CN103992263B - A kind of purification process of E2020 - Google Patents
A kind of purification process of E2020 Download PDFInfo
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- CN103992263B CN103992263B CN201410219985.7A CN201410219985A CN103992263B CN 103992263 B CN103992263 B CN 103992263B CN 201410219985 A CN201410219985 A CN 201410219985A CN 103992263 B CN103992263 B CN 103992263B
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- 0 COc(cc(CC(CC1CCN(*)CC1)C1=O)c1c1)c1OC Chemical compound COc(cc(CC(CC1CCN(*)CC1)C1=O)c1c1)c1OC 0.000 description 3
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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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Abstract
The present invention relates to the purification process of a kind of E2020 or its pharmacy acceptable salt.The method comprises: (1) provides a kind of mixed solution being dissolved with E2020 or its pharmacy acceptable salt, containing hydrophobic organic solvent and water in wherein said mixed solution; (2) by the acid of the mixed solution of step (1) or adjusting PH with base value to 3 ~ 5; (3) separating step (2) gained organic phase and aqueous phase; (4) optional, step (3) gained aqueous phase hydrophobic organic solvent is extracted one or many; (5) combining step (3) and (4) gained organic phase; (6) from step (5) gained organic phase, be separated the E2020 obtaining purifying; (7) optional, step (6) gained E2020 is changed into its pharmacy acceptable salt.Method of the present invention is simple to operate, and the E2020 purity finally obtained and yield are all very high, is applicable to very much commercially producing.
Description
[technical field]
The invention belongs to medical art, be specifically related to a kind of purification process of E2020.
[background technology]
E 2020 is s-generation Pseudocholinesterase (ChE) inhibitor researched and developed by Japanese Wei Cai Pharmaceutical Co., Ltd.This product obtains the special permission approval of U.S. FDA for clinical in November, 1996, commodity are called " Aricept ", and first went on the market in the U.S. in 1997, more than 50 the countries and regions listing in the whole world subsequently, be the leading kind in current global anti-senile dementia disease drug market, the structural formula of E2020 is as follows:
At present, the synthesis technique of E2020 has a lot, and wherein compound (III) is the key intermediate of synthesis E2020:
Chinese Pharmaceutical Journal volume the 18th phase September the 40th in 2005, Sheng Rong, Hu Yongzhou are in " study on the synthesis of E2020 " literary composition, disclose 5,6-dimethoxy-1-indone (V) and 1-benzyl-4-piperidinealdehyde (IV) are under sodium hydroxide exists, methyl alcohol makees solvent, and under room temperature, the method for compound (III) is prepared in reaction:
Find through many experiments, synthesize according to the method, can not get pure compound (III), in this reaction process, generate a kind of E2020 hydroxyl impurity (II):
Its content reaches 10-20%.Due to this impurity (II) and compound (III) and E2020 structural similitude, be therefore difficult to be removed by the method for recrystallization.
Chinese patent CN200810212668.7 discloses the method for a kind of purified compound (III):
The method comprises in the presence of an inorganic base, by compound (III) crude product at C
6-C
12aromatic solvent in reacting by heating, make E2020 hydroxyl impurity (II) change compound (III) into:
But the method needs to react at relatively high temperatures, but also use the aromatic solvent larger to human injury, be not suitable for commercially producing.
A kind of method removing E2020 hydroxyl impurity (II) is disclosed in WO2007108011A,
Comprise: under the existence of sulphonate and organic bases, in certain solvent, E2020 hydroxyl impurity (II) is transformed into compound (III):
Use mixed solvent methylsulfonyl chloride and triethylamine in the method, and methylsulfonyl chloride has stronger tearing property and pungency, toxicity is higher, not only has harm to environment, increases difficulty, and be unfavorable for commercial operation to the disposal of three wastes.
E2020 hydroxyl impurity (II) disclosed in prior art although minimizing technology can reduce the content of E2020 hydroxyl impurity (II) in finished product to a great extent, but still can remain a certain amount of E2020 hydroxyl impurity (II) in the E2020 product prepared after these method process, make E2020 quality product be difficult to meet pharmacopoeia of each country standard.Because E2020 hydroxyl impurity (II) and E2020 structure are closely similar, and rarely have report about the minimizing technology of this hydroxyl impurity (II) in E2020 product in prior art, therefore, be badly in need of a kind of simple to operate, mild condition, environmental protection, is easy to the E2020 hydroxyl impurity (II) in business-like method removal E2020 product.
[summary of the invention]
The object of the present invention is to provide the purification process of a kind of E2020 or its pharmacy acceptable salt, described E2020 or its pharmacy acceptable salt are containing, for example the E2020 hydroxyl impurity shown in following formula (II):
The method is simple to operate, and reaction conditions is gentle, is applicable to very much commercially producing.
Concrete scheme of the present invention is as follows:
The method of the E2020 shown in a kind of purifying formula (I) or its pharmacy acceptable salt,
Wherein said E2020 or its pharmacy acceptable salt contain such as formula the E2020 hydroxyl impurity shown in (II):
Described method comprises:
(1) a kind of mixed solution being dissolved with E2020 or its pharmacy acceptable salt is provided, containing hydrophobic organic solvent and water in wherein said mixed solution;
(2) by the acid of the mixed solution of step (1) or adjusting PH with base value to 3 ~ 5;
(3) separating step (2) gained organic phase and aqueous phase;
(4) optional, step (3) gained aqueous phase hydrophobic organic solvent is extracted one or many;
(5) combining step (3) and (4) gained organic phase;
(6) from step (5) gained organic phase, be separated the E2020 obtaining purifying;
(7) optional, step (6) gained E2020 is changed into its pharmacy acceptable salt.
Wherein, the hydrophobic organic solvent described in step (1) is selected from methylene dichloride, ethyl acetate, chloroform, or their mixture.
Wherein, in the mixed solution of step (1), the volume ratio of water and hydrophobic organic solvent has no particular limits, as long as described mixed solution can form the two-phase system of aqueous phase and organic phase, preferably, the volume ratio of water and hydrophobic organic solvent is 1/2 ~ 2:1, is more preferably 2/3 ~ 1:1.
Wherein, the acid described in step (2) is strong acid, is preferably hydrochloric acid or sulfuric acid, is more preferably hydrochloric acid.
Wherein, the alkali described in step (2) is highly basic, is preferably sodium hydroxide or potassium hydroxide.
Wherein, the pH value described in step (2) is 4 ~ 5.
In order to improve yield, step (3) can be separated the aqueous phase hydrophobic organic solvent obtained and extract one or many, then merging organic phase.Wherein, the hydrophobic organic solvent described in step (4) is selected from methylene dichloride, ethyl acetate, chloroform, or their mixture.
Wherein, the described E2020 pharmacy acceptable salt of step (7) is preferably donepezil hydrochloride.
Because E2020 hydroxyl impurity (II) is very close with E2020 structure, be difficult to remove this impurity by the method for recrystallization, the present invention, by the pH value of adjustment E2020 solution, then adopts simple solvent-extracted mode, is separated by hydroxyl impurity from finished product, do not need the reactions such as special High Temperature High Pressure, simple to operate, separating effect is better, and environmental pollution is little, very be applicable to suitability for industrialized production, the E2020 finally obtained meets standards of pharmacopoeia.
[specific embodiments]
Below by embodiment, the invention will be further described.It should be understood that preparation method described in the embodiment of the present invention is only used for the present invention being described, instead of limitation of the present invention, apply design of the present invention to the simple modifications of preparation method of the present invention all in the scope of protection of present invention.
Reagent in following examples is commercially available prod, E2020 and hydrochloride thereof can according to Chinese Journal of Pharmaceuticals the 36th volume o. 11ths in 2005, the method preparation that He Bingming, Qiu Youchun, Chen Jie, Zhang Fuli record in " synthesis of E 2020 ".
Embodiment 1
Get E2020 (HPLC purity 98.66%, wherein containing 1.34% hydroxyl impurity (II)) 5g, the methylene dichloride adding 150ml is dissolved to clearly, then adds the water of 100ml, then use the aqueous hydrochloric acid adjust pH of 1N to 4.5, stir 30 minutes, layering, be separated organic phase and aqueous phase, organic phase is evaporated to dry, obtain the E2020 white solid 3.8g of purifying, its HPLC purity: 99.76%, hydroxyl impurity (II): 0.05%.
Embodiment 2:
Get E2020 (HPLC purity 98.66%, wherein containing 1.34% hydroxyl impurity (II)) 5g, the acetic acid ethyl dissolution adding 150ml, to clear, then adds the water of 100ml, then use the aqueous hydrochloric acid adjust pH of 1N to 4.0, stir 30 minutes, layering, be separated organic phase and aqueous phase, organic phase is evaporated to dry, obtain the E2020 white solid 3.6g of purifying, its HPLC purity: 99.93%, hydroxyl impurity (II): 0.05%.
Embodiment 3:
(HPLC purity is 98.66% to get E2020, wherein containing 1.34% hydroxyl impurity (II)) 5g, the methylene dichloride adding 150ml is dissolved to clearly, then the water of 100ml is added, then use the aqueous hydrochloric acid adjust pH of 1N to 3.0, stir 30 minutes, layering, be separated organic phase and aqueous phase, methylene dichloride 150ml is added in aqueous phase, stir 30 minutes, layering, be separated organic phase and aqueous phase, merge organic phase, be evaporated to dry, obtain the E2020 white solid 3.6g of purifying, its HPLC purity; 99.75%, hydroxyl impurity (II): 0.05%.
Embodiment 4:
(HPLC purity is 98.66% to get E2020, wherein containing 1.34% hydroxyl impurity (II)) 5g, the methylene dichloride adding 150ml is dissolved to clearly, then the water of 100ml is added, then use the aqueous hydrochloric acid adjust pH of 1N to 5.0, stir 30 minutes, layering, be separated organic phase and aqueous phase, methylene dichloride 150ml is added in aqueous phase, stir 30 minutes, layering, be separated organic phase and aqueous phase, merge organic phase, be evaporated to dry, obtain the E2020 white solid 4.5g of purifying, its HPLC purity; 99.87%, hydroxyl impurity (II): 0.10%.
Embodiment 5:
(HPLC purity is 98.70% to get E 2020, wherein containing 1.03% hydroxyl impurity (II)) 5g, the methylene dichloride adding 150ml then adds the water of 100ml, stir 30min, dissolve clarification, then use the aqueous sodium hydroxide solution adjust pH of 1N to 3.0, stir 30 minutes, layering, be separated organic phase and aqueous phase, add methylene dichloride 150ml in aqueous phase, stir 30 minutes, layering, be separated organic phase and aqueous phase, merge organic phase, be evaporated to dry, obtain the E2020 white solid 3.2g of purifying, its HPLC purity; 99.91%, hydroxyl impurity (II): 0.04%.
Embodiment 6:
(HPLC purity is 98.70% to get E 2020, wherein containing 1.03% hydroxyl impurity (II)) 5g, the methylene dichloride adding 150ml then adds the water of 100ml, stirs 30min, dissolve clarification, then use the aqueous sodium hydroxide solution adjust pH of 1N to 5.0, stir 30 minutes, layering, be separated organic phase and aqueous phase, organic phase is evaporated to dry, obtains the E2020 white solid 3.7g of purifying, its HPLC purity; 99.80%, hydroxyl impurity (II): 0.09%.Embodiment 7:
(HPLC purity is 98.66% to get E2020, wherein containing 1.34% hydroxyl impurity (II)) 5g, add the methylene dichloride of 150ml, stirring and dissolving is clarified, then add the water of 100ml, with acetic acid adjust pH to 4.5, stir 30 minutes, layering, be separated organic phase and aqueous phase, add methylene dichloride 150ml in aqueous phase, stir 30 minutes, layering, be separated organic phase and aqueous phase, merge organic phase, be evaporated to dry, obtain the E2020 white solid 4.5g of purifying, its HPLC purity; 99.03%, hydroxyl impurity (II): 0.62%.
Claims (10)
1. a method for the E2020 shown in purifying formula I or its pharmacy acceptable salt,
Wherein said E2020 or its pharmacy acceptable salt are containing, for example the E2020 hydroxyl impurity shown in Formula Il:
It is characterized in that, described method comprises:
(1) a kind of mixed solution being dissolved with E2020 or its pharmacy acceptable salt is provided, containing hydrophobic organic solvent and water in wherein said mixed solution;
(2) by the acid of the mixed solution of step (1) or adjusting PH with base value to 3 ~ 5;
(3) separating step (2) gained organic phase and aqueous phase;
(4) optional, step (3) gained aqueous phase hydrophobic organic solvent is extracted one or many;
(5) combining step (3) and (4) gained organic phase;
(6) from step (5) gained organic phase, be separated the E2020 obtaining purifying;
(7) optional, step (6) gained E2020 is changed into its pharmacy acceptable salt.
2. method according to claim 1, is characterized in that, the hydrophobic organic solvent described in step (1) is selected from methylene dichloride, ethyl acetate, chloroform, or their mixture.
3. method according to claim 1 and 2, is characterized in that, the water described in step (1) and the volume ratio of hydrophobic organic solvent are 1/2 ~ 2:1.
4. method according to claim 3, is characterized in that, the water described in step (1) and the volume ratio of hydrophobic organic solvent are 2/3 ~ 1:1.
5. the method according to any one of claim 1 or 2, is characterized in that, the acid described in step (2) is strong acid, is selected from hydrochloric acid or sulfuric acid.
6. method according to claim 5, is characterized in that, described acid is hydrochloric acid.
7. the method according to any one of claim 1 or 2, is characterized in that, the alkali described in step (2) is highly basic, is selected from sodium hydroxide or potassium hydroxide.
8. the method according to any one of claim 1 or 2, is characterized in that, the pH value described in step (2) is 4 ~ 5.
9. the method according to any one of claim 1 or 2, is characterized in that, the hydrophobic organic solvent described in step (4) is selected from methylene dichloride, ethyl acetate, chloroform, or their mixture.
10. the method according to any one of claim 1 or 2, is characterized in that, described E2020 pharmacy acceptable salt is selected from donepezil hydrochloride.
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| CN103992263B true CN103992263B (en) | 2016-02-10 |
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| CN107188845A (en) * | 2017-05-18 | 2017-09-22 | 芜湖耄智生物科技有限公司 | The method of purification of Doneppezil Hydrochloride |
| CN108047131A (en) * | 2017-12-08 | 2018-05-18 | 重庆植恩药业有限公司 | Doneppezil Hydrochloride impurity and its preparation method and application |
| CN110540520B (en) * | 2019-09-12 | 2022-02-08 | 迪嘉药业集团有限公司 | Method for purifying donepezil |
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| US20100113793A1 (en) * | 2006-03-20 | 2010-05-06 | Ind-Swift Laboratories Limited | Process for the Preparation of Highly Pure Donepezil |
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