to 0~10 DEG C of crystallisation by cooling, is filtered, is used methanol
Filter cake is washed, 50~60 DEG C of dryings obtain Doneppezil Hydrochloride 17.50g, yield 89.7%, and HPLC detects purity 99.3%, maximum
Single miscellaneous 0.09%.
Embodiment 9: the preparation of Doneppezil Hydrochloride
15.00g compound IV is added in dichloromethane solvent, 5.92g sodium bicarbonate is added after 20~30 DEG C of dissolutions, after
Continuous stirring 10 minutes, in 35 DEG C of dropwise addition 5.92g benzyl chlorides, 20~30 DEG C of temperature control reactions filter after reaction, filtrate concentration,
Concentrate is dissolved with methanol, and 10% methanolic hydrogen chloride solution is added dropwise into salt, is cooled to 0~10 DEG C of crystallisation by cooling, is filtered, is used first
Alcohol washs filter cake, and 50~60 DEG C of dryings obtain Doneppezil Hydrochloride 17.85g, yield 91.5%, and HPLC detects purity 99.3%, most
It is big by single miscellaneous 0.09%.
Claims (8)
1. a kind of preparation method of Doneppezil Hydrochloride, it is characterised in that the following steps are included:
(1) compound I and compound II are dissolved in aprotic solvent, Wittig reaction occurs in the presence of alkali
Close object III；
(2) intramolecular asymmetry hydrogen acylation reaction occurs under the action of catalyst for compound III, and a kind of acid is added after reaction
30min is stirred, a kind of aqueous solution of alkali is then added, obtains compound IV；
(3) compound IV, which reacts with benzyl chloride in the presence of alkali and hydrochloric acid is added, obtains Doneppezil Hydrochloride at salt；Reaction route
It is as follows:
2. the preparation method of Doneppezil Hydrochloride according to claim 1, it is characterised in that aprotic solvent in step (1)
For one of methylene chloride, tetrahydrofuran, N,N-dimethylformamide.
3. the preparation method of Doneppezil Hydrochloride according to claim 1, it is characterised in that alkali used is hydrogen in step (1)
Sodium oxide molybdena, sodium carbonate, sodium ethoxide, one of sodium tert-butoxide.
4. the preparation method of Doneppezil Hydrochloride according to claim 1, it is characterised in that by compound II in step (1)
It is slowly dropped in compound I, time for adding is controlled in 30~60min.
5. the preparation method of Doneppezil Hydrochloride according to claim 1, it is characterised in that in step (2) catalyst be containing
Rh (dppe) ClO of norbornadiene (NBD) ligand4, Rh (dppp) ClO4, Rh (dppb) ClO4One of.
6. the preparation method of Doneppezil Hydrochloride according to claim 1, it is characterised in that the acid of addition is in step (2)
One of concentrated hydrochloric acid, formic acid, acetic acid.
7. the preparation method of Doneppezil Hydrochloride according to claim 1, it is characterised in that the alkali of addition is in step (2)
One of potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate.
8. the preparation method of Doneppezil Hydrochloride according to claim 1, it is characterised in that alkali used is three in step (3)
One of ethamine, sodium carbonate, sodium bicarbonate.
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| CN201811389075.8A CN109354580B (en) | 2018-11-21 | 2018-11-21 | Preparation method of donepezil hydrochloride |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN114105862A (en) * | 2020-08-29 | 2022-03-01 | 浙江华海药业股份有限公司 | Donepezil hydrochloride impurity and preparation method thereof |
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|---|---|---|---|---|
| US5606064A (en) * | 1994-11-08 | 1997-02-25 | Bayer Aktiengesellschaft | Process for the preparation of benzyl-piperidylmethyl-indanones |
| WO2008123469A1 (en) * | 2007-03-30 | 2008-10-16 | Japan Tobacco Inc. | Six-membered amide compound and use thereof |
| CN101723878A (en) * | 2008-10-10 | 2010-06-09 | 浙江东亚药业有限公司 | Preparation method of donepezil |
| CN103402979A (en) * | 2011-01-05 | 2013-11-20 | 先正达参股股份有限公司 | Chemical compounds |
| CN105418488A (en) * | 2015-12-31 | 2016-03-23 | 山东罗欣药业集团股份有限公司 | Preparation method of donepezil hydrochloride |
-
2018
- 2018-11-21 CN CN201811389075.8A patent/CN109354580B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5606064A (en) * | 1994-11-08 | 1997-02-25 | Bayer Aktiengesellschaft | Process for the preparation of benzyl-piperidylmethyl-indanones |
| WO2008123469A1 (en) * | 2007-03-30 | 2008-10-16 | Japan Tobacco Inc. | Six-membered amide compound and use thereof |
| CN101723878A (en) * | 2008-10-10 | 2010-06-09 | 浙江东亚药业有限公司 | Preparation method of donepezil |
| CN103402979A (en) * | 2011-01-05 | 2013-11-20 | 先正达参股股份有限公司 | Chemical compounds |
| CN105418488A (en) * | 2015-12-31 | 2016-03-23 | 山东罗欣药业集团股份有限公司 | Preparation method of donepezil hydrochloride |
Non-Patent Citations (3)
| Title |
|---|
| KOUSIK KUNDU，等: "Hydroacylation of 2-Vinyl Benzaldehyde Systems: An Efficient Method for the Synthesis of Chiral 3-Substituted Indanones", 《J. AM. CHEM. SOC.》 * |
| 李玉龙，等: "盐酸多奈哌齐的合成路线图解", 《江西化工》 * |
| 金辄，等: "多奈哌齐合成路线图解", 《中国药物化学杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN114105862A (en) * | 2020-08-29 | 2022-03-01 | 浙江华海药业股份有限公司 | Donepezil hydrochloride impurity and preparation method thereof |
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