CN114105862A - Donepezil hydrochloride impurity and preparation method thereof - Google Patents
Donepezil hydrochloride impurity and preparation method thereof Download PDFInfo
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- CN114105862A CN114105862A CN202010890593.9A CN202010890593A CN114105862A CN 114105862 A CN114105862 A CN 114105862A CN 202010890593 A CN202010890593 A CN 202010890593A CN 114105862 A CN114105862 A CN 114105862A
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- Prior art keywords
- impurity
- donepezil
- sodium
- quaternary ammonium
- ammonium salt
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- 239000012535 impurity Substances 0.000 title claims abstract description 36
- 229960003135 donepezil hydrochloride Drugs 0.000 title abstract description 7
- XWAIAVWHZJNZQQ-UHFFFAOYSA-N donepezil hydrochloride Chemical compound [H+].[Cl-].O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 XWAIAVWHZJNZQQ-UHFFFAOYSA-N 0.000 title abstract description 7
- 238000002360 preparation method Methods 0.000 title abstract description 5
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 11
- 229960003530 donepezil Drugs 0.000 claims abstract description 9
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 8
- 238000000926 separation method Methods 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 4
- 238000006462 rearrangement reaction Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 4
- 229940073608 benzyl chloride Drugs 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Chemical group 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- LJVOIDRAMCXPAS-UHFFFAOYSA-N potassium sodium methanolate Chemical compound [Na+].[K+].[O-]C.[O-]C LJVOIDRAMCXPAS-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000004458 analytical method Methods 0.000 abstract description 4
- 125000006278 bromobenzyl group Chemical group 0.000 abstract description 2
- 125000004803 chlorobenzyl group Chemical group 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000001514 detection method Methods 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 229940122041 Cholinesterase inhibitor Drugs 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a novel impurity of donepezil hydrochloride and a preparation method thereof, wherein the method comprises the steps of reacting donepezil with chlorobenzyl or bromobenzyl to generate quaternary ammonium salt, and then carrying out rearrangement reaction and separation to obtain a target compound. The impurities obtained by the present invention are very useful for the research of impurity sources and the development of new analytical methods.
Description
Technical Field
The invention relates to a novel impurity of donepezil hydrochloride and a preparation method thereof.
Background
Donepezil hydrochloride is a therapeutic drug for treating senile dementia, belongs to a second-generation cholinesterase inhibitor, is clinically used for treating mild or moderate Alzheimer dementia symptoms, and has the following structure:
the pharmaceutical impurities are closely related to the quality, safety and efficacy of the medicine, and the importance of impurity control in the development and research of the medicine is more and more emphasized.
Disclosure of Invention
During donepezil hydrochloride finished product detection, the applicant finds that 2 single impurities can appear during secondary sample detection, and finds that the peak emergence time of the impurities is later (the peak emergence is only carried out after 60 minutes), but the impurities cannot emerge under the existing detection method conditions, when the secondary sample detection is carried out, the impurities remained on the first needle can emerge from the second sample, and the impurities are completely new impurities which are never reported in two documents through structural identification, and the structural formula is as follows:
in view of the limitations of current analytical methods, in order to better control the impurities and ensure product quality, it is necessary to provide impurity standards for developing new analytical methods.
Accordingly, in another aspect of the present invention, there is provided a process for preparing impurity I and impurity II, comprising the steps of:
1) reacting the free donepezil with halogenated hydrocarbon to generate quaternary ammonium salt shown in formula III,
2) the quaternary ammonium salt shown in the formula III generates an impurity I and an impurity II through rearrangement reaction in an organic solvent under the alkaline condition,
3) impurities I and II are obtained by separation, and the synthetic route is as follows:
in the structural formula, X is chlorine or bromine.
The preferable scheme of the preparation method is as follows:
wherein the solvent used in step 1 is selected from dichloromethane, acetonitrile, chloroform, acetone or ethyl acetate, and dichloromethane is further preferred; the halogenated hydrocarbon is preferably benzyl chloride or benzyl bromide; the molar ratio of the chlorobenzyl or bromobenzyl to donepezil is 1:1-2:1, preferably 1.2: 1; the reaction temperature is preferably 25 to 80 ℃ and more preferably a solvent reflux temperature.
The solvent used in step 2 is an ether solvent such as tetrahydrofuran, methyl tert-butyl ether, methyl tetrahydrofuran, ethylene glycol dimethyl ether and the like, and tetrahydrofuran is further preferred; the base is organic base such as sodium methoxide, sodium potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, potassium ethoxide, etc.
The separation method of step 3 is preferably column chromatography.
The invention provides two brand-new donepezil impurity compounds, which are very useful for searching the source of the impurity and further researching the method for reducing the impurity from the source; on the other hand, the impurities prepared by the method can be used as standard substances for developing a donepezil analysis method, so that the impurities are effectively controlled and the quality of the medicine is ensured.
Detailed Description
Weighing 41.6g of donepezil hydrochloride crude product, adding 300ml of dichloromethane, stirring, weighing 4g of sodium hydroxide, adding 150ml of water to prepare a sodium hydroxide aqueous solution, then dropwise adding the sodium hydroxide aqueous solution, stirring for 0.5-1 hour, standing for 15 minutes, layering, adding 20.5 g of benzyl bromide into a dichloromethane layer, heating and refluxing for 8-10 hours, cooling and filtering, washing a filter cake with dichloromethane to obtain 50.6g of quaternary ammonium salt, wherein the yield is 92% and the purity is 99%.
Weighing 36g of quaternary ammonium salt, adding the quaternary ammonium salt into a 500ml three-neck flask, adding 350ml of tetrahydrofuran, adding 11g of sodium tert-butoxide, reacting for 15-20h at room temperature, carrying out suction filtration after the reaction is finished, washing a filter cake by tetrahydrofuran, mixing the filtrate with silica gel, loading the mixture into a column, wetting the column by triethylamine before the filtrate passes through the column, and separating. Separating to obtain impurity I and impurity II with yield of 25.8% and 36.9%, HPLC purity of 98% and 99%, ESI-MS [ M + H ]+]＝470.1。
Impurity I:1H NMR(400MHz,CDCl3)7.20～7.12(3H,m),7.11～6.99(6H,m),6.94～6.92(2H,d),6.76(1H,s),3.88(3H,s),3.82(3H,s),3.59(1H,s),3.29～3.27(1H,m),3.15～3.08(1H,dd),3.00～2.94(3H,t),2.63～2.55(2H,m),1.99～1.97(1H,m),1.84～1.74(2H,m),1.70～1.51(3H,m),1.35～1.17(4H,m)
13C NMR(100MHz,CDCl3)206.7,154.4,148.3,147.7,128.3,128.2,127.9,126.8,126.7,126.0,124.7,106.3,103.3,70.9,55.1,55.0,51.3,47.9,47.9,44.3,38.1,37.6,33.4,32.2,32.2,30.9,25.8
impurity II:1H NMR(400MHz,CDCl3)7.78～7.76(1H,d),7.36～7.35(2H,d),7.24～7.19(3H,m),7.17～7.12(2H,m),7.07～7.02(2H,m),6.82(1H,s),4.34(1H,s),3.88(3H,s),3.83(3H,s),3.17～3.11(1H,m),2.91～2.87(1H,m),2.72～2.60(3H,m),2.26(3H,s),1.89～1.74(3H,m),1.61(1H,s),1.55～1.52(1H,m),1.42～1.39(1H,m),1.31～1.17(3H,m)
13C NMR(100MHz,CDCl3)207.9,155.4,149.4,148.8,142.2,141.5,135.7,130.4,129.3,128.6,128.2,127.2,126.6,126.2,126.1,107.3,104.3,56.2,56.1,52.8,52.7,52.6,45.5,45.5,38.6,34.8,34.7,33.4,33.3,32.1,32.0,26.9,19.9。
Claims (10)
1. a donepezil impurity compound selected from the following compounds:
2. a process for preparing impurity I and impurity II comprising the steps of:
1) reacting donepezil with benzyl chloride or benzyl bromide to generate quaternary ammonium salt shown in formula III,
2) the quaternary ammonium salt shown in the formula III is subjected to rearrangement reaction in an organic solvent under the alkaline condition to generate an impurity I and an impurity II,
3) impurities I and II are obtained by separation, and the synthetic route is as follows:
in the structural formula, X is chlorine or bromine.
3. The method according to claim 2, wherein the solvent used in step 1 is selected from dichloromethane, acetonitrile, chloroform, acetone or ethyl acetate.
4. The method according to claim 2, wherein the molar ratio of benzyl chloride or benzyl bromide to donepezil in step 1 is from 1:1 to 2: 1.
5. The method according to claim 4, wherein the molar ratio of benzyl chloride or benzyl bromide to donepezil in step 1 is 1.2: 1.
6. The process according to claim 2, wherein the reaction temperature in step 1 is preferably 25 to 80 ℃.
7. The process of claim 6, wherein the reaction temperature in step 1 is the reflux temperature of the solvent.
8. The method according to claim 2, wherein the solvent used in step 2 is tetrahydrofuran, methyl t-butyl ether, methyltetrahydrofuran or ethylene glycol dimethyl ether.
9. The process according to claim 2, wherein the base used in step 2 is sodium methoxide, sodium potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide or potassium ethoxide.
10. The method of claim 2, wherein the separation method of step 3 is column chromatography.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010890593.9A CN114105862A (en) | 2020-08-29 | 2020-08-29 | Donepezil hydrochloride impurity and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010890593.9A CN114105862A (en) | 2020-08-29 | 2020-08-29 | Donepezil hydrochloride impurity and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114105862A true CN114105862A (en) | 2022-03-01 |
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| CN202010890593.9A Pending CN114105862A (en) | 2020-08-29 | 2020-08-29 | Donepezil hydrochloride impurity and preparation method thereof |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040192919A1 (en) * | 2002-08-14 | 2004-09-30 | Finetech Laboratories, Ltd. | Process for production of highly pure donepezil hydrochloride |
| CN101343248A (en) * | 2008-08-24 | 2009-01-14 | 浙江华海药业股份有限公司 | Fine purification method for key intermediate of Donepezil Hydrochloride |
| CN101628889A (en) * | 2008-07-20 | 2010-01-20 | 浙江华海药业股份有限公司 | Method for preparing improved donepezil hydrochloride key intermediate |
| 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 |
| CN109354580A (en) * | 2018-11-21 | 2019-02-19 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of Doneppezil Hydrochloride |
-
2020
- 2020-08-29 CN CN202010890593.9A patent/CN114105862A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040192919A1 (en) * | 2002-08-14 | 2004-09-30 | Finetech Laboratories, Ltd. | Process for production of highly pure donepezil hydrochloride |
| CN101628889A (en) * | 2008-07-20 | 2010-01-20 | 浙江华海药业股份有限公司 | Method for preparing improved donepezil hydrochloride key intermediate |
| CN101343248A (en) * | 2008-08-24 | 2009-01-14 | 浙江华海药业股份有限公司 | Fine purification method for key intermediate of Donepezil 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 |
| CN109354580A (en) * | 2018-11-21 | 2019-02-19 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of Doneppezil Hydrochloride |
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