CN110540520B - Method for purifying donepezil - Google Patents
Method for purifying donepezil Download PDFInfo
- Publication number
- CN110540520B CN110540520B CN201910866883.7A CN201910866883A CN110540520B CN 110540520 B CN110540520 B CN 110540520B CN 201910866883 A CN201910866883 A CN 201910866883A CN 110540520 B CN110540520 B CN 110540520B
- Authority
- CN
- China
- Prior art keywords
- donepezil
- organic solvent
- water
- pharmaceutically acceptable
- purifying
- 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
Images
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
Abstract
The invention relates to a method for purifying Donepezil (Donepezil), belonging to the technical field of preparation of raw material medicines. The method for purifying donepezil or pharmaceutically acceptable salts thereof comprises the following steps: firstly, adding a hydrophobic organic solvent and water into donepezil or a pharmaceutically acceptable salt thereof to obtain a mixed solution, wherein the hydrophobic organic solvent is selected from dichloromethane, ethyl acetate or toluene, or a mixture thereof; adjusting the pH value of the water phase of the mixed solution to be not less than 9 by using alkali, and separating an organic phase from the water phase; and concentrating the organic phase obtained in the third step under reduced pressure to obtain the purified donepezil. The invention provides a method for purifying donepezil or pharmaceutically acceptable salts thereof, which provides high-quality raw material medicines for the preparation.
Description
Technical Field
The invention relates to a method for purifying Donepezil (Donepezil), belonging to the technical field of preparation of raw material medicines.
Background
Donepezil hydrochloride is a second-generation specific reversible central acetylcholinesterase (AChE) inhibitor, and the donepezil hydrochloride can reversibly inhibit AChE activity to slow down the decomposition of synaptic interstitial acetylcholine (ACh), thereby increasing the content of ACh in receptor sites and improving the cognitive function of Alzheimer Disease (AD) patients. Has the advantages of high selectivity, small dosage, long half-life period, small adverse reaction, no liver toxicity and the like, and is suitable for treating mild or moderate Alzheimer dementia symptoms. Donepezil is the most important intermediate of donepezil hydrochloride, and is salified with hydrochloric acid to produce donepezil hydrochloride.
Donepezil is chemically named 2- [ (1-benzyl-4-piperidinyl) methyl ] -5, 6-dimethoxy-1-indanone. The chemical structure is shown as the following formula II:
at present, the synthesis routes of donepezil are various, and the following two routes are mainly adopted in industrial production:
route one:
the first route is disclosed in patent US4895841A by japan toilet, a former company. Donepezil is obtained by condensation and catalytic hydrogenation of 5, 6-dimethoxy-1-indanone and 1-benzyl-4-piperidine formaldehyde through Aldol.
And a second route:
the second route is disclosed in patent CN1524851A by Tianjin pharmaceutical research institute. Hydrogenating 5, 6-dimethoxy-2- (4-pyridyl) methylene-1-indanone, and reacting with benzyl chloride to obtain donepezil.
In the research process, the final product obtained by the process has 0.5 to 1 percent of impurity, and the impurity is determined to be quaternary ammonium salt impurity (I) in the United States Pharmacopeia (USP) described by the formula I, and the limit requirement of the impurity in the USP is less than 0.15 percent.
We have found that 1-benzyl-4-piperidinecarboxaldehyde used in route one contains corresponding dibenzylated impurities which participate in the subsequent condensation and hydrogenation reactions to produce quaternary ammonium salt impurities; route two in the last reaction process, the generated donepezil product further reacts with benzyl chloride to generate quaternary ammonium salt impurities. The amplification effect is obvious, and the larger the batch size is, the higher the impurity content is. The subsequent salification step is generally to dissolve donepezil by using an organic solvent (alcohols, ethyl acetate, dichloromethane and the like), add hydrochloric acid or a mixture of the hydrochloric acid and the organic solvent to salify, cool or concentrate or add an ether solvent to crystallize. The subsequent purification method usually comprises recrystallization with an alcohol solvent or dissolution with a benign solvent (alcohol, methylene chloride, etc.), and crystallization with addition of a poor solvent (ether, n-hexane, etc.). However, the quaternary ammonium salt impurity (I) has a structure similar to that of donepezil hydrochloride, and subsequent salt formation and refining or multiple refining can not be effectively removed. This impurity can only be controlled below relevant limits before donepezil is salified. Otherwise, the requirements of pharmacopoeia are difficult to meet, and the final product is unqualified.
In addition, in other routes, as long as the condensation reaction of the piperidine ring and benzyl halide exists, the risk of generating quaternary ammonium salt impurities exists, so that a purification method which is simple to operate, mild in conditions and capable of effectively removing the quaternary ammonium salt impurities is urgently needed.
Disclosure of Invention
The invention aims to provide a method for purifying donepezil or a pharmaceutically acceptable salt thereof, which is suitable for industrial production, wherein the donepezil or the pharmaceutically acceptable salt thereof contains donepezil quaternary ammonium salt impurities shown as a formula I:
according to the conventional knowledge, the salt substance can be easily dissolved by water, and the compound of formula I as a quaternary ammonium salt should have certain solubility in water, so the applicant tries to remove the impurity of formula I in formula II by washing with water, but the result is frustrated, no matter the amount of water is increased, or the washing times are increased, or the washing temperature is increased, or the washing time is prolonged, and the detection shows that the impurity of formula I is not removed at all, but a small amount of donepezil can be taken away by the water washing. The applicants speculate that formula I, although a quaternary ammonium salt, is strongly hydrophobic in the overall structure, even stronger than donepezil, and therefore is not removed by water washing. In a later unexpected experiment, only the compound of formula I and no donepezil are detected in the washing water phase. Through various researches, the applicant has surprisingly found that the impurity formula I can be effectively removed by adjusting the pH of the donepezil solution to be more than 9.3, and the donepezil can not be washed away. If the pH is less than 9.0, the removal effect is hardly obtained.
Washing and separating an organic phase by alkaline water, then decompressing and concentrating to obtain a part of the organic phase, adding an aliphatic hydrocarbon organic solvent for crystallization and filtering, not only effectively removing quaternary ammonium salt impurities, but also obtaining high-purity donepezil, directly salifying to obtain the high-purity donepezil hydrochloride, and not needing to add extra refining.
The specific scheme of the invention is as follows:
a method for purifying donepezil shown in formula II or a pharmaceutically acceptable salt thereof, comprising the steps of:
firstly, adding a hydrophobic organic solvent and water into donepezil or pharmaceutically acceptable salt thereof to obtain a mixed solution;
the hydrophobic organic solvent is selected from dichloromethane, ethyl acetate, toluene, or a mixture thereof.
The amount of water and the hydrophobic organic solvent used in the mixed solution is not particularly limited as long as donepezil or a pharmaceutically acceptable salt thereof can be dissolved therein, and the total amount of water and the hydrophobic organic solvent is preferably 14 to 30mL/g relative to donepezil or a pharmaceutically acceptable salt thereof.
The volume ratio of water to the hydrophobic organic solvent in the mixed solution is not particularly limited as long as the mixed solution can form a two-phase system of an aqueous phase and an organic phase, and preferably the volume ratio of water to the hydrophobic organic solvent is 0.5 to 1: 1.
Secondly, adjusting the pH of the water phase of the mixed solution obtained in the first step to be not less than 9.3 by using alkali;
the alkali in the step can be organic alkali or inorganic alkali, and is selected from sodium carbonate, potassium carbonate, sodium hydroxide, ammonia water, triethylamine and the like. The sodium carbonate, potassium carbonate and sodium hydroxide can be in solid form or can be in solution with proper concentration.
The pH value in the step is preferably 9.8-13.5.
Thirdly, separating the organic phase and the water phase obtained in the second step and keeping the organic phase;
and fourthly, decompressing and concentrating the organic phase obtained in the third step to one half of the original organic phase, adding an aliphatic hydrocarbon organic solvent, cooling to 0-10 ℃, maintaining, stirring for crystallization for 1 hour, filtering and drying to obtain the high-purity donepezil.
Preferably, the aliphatic hydrocarbon organic solvent in this step is selected from n-hexane, n-heptane, cyclohexane or their mixture.
Preferably, the dosage of the aliphatic hydrocarbon organic solvent in the step is 5-10 mL/g relative to donepezil or pharmaceutically acceptable salt thereof.
Preferably, the stirring crystallization temperature in the step is 4-7 ℃.
The invention provides a preparation method of high-purity donepezil, which effectively removes the impurities of the quaternary ammonium salt of donepezil shown in formula I. Because the donepezil quaternary ammonium salt impurity in the formula I has a similar structure with donepezil hydrochloride, the impurity is difficult to be effectively removed by a recrystallization method, the technical scheme of the invention adjusts the pH value of the donepezil solution to be more than 9.3, then separates an organic phase, then carries out reduced pressure concentration to obtain a part of the organic phase, adds an aliphatic hydrocarbon organic solvent for crystallization, and carries out filtration to obtain the product. The content of quaternary ammonium salt impurities in the donepezil can reach below 0.1 percent, the purity of the donepezil reaches above 99.8 percent, and the high-purity donepezil hydrochloride can be obtained by directly salifying without additional refining.
Drawings
FIG. 1 is a high performance liquid chromatogram of a donepezil product of comparative example 1;
FIG. 2 is a high performance liquid chromatogram of a fine donepezil hydrochloride product of comparative example 1;
FIG. 3 is a high performance liquid chromatogram of a fine donepezil hydrochloride product of comparative example 2;
FIG. 4 is a high performance liquid chromatogram of a fine donepezil hydrochloride product of comparative example 3;
FIG. 5 high performance liquid chromatogram of the product of example 5.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The following examples are intended to further illustrate the invention, but not to limit the scope of the invention.
Comparative example 1
The applicant prepared donepezil hydrochloride with reference to patent CN1524851A under magnification:
adding 1000g of 5, 6-dimethoxy-2- (4-piperidinylmethyl) -indan-1-one acetate, 467g of benzyl chloride, 20L of absolute ethyl alcohol and 1194g of sodium carbonate into a 50L glass reaction kettle, stirring and heating to 79 ℃, reacting for 4h, concentrating under reduced pressure to obtain a solid, adding 24L of water, stirring for 30 min, adding 24L of ethyl acetate, extracting, and concentrating to obtain 978.8g of solid donepezil. Wherein the content of impurity I is 0.71%, the high performance liquid chromatography with purity of 98.64% is shown in figure 1, and the total analysis results are shown in Table 1.
TABLE 1
180g of donepezil is taken, 500ml of ethyl acetate is added, 360ml of ethyl acetate hydrochloride is added for salification, and 200.5g of crude donepezil hydrochloride is obtained after concentration and drying. Adding 3000ml ethanol and 6g active carbon, heating and refluxing, filtering, stirring and crystallizing to obtain 141.7g donepezil hydrochloride competitive product. Wherein the content of impurity I is 0.45%, the purity is 99.14%, the high performance liquid chromatography is shown in figure 2, and the total analysis result is shown in table 2.
TABLE 2
Comparative example 1 shows that the impurity I content in donepezil is large, the donepezil is not effectively removed after being refined, and the product purity is not very high.
Comparative example 2
The applicant prepared donepezil hydrochloride with reference to patent US 4895841A:
100g of donepezil prepared in comparative example 1 is taken, 500ml of dichloromethane is added, 360ml of ethyl acetate hydrochloride is added for salification, and the crude donepezil hydrochloride product is obtained by concentration and drying, namely 111.5 g. Adding 1000ml of methanol, heating to dissolve, adding 2000ml of isopropyl ether, stirring at room temperature, crystallizing and filtering to obtain 89.2g of fine donepezil hydrochloride. Wherein the content of impurity I is 0.50%, the purity is 99.37%, the high performance liquid chromatography is shown in figure 3, and the total analysis result is shown in table 3.
TABLE 3
Comparative example 2 the test shows that impurity I is not effectively removed by the shift refining process.
Comparative example 3
The applicant further prepared donepezil hydrochloride in large scale and refined 2 times with reference to patent CN 1524851A:
adding 4.0kg of 5, 6-dimethoxy-2- (4-piperidylmethyl) -indan-1-one acetate, 1.8kg of benzyl chloride, 80L of absolute ethyl alcohol and 4.8kg of sodium carbonate into a 200L enamel reaction kettle, stirring and heating to 79 ℃, reacting for 4h, concentrating under reduced pressure to obtain a solid, adding 100L of water, stirring for 30 min, adding 100L of ethyl acetate for extraction, concentrating the residual small amount of ethyl acetate, adding 10L of ethyl acetate hydrochloride for salification, and concentrating and drying to obtain a donepezil hydrochloride crude product. Adding 60L ethanol and 100g active carbon, heating and refluxing, filtering, stirring and crystallizing, and centrifuging to obtain solid. Then 60L of ethanol is added, the mixture is heated and refluxed, stirred and crystallized, and centrifuged to obtain 2.2kg of fine donepezil hydrochloride. Wherein the content of impurity I is 1.34%, the high performance liquid chromatography with purity of 98.48% is shown in figure 4, and the total analysis results are shown in Table 4.
TABLE 4
Comparative example 3 shows that the content of the impurity I in the product is increased along with the batch amplification, and the content of the impurity I in the product after 2 times of refining is up to 1.34 percent, which seriously affects the product quality and limits the industrial production.
Example 1
Adding 20 g of donepezil prepared in comparative example 1 into a 500ml four-mouth bottle, adding 180ml of ethyl acetate, stirring to dissolve, adding 120ml of water, slowly adding potassium carbonate solid under stirring to adjust the pH value to 11.4, stirring for 30 minutes, layering, separating an organic phase and an aqueous phase, concentrating the organic phase to half under pressure, adding 100ml of n-hexane, cooling to 10 ℃, stirring for 1 hour, filtering and drying to obtain 19.3g of donepezil white solid, wherein the yield is 96.5%, the HPLC purity is 99.93% and the quaternary ammonium salt impurity is 0.03%.
Example 2
Adding 15 g of donepezil prepared in comparative example 1 into a 500ml four-mouth bottle, adding 180ml of ethyl acetate, stirring to dissolve, adding 120ml of water, slowly adding sodium hydroxide solid under stirring to adjust the pH value to 13.5, stirring for 30 minutes, layering, separating an organic phase from an aqueous phase, concentrating the organic phase to half under pressure, adding 150ml of n-hexane, cooling to 5 ℃, stirring for 1 hour, filtering and drying to obtain 14.3g of purified donepezil white solid, wherein the yield is 95.3%, the HPLC purity is 99.98% and the quaternary ammonium salt impurity is 0.02%.
Example 3
Adding 10 g of donepezil prepared in comparative example 1 into a 500ml four-neck flask, adding 180ml of ethyl acetate, stirring to dissolve, adding 90ml of water, adding ammonia water while stirring to adjust the pH value to 12.6, stirring for 30 minutes, layering, separating an organic phase from an aqueous phase, concentrating the organic phase to half under reduced pressure, adding 100ml of cyclohexane, cooling to 10 ℃, stirring for 1 hour, filtering, and drying to obtain 9.5 g of purified donepezil white solid with the yield of 95.0%, the HPLC purity of 99.94% and the quaternary ammonium salt impurity of 0.02%.
Example 4
Adding 20 g of donepezil prepared in comparative example 1 into a 500ml four-neck flask, adding 180ml of dichloromethane, stirring to dissolve, adding 120ml of water, slowly adding potassium carbonate solid while stirring to adjust the pH to 9.3, stirring for 30 minutes, layering, separating an organic phase from an aqueous phase, concentrating the organic phase to half under reduced pressure, adding 150ml of n-heptane, cooling to 0 ℃, stirring for 1 hour, filtering, and drying to obtain 19.3g of purified donepezil white solid with yield of 96.5%, HPLC purity of 99.91% and quaternary ammonium salt impurity of 0.04%.
Example 5
Adding 200g of donepezil prepared in comparative example 1 into a 5000 ml four-mouth bottle, adding 1800ml of ethyl acetate and 1000ml of water, slowly adding potassium carbonate solid under stirring to adjust the pH value to 12.2, stirring for 30 minutes, demixing, separating an organic phase and an aqueous phase, concentrating the organic phase to half under pressure, adding 1500ml of n-hexane, cooling to 5 ℃, stirring for 1 hour, filtering, and drying to obtain 192.4 g of purified donepezil white solid with the yield of 96.2%, the HPLC purity of 99.95% and the quaternary ammonium salt impurity of 0.01%. Its high performance liquid chromatography spectrum is shown in figure 5, and the total analysis results are shown in table 5.
TABLE 5
Example 6
Adding 20 g of donepezil hydrochloride prepared in comparative example 1 into a 500ml four-neck flask, adding 180ml of ethyl acetate and 180ml of water, slowly adding sodium hydroxide solid under stirring to adjust the pH to 11.7, stirring for 30 minutes, layering, separating an organic phase from an aqueous phase, concentrating the organic phase to half under pressure, adding 100ml of n-heptane, cooling to 7 ℃, stirring for 1 hour, filtering, and drying to obtain 19.5 g of purified donepezil white solid with the yield of 97.5%, the HPLC purity of 99.96% and the quaternary ammonium salt impurity of 0.01%.
Example 7
Adding 10 g of donepezil hydrochloride prepared in comparative example 2 into a 500ml four-mouth bottle, adding 180ml of toluene and 120ml of water, slowly adding potassium carbonate solid under stirring to adjust the pH value to 10.6, stirring for 30 minutes, layering, separating an organic phase from an aqueous phase, concentrating the organic phase to half under pressure, adding 100ml of cyclohexane, cooling to 4 ℃, stirring for 1 hour, filtering, and drying to obtain 9.4 g of purified donepezil white solid with the yield of 94.0%, the HPLC purity of 99.94% and the quaternary ammonium salt impurity of 0.02%.
Example 8
150 g of donepezil hydrochloride prepared in comparative example 3 is added into a 5000 ml four-mouth bottle, 1800ml of ethyl acetate and 900ml of water are added, triethylamine is added under stirring to adjust the pH value to 13.1, stirring is carried out for 30 minutes, layering is carried out, an organic phase and a water phase are separated, the organic phase is concentrated to half by pressure, 750ml of n-hexane is added, cooling is carried out to 5 ℃, stirring is carried out for 1 hour, filtration and drying are carried out, 143.4g of purified donepezil white solid is obtained, the yield is 95.6%, the HPLC purity is 99.99%, and the quaternary ammonium salt impurity is 0.02%.
Claims (4)
1. A method for purifying donepezil shown in formula II or pharmaceutically acceptable salts thereof, which comprises the following steps:
adding a hydrophobic organic solvent and water into donepezil or a pharmaceutically acceptable salt thereof to obtain a mixed solution, wherein the hydrophobic organic solvent is dichloromethane, ethyl acetate or toluene or a mixture thereof, the total amount of the water and the hydrophobic organic solvent in the mixed solution is 14-30 mL/g relative to the donepezil or the pharmaceutically acceptable salt thereof, and the volume ratio of the water to the hydrophobic organic solvent is 0.5-1: 1;
secondly, adjusting the pH value of the water phase of the mixed solution obtained in the first step to be not less than 9.3 by using alkali, wherein the alkali is organic alkali or inorganic alkali;
thirdly, separating the organic phase and the water phase obtained in the second step;
and fourthly, concentrating the organic phase obtained in the third step to one half of the original phase under reduced pressure, adding an aliphatic hydrocarbon organic solvent, cooling to 0-10 ℃, maintaining, stirring for 1 hour for crystallization, filtering, and drying to obtain the high-purity donepezil, wherein the aliphatic hydrocarbon organic solvent is selected from n-hexane, n-heptane, cyclohexane or a mixture of the n-hexane, the n-heptane and the cyclohexane, and the dosage of the aliphatic hydrocarbon organic solvent is 5-10 mL/g relative to the donepezil or the pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein the base in the second step is selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide, ammonia water and triethylamine.
3. The method for purifying donepezil or its pharmaceutically acceptable salt according to claim 1, wherein the pH of the aqueous phase in the second step is adjusted to 9.8 to 13.5 with a base.
4. The method for purifying donepezil or its pharmaceutically acceptable salt according to claim 1, wherein the fourth step is carried out at a temperature of 4 to 7 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910866883.7A CN110540520B (en) | 2019-09-12 | 2019-09-12 | Method for purifying donepezil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910866883.7A CN110540520B (en) | 2019-09-12 | 2019-09-12 | Method for purifying donepezil |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110540520A CN110540520A (en) | 2019-12-06 |
| CN110540520B true CN110540520B (en) | 2022-02-08 |
Family
ID=68713517
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910866883.7A Active CN110540520B (en) | 2019-09-12 | 2019-09-12 | Method for purifying donepezil |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110540520B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007057226A2 (en) * | 2005-11-18 | 2007-05-24 | Synthon B.V. | Process for making donepezil |
| WO2007108011A2 (en) * | 2006-03-20 | 2007-09-27 | Ind-Swift Laboratories Limited | Process for the preparation of highly pure donepezil |
| WO2009118516A1 (en) * | 2008-03-25 | 2009-10-01 | Cipla Limited | Process for the preparation of donepezil hydrochloride |
| CN103804280A (en) * | 2012-11-07 | 2014-05-21 | 丁林洪 | Preparation method of donepezil HCl |
| CN103992263A (en) * | 2014-05-22 | 2014-08-20 | 浙江海正药业股份有限公司 | Donepezil purifying method |
| WO2015109377A1 (en) * | 2013-11-29 | 2015-07-30 | Cristália Produtos Químicos Farmacêuticos Ltda. | Process for preparing donepezil hydrochloride forms i and iii; and an intermediate compound thereof |
-
2019
- 2019-09-12 CN CN201910866883.7A patent/CN110540520B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007057226A2 (en) * | 2005-11-18 | 2007-05-24 | Synthon B.V. | Process for making donepezil |
| WO2007108011A2 (en) * | 2006-03-20 | 2007-09-27 | Ind-Swift Laboratories Limited | Process for the preparation of highly pure donepezil |
| WO2009118516A1 (en) * | 2008-03-25 | 2009-10-01 | Cipla Limited | Process for the preparation of donepezil hydrochloride |
| CN103804280A (en) * | 2012-11-07 | 2014-05-21 | 丁林洪 | Preparation method of donepezil HCl |
| WO2015109377A1 (en) * | 2013-11-29 | 2015-07-30 | Cristália Produtos Químicos Farmacêuticos Ltda. | Process for preparing donepezil hydrochloride forms i and iii; and an intermediate compound thereof |
| CN103992263A (en) * | 2014-05-22 | 2014-08-20 | 浙江海正药业股份有限公司 | Donepezil purifying method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110540520A (en) | 2019-12-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108948020B (en) | Refining method of tofacitinib citrate | |
| EA012911B1 (en) | Process for production of highly pure polymorph (i) donepezil hydrochloride | |
| JP2000517288A (en) | Optical Resolution of Methylphenidate by O, O'-Bisaroyl Tartaric Acids | |
| CA2719778C (en) | Method for preparing argatroban monohydrate | |
| CN112574058B (en) | Synthetic route of lacosamide | |
| ES2320012T3 (en) | INTERMEDIATE PROCEDURES AND PRODUCTS FOR THE PREPARATION OF STEREO-ISOMEROS OF PIPERIDINA 2-REPLACED. | |
| CN110540520B (en) | Method for purifying donepezil | |
| CN111533746A (en) | Synthesis method of tofacitinib citrate | |
| ES2465219T3 (en) | Process for the preparation of methylphenidate hydrochloride | |
| JP4268055B2 (en) | Purified lasofoxifene and a method for purifying racemic rasofoxifene by recrystallization | |
| TW201335110A (en) | Process for recovery of nalmefene hydrochloride | |
| JPH10182635A (en) | Optically active piperidine derivative and its production | |
| BR102013030928A2 (en) | process for the preparation of donepezil hydrochloride forms i and iii; and an intermediate compound thereof | |
| EP3068746B1 (en) | Process for the preparation of enantiomerically pure 1-aminoindan | |
| CN115197178B (en) | Synthesis method of brivaracetam key intermediate | |
| JP5419570B2 (en) | Method for purifying 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine | |
| KR20180079967A (en) | A new synthesis method of (+)-Decursinol | |
| EP3031800B1 (en) | Process for the preparation of high purity miglustat | |
| EP3247697A1 (en) | Process and intermediates for the racemization of enantiomerically enriched 1-aminoindane | |
| CN113461554A (en) | Purification method of rivastigmine intermediate | |
| CN110885315A (en) | Preparation method of important intermediate of levosimendan | |
| JP2003146943A (en) | Method for producing optically active 2-hydroxy-3- nitropropionic acid | |
| TWI453182B (en) | Process for the preparation of (r)-β-amino-phenyl butyric acid derivatives | |
| JPH07258215A (en) | Production of optically active 1-(4-chloropyridin-2-yl)-2-(pyridin-2-yl)ethylamine | |
| JPH06107602A (en) | Production of optically active 1-phenylethylamine |
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 | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20200813 Address after: 264205 Guangzhou East Road South and an East Road East, Wendeng economic and Technological Development Zone, Weihai City, Shandong Province Applicant after: Dijia Pharmaceutical Group Co.,Ltd. Applicant after: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Address before: 264205 No.1, South Qingdao Road, Weihai Economic and Technological Development Zone, Weihai City, Shandong Province Applicant before: WEIHAI DISU PHARMACEUTICAL Co.,Ltd. Applicant before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. |
|
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20210929 Address after: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Applicant after: Dijia Pharmaceutical Group Co.,Ltd. Address before: 264205 Wendeng economic and Technological Development Zone, Weihai City, Shandong Province Applicant before: Dijia Pharmaceutical Group Co.,Ltd. Applicant before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP03 | Change of name, title or address |
Address after: No. 268, Tianrun Road, Wendeng Economic and Technological Development Zone, Weihai City, Shandong Province, 264200 Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Patentee before: Dijia Pharmaceutical Group Co.,Ltd. |
|
| CP03 | Change of name, title or address |