CN109651234B - Synthesis method of donepezil hydrochloride - Google Patents
Synthesis method of donepezil hydrochloride Download PDFInfo
- Publication number
- CN109651234B CN109651234B CN201811653454.3A CN201811653454A CN109651234B CN 109651234 B CN109651234 B CN 109651234B CN 201811653454 A CN201811653454 A CN 201811653454A CN 109651234 B CN109651234 B CN 109651234B
- Authority
- CN
- China
- Prior art keywords
- catalyst
- donepezil hydrochloride
- compound
- reaction
- synthesizing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and discloses a method for synthesizing donepezil hydrochloride. 5, 6-dimethoxy-1-indanone and 4-pyridylaldehyde are used as initial raw materials, a mixed catalyst is adopted to generate an intermediate I, a hydrogen source reagent is adopted to replace hydrogen to perform catalytic transfer hydrogenation reaction, and finally the intermediate I is reacted with benzyl chloride to form salt so as to obtain donepezil hydrochloride. The catalyst used in the invention can be completely removed by filtering, the post-treatment is simple, the reaction condition is mild, the problem of selectivity of hydrogen reduction in the prior art is solved, the yield and the purity are high, and the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a method for synthesizing donepezil hydrochloride.
Background
Donepezil hydrochloride is an acetylcholinesterase inhibitor developed by kawasaki corporation, which is highly selective, long-acting, and reversible for treating mild to moderate alzheimer's disease. The synthesis route of the sanitary material pharmacy comprises the following steps:
the total yield of the route is less than 20%.
The existing methods for synthesizing donepezil hydrochloride mainly comprise the following methods
The method comprises the following steps: the German Bayer company in patent EP0711756A1 discloses the following reaction scheme:
the last step of hydrogenation of the process method has the selectivity problem, so that the impurities are increased (the crude product contains 5 percent), the yield is low and unstable, the catalyst is not easy to recover, and the like, thereby bringing a lot of difficulties to industrial production.
CN1030752 discloses a method for producing donepezil by using Boc-protected piperidyl formaldehyde and 5, 6-dimethyl-1-indanone as raw materials, hydrogenating, removing Boc protection, and reacting with chlorobenzyl. The disadvantage of this synthesis process is that there is a problem of selectivity of the carbon-carbon double bond and the carbonyl function in the reduction of the α, β -unsaturated carbonyl condensation product, affecting the product quality and yield.
The second method comprises the following steps: US2004014321A1 discloses a method for preparing donepezil by catalytically hydrogenating 5, 6-dimethoxy-2- [ (4-pyridyl) methylene ] -1-indanone to obtain hydride, and then reacting the hydride with benzyl bromide
The disadvantage is that the donepezil product obtained by the last step of the process reacts with benzyl bromide to generate impurities which can be removed by refining, and the yield is only 70-75%.
EP0711756A1 reacts 5, 6-dimethoxy-2- [ (4-pyridyl) methylene ] -1-indanone with benzyl bromide to obtain donepezil through catalytic hydrogenation, the benzyl in the process is easy to remove in the reduction process to generate more impurities, and the product can be qualified only by refining for many times, so that the yield is low.
CN101723878A directly uses hydride 5, 6-dimethoxy-2- (4-piperidylmethyl) -1-indanone as raw material to be condensed with substituted benzyl sulfonate to obtain donepezil, the yield is high, the purity is about 97%, but the preparation process of hydride is still complex.
In addition, patent publication No. CN100436416C discloses a method for preparing donepezil hydrochloride from 1-Boc-4-piperidinecarboxaldehyde and diethyl malonate as raw materials, the route is as follows:
the disadvantage of this process is that the number of operating steps is large, resulting in a low yield.
The invention content is as follows:
in order to solve the defects in the prior art, the invention provides the method for synthesizing donepezil hydrochloride, and compared with the prior art, the method provided by the invention has the advantages of easily available raw materials, mild reaction conditions, wide equipment requirements, higher product yield and purity, and suitability for industrial production.
The synthesis method of donepezil hydrochloride provided by the invention comprises the following steps:
(1) dissolving a compound I and a compound II in acetone, adding a catalyst 1 and a catalyst 2, controlling the temperature to react, filtering out solids after the reaction is finished, concentrating the filtrate, adding a solvent, and crystallizing to obtain a compound III;
(2) dissolving the compound III in absolute ethyl alcohol, adding a hydrogen source reagent and Pd/C, reacting at a controlled temperature, and adding hydrochloric acid to form a salt after the reaction is finished to obtain a compound IV;
(3) reacting the compound IV with benzyl chloride under the action of an acid-binding agent, and adding hydrochloric acid to adjust the pH value to obtain donepezil hydrochloride;
the reaction route is as follows:
wherein:
in the step (1), the catalyst 1 is one of potassium carbonate, anhydrous calcium chloride and anhydrous copper sulfate, and the molar ratio of the catalyst I to the compound I is 1.0-1.5: 1; catalyst 2 was potassium iodide.
The reaction temperature in the step (1) is 40-50 ℃.
The crystallization solvent used in the step (1) is one of ethyl acetate, 2-butanone and chloroform.
The hydrogen source reagent used in the step (2) is ammonium formate, and the molar ratio of the ammonium formate to the compound III is 4-8: 1.
The reaction temperature in the step (2) is 40-50 ℃.
And (3) the acid-binding agent used in the step (3) is one or more of triethylamine, sodium carbonate and sodium bicarbonate.
The PH value in the step (3) is 1.5-2.0.
Compared with the prior art, the invention has the following beneficial effects:
(1) in the synthesis process of the compound III, a solid metal salt catalyst is adopted, and a phase transfer catalyst is mixed, so that the catalytic effect is improved, and the catalyst can be completely removed by filtering in the post-treatment, the operation is simple, the reaction time is shortened, and the product yield and the purity are improved.
(2) Adopt hydrogen source reagent ammonium formate to replace hydrogen and carry out catalytic transfer hydrogenation, can the double bond of selective reduction conjugate ketene when ammonium formate is as hydrogen source reagent and do not influence the carbonyl, equipment requirement is wide, and factor of safety is high, and reaction condition is more mild, and has solved the selectivity problem of hydrogen reduction double bond among the prior art.
(3) After the catalytic transfer hydrogenation reaction, hydrochloric acid is added to salify the piperidine group, so that the protection effect is achieved, the generation of byproducts is reduced, and the product yield and purity are improved.
The specific implementation mode is as follows:
example 1: synthesis of Compound III
60mL of acetone, 9.6g of 5, 6-dimethoxy-1-indanone, 5.55g (0.05mol) of anhydrous calcium chloride, 5.89g of 4-pyridylaldehyde and 0.96g of potassium iodide are sequentially added into a three-neck flask provided with a condenser and a stirrer, stirred for 4 hours at 40-50 ℃, subjected to HPLC monitoring for basic reaction completion, cooled to room temperature, filtered, concentrated in filtrate, added with 100mL of ethyl acetate for crystallization, filtered and dried in vacuum to obtain the compound III12.96g, the yield is 92.2%, and the purity is 99.7% by HPLC detection.
Example 2: synthesis of Compound III
60mL of acetone, 9.6g of 5, 6-dimethoxy-1-indanone, 11.97g (0.075mol) of anhydrous copper sulfate, 5.89g of 4-pyridylaldehyde and 0.96g of potassium iodide are sequentially added into a three-neck flask provided with a condenser and a stirrer, the mixture is stirred for 4 hours at the temperature of 40-50 ℃, HPLC (high performance liquid chromatography) is used for monitoring the basic reaction to be complete, the mixture is cooled to room temperature, filtered, the filtrate is concentrated, 100mL of 2-butanone is added for crystallization, filtered and dried in vacuum, 12.89g of a compound III is obtained, the yield is 91.7%, and the purity is 99.6% by HPLC detection.
Example 3: synthesis of Compound III
60mL of acetone, 9.6g of 5, 6-dimethoxy-1-indanone, 8.98g (0.065mol) of potassium carbonate, 5.89g of 4-pyridylaldehyde and 0.96g of potassium iodide are sequentially added into a three-neck flask provided with a condenser tube and a stirrer, stirred for 4 hours at 40-50 ℃, subjected to HPLC monitoring for basic reaction completion, cooled to room temperature, filtered, concentrated in filtrate, added with 100mL of chloroform for crystallization, filtered and dried in vacuum to obtain 12.93g of a compound III, the yield is 92.0%, and the purity is 99.8% by HPLC detection.
Example 4: synthesis of Compound IV
Adding 60mL of absolute ethyl alcohol into a 500mL three-necked bottle, adding 11.24g of a compound III, adding 10.08g (0.16mol) of ammonium formate and 1.12g of 10% palladium-carbon, stirring and reacting at the temperature of 40-50 ℃, detecting the reaction by HPLC after 1.5h, filtering out Pd/C, concentrating the filtrate, adding 80mL of dichloromethane, adding concentrated hydrochloric acid while stirring to adjust the pH to 3.0, growing crystals for 2h, filtering, and drying in vacuum to obtain 11.65g of a compound IV, wherein the yield is 89.6%, and the purity is 99.4% by HPLC.
Example 5: synthesis of Compound IV
Adding 60mL of absolute ethyl alcohol into a 500mL three-necked flask, adding 11.24g of a compound III, adding 15.12g (0.24mol) of ammonium formate and 1.12g of 10% palladium-carbon, stirring and reacting at the temperature of 40-50 ℃, detecting the reaction by HPLC after 1.5h, filtering out Pd/C, concentrating the filtrate, adding 80mL of dichloromethane, adding concentrated hydrochloric acid while stirring to adjust the pH value to 4.0, growing crystals for 2h, filtering, and drying in vacuum to obtain 11.47g of a compound IV, wherein the yield is 88.2%, and the purity is 99.5% by HPLC.
Example 6: synthesis of Compound IV
Adding 60mL of absolute ethyl alcohol into a 500mL three-necked flask, adding 11.24g of a compound III, adding 20.16g (0.32mol) of ammonium formate and 1.12g of 10% palladium-carbon, stirring and reacting at the temperature of 40-50 ℃, detecting the reaction by HPLC after 1.5h, filtering out Pd/C, concentrating the filtrate, adding 80mL of dichloromethane, adding concentrated hydrochloric acid while stirring to adjust the pH to 4.5, growing crystals for 2h, filtering, and drying in vacuum to obtain 11.71g of a compound IV, wherein the yield is 90.1%, and the purity is 99.5% by HPLC.
Example 7: synthesis of donepezil hydrochloride
Adding 9.75g of compound IV into a dichloromethane solvent, dropwise adding 3.34g of triethylamine after dissolving at 20-30 ℃, continuously stirring for 10 minutes, dropwise adding 3.78g of benzyl chloride at 35 ℃, controlling the temperature to be 20-30 ℃ for reaction, performing suction filtration after the reaction is finished, concentrating the filtrate, dissolving the concentrate with methanol, dropwise adding 10% methanol hydrogen chloride solution for salification, cooling to 0-10 ℃, cooling for crystallization, filtering, washing the filter cake with methanol, and performing vacuum drying to obtain 11.13g of donepezil hydrochloride, wherein the yield is 89.3%, the purity is 99.6% by HPLC (high performance liquid chromatography) detection, and the maximum single impurity content is 0.08%.
Example 8: synthesis of donepezil hydrochloride
Adding 9.75g of compound IV into a dichloromethane solvent, dissolving at 20-30 ℃, adding 4.13g of sodium carbonate, continuously stirring for 10 minutes, dropwise adding 3.78g of benzyl chloride at 35 ℃, controlling the temperature to be 20-30 ℃ for reaction, performing suction filtration after the reaction is finished, concentrating the filtrate, dissolving the concentrate with methanol, dropwise adding 10% methanol hydrogen chloride solution for salification, cooling to 0-10 ℃, cooling for crystallization, filtering, washing the filter cake with methanol, and performing vacuum drying to obtain 11.36g of donepezil hydrochloride, wherein the yield is 91.2%, the purity is 99.7% by HPLC (high performance liquid chromatography) detection, and the maximum single impurity content is 0.09%.
Example 9: synthesis of donepezil hydrochloride
Adding 9.75g of compound IV into a dichloromethane solvent, dissolving at 20-30 ℃, adding 3.78g of sodium bicarbonate, continuously stirring for 10 minutes, dropwise adding 3.78g of benzyl chloride at 35 ℃, controlling the temperature to be 20-30 ℃ for reaction, performing suction filtration after the reaction is finished, concentrating the filtrate, dissolving the concentrate with methanol, dropwise adding 10% of methanol hydrogen chloride solution for salification, cooling to 0-10 ℃, cooling for crystallization, filtering, washing the filter cake with methanol, and performing vacuum drying to obtain 11.33g of donepezil hydrochloride, wherein the yield is 90.9%, the purity is 99.7% by HPLC (high performance liquid chromatography) detection, and the maximum single impurity content is 0.06%.
Comparative example 1:
60mL of acetone, 9.6g of 5, 6-dimethoxy-1-indanone, 5.55g of anhydrous calcium chloride and 5.89g of 4-pyridylaldehyde are sequentially added into a three-neck flask provided with a condenser tube and a stirrer, the mixture is stirred at 40-50 ℃, after 8 hours, the HPLC is used for monitoring the basic reaction to be complete, the mixture is cooled to room temperature, the solid is filtered out, the filtrate is concentrated, 100mL of ethyl acetate is added for crystallization, the mixture is filtered and dried in vacuum, 11.30g of the compound III is obtained, the yield is 80.4%, and the purity of HPLC detection is 97.9%.
Comparative example 2:
60mL of acetone, 9.6g of 5, 6-dimethoxy-1-indanone, 4.99g (0.045mol) of anhydrous calcium chloride, 5.89g of 4-pyridylaldehyde and 0.96g of potassium iodide are sequentially added into a three-neck flask provided with a condenser tube and a stirrer, the mixture is stirred at the temperature of 40-50 ℃, HPLC (high performance liquid chromatography) is used for monitoring the basic reaction to be complete after 6 hours, the mixture is cooled to room temperature, solid is filtered out, filtrate is concentrated, 100mL of ethyl acetate is added into the filtrate for crystallization, and the mixture is filtered and dried in vacuum to obtain 11.91g of a compound III, wherein the yield is 84.7 percent, and the purity is 98.3 percent through HPLC detection.
Comparative example 3:
60mL of acetone, 9.6g of 5, 6-dimethoxy-1-indanone, 9.99g (0.09mol) of anhydrous calcium chloride, 5.89g of 4-pyridylaldehyde and 0.96g of potassium iodide are sequentially added into a three-neck flask provided with a condenser tube and a stirrer, the mixture is stirred at the temperature of 40-50 ℃, HPLC (high performance liquid chromatography) is used for monitoring the basic reaction to be complete after 6 hours, the mixture is cooled to room temperature, solids are filtered out, filtrate is concentrated, 100mL of ethyl acetate is added into the filtrate for crystallization, and the mixture is filtered and dried in vacuum to obtain 11.06g of a compound III, the yield is 85.1 percent, and the purity is 97.7 percent through HPLC detection.
Comparative example 4:
60mL of acetone, 9.6g of 5, 6-dimethoxy-1-indanone, 5.55g of anhydrous calcium chloride, 5.89g of 4-pyridylaldehyde and 0.96g of tetrabutylammonium bromide are sequentially added into a three-neck flask provided with a condenser tube and a stirrer, the mixture is stirred at the temperature of 40-50 ℃, HPLC (high performance liquid chromatography) is used for monitoring the basic reaction to be complete after 8 hours, the mixture is cooled to the room temperature, solid is filtered out, filtrate is concentrated, 100mL of ethyl acetate is added for crystallization, the mixture is filtered and dried in vacuum, 10.65g of a compound III is obtained, the yield is 81.9%, and the purity is 98.1% by HPLC detection.
Comparative example 5:
60mL of absolute ethanol was added to the reaction vessel, and 11.24g of the compound III prepared by the method of example 1 and 10% Pd/C1.12g were added. Heating to 40-50 ℃, introducing hydrogen under 2.0MPa for reaction, after 2h, basically stopping TLC detection, filtering Pd/C, concentrating the filtrate, adding 80mL of dichloromethane, adding concentrated hydrochloric acid while stirring to adjust the pH to 3.0, growing crystals for 2h, filtering, and drying in vacuum to obtain a compound IV 10.61g, wherein the yield is 81.6%, and the purity is 97.0% by HPLC detection.
Comparative example 6:
60mL of absolute ethanol is added into a 500mL three-necked flask, the compound III11.24g prepared by the method in example 1 is added, 7.56g (0.12mol) of ammonium formate and 1.12g of 10% palladium-carbon are added, the temperature is controlled to be 40-50 ℃, stirring reaction is carried out, HPLC detection reaction is stopped after 2h, filtration is carried out, filtrate is concentrated, 80mL of dichloromethane is added, concentrated hydrochloric acid is added under stirring to adjust the pH value to 3.0, crystal growth is carried out for 2h, filtration and vacuum drying are carried out, 10.99g of the compound IV is obtained, the yield is 84.5%, and the purity of HPLC detection is 97.9%.
Comparative example 7:
adding 60mL of absolute ethanol into a 500mL three-necked flask, adding 11.24g of the compound IIIprepared by the method in example 1, adding 25.20g (0.40mol) of ammonium formate and 1.12g of 10% palladium-carbon, stirring and reacting at the temperature of 40-50 ℃, stopping HPLC detection reaction after 1.5h, filtering, concentrating the filtrate, adding 80mL of dichloromethane, adding concentrated hydrochloric acid to adjust the pH to 3.0 under stirring, growing crystals for 2h, filtering, and drying in vacuum to obtain 11.14g of the compound IV, wherein the yield is 85.7%, and the purity is 91.3% by HPLC detection.
Claims (6)
1. The method for synthesizing donepezil hydrochloride is characterized by comprising the following steps:
(1) dissolving a compound I and a compound II in acetone, adding a catalyst, controlling the temperature to react, filtering out solids after the reaction is finished, concentrating the filtrate, adding an organic solvent to crystallize to obtain a compound III, wherein the catalyst is a mixture of a catalyst 1 and a catalyst 2, the catalyst 1 is one of anhydrous calcium chloride and anhydrous copper sulfate, the molar ratio of the catalyst 1 to the compound I is 1-1.5: 1, and the catalyst 2 is potassium iodide;
(2) performing temperature-controlled reaction on the compound III under the action of a hydrogen source reagent and a Pd/C catalyst, adding hydrochloric acid to salify after the reaction is finished to obtain a compound IV, wherein the hydrogen source reagent is ammonium formate, and the molar ratio of the ammonium formate to the compound III is 4-8: 1;
(3) reacting the compound IV with benzyl chloride under the action of an acid binding agent, and adding hydrochloric acid to adjust the pH value to obtain donepezil hydrochloride;
the reaction route is as follows:
2. the method for synthesizing donepezil hydrochloride according to claim 1, wherein the reaction temperature in step (1) is 40 to 50 ℃.
3. The method for synthesizing donepezil hydrochloride according to claim 1, wherein the organic solvent used for crystallization in step (1) is one of ethyl acetate, 2-butanone, and chloroform.
4. The method for synthesizing donepezil hydrochloride according to claim 1, wherein the reaction temperature in step (2) is 40 to 50 ℃.
5. The method for synthesizing donepezil hydrochloride according to claim 1, wherein the acid-binding agent used in step (3) is one or more of triethylamine, sodium carbonate and sodium bicarbonate.
6. The method for synthesizing donepezil hydrochloride according to claim 1, wherein the pH value in step (3) is 1.5 to 2.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811653454.3A CN109651234B (en) | 2018-12-29 | 2018-12-29 | Synthesis method of donepezil hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811653454.3A CN109651234B (en) | 2018-12-29 | 2018-12-29 | Synthesis method of donepezil hydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109651234A CN109651234A (en) | 2019-04-19 |
| CN109651234B true CN109651234B (en) | 2021-01-01 |
Family
ID=66118692
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811653454.3A Active CN109651234B (en) | 2018-12-29 | 2018-12-29 | Synthesis method of donepezil hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109651234B (en) |
Families Citing this family (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 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU227474B1 (en) * | 2005-12-20 | 2011-07-28 | Richter Gedeon Nyrt | Process for industrial scale production of high purity donepezil hydrochloride polymorph i. |
| US20140128613A1 (en) * | 2011-03-25 | 2014-05-08 | Piramal Enterprises Limited | A process for preparation of intermediates of donepezil hydrochloride |
| CN103012268B (en) * | 2013-01-05 | 2015-02-25 | 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
Also Published As
| Publication number | Publication date |
|---|---|
| CN109651234A (en) | 2019-04-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110590635A (en) | Preparation method of levetiracetam and intermediate thereof | |
| EP3988545A1 (en) | Methods for preparing cdk4/6 inhibitor and salt and intermediate thereof | |
| CN107778223B (en) | Preparation method of betrixaban maleate | |
| CN109096122B (en) | Process for preparing spermidine | |
| CN109651234B (en) | Synthesis method of donepezil hydrochloride | |
| CN103864802A (en) | Preparation method of high-purity asenapine maleate | |
| EA036663B1 (en) | Method for preparing azoxystrobin | |
| KR101595747B1 (en) | Method for preparing of nafamostat mesilate | |
| CN110437125B (en) | Preparation method of Tezacaftor intermediate II | |
| CN111138351A (en) | Synthetic method of 2-aminomethyl-3-chloro-5-trifluoromethylpyridine acetate | |
| CN113278021B (en) | Preparation method of 1, 7-diazaspiro [3.5] nonane-7-tert-butyl formate and oxalate thereof | |
| CN111100062A (en) | Synthesis method of donepezil hydrochloride | |
| CN111320570B (en) | Preparation method of lansoprazole key intermediate | |
| CN104876812B (en) | Process for preparing sertraline hydrochloride intermediates and impurities | |
| CN114478837A (en) | Preparation method of sugammadex sodium derivative | |
| JP2012020970A (en) | Method for producing {3-(1-diphenylmethylazetidin-3-yl)ester-5-isopropyl ester 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate} | |
| WO2016078584A1 (en) | Emtricitabine purification method | |
| CN110724098A (en) | Synthetic method of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline-6-carboxylic acid hydrochloride | |
| CN114105848B (en) | Preparation method of cis-D-hydroxyproline derivative | |
| JP5952748B2 (en) | Novel crystalline form of phthaloyl amlodipine and process for producing high purity amlodipine besylate using the same | |
| KR102645122B1 (en) | Methods for Preparing Olaparib | |
| CN114149360B (en) | Preparation method of high-purity nitrendipine bulk drug | |
| JP2013119518A (en) | Method for producing (s)-2-benzyl-3-(cis-hexahydro-2-isoindonilylcarbonyl)benzyl propionate | |
| CN113582920B (en) | Synthetic method of 4- (4-pyridyl) morpholine | |
| CN115611739A (en) | Preparation method of benzoic acid intermediate and intermediate thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CB03 | Change of inventor or designer information | ||
| CB03 | Change of inventor or designer information |
Inventor after: Li Minghua Inventor after: Li Mingjie Inventor after: Li Junguang Inventor after: Li Cheng Inventor before: Li Mingjie Inventor before: Li Junguang Inventor before: Li Cheng |