KR20090016201A - Process for preparing donepezil or its synthetic intermediate - Google Patents
Process for preparing donepezil or its synthetic intermediate Download PDFInfo
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- KR20090016201A KR20090016201A KR1020070080674A KR20070080674A KR20090016201A KR 20090016201 A KR20090016201 A KR 20090016201A KR 1020070080674 A KR1020070080674 A KR 1020070080674A KR 20070080674 A KR20070080674 A KR 20070080674A KR 20090016201 A KR20090016201 A KR 20090016201A
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- tetrabutylammonium
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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
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- 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
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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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- 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
- C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
Abstract
Description
본 발명은 도네페질의 제조용 중간체인 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘의 제조방법; 및/또는 상기 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘으로부터 도네페질을 제조하는 방법에 관한 것이다. 또한, 본 발명은 상기 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘의 제조방법 및 이로부터 도네페질을 제조하는 방법을 순차적으로 수행하는 도네페질의 제조방법에 관한 것이다.The present invention provides a method for preparing 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine as an intermediate for preparing donepezil; And / or a process for preparing donepezil from said 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine. In addition, the present invention provides a method for preparing 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-ylidenyl] -methylpiperidine and a method for preparing donepezil therefrom. It relates to a production method of donepezil to perform sequentially.
도네페질 또는 그의 염(예를 들어 염산염)은 화학명이 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일]메틸피페리딘으로서, 노인성 치매의 예방 및 치료, 특히 알츠하이머 질환의 예방 및 치료에 유용한 약물로 알려져 있다(유럽특허 296,560; 미국 특허 제4,895,841호). Donepezil or a salt thereof (e.g. hydrochloride) has the chemical name 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yl] methylpiperidine to prevent senile dementia And drugs useful for the treatment, in particular for the prevention and treatment of Alzheimer's disease (European Patent 296,560; US Pat. No. 4,895,841).
도네페질 또는 그의 염을 제조하기 위한 종래의 제조방법으로는 하기 반응식 1에 나타낸 바와 같이, 5,6-다이메톡시-1-인다논-2-일 포스포네이트(화학식 5) 또는 5,6-다이메톡시인다논(화학식 3)과 1-벤질-4-피페리딘카르보알데히드(화학식 4) 를 반응시켜 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘을 제조하고, 이를 팔라듐/탄소(Pd/C) 등의 금속 촉매를 사용하여 수소화반응을 수행하여 도네페질 또는 그의 염을 제조하는 방법이 알려져 있다 (대한민국 특허등록 제46,400호; 미국 특허 제4,895,841호; 미국 특허 제5,100,901호; J. Med . Chem 1995 38 481).Conventional preparation methods for preparing donepezil or salts thereof include 5,6-dimethoxy-1-indannon-2-yl phosphonate (Formula 5) or 5,6, as shown in Scheme 1 below. -Dimethoxyindanone (Formula 3) and 1-benzyl-4-piperidinecarboaldehyde (Formula 4) to react 1-benzyl-4-[(5,6-dimethoxy-1-indanonone A method of preparing donepezil or a salt thereof is prepared by preparing) -2-ylideneyl] -methylpiperidine and carrying out a hydrogenation reaction using a metal catalyst such as palladium / carbon (Pd / C) ( Korean Patent Registration No. 46,400; US Patent No. 4,895,841; US Patent No. 5,100,901; J. Med . Chem 1995 38 481).
상기 반응식 1에 따른 제조방법은 공업적으로 사용이 어려운 수소화나트륨 또는 리튬 다이아이소프로필아민(LDA)과 같은 염기를 무수 조건에서 사용하고 저온 반응(-80 ℃) 조건이 요구되는 단점을 가지고 있다. 또한 상기 화학식 2의 화합물로부터 도네페질(화학식 1)을 제조하기 위하여 특수 시설을 갖춘 고압 반응기가 필요하고, 사용에 있어서 취급이 까다로운 고가의 금속 촉매를 사용하는 수소화 반응 을 수행하여야하므로 대량 생산에 적용하기가 곤란하다. The preparation method according to Scheme 1 has a disadvantage in that a base such as sodium hydride or lithium diisopropylamine (LDA), which is difficult to use industrially, is used in anhydrous conditions and low temperature reaction (-80 ° C) is required. In addition, a high pressure reactor equipped with a special facility is required to prepare donepezil (Formula 1) from the compound represented by Chemical Formula 2, and it is applied to mass production because a hydrogenation reaction using an expensive metal catalyst, which is difficult to handle in use, must be performed. Difficult to do
이 외에도, 미국 특허 제5,606,064호, 미국 특허 제6,252,081호, 미국 특허 공개 제20040146121호에서도 도네페질을 제조하기 위하여 이중 결합 또는 피리딘 환의 환원반응 조건으로 금속 촉매 수소화 반응을 채용하고 있으며, 따라서 이들 제조방법도 상기한 바와 같이 대량 생산에 적용하기가 곤란한 단점을 가지고 있다. In addition, US Pat. No. 5,606,064, US Pat. No. 6,252,081, and US Patent Publication No. 20040146121 also employ metal-catalyzed hydrogenation reactions under the conditions of reduction of double bonds or pyridine rings to prepare donepezil, and therefore, these preparation methods. As described above, it has a disadvantage that it is difficult to apply to mass production.
미국 특허 제6,844,440호는, 하기 반응식 2에 나타낸 바와 같이, 5,6-다이메톡시-2-메톡시카보닐인단-1-온과 t-Boc-피페리딜-4-메틸요오드를 출발물질로 사용함으로써 금속 촉매 수소화 반응을 수행하지 않는 점에서 장점을 가지지만, 별도의 공정을 통해 출발 물질로 사용되는 5,6-다이메톡시-2-메톡시카보닐인단-1-온과 t-Boc-피페리딜-4-메틸요오드를 제조해야 하므로 전체 공정이 길고, 수율이 매우 낮은 단점을 가지고 있다. US Pat. No. 6,844,440 discloses starting materials for 5,6-dimethoxy-2-methoxycarbonylindan-1-one and t-Boc-piperidyl-4-methyliodine, as shown in Scheme 2 below. Although it has an advantage in that it does not carry out the metal-catalyzed hydrogenation reaction, the 5,6-dimethoxy-2-methoxycarbonylindan-1-one and t- are used as starting materials through a separate process. Since Boc-piperidyl-4-methyl iodine needs to be prepared, the overall process is long and the yield is very low.
본 발명자들은 상기한 종래의 제조방법 상의 문제점을 개선하고, 저렴한 제조단가로 온화한 조건에서 도네페질을 제조하는 방법을 개발하기 위하여 다양한 연구를 수행하였다. 그 결과, 상전이 촉매 존재하에서의 2상 반응(two-phase reaction)에 의하여 도네페질의 중간체인 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘을 제조할 경우, 실온에서 온화한 반응 조건으로 반응을 수행할 수 있어 대량생산에 적합하다는 것을 발견하였다. 또한, 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘을 취급이 용이하고 저렴한 차아황산나트륨(Na2S2O4)과 반응시킬 경우, 제조비용을 낮출 수 있을 뿐만 아니라 특수 설비인 고압 반응기를 사용할 필요가 없으므로, 대량생산에 적합하다는 것을 발견하였다. The present inventors carried out various studies to improve the problems of the conventional manufacturing method described above, and to develop a method for producing donepezil under mild conditions at low manufacturing costs. As a result, 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yldenyl], an intermediate of donepezil, by a two-phase reaction in the presence of a phase transfer catalyst. When preparing methylpiperidine, it was found that the reaction can be carried out under mild reaction conditions at room temperature, making it suitable for mass production. In addition, 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine is easy to handle and inexpensive sodium hyposulfite (Na 2 S 2 O 4 ) When it is reacted with, it has been found to be suitable for mass production because it not only lowers the manufacturing cost but also eliminates the need for using a special equipment, a high pressure reactor.
따라서, 본 발명은 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일]메틸피페리딘의 제조방법을 제공하는 것을 목적으로 한다.It is therefore an object of the present invention to provide a process for the preparation of 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yl] methylpiperidine.
또한, 본 발명은 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일]메틸피페리딘으로부터 도네페질을 제조하는 방법을 제공하는 것을 목적으로 한다.It is also an object of the present invention to provide a method for producing donepezil from 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yl] methylpiperidine.
또한, 본 발명은 상기 제조방법을 순차적으로 수행하는 도네페질의 제조방법을 제공하는 것을 목적으로 한다.In addition, an object of the present invention is to provide a method for producing donepezil to sequentially perform the above production method.
본 발명의 일 태양에 따라, 5,6-다이메톡시인다논과 1-벤질-4-피페리딘카르보알데히드를, 상전이 촉매 존재하에서의 2상 반응(two-phase reaction)에 의하여, 축합시키는 단계를 포함하는 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘의 제조방법이 제공된다.According to one aspect of the invention, condensing 5,6-dimethoxyindanon and 1-benzyl-4-piperidinecarboaldehyde by a two-phase reaction in the presence of a phase transfer catalyst Provided is a method for preparing 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine comprising a.
상기 상전이 촉매는 테트라뷰틸암모늄 브로마이드, 테트라뷰틸암모늄 클로라이드, 테트라뷰틸암모늄 플루오라이드(또는 그의 3수화물), 테트라뷰틸암모늄 요오드, 테트라뷰틸암모늄 티오시아네이트, 테트라뷰틸암모늄 하이드로겐 설페이트, 벤질트리뷰틸암모늄 브로마이드, 벤질트리뷰틸암모늄 클로라이드, 테트라에틸암모늄 브로마이드, 테트라에틸암모늄 클로라이드, 테트라뷰틸암모늄 나이트레이트, 및 벤질트리에틸암모늄 클로라이드로 이루어진 군으로부터 1 종 이상 선택될 수 있다. 상기 축합반응은 수산화나트륨, 수산화칼륨, 수산화리튬, 탄산나트륨, 탄산칼륨, 탄산수소나트륨, 탄산수소칼륨, 및 제3인산칼륨으로 이루어진 군으로부터 1 종 이상 선택된 염기 존재하에서 바람직하게 수행될 수 있다. 또한 상기 반응은 아세토나이트릴, 톨루엔, 메틸렌 클로라이드, 테트라하이드로퓨란, 메틸 아세테이트, 에틸 아세테이트, 및 아이소프로필 아세테이트로 이루어진 군으로부터 1종 이상 선택된 유기용매와 물과의 혼합 용매 중에서 바람직하게 수행될 수 있다.The phase transfer catalyst may be tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium fluoride (or trihydrate thereof), tetrabutylammonium iodine, tetrabutylammonium thiocyanate, tetrabutylammonium hydrogen sulfate, benzyl dimethyl ammonium At least one member may be selected from the group consisting of bromide, benzyltaxyl ammonium chloride, tetraethylammonium bromide, tetraethylammonium chloride, tetrabutylammonium nitrate, and benzyltriethylammonium chloride. The condensation reaction may be preferably carried out in the presence of at least one base selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, and potassium triphosphate. In addition, the reaction may be preferably performed in a mixed solvent of water and at least one organic solvent selected from the group consisting of acetonitrile, toluene, methylene chloride, tetrahydrofuran, methyl acetate, ethyl acetate, and isopropyl acetate. .
본 발명의 다른 태양에 따라, 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘과 차아황산나트륨(Na2S2O4)을 반응시키는 단계를 포함하는 도네페질의 제조방법이 제공된다.According to another aspect of the invention, 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine and sodium hyposulfite (Na 2 S 2 O 4 There is provided a method for producing donepezil comprising the step of reacting.
상기 반응은 상전이 촉매 존재하에서의 2상 반응(two-phase reaction)에 의하여 바람직하게 수행될 수 있으며, 상기 상전이 촉매는 테트라뷰틸암모늄 브로마 이드, 테트라뷰틸암모늄 클로라이드, 테트라뷰틸암모늄 플루오라이드(또는 그의 3수화물), 테트라뷰틸암모늄 요오드, 테트라뷰틸암모늄 티오시아네이트, 테트라뷰틸암모늄 하이드로겐 설페이트, 벤질트리뷰틸암모늄 브로마이드, 벤질트리뷰틸암모늄 클로라이드, 테트라에틸암모늄 브로마이드, 테트라에틸암모늄 클로라이드, 테트라뷰틸암모늄 나이트레이트, 및 벤질트리에틸암모늄 클로라이드로 이루어진 군으로부터 1 종 이상 선택될 수 있다. 상기 반응은 수산화나트륨, 탄산나트륨, 탄산칼륨, 탄산수소나트륨, 탄산수소칼륨, 제3인산칼륨, 및 제2인산칼륨으로 이루어진 군으로부터 1 종 이상 선택된 염기 존재하에서 바람직하게 수행될 수 있다. The reaction may be preferably carried out by a two-phase reaction in the presence of a phase transfer catalyst, wherein the phase transfer catalyst is tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium fluoride (or 3 thereof). Hydrate), tetrabutylammonium iodine, tetrabutylammonium thiocyanate, tetrabutylammonium hydrogen sulphate, benzyl butylammonium bromide, benzyl butylammonium chloride, tetraethylammonium bromide, tetraethylammonium chloride, tetrabutylammonium nitrate And at least one selected from the group consisting of benzyltriethylammonium chloride. The reaction may be preferably carried out in the presence of at least one base selected from the group consisting of sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, potassium triphosphate, and potassium diphosphate.
또한, 상기 도네페질 제조방법은 아세토나이트릴, 테트라하이드로퓨란, 톨루엔, 메틸렌 클로라이드, 메틸 아세테이트, 및 에틸 아세테이트로 이루어진 군으로부터 1종 이상 선택된 유기용매와 물과의 혼합 용매 중에서 바람직하게 수행될 수 있으며, 최종 단계에서 C1 - C5 알코올류; 또는 메틸렌 클로라이드, 아세토나이트릴, 톨루엔, 아세톤, 메틸에틸케톤, 2-펜탄온, 메틸 아세테이트, 에틸 아세테이트, 아이소프로필 아세테이트, 및 아이소프로필 에테르로 이루어진 군으로부터 1 종 이상 선택된 유기용매와 C1 - C5 알코올류와의 혼합용매를 사용한 재결정 단계를 더 포함할 수 있다.In addition, the donepezil production method may be preferably carried out in a mixed solvent of water and at least one organic solvent selected from the group consisting of acetonitrile, tetrahydrofuran, toluene, methylene chloride, methyl acetate, and ethyl acetate , C 1 -C 5 alcohols in the final step; Or at least one organic solvent selected from the group consisting of methylene chloride, acetonitrile, toluene, acetone, methylethylketone, 2-pentanone, methyl acetate, ethyl acetate, isopropyl acetate, and isopropyl ether and C 1 -C It may further comprise a recrystallization step using a mixed solvent with five alcohols.
본 발명의 다른 태양에 따라, (a) 5,6-다이메톡시인다논과 1-벤질-4-피페리딘카르보알데히드를, 상전이 촉매 존재하에서의 2상 반응(two-phase reaction)에 의하여, 축합시켜 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘 을 제조하는 단계; 및 (b) 단계(a)에서 얻어진 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘과 차아황산나트륨(Na2S2O4)을 반응시키는 단계를 포함하는 도네페질의 제조방법이 제공된다.According to another aspect of the present invention, (a) 5,6-dimethoxyindanon and 1-benzyl-4-piperidinecarboaldehyde by a two-phase reaction in the presence of a phase transfer catalyst, Condensation to prepare 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine; And (b) 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine and sodium hyposulfite (Na 2 S 2 ) obtained in step (a). Provided is a method for producing donepezil, comprising the step of reacting O 4 ).
상기 단계(a) 및 단계(b)는 각각의 단계에 대하여 상기한 바와 같은 상전이 촉매, 염기, 및 반응용매를 사용하여 바람직하게 수행될 수 있으며, 최종 단계에서 C1 - C5 알코올류; 또는 메틸렌 클로라이드, 아세토나이트릴, 톨루엔, 아세톤, 메틸에틸케톤, 2-펜탄온, 메틸 아세테이트, 에틸 아세테이트, 아이소프로필 아세테이트, 및 아이소프로필 에테르로 이루어진 군으로부터 1 종 이상 선택된 유기용매와 C1 - C5 알코올류와의 혼합용매를 사용한 재결정 단계를 더 포함할 수 있다.Step (a) and step (b) may be preferably carried out using a phase transfer catalyst, a base, and a reaction solvent as described above for each step, in the final step C 1 -C 5 alcohols; Or at least one organic solvent selected from the group consisting of methylene chloride, acetonitrile, toluene, acetone, methylethylketone, 2-pentanone, methyl acetate, ethyl acetate, isopropyl acetate, and isopropyl ether and C 1 -C It may further comprise a recrystallization step using a mixed solvent with five alcohols.
본 발명의 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘 즉, 도네페질 중간체의 제조방법은 실온(예를 들어, 15 내지 30 ℃, 바람직하게는 20 내지 25 ℃)에서 수행할 수 있으므로 대량생산에 적합하다. 또한, 상기 반응은 수소화나트륨 또는 리튬 다이아이소프로필아민 등의 강염기를 사용하지 않고 통상의 염기, 바람직하게는 통상의 무기 염기로 수행되므로, 무수 또는 저온 반응 조건 등을 채용할 필요가 없이 온화한 반응 조건에서 도네페질 중간체 즉, 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘을 높은 수율로 제조할 수 있다.The process for preparing 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine, i.e., donepezil intermediate of the present invention is performed at room temperature (e.g., 15 to 30 ° C., preferably 20 to 25 ° C.), which is suitable for mass production. In addition, since the reaction is carried out with a common base, preferably a conventional inorganic base without using a strong base such as sodium hydride or lithium diisopropylamine, mild reaction conditions without the need to employ anhydrous or low temperature reaction conditions, and the like. Donepezil intermediate, i.e., 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine, can be prepared in high yield.
또한, 본 발명에 따른 상기 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데 닐]-메틸피페리딘으로부터 도네페질을 제조하는 방법은 고가의 금속 촉매를 이용한 수소화 반응 대신 취급이 용이하고 저렴한 차아황산나트륨(Na2S2O4)을 사용하여 반응을 수행하므로 제조비용을 낮출 수 있을 뿐만 아니라 특수한 고압 반응기를 사용할 필요가 없으므로, 대량생산에 적합하다. In addition, a method for preparing donepezil from the 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-ylideneyl] -methylpiperidine according to the present invention is expensive. Instead of the hydrogenation reaction using a metal catalyst, the reaction is carried out using easy and inexpensive sodium hyposulfite (Na 2 S 2 O 4 ), which not only lowers the manufacturing cost but also requires the use of a special high pressure reactor, which is suitable for mass production. Do.
따라서, 상기 본 발명의 제조방법들을 일련의 단위 공정으로 수행할 경우, 도네페질을 실온에서, 온화한 반응조건으로, 낮은 제조비용으로, 높은 수율 및 순도로 제조할 수 있으므로, 본 발명의 제조방법은 공업적 대량생산에 특히 적합하다.Therefore, when the production methods of the present invention are carried out in a series of unit processes, donepezil can be prepared at room temperature, under mild reaction conditions, at low production costs, in high yield and purity, and thus the production method of the present invention It is particularly suitable for industrial mass production.
본 발명은 5,6-다이메톡시인다논과 1-벤질-4-피페리딘카르보알데히드를, 상전이 촉매 존재하에서의 2상 반응(two-phase reaction)에 의하여, 축합시키는 단계를 포함하는 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘의 제조방법을 포함한다.The present invention includes condensing 5,6-dimethoxyindanon and 1-benzyl-4-piperidinecarboaldehyde by a two-phase reaction in the presence of a phase transfer catalyst. A method for producing benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine.
상기 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘 즉, 도네페질 중간체의 제조방법은 실온(예를 들어, 15 내지 30 ℃, 바람직하게는 20 내지 25 ℃)에서 수행할 수 있으며, 온화한 반응조건에서 짧은 반응시간(예를 들어, 2 ∼ 4 시간 동안) 동안 반응을 수행하여 높은 수율 및 순도로 상기 중간체를 제조할 수 있다.The method for preparing 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine, that is, donepezil intermediate, is room temperature (eg, 15 to 15). 30 to 30 DEG C, preferably 20 to 25 DEG C, and the reaction may be carried out under mild reaction conditions for a short reaction time (e.g., for 2 to 4 hours) to prepare the intermediate in high yield and purity. Can be.
상기 상전이 촉매는 암모늄 염에 기초한 상전이 촉매, 포스포늄 염에 기초한 상전이 촉매, 크라운(crown) 에테르와 폴리에틸렌글리콜(PEG)에 기초한 상전이 촉매 등을 포함한다. 예를 들면, 상기 상전이 촉매는 테트라뷰틸암모늄 브로마이드, 테트라뷰틸암모늄 클로라이드, 테트라뷰틸암모늄 플루오라이드(또는 그의 3수화물), 테트라뷰틸암모늄 요오드, 테트라뷰틸암모늄 티오시아네이트, 테트라뷰틸암모늄 하이드로겐 설페이트, 벤질트리뷰틸암모늄 브로마이드, 벤질트리뷰틸암모늄 클로라이드, 테트라에틸암모늄 브로마이드, 테트라에틸암모늄 클로라이드, 테트라뷰틸암모늄 나이트레이트, 및 벤질트리에틸암모늄 클로라이드로 이루어진 군으로부터 1 종 이상 선택될 수 있다. 더욱 바람직하게는 상기 상전이 촉매로는 테트라뷰틸암모늄 브로마이드, 테트라뷰틸암모늄 하이드로겐 설페이트를 사용할 수 있다. 상기 상전이 촉매의 사용량은 크게 제한되는 것은 아니나, 바람직하게는 약 0.1 ∼ 1 당량의 범위로 사용될 수 있다.The phase transfer catalysts include phase transfer catalysts based on ammonium salts, phase transfer catalysts based on phosphonium salts, phase transfer catalysts based on crown ethers and polyethylene glycol (PEG), and the like. For example, the phase transfer catalyst may be tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium fluoride (or trihydrate thereof), tetrabutylammonium iodine, tetrabutylammonium thiocyanate, tetrabutylammonium hydrogen sulfate, benzyl Tributylammonium bromide, benzyltaxylammonium chloride, tetraethylammonium bromide, tetraethylammonium chloride, tetrabutylammonium nitrate, and benzyltriethylammonium chloride. More preferably, as the phase transfer catalyst, tetrabutylammonium bromide or tetrabutylammonium hydrogen sulfate may be used. The amount of the phase transfer catalyst is not particularly limited, but may be preferably used in the range of about 0.1 to 1 equivalent.
본 발명의 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘 즉, 도네페질 중간체의 제조방법은 통상의 염기를 사용하여 축합반응을 수행할 수 있으며, 바람직하게는 통상의 무기염기 예를 들면, 알칼리 금속 수산화물, 알칼리 금속 탄산류, 또는 알칼리 금속 인산류 등을 사용할 수 있다. 구체적으로는 수산화나트륨, 수산화칼륨, 수산화리튬, 탄산나트륨, 탄산칼륨, 탄산수소나트륨, 탄산수소칼륨, 제3인산칼륨 등을 단독으로 또는 혼합하여 사용할 수 있으며, 더욱 바람직하게는 수산화나트륨, 수산화칼륨, 제3인산칼륨 등을 사용할 수 있다. 상기 염기의 사용량은 크게 제한되는 것은 아니나, 바람직하게는 약 3 ∼ 5 당량의 범위로 사용될 수 있다.The process for preparing 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine, i.e., donepezil intermediate of the present invention may be carried out using conventional bases. The condensation reaction can be carried out, and conventional inorganic bases such as alkali metal hydroxides, alkali metal carbonates, or alkali metal phosphates can be used. Specifically, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, potassium triphosphate, or the like may be used alone or in combination, more preferably sodium hydroxide, potassium hydroxide, Potassium triphosphate or the like can be used. The amount of the base used is not particularly limited, but may be preferably used in the range of about 3 to 5 equivalents.
본 발명에 따른 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘의 제조방법은 물과 유기용매와의 혼합 용매 중에서 바람직하게 수행될 수 있으며, 예를 들면, 아세토나이트릴, 톨루엔, 메틸렌 클로라이드, 테트라하이드로퓨란, 메틸 아세테이트, 에틸 아세테이트, 및 아이소프로필 아세테이트로 이루어진 군으로부터 1종 이상 선택된 유기용매와 물과의 혼합 용매 중에서 수행될 수 있다. 이 중, 메틸렌 클로라이드와 물과의 혼합 용매가 부반응이 적어, 후처리과정(workup) 후 선택적으로 간단한 결정화 단계(예를 들어, 아세톤을 사용한 결정화)를 통하여(즉, 추가의 정제 단계를 수행할 필요 없이) 상기 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘을 분리할 수 있으므로, 바람직하게 사용될 수 있다.The process for preparing 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine according to the present invention is preferred in a mixed solvent of water and an organic solvent. And, for example, in a mixed solvent of water with at least one organic solvent selected from the group consisting of acetonitrile, toluene, methylene chloride, tetrahydrofuran, methyl acetate, ethyl acetate, and isopropyl acetate. Can be performed. Among these, the mixed solvent of methylene chloride and water has less side reactions, and after workup, optionally through a simple crystallization step (e.g., crystallization with acetone) (i.e., an additional purification step can be performed). The 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine can be separated without necessity), and thus can be preferably used.
본 발명은 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘과 차아황산나트륨(Na2S2O4)을 반응시키는 단계를 포함하는 도네페질(즉, 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일]메틸피페리딘)의 제조방법을 포함한다.The present invention is a step of reacting 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine with sodium hyposulfite (Na 2 S 2 O 4 ) It includes a method for producing donepezil (ie, 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yl] methyl piperidine) comprising a.
본 발명에 따른 상기 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘으로부터 도네페질을 제조하는 방법은, 특수한 고압 반응기를 사용하여야 하고 고가의 금속 촉매를 이용한 장시간의 반응시간이 필요한 수소화 반응 대신, 취급이 용이하고 저렴한 차아황산나트륨(Na2S2O4)을 사용하여 상대적으로 짧은 시간 내(예를 들어, 3 ∼ 6 시간)에 반응을 수행하므로 제조비용을 낮출 수 있을 뿐만 아니라 특수한 고압 반응기를 사용할 필요가 없으므로, 대량생산에 적합하다. 또한, 상기 본 발명의 제조방법은 높은 수율 및 순도로 도네페질을 제조할 수 있다. The process for producing donepezil from the 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine according to the present invention comprises a special high pressure reactor. Instead of hydrogenation, which requires the use of an expensive metal catalyst and a long reaction time, it is easy to handle and uses sodium hyposulfite (Na 2 S 2 O 4 ) in a relatively short time (for example, 3 to 6 The reaction can be carried out in time, which not only lowers the manufacturing cost but also eliminates the need for using a special high pressure reactor, which is suitable for mass production. In addition, the production method of the present invention can produce donepezil in high yield and purity.
상기 차아황산나트륨(Na2S2O4)은 가격이 저렴하고, 독성이 없고, 취급이 용이한 장점이 있다. 본 발명의 제조방법에 있어서, 상기 차아황산나트륨(Na2S2O4)의 사용량은 반응물인 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘 1 당량에 대하여 1.1 ∼ 10 당량을 사용할 수 있으며, 더욱 바람직하게는 약 4 ∼ 6 당량 사용할 수 있다.The sodium hyposulfite (Na 2 S 2 O 4 ) has the advantages of low cost, no toxicity, easy handling. In the preparation method of the present invention, the amount of sodium hyposulfite (Na 2 S 2 O 4 ) is 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-ylideneyl as a reactant. 1.1-10 equivalents can be used with respect to 1 equivalent of] -methylpiperidine, More preferably, about 4-6 equivalents can be used.
차아황산나트륨은 통상적으로 사용되는 유기용매 중에서의 용해도가 상대적으로 낮으므로, 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘과 차아황산나트륨과의 반응은 상전이 촉매 존재하에서의 2상 반응(two-phase reaction)에 의하여 수행되는 것이 바람직하다. Sodium hyposulfite has a relatively low solubility in commonly used organic solvents, so 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-ylidenyl] -methylpiperidine The reaction with and sodium hyposulfite is preferably carried out by a two-phase reaction in the presence of a phase transfer catalyst.
상기 상전이 촉매는 암모늄 염에 기초한 상전이 촉매, 포스포늄 염에 기초한 상전이 촉매, 크라운(crown) 에테르와 폴리에틸렌글리콜(PEG)에 기초한 상전이 촉매 등을 포함한다. 예를 들면, 상기 상전이 촉매는 테트라뷰틸암모늄 브로마이드, 테트라뷰틸암모늄 클로라이드, 테트라뷰틸암모늄 플루오라이드(또는 그의 3수화물), 테트라뷰틸암모늄 요오드, 테트라뷰틸암모늄 티오시아네이트, 테트라뷰틸암모늄 하이드로겐 설페이트, 벤질트리뷰틸암모늄 브로마이드, 벤질트리뷰틸암모늄 클로라이드, 테트라에틸암모늄 브로마이드, 테트라에틸암모늄 클로라이드, 테트라뷰틸암모늄 나이트레이트, 및 벤질트리에틸암모늄 클로라이드로 이루어진 군으로부터 1 종 이상 선택될 수 있다. 더욱 바람직하게는 상기 상전이 촉매로는 테트라뷰틸암모늄 브로마이드, 테트라뷰틸암모늄 하이드로겐 설페이트를 사용할 수 있다. 상기 상전이 촉매의 사용량은 크게 제한되는 것은 아니나, 바람직하게는 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘 1 당량에 대하여 약 0.01 ∼ 1 당량의 범위로 사용될 수 있다.The phase transfer catalysts include phase transfer catalysts based on ammonium salts, phase transfer catalysts based on phosphonium salts, phase transfer catalysts based on crown ethers and polyethylene glycol (PEG), and the like. For example, the phase transfer catalyst may be tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium fluoride (or trihydrate thereof), tetrabutylammonium iodine, tetrabutylammonium thiocyanate, tetrabutylammonium hydrogen sulfate, benzyl Tributylammonium bromide, benzyltaxylammonium chloride, tetraethylammonium bromide, tetraethylammonium chloride, tetrabutylammonium nitrate, and benzyltriethylammonium chloride. More preferably, as the phase transfer catalyst, tetrabutylammonium bromide or tetrabutylammonium hydrogen sulfate may be used. The amount of the phase transfer catalyst is not particularly limited, but preferably 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-ylidenyl] -methylpiperidine in 1 equivalent It can be used in the range of about 0.01 to 1 equivalent.
또한, 상기 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘과 차아황산나트륨과의 반응은 통상의 염기, 바람직하게는 통상의 무기 염기 존재하에서 수행될 수 있으며, 구체적으로는 수산화나트륨, 탄산나트륨, 탄산칼륨, 탄산수소나트륨, 탄산수소칼륨, 제3인산칼륨, 및 제2인산칼륨 등을 사용할 수 있고, 이 중 탄산수소나트륨을 더욱 바람직하게 사용할 수 있다.Further, the reaction of the 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine with sodium hyposulfite is a common base, preferably Sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, potassium triphosphate, potassium diphosphate, etc. may be used, among which sodium hydrogen carbonate is used. Can be used more preferably.
상기 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘과 차아황산나트륨과의 반응은 물과 유기용매와의 혼합 용매 중에서 바람직하게 수행될 수 있으며, 예를 들면, 아세토나이트릴, 테트라하이드로퓨란, 톨루엔, 메틸렌 클로라이드, 메틸 아세테이트, 및 에틸 아세테이트로 이루어진 군으로부터 1종 이상 선택된 유기용매와 물과의 혼합 용매 중에서 수행될 수 있다. 이 중, 메틸렌 클로라이드와 물과의 혼합 용매가 바람직하게 사용될 수 있다.The reaction of 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine with sodium hyposulfite is preferred in a mixed solvent of water and an organic solvent. And, for example, acetonitrile, tetrahydrofuran, toluene, methylene chloride, methyl acetate, and ethyl acetate may be performed in a mixed solvent of water and an organic solvent selected from one or more selected from the group consisting of. . Among these, a mixed solvent of methylene chloride and water can be preferably used.
또한, 상기 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘과 차아황산나트륨과의 반응은 실온(예를 들어, 15 내지 30 ℃, 바람직하게는 20 내지 25 ℃) 내지 사용된 반응 용매의 환류 온도 사이에서 바람직하게 수행할 수 있다.In addition, the reaction of the 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine with sodium hyposulfite is room temperature (eg, 15 to Preferably 30 ° C., preferably 20-25 ° C.) to the reflux temperature of the reaction solvent used.
상기 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘과 차아황산나트륨과의 반응은 또한 최종적으로 C1 - C5 알코올류; 또는 메틸렌 클로라이드, 아세토나이트릴, 톨루엔, 아세톤, 메틸에틸케톤, 2-펜탄온, 메틸 아세테이트, 에틸 아세테이트, 아이소프로필 아세테이트, 및 아이소프로필 에테르로 이루어진 군으로부터 1 종 이상 선택된 유기용매와 C1 - C5 알코올류와의 혼합용매를 사용한 재결정 단계를 더 포함함으로써 도네페질을 더 높은 순도로 제조할 수 있다. 상기 C1 - C5 알코올류는 메탄올, 에탄올, n-프로판올, 아이소프로판올, n-뷰탄올, 2-메틸프로판올, t-뷰탄올, 2-메틸뷰탄올 등을 열거할 수 있다. The reaction of the 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-ylideneyl] -methylpiperidine with sodium hyposulfate also finally leads to C 1 -C 5 alcohols. ; Or at least one organic solvent selected from the group consisting of methylene chloride, acetonitrile, toluene, acetone, methylethylketone, 2-pentanone, methyl acetate, ethyl acetate, isopropyl acetate, and isopropyl ether and C 1 -C By further comprising a recrystallization step using a mixed solvent with five alcohols it can be prepared in higher purity. The C 1 -C 5 alcohols may include methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-methylpropanol, t-butanol, 2-methylbutanol, and the like.
상기한 재결정 용매 중, n-프로판올, 아이소프로판올 등의 알코올류; 또는 n-프로판올, 아이소프로판올 등의 알코올류와 메틸렌 클로라이드와의 혼합 용매를 더욱 바람직하게 사용할 수 있다.Alcohols, such as n-propanol and isopropanol, in said recrystallization solvent; Alternatively, a mixed solvent of alcohols such as n-propanol and isopropanol and methylene chloride can be used more preferably.
본 발명은 상기 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘(도네페질의 합성 중간체)의 제조방법 및 상기 도네페질의 합성 중간체로부터 도네페질을 제조하는 방법을 순차적으로 수행함으로써, 도네페질을 온화한 조건에서 높은 수율 및 순도로 제조하는 방법을 포함한다. 즉, 본 발명은 (a) 5,6-다이메톡시인다논과 1-벤질-4-피페리딘카르보알데히드를, 상전이 촉매 존재하에서의 2상 반응(two-phase reaction)에 의하여, 축합시켜 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘을 제조하는 단계; 및 (b) 단계(a)에서 얻어진 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘과 차아황산나트 륨(Na2S2O4)을 반응시키는 단계를 포함하는 도네페질의 제조방법을 포함한다.The present invention provides a method for preparing the 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine (synthetic intermediate of donepezil) and the donepe By sequentially performing the method of preparing donepezil from the synthetic intermediate of the vagina, the process includes preparing the donepezil in high yield and purity under mild conditions. That is, the present invention condenses (a) 5,6-dimethoxyindanon and 1-benzyl-4-piperidinecarboaldehyde by a two-phase reaction in the presence of a phase transfer catalyst, thereby condensing 1 Preparing -benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine; And (b) 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine and sodium hyposulfite (Na 2 ) obtained in step (a). S 2 O 4 ) includes a method for producing donepezil comprising the step of reacting.
단계(a)는 상기한 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘의 제조방법에서 채용하는 조건에 따라 수행될 수 있으며, 단계(b)는 상기한 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘으로부터 도네페질을 제조하는 방법에서 채용하는 조건에 따라 수행될 수 있다. 단계(a) 및 단계(b)를 포함한 상기 제조방법을 반응식으로 나타내면 반응식 3과 같다.Step (a) may be carried out according to the conditions employed in the process for preparing 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine described above. Step (b) in the process for preparing donepezil from 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine as described above It may be performed according to the conditions employed. The preparation method including the step (a) and step (b) is represented by the reaction scheme 3.
상기한 바와 같이 제조된 도네페질은 통상의 방법에 따라 무기산 또는 유기산을 이용하여 다양한 염 형태로 제조될 수 있으며, 예를 들어 염산염, 옥살산염 등의 형태로 제조될 수 있다.Donepezil prepared as described above may be prepared in various salt forms using inorganic or organic acids according to a conventional method, for example, in the form of hydrochloride, oxalate, and the like.
이하, 실시예를 통하여 본 발명을 더욱 상세하게 설명한다. 그러나, 이들 실 시예는 본 발명을 예시적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 제한되는 것은 아니다. Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.
실시예 1. 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘의 제조 Example 1. Preparation of 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine
정제수 50 ㎖에 8.3 g의 수산화나트륨과 1.8 g의 테트라뷰틸암모늄 하이드로겐 설페이트를 용해시켰다. 메틸렌 클로라이드 100 ㎖에 10 g의 5,6-다이메톡시인다논과 11.7 g의 1-벤질-4-피페리딘카르보알데히드을 용해시킨 후, 상기 용액과 혼합하고 상온에서 2 시간 동안 교반하였다. 반응 혼합물을 층분리하여, 유기층을 정제수로 세척한 다음, 감압 농축하였다. 얻어진 잔사를 아세톤 250 ㎖ 중에서 재결정하여 17.7 g(수율: 90 %)의 표제화합물을 얻었다. In 50 ml of purified water, 8.3 g of sodium hydroxide and 1.8 g of tetrabutylammonium hydrogen sulfate were dissolved. 10 g of 5,6-dimethoxyindanon and 11.7 g of 1-benzyl-4-piperidinecarboaldehyde were dissolved in 100 ml of methylene chloride, and then mixed with the solution and stirred at room temperature for 2 hours. The reaction mixture was separated and the organic layer was washed with purified water and then concentrated under reduced pressure. The obtained residue was recrystallized in 250 ml of acetone to give 17.7 g (yield: 90%) of the title compound.
융점: 176.8∼177.1 ℃ Melting Point: 176.8 ~ 177.1 ℃
1H-NMR (400 MHz, CDCl3, ppm): δ 1.61∼1.72(m, 4H), 2.03∼2.09(m, 2H), 2.32∼2.35(m, 1H), 2.91∼2.94(m, 2H), 3.53(s, 2H), 3.59(s, 2H), 3.92(s, 3H), 3.97(s, 3H), 6.66(d, 1H, J=9.6), 6.90(s, 1H), 7.24(m, 6Hz) 1 H-NMR (400 MHz, CDCl 3 , ppm): δ 1.61 to 1.72 (m, 4H), 2.03 to 2.09 (m, 2H), 2.32 to 2.25 (m, 1H), 2.91 to 2.94 (m, 2H) , 3.53 (s, 2H), 3.59 (s, 2H), 3.92 (s, 3H), 3.97 (s, 3H), 6.66 (d, 1H, J = 9.6), 6.90 (s, 1H), 7.24 (m , 6 Hz)
실시예 2. 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘의 제조 Example 2. Preparation of 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine
수산화나트륨 대신 11.3 g의 수산화칼륨을 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 15.5 g(수율 79%)의 표제화합물을 얻었다.15.5 g (yield 79%) of the title compound were obtained in the same manner as in Example 1, except that 11.3 g of potassium hydroxide was used instead of sodium hydroxide.
실시예 3. 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘의 제조 Example 3. Preparation of 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-ylideneyl] -methylpiperidine
수산화나트륨 대신 4.8 g의 수산화리륨을 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 15.7 g(수율 80%)의 표제화합물을 얻었다.15.7 g (yield 80%) of the title compound were obtained in the same manner as in Example 1, except that 4.8 g of lithium hydroxide was used instead of sodium hydroxide.
실시예 4. 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘의 제조 Example 4. Preparation of 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine
수산화나트륨 대신 21.3 g의 탄산나트륨을 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 16.0 g(수율 81.4%)의 표제화합물을 얻었다.16.0 g (yield 81.4%) of the title compound were obtained in the same manner as in Example 1, except that 21.3 g of sodium carbonate was used instead of sodium hydroxide.
실시예 5. 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘의 제조 Example 5. Preparation of 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-ylideneyl] -methylpiperidine
수산화나트륨 대신 20.1 g의 탄산칼륨을 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 16.2 g(수율 82.7%)의 표제화합물을 얻었다.16.2 g (yield 82.7%) of the title compound were obtained in the same manner as in Example 1, except that 20.1 g of potassium carbonate was used instead of sodium hydroxide.
실시예 6. 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘의 제조 Example 6. Preparation of 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] -methylpiperidine
수산화나트륨 대신 44.2 g의 제3인산칼륨을 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 17.8 g(수율 90.5%)의 표제화합물을 얻었다.17.8 g (yield 90.5%) of the title compound were obtained in the same manner as in Example 1, except that 44.2 g of potassium triphosphate was used instead of sodium hydroxide.
실시예 7. 도네페질의 제조 Example 7 Preparation of Donepezil
정제수 100 ㎖와 메틸렌 클로라이드 100 ㎖에 17.8 g의 탄산수소나트륨과 0.45 g의 테트라뷰틸암모늄 하이드로겐 설페이트를 용해시키고, 10 g의 1-벤질-4-[(5,6-다이메톡시-1-인다논)-2-일리데닐]-메틸피페리딘과 23.1 g의 차아황산나트륨을 순차적으로 투입한 후 4 시간 동안 환류 교반하였다. 반응 혼합물을 층분리하여, 유기층을 정제수로 세척하고, 감압 농축하였다. 얻어진 잔사를 아이소프로필 알코올 90 ㎖에서 재결정하여 9.05 g(수율 90%, HPLC 순도 99.5% 이상)의 표제화합물을 얻었다.Dissolve 17.8 g of sodium bicarbonate and 0.45 g of tetrabutylammonium hydrogen sulfate in 100 ml of purified water and 100 ml of methylene chloride, and 10 g of 1-benzyl-4-[(5,6-dimethoxy-1- Indanone) -2-ylideneyl] -methylpiperidine and 23.1 g of sodium hyposulfite were sequentially added, followed by stirring under reflux for 4 hours. The reaction mixture was separated and the organic layer was washed with purified water and concentrated under reduced pressure. The obtained residue was recrystallized in 90 ml of isopropyl alcohol to obtain 9.05 g (yield 90%, HPLC purity 99.5% or more) of the title compound.
1H-NMR (400 MHz, CDCl3, ppm): δ 1.31∼1.38(m, 3H), 1.43∼1.61(m, 1H), 1.64∼1.72(m, 2H), 1.91∼1.98(m, 3H), 2.67∼2.72(m, 2H), 2.87∼2.92(m, 2H), 3.12∼3.24(m, 1H), 3.50(s, 2H), 3.91(s, 3H), 3.96(s, 3H), 6.85(s, 1H), 7.17(s, 1H), 7.23∼7.27(m, 1Hz), 7.29∼7.32(m, 4H) 1 H-NMR (400 MHz, CDCl 3 , ppm): δ 1.31 to 1.38 (m, 3H), 1.43 to 1.61 (m, 1H), 1.64 to 1.72 (m, 2H), 1.91 to 1.98 (m, 3H) , 2.67 to 2.72 (m, 2H), 2.87 to 2.92 (m, 2H), 3.12 to 3.24 (m, 1H), 3.50 (s, 2H), 3.91 (s, 3H), 3.96 (s, 3H), 6.85 (s, 1H), 7.17 (s, 1H), 7.23-7.27 (m, 1 Hz), 7.29-7.72 (m, 4H)
실시예 8. 도네페질의 제조 Example 8 Preparation of Donepezil
테트라뷰틸암모늄 하이드로겐 설페이트 대신 2.43 g의 테트라뷰틸암모늄 나이트레이트를 사용한 것을 제외하고는, 실시예 7과 동일한 방법으로 9.33 g(수율 93%)의 표제화합물을 얻었다. 9.33 g (yield 93%) of the title compound were obtained in the same manner as in Example 7, except that 2.43 g of tetrabutylammonium nitrate was used instead of tetrabutylammonium hydrogen sulfate.
실시예 9. 도네페질의 제조 Example 9 Preparation of Donepezil
테트라뷰틸암모늄 하이드로겐 설페이트 대신 2.56 g의 테트라뷰틸암모늄 브로마이드를 사용한 것을 제외하고는, 실시예 7과 동일한 방법으로 7.99 g(수율 80%)의 표제화합물을 얻었다.7.99 g (yield 80%) of the title compound were obtained in the same manner as in Example 7, except that 2.56 g of tetrabutylammonium bromide was used instead of tetrabutylammonium hydrogen sulfate.
실시예 10. 도네페질의 제조 Example 10 Preparation of Donepezil
메틸렌 클로라이드 대신 에틸 아세테이트를 사용한 것을 제외하고는, 실시예 7과 동일한 방법으로 9.55 g(수율 95%)의 표제화합물을 얻었다.9.55 g (yield 95%) of the title compound were obtained in the same manner as in Example 7, except that ethyl acetate was used instead of methylene chloride.
실시예 11. 도네페질의 제조 Example 11 Preparation of Donepezil
탄산수소나트륨 대신 21.2 g의 탄산수소칼륨을 사용한 것을 제외하고는, 실시예 7과 동일한 방법으로 8.33 g(수율 83%)의 표제화합물을 얻었다.8.33 g (yield 83%) of the title compound was obtained in the same manner as in Example 7, except that 21.2 g of potassium hydrogen carbonate was used instead of sodium hydrogen carbonate.
실시예 12. 도네페질의 제조 Example 12 Preparation of Donepezil
탄산수소나트륨 대신 22.5 g의 탄산나트륨을 사용한 것을 제외하고는, 실시예 7과 동일한 방법으로 9.15 g(수율 91%)의 표제화합물을 얻었다.9.15 g (yield 91%) of the title compound were obtained in the same manner as in Example 7, except that 22.5 g of sodium carbonate was used instead of sodium hydrogen carbonate.
실시예 13. 도네페질의 제조 Example 13. Preparation of Donepezil
아이소프로필 알코올 대신 n-프로필 알코올을 사용한 것을 제외하고는, 실시 예 7과 동일한 방법으로 8.04 g(수율 80%)의 표제화합물을 얻었다.Except for using n-propyl alcohol instead of isopropyl alcohol, 8.04 g (yield 80%) of the title compound were obtained in the same manner as in Example 7.
실시예 14. 도네페질의 제조 Example 14 Preparation of Donepezil
아이소프로필 알코올 대신 아이소프로필 알코올/메틸렌 클로라이드의 혼합 용매를 사용하는 것을 제외하고는, 실시예 7과 동일한 방법으로 8.55 g(수율 85%)의 표제화합물을 얻었다.8.55 g (yield 85%) of the title compound were obtained in the same manner as in Example 7, except that a mixed solvent of isopropyl alcohol / methylene chloride was used instead of isopropyl alcohol.
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| JP2013040150A (en) * | 2011-08-19 | 2013-02-28 | Taiwan Biotech Co Ltd | Method for producing donepezil |
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| EP1773339A4 (en) | 2004-07-30 | 2009-07-29 | Reddys Lab Ltd Dr | Crystalline form of donepezil hydrochloride |
| US20060172992A1 (en) | 2004-08-13 | 2006-08-03 | Eisai Co., Ltd. | Therapeutic agent for overactive bladder resulting from cerebral infarction |
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2007
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102757381A (en) * | 2011-04-25 | 2012-10-31 | 信东生技股份有限公司 | Method for preparing donepezil |
| JP2013040150A (en) * | 2011-08-19 | 2013-02-28 | Taiwan Biotech Co Ltd | Method for producing donepezil |
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| Publication number | Publication date |
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| KR100914691B1 (en) | 2009-08-28 |
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