WO2008126995A1 - A process for preparing intermediate of donepezil - Google Patents
A process for preparing intermediate of donepezil Download PDFInfo
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- WO2008126995A1 WO2008126995A1 PCT/KR2008/001790 KR2008001790W WO2008126995A1 WO 2008126995 A1 WO2008126995 A1 WO 2008126995A1 KR 2008001790 W KR2008001790 W KR 2008001790W WO 2008126995 A1 WO2008126995 A1 WO 2008126995A1
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- WIPO (PCT)
- Prior art keywords
- formula
- compound
- indanone
- compound represented
- benzyl
- Prior art date
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- 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 title abstract description 20
- 229960003530 donepezil Drugs 0.000 title abstract description 10
- 238000004519 manufacturing process Methods 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 30
- -1 5,6-dimethoxy-l-indanone compound Chemical class 0.000 claims abstract description 29
- LPMOTUSFDTTWJL-UDWIEESQSA-N (2e)-2-[(1-benzylpiperidin-4-yl)methylidene]-5,6-dimethoxy-3h-inden-1-one Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2C\C1=C/C(CC1)CCN1CC1=CC=CC=C1 LPMOTUSFDTTWJL-UDWIEESQSA-N 0.000 claims abstract description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- QNXSIUBBGPHDDE-UHFFFAOYSA-N alpha-indanone Natural products C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 claims description 8
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012458 free base Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims 1
- 239000011734 sodium Substances 0.000 abstract description 3
- 229910052708 sodium Inorganic materials 0.000 abstract description 3
- 206010012289 Dementia Diseases 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- IHMQOBPGHZFGLC-UHFFFAOYSA-N 5,6-dimethoxy-2,3-dihydroinden-1-one Chemical compound C1=C(OC)C(OC)=CC2=C1C(=O)CC2 IHMQOBPGHZFGLC-UHFFFAOYSA-N 0.000 description 7
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 150000003840 hydrochlorides Chemical class 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 4
- 150000007514 bases Chemical class 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000010189 synthetic method 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
- C07D211/20—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 singly bound oxygen or sulphur atoms
- C07D211/22—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 singly bound oxygen or sulphur atoms by oxygen atoms
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
Abstract
There is provided a method for preparing a compound 2-[(E)-l-(l-benzyl-4-piperidyl)methylidene]-5,6-dimethoxy-l-indanone that is an intermediate of donepezil that has been widely known as a therapeutic agent for treating dementia. The present invention is related to the method for preparing a compound 2-[(E)-l-(l-benzyl-4-piperidyl)methylidene]-5,6-dimethoxy-l-indanone by reacting a 5,6-dimethoxy-l-indanone compound with a l-benzyl-piperidine-4-carbaldehyde compound under a basic condition as in sodium alkoxide. The method for preparing an intermediate of donepezil according to the present invention may be useful to facilitate the commercial mass- production and enhance the production yield.
Description
Description
A PROCESS FOR PREPARING INTERMEDIATE OF
DONEPEZIL
Technical Field
[1] The present invention relates to a method for preparing a compound represented by the following Formula 1. [2] <Formula 1>
[3]
[4]
Background Art
[5] The compound 2-[(E)- l-(l-benzyl-4-piperidyl)methylidene] -
5,6-dimethoxy-l-indanone uses herein is an intermediate of donepezil that has been widely known as a therapeutic agent for treating dementia, and is disclosed in European Patent Publication No. 0296560.
[6]
[7] A method for preparing a compound of Formula 1 as disclosed in the known literature may be described in brief, as represented by the following Schemes 1, 2 and 3.
[8] <Scheme 1>
[9]
(2) (3) (1)
[10]
[11] According to the Scheme 1, a target compound represented by Formula 1 may be obtained by reacting a 1-indanone compound represented by Formula 2 with an aldehyde compound represented by Formula 3, but this reaction has a problem that lithium diisopropylamide (LDA) that may not be used for the commercial purpose
should be used as a base. The lithium diisopropylamide has a disadvantage that this compound is generally obtained through the reaction of diisopropylamine and n-butyl lithium at around -8O0C in a solvent such as tetrahydrofuran and used directly, but very carefully handled at a low temperature since the compound is very sensitive to moisture.
[12] <Scheme 2> [13]
(2) (4) (5)
(5) (3) (1)
[14] [15] An alternative method that does not use lithium diisopropylamide that may not used for the commercial purpose is introduced in Scheme 2. According to the Scheme 2, this method is carried out by first preparing a bromo compound represented by Formula 4 and preparing a phosphonate compound represented by Formula 5 so as to react a 1-indanone compound represented by Formula 2 with an aldehyde compound represented by Formula 3, but this reaction has a disadvantage that the two reaction steps are further employed and its yield is low.
[16] <Scheme 3> [17]
(2) (6) (7)
(8) (9) (10)
[18] [19] Another alternative method that does not use lithium diisopropylamide that may not used for the commercial purpose is also introduced in Scheme 3, and an intermediate of donepezil that is not identical that of the present invention may be obtained in this method. According to the Scheme 3, a compound having a benzoyl group compound represented by Formula 7 is prepared by reacting a 1-indanone compound represented by Formula 2 with an aldehyde compound that is represented by Formula 6 but different from the Formula 3 under a basic condition, as in sodium methoxide (MeONa), sodium ethoxide (EtONa), potassium t-butoxide and sodium hydride, that is more easily used for the commercial purpose than the lithium diisopropylamide, and performing a reduction reaction on them. Next, a final target compound represented by Formula 10 is obtained by removing a benzoyl group to prepare a compound in the form of HCl salt and introducing a benzyl group. However, this reaction has a disadvantage that the two reaction steps are further employed.
[20] [21] Therefore, the present inventors have ardent attempts to develop a synthetic method that is suitable for mass-producing an intermediate of donepezil as a more easy and simple method. As a result, the present inventors have found that a target compound represented by Formula 1 was obtained by reacting a 1-indanone compound represented by Formula 2 with an aldehyde compound represented by Formula 3 in the Scheme 1 whose reaction steps are simplest in the art. In this case, lithium diisopropylamide (LDA) that may not be used commercially was used as a base in this reaction, but the optimum condition for this reaction was established using a base, such as sodium methoxide (MeONa), sodium ethoxide (EtONa), potassium t-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide and sodium amide, that may
be used more easily for the commercial purpose instead of the lithium diiso- propylamide, thereby improving the production yield. Therefore, the present invention was completed on the basis of the above facts. [22]
Disclosure of Invention
Technical Problem [23] Accordingly, the present invention is designed to solve such drawbacks of the prior art, and therefore an object of the present invention is to provide a method for preparing capable of preparing an intermediate,
2- [(E)- 1 - ( 1 -benzyl-4-piperidyl)methylidene] -5 ,6-dimethoxy- 1 -indanone, of donepezil in more safe manner and higher yield than the known conventional methods. [24]
Technical Solution [25] According to an aspect of the present invention, there is provided a method for preparing a compound represented by the following formula 1. Here, the compound of the following formula 1 is prepared by reacting a 1 -indanone compound represented by
Formula 2 with an aldehyde compound represented by Formula 3 under a basic condition as in sodium alkoxide. [26] <Formula 1>
[27]
[28]
[29] <Formula 2>
[30]
[31]
[32] <Formula 3>
[33]
[34]
[35] Hereinafter, the method according to the present invention will be described in detail in the following Scheme 4.
[36] European Patent Publication No. 0296560 disclosed a method for preparing a compound of the following formula 1 by reacting a 1-indanone compound represented by Formula 2 with an aldehyde compound represented by Formula 3 in the following Scheme 4.
[37] Lithium diisopropylamide has been used as a base in the reaction of the compound of Formula 2 with the compound of Formula 3 in the prior art, but sodium alkoxide that is easily used for the commercial purpose is used as a base in the method according to the present invention since the lithium diisopropylamide has problems that it is difficult to be used for the commercial purpose due to the high instability, and its yield is very low.
[38]
[39] <Scheme 4>
[40]
(2) (3) (1)
[41]
[42] A reaction solvent, that may be used in the present invention, includes lower alcohols such as methanol, ethanol, isopropanol, and t-butanol, ethers such as tetrahydrofuran, 1,4-dioxane and diisopropyl ether, and polar solvents such as dimethylformamide, dimethylsulfoxide and nitromethane, or combinations thereof.
[43] In this case, a base that is easily used for the commercial purpose is used to adjust the reaction condition to a basic condition, and includes inorganic basic compounds such as sodium methoxide (MeONa), sodium ethoxide (EtONa), potassium t-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide and sodium amide, and the other conventional basic compounds may be also used herein. An amount of the used basic compound ranges from 0.8 to 1.5 equivalent weight, based on the total amount of the compound represented by Formula 2.
[44] In this case, the reaction temperature is preferably maintained to a temperature range from -4O0C to 8O0C, and more preferably from -2O0C to 3O0C.
[45]
[46] As seen from the Scheme 1, lithium diisopropylamide (LDA) that may not be used for the commercial purpose was used in the reaction for preparing a target compound represented by Formula 1 by reacting a 1-indanone compound represented by Formula 2 with an aldehyde compound represented by Formula 3 in the prior art.
[47]
[48] The method according to the present invention may be useful to mass-produce an intermediate of donepezil by establishing a condition where the reaction of the present invention is completed using a base, such as sodium methoxide (MeONa), sodium ethoxide (EtONa), potassium t-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide and sodium amide, that may be more easily used for the commercial purpose and enhancing its yield.
[49]
[50] Comparing the yields in the main reaction steps of the present invention with the yield of the conventional methods, in the case of the method disclosed in European Patent Publication No. 0296560, the target compound, in the form of HCl salt, is obtained at a yield of 62% in Example 3 according to Process C in which lithium diisopropylamide that may not be used for commercial purpose is used as base (Scheme 1). Secondly, the target compound, in the form of HCl salt, is obtained in a low yield of 27% in Example 2 according to Process B except for two reaction steps (Scheme 2), and thirdly, the target compounds are obtained respectively in yields of 71%, 85% (except for the hydrogenation reaction) and 72% in the reactions of Example 178, Example 179 and Example 180, but the total yield is low with 43.5% (Scheme 3). On the contrary, the target compound is obtained in a significantly increased yield of 93% in the method according to the present invention.
[51]
[52] Also, all the final products are obtained in the form of HCl salt in the reaction
(Example 3 and Example 2)of obtaining target compounds represented by Formula 1 in the Schemes 1 and 2 (there is no Example where the target compound is obtained in the form of free base but the target compound represented by Formula 1 is used as a free base in the next hydrogenated reduction reaction of Example 4; the target compound represented by Formula 1 does not easily proceed into the hydrogenated reduction reaction and has difficulty to finish the reduction reaction when the target compound is in the form of HCl salt, and therefore the target compound needs to be handled to remove the HCl salt at any costs), but the target compound represented by Formula 1 may be obtained in the form of free base in the method of the present
invention, which may be advantageously directly used in the next reaction.
[53]
[54] When the method of the present invention is carried out as described above, a production yield of a desired intermediate of donepezil, which is a target compound represented by Formula 1 synthesized from the compound represented by the Formula 2, is in a range of about 93%, which indicates that the method of the present invention shows a significantly high yield of the target compound, compared to the recently published methods.
[55]
Advantageous Effects
[56] The method according to the present invention may be useful to prepare a compound represented by Formula 1 using a base, such as sodium methoxide (MeONa), sodium ethoxide (EtONa), potassium t-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide and sodium amide, that is easily used for the commercial purpose instead of lithium diisopropylamide that may not be used for the commercial purpose.
[57] Also, the method according to the present invention may be useful to enhance the production yield of the compound of Formula 1, and mass-produce the compound of Formula 1.
[58]
Best Mode for Carrying Out the Invention
[59] Hereinafter, preferable embodiments according to the present invention will be described in detail. However, the description proposed herein is just a preferable example for the purpose of illustrations only, not intended to limit the scope of the invention, so it should be understood that other equivalents and modifications could be made thereto without departing from the spirit and scope of the invention as apparent to those skilled in the art. Therefore, it should be understood that the present invention might be not defined within the scope of which is described in detailed description but within the scope of which is defined in the claims and their equivalents.
[60]
[61] Example 1: Preparation of 2-[(E)-l-(l-benzyl-4-piperidyl)methylidene] -
5,6-dimethoxy-l-indanone compound
[62] 20 g of 5,6-dimethoxy-l-indanone and 23.27 g of l-benzyl-piperidine-4-carbaldehyde were added to 200 ml of tetrahydrofuran, and 6.75 g of sodium methoxide was added dropwise at 0 to 1O0C under nitrogen current. The resulting mixture was stirred at 0 to 1O0C for 15 minutes, and slowly warmed to a temperature of 20 to 250C and stirred for 3 hours. 160 ml of dichloromethane and 100
ml of purified water were added to the reaction mixture, and then adjusted to a pH range of 9.5 to 9.8 with 20% HCl. Then an organic phase was separated and distilled to remove a solvent. 60 ml of methanol was added to the residue, stirred at reflux for one hour, cooled to a temperature of 0 to 1O0C, and stirred for one hour. The resulting mixture was filtered, washed, and dried under a vacuum condition to obtain 36.53 g of a target compound (yield: 93.0%).
[63] m.p. 175-1770C;
[64] m/e 377.5 (parent ion);
[65] 1U NMR (CDCl ) δl.62~1.83 (m, 4H), 2.08-2.26 (m, 2H), 2.27-2.42 (m, IH),
2.92-3.03 (m, 2H), 3.55-3.67 (m, 4H), 3.92 (s, 3H), 3.97 (s, 3H), 6.65 (d, IH), 6.89 (s, IH), 7.28 (s, IH), 7.30-7.39 (m, 5H)
[66]
[67] Example 2: Preparation of 2-[(E)-l-(l-benzyl-4-piperidyl)methylidene] -
5,6-dimethoxy-l-indanone compound
[68] 20 g of 5,6-dimethoxy-l-indanone and 23.27 g of l-benzyl-piperidine-4-carbaldehyde were added to 200 ml of tetrahydrofuran, and 8.50 g of sodium methoxide was added dropwise at 0 to 1O0C under nitrogen current. The resulting mixture was stirred at 0 to 1O0C for 15 minutes, and slowly warmed to a temperature of 20 to 250C and stirred for 3 hours. 160 ml of dichloromethane and 100 ml of purified water were added to the reaction mixture, and then adjusted to a pH range of 9.5 to 9.8 with 20% HCl. Then an organic phase was separated and distilled to remove a solvent. 60 ml of methanol was added to the residue, stirred at reflux for one hour, cooled to a temperature of 0 to 1O0C, and stirred for one hour. The resulting mixture was filtered, washed, and dried under a vacuum condition to obtain 33.86 g of a target compound (yield: 86.2%).
[69]
[70] Example 3: Preparation of 2-[(E)-l-(l-benzyl-4-piperidyl)methylidene] -
5,6-dimethoxy-l-indanone compound
[71] 20 g of 5,6-dimethoxy-l-indanone and 23.27 g of l-benzyl-piperidine-4-carbaldehyde were added to 200 ml of tetrahydrofuran, and 14.01 g of potassium t-butoxide was added dropwise at 0 to 1O0C under nitrogen current. The resulting mixture was stirred at 0 to 1O0C for 15 minutes, and slowly warmed to a temperature of 20 to 250C and stirred for 1 hour. 160 ml of dichloromethane and 100 ml of purified water were added to the reaction mixture, and then adjusted to a pH range of 9.5 to 9.8 with 20% HCl. Then an organic phase was separated and distilled to remove a solvent. 60 ml of methanol was added to the residue, stirred at reflux for one hour, cooled to a temperature of 0 to 1O0C, and stirred for one hour. The resulting mixture was filtered, washed, and dried under a vacuum
condition to obtain 35.15 g of a target compound (yield: 89. f [72] [73] Example 4: Preparation of 2-[(E)-l-(l-benzyl-4-piperidyl)methylidene] -
5,6-dimethoxy-l-indanone compound
[74] 20 g of 5,6-dimethoxy-l-indanone and 23.27 g of l-benzyl-piperidine-4-carbaldehyde were added to 200 ml of t-butanol, and 14.01 g of potassium t-butoxide was added drop wise at 0 to 1O0C under nitrogen current. The resulting mixture was stirred at 0 to 1O0C for 15 minutes, and slowly warmed to a temperature of 20 to 250C and stirred for 1 hour. 160 ml of dichloromethane and 100 ml of purified water were added to the reaction mixture, and then adjusted to a pH range of 9.5 to 9.8 with 20% HCl. Then an organic phase was separated and distilled to remove a solvent. 60 ml of methanol was added to the residue, stirred at reflux for one hour, cooled to a temperature of 0 to 1O0C, and stirred for one hour. The resulting mixture was filtered, washed, and dried under a vacuum condition to obtain 36.2 g of a target compound (yield: 92.2%).
[75]
[76]
[77] Example 5: Preparation of 2-[(E)-l-(l-benzyl-4-piperidyl)methylidene] -
5,6-dimethoxy-l-indanone compound
[78] 20 g of 5,6-dimethoxy-l-indanone and 23.27 g of l-benzyl-piperidine-4-carbaldehyde were added to 200 ml of isopropanol, and 6.75 g of sodium methoxide was added drop wise at 0 to 1O0C under nitrogen current. The resulting mixture was stirred at 0 to 1O0C for 15 minutes, and slowly warmed to a temperature of 20 to 250C and stirred for 3 hours. 160 ml of dichloromethane and 100 ml of purified water were added to the reaction mixture, and then adjusted to a pH range of 9.5 to 9.8 with 20% HCl. Then an organic phase was separated and distilled to remove a solvent. 60 ml of methanol was added to the residue, stirred at reflux for one hour, cooled to a temperature of 0 to 1O0C, and stirred for one hour. The resulting mixture was filtered, washed, and dried under a vacuum condition to obtain 36.33 g of a target compound (yield: 92.5%).
[79]
[80] Example 6: Preparation of 2-[(E)-l-(l-benzyl-4-piperidyl)methylidene] -
5,6-dimethoxy-l-indanone compound
[81] 20 g of 5,6-dimethoxy-l-indanone and 23.27 g of l-benzyl-piperidine-4-carbaldehyde were added to 200 ml of ethanol, and 6.75 g of sodium methoxide was added drop wise at 0 to 1O0C under nitrogen current. The resulting mixture was stirred at 0 to 1O0C for 15 minutes, and slowly warmed to a temperature of 20 to 250C and stirred for 3 hours. 160 ml of dichloromethane and 100
ml of purified water were added to the reaction mixture, and then adjusted to a pH range of 9.5 to 9.8 with 20% HCl. Then an organic phase was separated and distilled to remove a solvent. 60 ml of methanol was added to the residue, stirred at reflux for one hour, cooled to a temperature of 0 to 1O0C, and stirred for one hour. The resulting mixture was filtered, washed, and dried under a vacuum condition to obtain 33.78 g of a target compound (yield: 86.0%).
Claims
[ 1 ] A method for preparing a compound 2- [(E)- 1 -( 1 -benzyl-4-piperidyl)methylidene
]-5,6-dimethoxy-l-indanone represented by the following formula 1 by reacting a 1-indanone compound represented by the following formula 2 with an aldehyde compound represented by the following formula 3, wherein a base selected from the group consisting of sodium methoxide (MeONa), sodium ethoxide (EtONa), potassium t-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide and sodium amide is used in the reaction. <Formula 1>
[2] The method according to claim 1, wherein the compound
2-[(E)- l-(l-benzyl-4-piperidyl)methylidene]-5,6-dimethoxy- 1-indanone is prepared in the form of a free base. [3] The method according to claim 1, wherein the base is added at a content of 0.8 to
1.5 equivalent weight, based on the total content of the compound represented by the Formula 2. [4] The method according to claim 1, wherein the reaction solvent is selected from the group consisting of methanol, ethanol, isopropanol, t-butanol, tetrahydrofuran, 1,4-dioxane, diisopropyl ether, dimethylformamide, dimethyl- sulfoxide, nitromethane, and combinations thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020070035881A KR20080092515A (en) | 2007-04-12 | 2007-04-12 | A process for preparing intermediate of donepezil |
| KR10-2007-0035881 | 2007-04-12 |
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| WO2008126995A1 true WO2008126995A1 (en) | 2008-10-23 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2008/001790 WO2008126995A1 (en) | 2007-04-12 | 2008-03-31 | A process for preparing intermediate of donepezil |
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| KR (1) | KR20080092515A (en) |
| WO (1) | WO2008126995A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7994328B2 (en) | 2006-02-16 | 2011-08-09 | Aurobindo Pharma Ltd. | Process for the preparation of donepezil hydrochloride |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR890000465A (en) * | 1987-06-22 | 1989-03-14 | 나이또오 유우지 | Cyclic amine compounds |
| JPH11171861A (en) * | 1997-12-12 | 1999-06-29 | Eisai Co Ltd | Production of donepezil |
| WO2004016589A2 (en) * | 2002-08-14 | 2004-02-26 | Finetech Laboratories Ltd. | Process for production of highly pure donepezil hydrochloride |
| WO2005076749A2 (en) * | 2004-02-11 | 2005-08-25 | Jubilant Organosys Limited | A novel process for the preparation of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine |
| WO2005105742A1 (en) * | 2004-04-28 | 2005-11-10 | Eisai R&D Management Co., Ltd. | Processes for producing 1-benzyl-4-[(5,6-dimethoxy-1indanon)-2-yl]methylpiperidine and hydrochloride thereof |
-
2007
- 2007-04-12 KR KR1020070035881A patent/KR20080092515A/en not_active Application Discontinuation
-
2008
- 2008-03-31 WO PCT/KR2008/001790 patent/WO2008126995A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR890000465A (en) * | 1987-06-22 | 1989-03-14 | 나이또오 유우지 | Cyclic amine compounds |
| JPH11171861A (en) * | 1997-12-12 | 1999-06-29 | Eisai Co Ltd | Production of donepezil |
| WO2004016589A2 (en) * | 2002-08-14 | 2004-02-26 | Finetech Laboratories Ltd. | Process for production of highly pure donepezil hydrochloride |
| WO2005076749A2 (en) * | 2004-02-11 | 2005-08-25 | Jubilant Organosys Limited | A novel process for the preparation of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine |
| WO2005105742A1 (en) * | 2004-04-28 | 2005-11-10 | Eisai R&D Management Co., Ltd. | Processes for producing 1-benzyl-4-[(5,6-dimethoxy-1indanon)-2-yl]methylpiperidine and hydrochloride thereof |
Non-Patent Citations (1)
| Title |
|---|
| SUGIMOTO H. ET AL.: "Synthesis and Structure-Activity Relationships of Acetylcholinesterase Inhibitors: 1-Benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine Hydrochloride and Related Compounds", JOURNAL OF MEDICINAL CHEMISTRY, vol. 38, no. 24, 1995, pages 4821 - 4829, XP002018694 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7994328B2 (en) | 2006-02-16 | 2011-08-09 | Aurobindo Pharma Ltd. | Process for the preparation of donepezil hydrochloride |
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| KR20080092515A (en) | 2008-10-16 |
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