CN109651234A - A kind of synthetic method of Doneppezil Hydrochloride - Google Patents
A kind of synthetic method of Doneppezil Hydrochloride Download PDFInfo
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- CN109651234A CN109651234A CN201811653454.3A CN201811653454A CN109651234A CN 109651234 A CN109651234 A CN 109651234A CN 201811653454 A CN201811653454 A CN 201811653454A CN 109651234 A CN109651234 A CN 109651234A
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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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- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to pharmaceutical technology fields, disclose a kind of synthetic method of Doneppezil Hydrochloride.With 5,6- dimethoxy -1- indone and 4- pyridine carboxaldehyde for starting material, intermediate compound I is generated using mixed catalyst, replaces hydrogen to carry out catalytic transfer hydrogenation reaction using hydrogen source reagent, is finally reacted with benzyl chloride and obtain Doneppezil Hydrochloride at salt.Used catalyst of the present invention can be removed all by filtering, and post-processing is simple, and reaction condition is mild, and solves the selective problems of hydrogen reducing in the prior art, and yield and purity are higher, be suitble to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of synthetic 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%.
The method of synthetic hydrochloric acid donepezil is mainly the following at present
Method one: German Bayer AG discloses following formulas in patent EP0711756A1:
Above-mentioned process final step adds hydrogen, and there are selective problems, cause impurity to increase (crude product contains 5%), yield is low
And unstable, the disadvantages of catalyst is not easily recycled, many difficulties are brought 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 solve the deficiencies in the prior art, the present invention provides a kind of synthetic method of Doneppezil Hydrochloride, with
The prior art is compared, and method raw material provided by the invention is easy to get, and reaction condition is mild, and equipment requirement is wide, product yield and purity
It is higher, it is suitble to industrialized production.
The synthetic method of Doneppezil Hydrochloride provided by the invention, sequentially includes the following steps:
(1) compound I and compound II are dissolved in acetone, and catalyst 1 and catalyst 2 is added, and temperature control reaction has been reacted
Finish and filter out solid, filtrate concentration is added solvent crystallization and obtains compound III；
(2) compound III is dissolved in dehydrated alcohol, and hydrogen source reagent and Pd/C, temperature control reaction is added, and salt is added in end of reaction
Acid obtains compound IV at salt；
(3) compound IV reacts under the action of acid binding agent with benzyl chloride, be added hydrochloric acid adjust PH, obtain hydrochloric acid mostly how piperazine
Together；
Reaction route is as follows:
Wherein:
Catalyst 1 is one of potassium carbonate, anhydrous calcium chloride, anhydrous cupric sulfate, catalyst I and chemical combination in step (1)
The molar ratio of object I is 1.0~1.5:1；Catalyst 2 is potassium iodide.
Reaction temperature is 40~50 DEG C in step (1).
Crystallization solvent used is one of ethyl acetate, 2- butanone, chloroform in step (1).
Hydrogen source reagent used is ammonium formate in step (2), and the molar ratio of ammonium formate and compound III are 4~8:1.
Reaction temperature is 40~50 DEG C in step (2).
Acid binding agent used is one of triethylamine, sodium carbonate, sodium bicarbonate or a variety of in step (3).
PH value is 1.5~2.0 in step (3).
Compared with the existing technology, the present invention obtain it is following the utility model has the advantages that
(1) in the synthesis process of compound III, using solid metal salt catalyst, and phase transfer catalyst is mixed,
While improving catalytic effect, can all it be removed in post-processing by filtering, it is easy to operate, reduce the reaction time, mentions
High product yield and purity.
(2) hydrogen is replaced to carry out catalytic transfer hydrogenation reaction using hydrogen source reagent ammonium formate, ammonium formate is as hydrogen source reagent
When the property of can choose reduction conjugation ketenes double bond without influencing carbonyl, equipment requirement is wide, and safety coefficient is high, and reaction condition is more
Mildly, and the selective problems of hydrogen reducing double bond in the prior art are solved.
(3) after catalytic transfer hydrogenation reaction, hydrochloric acid is added by piperidines group into salt, plays a protective role, reduces by-product
The generation of object, improves product yield and purity.
Specific embodiment:
Embodiment 1: the synthesis of compound III
In the three-necked flask equipped with condenser pipe and blender, acetone 60mL, 5,6- dimethoxy -1- indones are sequentially added
9.6g, anhydrous calcium chloride 5.55g (0.05mol), 4- pyridine carboxaldehyde 5.89g, potassium iodide 0.96g are stirred under the conditions of 40~50 DEG C
4h is mixed, HPLC monitoring fundamental reaction is complete, is cooled to room temperature, and filters, and filtrate is concentrated, and ethyl acetate 100mL crystallization, mistake is added
Filter, vacuum drying obtain compound III12.96g, yield 92.2%, and HPLC detects purity 99.7%.
Embodiment 2: the synthesis of compound III
In the three-necked flask equipped with condenser pipe and blender, acetone 60mL, 5,6- dimethoxy -1- indones are sequentially added
9.6g, anhydrous cupric sulfate 11.97g (0.075mol), 4- pyridine carboxaldehyde 5.89g, potassium iodide 0.96g, under the conditions of 40~50 DEG C
4h is stirred, HPLC monitoring fundamental reaction is complete, is cooled to room temperature, and filters, and filtrate is concentrated, and 2- butanone 100mL crystallization, mistake is added
Filter, vacuum drying obtain compound III 12.89g, yield 91.7%, and HPLC detects purity 99.6%.
Embodiment 3: the synthesis of compound III
In the three-necked flask equipped with condenser pipe and blender, acetone 60mL, 5,6- dimethoxy -1- indones are sequentially added
9.6g, potassium carbonate 8.98g (0.065mol), 4- pyridine carboxaldehyde 5.89g, potassium iodide 0.96g are stirred under the conditions of 40~50 DEG C
4h, HPLC monitoring fundamental reaction are complete, are cooled to room temperature, and filter, and filtrate is concentrated, and chloroform 100mL crystallization, filtering, vacuum is added
It is dry, compound III 12.93g, yield 92.0% are obtained, HPLC detects purity 99.8%.
Embodiment 4: the synthesis of compound IV
Dehydrated alcohol 60mL is added in 500mL there-necked flask, compound III 11.24g is added, ammonium formate 10.08g is added
(0.16mol), 10% palladium charcoal 1.12g, 40-50 DEG C of temperature control is stirred to react, and HPLC detects fully reacting after 1.5h, filters out Pd/C,
Filtrate concentration, is added methylene chloride 80mL, is added with stirring concentrated hydrochloric acid and adjusts PH to 3.0, growing the grain 2h, filters, and vacuum drying obtains
Compound IV 11.65g, yield 89.6%, HPLC detect purity 99.4%.
Embodiment 5: the synthesis of compound IV
Dehydrated alcohol 60mL is added in 500mL there-necked flask, compound III 11.24g is added, ammonium formate 15.12g is added
(0.24mol), 10% palladium charcoal 1.12g, 40-50 DEG C of temperature control is stirred to react, and HPLC detects fully reacting after 1.5h, filters out Pd/C,
Filtrate concentration, is added methylene chloride 80mL, is added with stirring concentrated hydrochloric acid and adjusts PH to 4.0, growing the grain 2h, filters, and vacuum drying obtains
Compound IV 11.47g, yield 88.2%, HPLC detect purity 99.5%.
Embodiment 6: the synthesis of compound IV
Dehydrated alcohol 60mL is added in 500mL there-necked flask, compound III 11.24g is added, ammonium formate 20.16g is added
(0.32mol), 10% palladium charcoal 1.12g, 40-50 DEG C of temperature control is stirred to react, and HPLC detects fully reacting after 1.5h, filters out Pd/C,
Filtrate concentration, is added methylene chloride 80mL, is added with stirring concentrated hydrochloric acid and adjusts PH to 4.5, growing the grain 2h, filters, and vacuum drying obtains
Compound IV 11.71g, yield 90.1%, HPLC detect purity 99.5%.
Embodiment 7: the synthesis of Doneppezil Hydrochloride
9.75g compound IV is added in dichloromethane solvent, triethylamine 3.34g is added dropwise after 20~30 DEG C of dissolutions, continues
Stirring 10 minutes, in 35 DEG C of dropwise addition 3.78g 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, vacuum drying obtains Doneppezil Hydrochloride 11.13g, yield 89.3%, and HPLC detects purity 99.6%, largest single impurity
0.08%.
Embodiment 8: the synthesis of Doneppezil Hydrochloride
9.75g compound IV is added in dichloromethane solvent, sodium carbonate 4.13g is added after 20~30 DEG C of dissolutions, continues
Stirring 10 minutes, in 35 DEG C of dropwise addition 3.78g 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, vacuum drying obtains Doneppezil Hydrochloride 11.36g, yield 91.2%, and HPLC detects purity 99.7%, largest single impurity
0.09%.
Embodiment 9: the synthesis of Doneppezil Hydrochloride
9.75g compound IV is added in dichloromethane solvent, sodium bicarbonate 3.78g is added after 20~30 DEG C of dissolutions, after
Continuous stirring 10 minutes, in 35 DEG C of dropwise addition 3.78g 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 vacuum drying obtains Doneppezil Hydrochloride 11.33g, yield 90.9%, and HPLC detects purity 99.7%, maximum single
Miscellaneous 0.06%.
Comparative example 1:
In the three-necked flask equipped with condenser pipe and blender, acetone 60mL, 5,6- dimethoxy -1- indones are sequentially added
9.6g, anhydrous calcium chloride 5.55g, 4- pyridine carboxaldehyde 5.89g, is stirred under the conditions of 40~50 DEG C, and HPLC monitoring is substantially anti-after 8h
It should be cooled to room temperature completely, filter out solid, filtrate is concentrated, ethyl acetate 100mL crystallization is added, filter, vacuum drying obtains
Compound III 11.30g, yield 80.4%, HPLC detect purity 97.9%.
Comparative example 2:
In the three-necked flask equipped with condenser pipe and blender, acetone 60mL, 5,6- dimethoxy -1- indones are sequentially added
9.6g, anhydrous calcium chloride 4.99g (0.045mol), 4- pyridine carboxaldehyde 5.89g, potassium iodide 0.96g are stirred under the conditions of 40~50 DEG C
It mixes, HPLC monitoring fundamental reaction is complete after 6h, is cooled to room temperature, and filters out solid, and filtrate is concentrated, and ethyl acetate 100mL analysis is added
Crystalline substance filters, vacuum drying, obtains compound III 11.91g, yield 84.7%, and HPLC detects purity 98.3%.
Comparative example 3:
In the three-necked flask equipped with condenser pipe and blender, acetone 60mL, 5,6- dimethoxy -1- indones are sequentially added
9.6g, anhydrous calcium chloride 9.99g (0.09mol), 4- pyridine carboxaldehyde 5.89g, potassium iodide 0.96g are stirred under the conditions of 40~50 DEG C
It mixes, HPLC monitoring fundamental reaction is complete after 6h, is cooled to room temperature, and filters out solid, and filtrate is concentrated, and ethyl acetate 100mL analysis is added
Crystalline substance filters, vacuum drying, obtains compound III 11.06g, yield 85.1%, and HPLC detects purity 97.7%.
Comparative example 4:
In the three-necked flask equipped with condenser pipe and blender, acetone 60mL, 5,6- dimethoxy -1- indones are sequentially added
9.6g, anhydrous calcium chloride 5.55g, 4- pyridine carboxaldehyde 5.89g, tetrabutylammonium bromide 0.96g are stirred under the conditions of 40~50 DEG C,
HPLC monitoring fundamental reaction is complete after 8h, is cooled to room temperature, and filters out solid, and filtrate is concentrated, and ethyl acetate 100mL crystallization is added,
Filtering, vacuum drying obtain compound III 10.65g, yield 81.9%, and HPLC detects purity 98.1%.
Comparative example 5:
In reaction kettle be added dehydrated alcohol 60mL, be added by 1 method of embodiment preparation compound III 11.24g and
10%Pd/C1.12g.40~50 DEG C are warming up to, is passed through under hydrogen 2.0MPa and reacts, TLC detection is basic after 2h stops, and filters out Pd/
C, filtrate concentration, is added methylene chloride 80mL, is added with stirring concentrated hydrochloric acid and adjusts PH to 3.0, growing the grain 2h, filters, vacuum drying,
Compound IV 10.61g, yield 81.6% are obtained, HPLC detects purity 97.0%.
Comparative example 6:
Dehydrated alcohol 60mL is added in 500mL there-necked flask, the compound III11.24g by the preparation of 1 method of embodiment is added,
It is added ammonium formate 7.56g (0.12mol), 10% palladium charcoal 1.12g, 40-50 DEG C of temperature control is stirred to react, and HPLC detection reaction stops after 2h
Only, it filters, methylene chloride 80mL is added in filtrate concentration, is added with stirring concentrated hydrochloric acid and adjusts PH to 3.0, growing the grain 2h, filters, very
Sky is dry, obtains compound IV 10.99g, yield 84.5%, and HPLC detects purity 97.9%.
Comparative example 7:
Dehydrated alcohol 60mL is added in 500mL there-necked flask, the compound III11.24g by the preparation of 1 method of embodiment is added,
It is added ammonium formate 25.20g (0.40mol), 10% palladium charcoal 1.12g, 40-50 DEG C of temperature control is stirred to react, and HPLC detection is anti-after 1.5h
It should stop, filtering, methylene chloride 80mL is added in filtrate concentration, is added with stirring concentrated hydrochloric acid and adjusts PH to 3.0, growing the grain 2h, mistake
Filter, vacuum drying obtain compound IV 11.14g, yield 85.7%, and HPLC detects purity 91.3%.
Claims (9)
1. a kind of synthetic method of Doneppezil Hydrochloride, it is characterised in that the following steps are included:
(1) compound I and compound II are dissolved in acetone, and catalyst, temperature control reaction is added, and end of reaction filters out solid, filters
Liquid concentration is added organic solvent crystallization and obtains compound III；
(2) compound III temperature control under the action of hydrogen source reagent and Pd/C catalyst reacts, and hydrochloric acid is added after reaction into salt
Obtain compound IV；
(3) compound IV reacts under the action of acid binding agent with benzyl chloride, and hydrochloric acid is added and adjusts PH, obtains Doneppezil Hydrochloride；
Reaction route is as follows:
2. a kind of synthetic method of Doneppezil Hydrochloride as described in claim 1, which is characterized in that catalysis used in step (1)
Agent is the mixture of catalyst 1 and catalyst 2.
3. a kind of synthetic method of Doneppezil Hydrochloride as claimed in claim 2, which is characterized in that catalyst 1 is in step (1)
The molar ratio of one of potassium carbonate, anhydrous calcium chloride, anhydrous cupric sulfate, catalyst 1 and compound I are 1~1.5:1；Catalysis
Agent 2 is potassium iodide.
4. a kind of synthetic method of Doneppezil Hydrochloride as described in claim 1, which is characterized in that reaction temperature in step (1)
It is 40~50 DEG C.
5. a kind of synthetic method of Doneppezil Hydrochloride as described in claim 1, which is characterized in that in step (1) used in crystallization
Organic solvent is one of ethyl acetate, 2- butanone, chloroform.
6. a kind of synthetic method of Doneppezil Hydrochloride as described in claim 1, which is characterized in that hydrogen source used in step (2)
Reagent is ammonium formate, and the molar ratio of ammonium formate and compound III are 4~8:1.
7. a kind of synthetic method of Doneppezil Hydrochloride as described in claim 1, which is characterized in that reaction temperature in step (2)
It is 40~50 DEG C.
8. a kind of synthetic method of Doneppezil Hydrochloride as described in claim 1, which is characterized in that used in step (3) to tie up acid
Agent is one or more of triethylamine, sodium carbonate, sodium bicarbonate.
9. such as a kind of claim synthetic method of Doneppezil Hydrochloride as described in claim 1, which is characterized in that step (3)
Middle pH value is 1.5~2.0.
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Cited By (1)
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101341122A (en) * | 2005-12-20 | 2009-01-07 | 吉瑞工厂 | Novel process for production of highly pure polymorph (I) donepezil hydrochloride |
| WO2012131540A1 (en) * | 2011-03-25 | 2012-10-04 | Piramal Healthcare Limited | A process for preparation of intermediates of donepezil hydrochloride |
| CN103012268A (en) * | 2013-01-05 | 2013-04-03 | 江苏宇田生物医药科技有限公司 | Novel preparation method for ivabradine |
-
2018
- 2018-12-29 CN CN201811653454.3A patent/CN109651234B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101341122A (en) * | 2005-12-20 | 2009-01-07 | 吉瑞工厂 | Novel process for production of highly pure polymorph (I) donepezil hydrochloride |
| WO2012131540A1 (en) * | 2011-03-25 | 2012-10-04 | Piramal Healthcare Limited | A process for preparation of intermediates of donepezil hydrochloride |
| CN103012268A (en) * | 2013-01-05 | 2013-04-03 | 江苏宇田生物医药科技有限公司 | Novel preparation method for ivabradine |
Non-Patent Citations (1)
| Title |
|---|
| 王晓琴等: "盐酸多奈哌齐的合成研究", 《化学试剂》 * |
Cited By (1)
| 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 |
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