KR100453379B1 - Method for preparing piperidine derivatives - Google Patents
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- KR100453379B1 KR100453379B1 KR10-2002-0004259A KR20020004259A KR100453379B1 KR 100453379 B1 KR100453379 B1 KR 100453379B1 KR 20020004259 A KR20020004259 A KR 20020004259A KR 100453379 B1 KR100453379 B1 KR 100453379B1
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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
- C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
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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
Abstract
본 발명은 피페리딘 유도체의 제조방법에 관한 것으로, 구체적으로 하기 화학식 3의 화합물을 마그네슘 존재하에 화학식 2의 화합물과 반응시켜 화학식 1의 피페리딘 유도체를 제조하는 방법에 관한 것으로, 기존의 피페리딘 제조방법에 비해 제조공정이 단순하고, 저가(低價)의 출발물질을 사용하며 고수율로 얻을 수 있어 경제적으로 피페리딘 유도체를 제조할 수 있다.The present invention relates to a method for preparing a piperidine derivative, and more particularly, to a method for preparing a piperidine derivative of Formula 1 by reacting a compound of Formula 3 with a compound of Formula 2 in the presence of magnesium. Compared to the ferridine manufacturing method, the manufacturing process is simple, using a low-cost starting material, and can be obtained in high yield, thereby economically preparing piperidine derivatives.
반응식 3Scheme 3
(상기식에서, R1, R2및 X는 명세서에 기재된 바와 같다.)(Wherein R 1 , R 2 and X are as described in the specification).
Description
본 발명은 역가가 높은 선택적인 히스타민 수용체 차단 활성 및 칼슘 길항작용을 나타내는 하기 화학식 1로 표시되는 피페리딘 유도체의 제조방법에 관한 것이다.The present invention relates to a method for preparing a piperidine derivative represented by the following formula (1) showing selective histamine receptor blocking activity and calcium antagonism with high titer.
상기 화학식 1로 표시되는 피페리딘 유도체는 시험관내 및 생체 내에서 기관지 및 혈관 평활근을 이완하여, 노르아드레날린, 칼슘 이온 및 기타 길항 약제의 수축작용을 억제하며, 히스타민, 아세틸콜린 및 염화바륨에 대한 위장관 및 기관계 약제의 반응을 억제하며, 기니아픽에 체중 1 ㎏당 1 ㎎을 경구투여할 경우에 히스타민 에어로절에 의해 유발된 기관지 수축을 차단하는 것으로 알려져 있으며, 쥐에서 항아나필락시 활성을 가지며, 감작된 기니아픽에서 슐츠-데일(Schultz-Dale)반응을 길항한다.Piperidine derivative represented by the formula (1) relaxes the bronchial and vascular smooth muscle in vitro and in vivo, inhibits the contractile action of noradrenaline, calcium ions and other antagonists, to histamine, acetylcholine and barium chloride Inhibits the response of gastrointestinal and organ-based drugs, and is known to block the histamine aerobronchial contraction caused by oral administration of 1 mg / kg body weight to guinea pigs, and has anti-anaphylactic activity in rats. Antagonizes the Schultz-Dale reaction in guinea pigs.
또한, 상기 피페리딘 유도체는 알레르기 반응 중 비만세포로부터 방출된 화학 중개자에 대한 말단 장기의 반응 또는 화학적 중개자의 유리를 억제하는 화합물 및 비진정성 항히스타민제의 사용이 필요한 알레르기, 비염 및 천식 등에 사용될 수 있으며, 이들의 혈관 활성으로 인해 뇌 또는 말초혈관 부전증 및 몇몇 경우 편두통과 현기증 등에 사용될 수 있다.In addition, the piperidine derivative may be used for allergies, rhinitis and asthma that require the use of compounds and non-real antihistamines that inhibit the reaction of terminal organs to chemical mediators released from mast cells or the release of chemical mediators during allergic reactions. Due to their vascular activity, they may be used in brain or peripheral vascular insufficiency and in some cases, migraine and dizziness.
상술한 바와 같은 효능을 가지는 상기 화학식 1로 표시되는 피페리딘 유도체에 대한 제조방법은 미합중국특허 제4550116호와 이를 근거로 한 국내특허등록 제0050769호에 개시되어 있다.Method for producing a piperidine derivative represented by the formula (1) having the efficacy as described above is disclosed in US Patent No. 4550116 and Korean Patent Registration No. 0050769 based on the same.
구체적으로, 피페리딘 유도체의 제조방법은 하기 반응식 1 및 반응식 2에 나타낸 바와 같이 2 가지의 반응식으로 나타낸다.Specifically, the method for producing a piperidine derivative is represented by two schemes as shown in Scheme 1 and Scheme 2 below.
(상기식에서, X는 염소, 브롬, 요오드,p-톨루엔설폰에이트 또는 메탄설폰에이트이다.)(Wherein X is chlorine, bromine, iodine, p -toluenesulfonate or methanesulfonate.)
(상기식에서, X는 염소, 브롬, 요오드,p-톨루엔설폰에이트 또는 메탄설폰에이트이다.)(Wherein X is chlorine, bromine, iodine, p -toluenesulfonate or methanesulfonate.)
상기 반응식 1은 매우 고가(高價)인 화학식(a)의 4-히드록시피페리딘을 출발물질로 화학식(b)의 4-t-부틸-클로로부틸로페논과N-알킬화반응을 수행하여 화학식(c)의 화합물을 얻은 후, 화학식(d)의 디페닐메틸브로마이드를 결합시켜 화학식 1로 표시되는 화합물을 얻는다. 이때 출발물질이 고가일뿐만 아니라, O-알킬화반응시에 디페닐메틸브로마이드를 연속적으로 조금씩 과량을(최소 2당량이상) 첨가하여야 하는 단점을 지니고 있다. 또한 상기 반응식 2는 O-알킬화된 화합물을 먼저 제조한 후, 화학식 1로 표시되는 화합물을 얻고자 출발물질을N-에톡시카보닐-4-히드록시피페리딘(화학식(e))을 사용하였으나, 상기 반응식 1에서 문제점을 포함하는 O-알킬화반응을 수행해야하며, 반응 후 에톡시카르보닐을 제거해야하는 불필요한 단계를 포함하는 단점을 지니고 있다.Scheme 1 is a very expensive (High) 4-hydroxypiperidine of the formula (a) as a starting material 4- N -alkyl-butyl N -alkylation reaction with 4- t -butyl-chlorobutyllophenone of the formula (b) After obtaining the compound of (c), diphenylmethylbromide of the formula (d) is combined to obtain the compound represented by the formula (1). At this time, not only the starting material is expensive, but it also has a disadvantage in that an excessive amount (at least 2 equivalents) of diphenylmethyl bromide is continuously added little by little in the O-alkylation reaction. In addition, in Scheme 2, an O-alkylated compound is first prepared, and then N -ethoxycarbonyl-4-hydroxypiperidine (formula (e)) is used as a starting material to obtain a compound represented by Formula 1. However, the O-alkylation reaction including the problem in Scheme 1 should be carried out, and has the disadvantage of including an unnecessary step of removing ethoxycarbonyl after the reaction.
이에, 본 발명자들은 상기 문제점을 해결하기 위해 연구한 결과, 반응식 3에서 보는 바와 같이, 화학식 3의 화합물을 마그네슘 존재하에 화학식 2의 화합물과 반응시켜 화학식 1의 피페리딘 유도체를 제조하였으며, 상기 제조방법에 의해 기존의 피페리딘 제조방법에 비해 제조공정이 단순하며, 저가(低價)의 출발 물질을 사용하여 피페리딘 유도체를 고수율로 제조할 수 있음을 알아내어 본 발명을 완성하였다.Accordingly, the present inventors have studied to solve the above problems, as shown in Scheme 3, the compound of formula 3 was reacted with the compound of formula 2 in the presence of magnesium to prepare a piperidine derivative of formula 1, the preparation The present invention was completed by finding out that the manufacturing process is simple compared to the conventional piperidine production method, and that the piperidine derivative can be produced in high yield using a low-cost starting material.
본 발명의 목적은 피페리딘 유도체 및 그의 약학적으로 허용되는 염을 고수율 및 경제적으로 제조하는 방법을 제공하는 것이다.It is an object of the present invention to provide a process for producing piperidine derivatives and their pharmaceutically acceptable salts in high yield and economically.
상기 목적을 달성하기 위하여, 본 발명은 화학식 1로 표시되는 피페리딘 유도체 및 그의 약학적으로 허용되는 염의 제조방법을 제공한다.In order to achieve the above object, the present invention provides a piperidine derivative represented by the formula (1) and a method for preparing a pharmaceutically acceptable salt thereof.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 하기 반응식 3과 같이, 화학식 3의 화합물을 마그네슘 존재하에 화학식 2의 화합물과 반응시켜 화학식 1의 피페리딘 유도체의 제조하는 방법을 포함한다.The present invention includes a method for preparing a piperidine derivative of Formula 1 by reacting a compound of Formula 3 with a compound of Formula 2 in the presence of magnesium, as shown in Scheme 3 below.
(상기식에서, R1및 R2는 각각 독립적으로, 수소, C1∼C6의 직쇄 또는 가지달린 알킬기 또는 C3∼C6의 사이클로알킬기이며,(In the formula, R 1 and R 2 are each independently hydrogen, a straight or branched alkyl group of C 1 to C 6 , or a cycloalkyl group of C 3 to C 6 ,
X는 염소, 브롬 또는 요오드이며, 바람직하게는 염소이다.)X is chlorine, bromine or iodine, preferably chlorine.)
상기 화학식 1의 피페리딘 유도체는 화학식 3의 화합물을 마그네슘 존재하에화학식 2의 화합물과 반응시켜 제조하는 것으로, 화학식 2의 화합물과 마그네슘을 반응시켜 그리그나드 시약를 형성한 후 화학식 3의 화합물과 반응을 수행한다. 이러한 반응은 통상적인 유기 용매를 사용하며, 바람직하게는 테트라히드로퓨란, 디옥산, 디클로로메탄 또는 디에틸에테르를 사용하여 -78∼100℃에서 수행한다.The piperidine derivative of Formula 1 is prepared by reacting a compound of Formula 3 with a compound of Formula 2 in the presence of magnesium, and reacting the compound of Formula 2 with magnesium to form a Grignard reagent and then reacting with the compound of Formula 3 Do this. This reaction is carried out using a conventional organic solvent, preferably at -78 to 100 ° C using tetrahydrofuran, dioxane, dichloromethane or diethyl ether.
본 발명의 출발물질 중 하나인 상기 화학식 2의 화합물은 화학식 6의 화합물로부터 유도된 하기 화학식 4의 화합물과 하기 화학식 5의 화합물을 염기 존재하에 반응시켜 얻어진다.The compound of Formula 2, which is one of the starting materials of the present invention, is obtained by reacting a compound of Formula 4 with a compound of Formula 5, derived from a compound of Formula 6, in the presence of a base.
(상기식에서, X는 염소, 브롬 또는 요오드이며, 바람직하게는 염소이며,(Wherein X is chlorine, bromine or iodine, preferably chlorine,
Y는 염소, 브롬, 요오드,p-톨루엔설폰에이트 또는 메탄설폰에이트이며, 바람직하게는 브롬이다.)Y is chlorine, bromine, iodine, p -toluenesulfonate or methanesulfonate, preferably bromine.)
상기 반응은 톨루엔, 크실렌, 디옥산, 메틸에틸케톤, 메틸이소부틸케톤 또는N,N-디메틸포름아미드와 같은 유기 용매의 환류온도에서 염기 존재하에 축합반응을 수행한다. 상기 염기는 통상적인 염기를 사용하며, 바람직하게는 알칼리금속의 중탄산염, 알칼리금속의 탄산염 등과 같은 무기염기, 트리에틸아민, 트리 n-부틸아민 4-디메틸아미노피리딘, 루티딘 및N-메틸모르폴린으로 이루어진 군에서 선택된 것을 사용한다.The reaction is carried out in the presence of a base at the reflux temperature of an organic solvent such as toluene, xylene, dioxane, methyl ethyl ketone, methyl isobutyl ketone or N, N -dimethylformamide. The base uses a conventional base, preferably inorganic bases such as bicarbonates of alkali metals, carbonates of alkali metals, and the like, triethylamine, tri n-butylamine 4-dimethylaminopyridine, lutidine and N -methylmorpholine Use the one selected from the group consisting of.
화학식 4의 화합물은 화학식 6의 화합물로부터 유도된 것으로, 화학식 6의 화합물을 적절한 유기 용매 및 염기 존재하에서 에틸클로로포르메이트와 같은 통상적인 탈메틸화 시약으로 반응시킨 후, 또 다른 염기를 첨가시킴으로서 얻어진다. 상기 유기 용매는 벤젠, 톨루엔, 크실렌, 에틸이소부틸케톤, 테트라히드로퓨란 또는N,N-디메틸포름아미드을 사용하며, 바람직하게는 톨루엔 또는 크실렌을 사용한다. 또한 상기 염기는 트리에틸아민, 피리딘 또는 루티딘 등의 유기염기와 수산화칼륨, 수산화나트륨, 수산화칼슘, 탄산칼륨 또는 탄산나트륨 등의 무기염기를 사용할 수 있으며, 바람직하게는 트리에틸아민, 피리딘, 수산화칼륨 또는 수산화나트륨을 사용한다.The compound of formula 4 is derived from the compound of formula 6, which is obtained by reacting a compound of formula 6 with conventional demethylation reagents such as ethylchloroformate in the presence of a suitable organic solvent and a base, followed by addition of another base. . The organic solvent is benzene, toluene, xylene, ethyl isobutyl ketone, tetrahydrofuran or N, N- dimethylformamide, preferably toluene or xylene. In addition, the base may be an organic base such as triethylamine, pyridine or lutidine and an inorganic base such as potassium hydroxide, sodium hydroxide, calcium hydroxide, potassium carbonate or sodium carbonate, preferably triethylamine, pyridine, potassium hydroxide or Sodium hydroxide is used.
또한, 본 발명의 출발 물질 중 다른 하나인 화학식 3의 화합물은 통상적인 방법으로 제조할 수 있으며, 바람직하게는 하기 화학식 7의 화합물과 화학식 8의 화합물을 염기 존재하에 반응시켜 얻어진다.In addition, another compound of formula 3, which is one of the starting materials of the present invention, may be prepared by a conventional method, and is preferably obtained by reacting a compound of formula 7 with a compound of formula 8 in the presence of a base.
(상기식에서, R1및 R2는 각각 독립적으로, 수소, C1∼C6의 직쇄 또는 가지달린 알킬기 또는 C3∼C6의 사이클로알킬기이다.)(In the formula, R 1 and R 2 are each independently hydrogen, a straight or branched alkyl group of C 1 to C 6 , or a cycloalkyl group of C 3 to C 6. )
상기 반응은 테트라히드로퓨란, 디옥산, 클로로포름, 디클로로메탄, 아세톤, 아세토니트릴, 디메틸포름아미드 또는 디메틸설폭사이드 등과 같은 유기 용매를 사용하며, 상기 염기는 상기 화학식 2의 화합물을 제조시 사용하는 모든 것을 사용할 수 있으며, 또한 디사이클로헥실디이미드(DCC) 또는 1-(3-디메틸아미노프로필)-3-에틸카보디이미드 반응과 같은 축합 반응을 수행한다.The reaction uses an organic solvent such as tetrahydrofuran, dioxane, chloroform, dichloromethane, acetone, acetonitrile, dimethylformamide or dimethylsulfoxide, and the base is used to prepare all compounds of formula 2 May be used, and also condensation reactions such as dicyclohexyldiimid (DCC) or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide reaction are carried out.
본 발명의 화학식 1로 표시되는 피페리딘 유도체의 제조방법은 종래 여러 과정의 제조방법에 비해 하나의 과정으로 이루어져 있어 피페리딘 제조에 매우 효과적이며, 저가(低價)의 출발물질을 사용하며, 피페리딘 유도체를 고수율로 얻을 수 있어 고수율 및 경제적으로 제조할 수 있다. 하기 실시예에서 보는 바와 같이, 출발물질인 4-디페닐메톡시-1-(3-클로로페닐)피페리딘(화학식 2) 및 4-t-부틸-N-메톡시-N-메틸벤즈아미드(화학식 3)을 저가의 물질로부터 용이하게 제조할 수 있으며, 마그네슘 존재하에 이들을 반응시켜 75 %의 수율로 피페리딘 유도체를 얻을 수 있었다.The method for preparing a piperidine derivative represented by Formula 1 of the present invention is very effective in the production of piperidine, because it consists of a single process compared to the manufacturing method of the prior art, and uses a low-cost starting material. The piperidine derivatives can be obtained in high yield and can be produced in high yield and economically. As shown in the examples below, the starting materials 4-diphenylmethoxy-1- (3-chlorophenyl) piperidine (Formula 2) and 4- t -butyl- N -methoxy- N -methylbenzamide Formula 3 can be easily prepared from inexpensive materials, and reacted in the presence of magnesium to obtain a piperidine derivative in a yield of 75%.
또한, 본 발명은 화학식 1의 피페리딘 유도체의 약학적으로 허용가능한 염의 제조방법을 제공한다.The present invention also provides a method for preparing a pharmaceutically acceptable salt of the piperidine derivative of formula (1).
구체적으로, 본 발명에 의해 제조된 화학식 1의 피페리딘 유도체에 공지된 방법으로 약학적으로 허용 가능한 유리산(free acid)의 부가에 의해 약학적으로 허용 가능한 염의 제조가 가능하다. 유리산으로는 유기산과 무기산을 사용할 수 있으며, 유기산으로는 구연산, 초산, 젖산, 주석산, 말레인산, 후마린산, 글루콘산, 메탄술폰산, 글리콜산, 숙신산, 4-톨루엔술폰산, 갈룩투론산, 엠본산, 글루탐산 또는 아스파르트산 등을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 황산 또는 인산 등을 사용할 수 있다.Specifically, the preparation of pharmaceutically acceptable salts is possible by the addition of pharmaceutically acceptable free acids by known methods to the piperidine derivatives of formula (1) prepared by the present invention. Organic acids and inorganic acids may be used as the free acid, and citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, galluxuronic acid, and m. Main acid, glutamic acid or aspartic acid may be used, and the like may be hydrochloric acid, bromic acid, sulfuric acid or phosphoric acid.
이하, 본 발명을 실시예에 의해 더욱 상세하게 설명한다.Hereinafter, an Example demonstrates this invention further in detail.
단, 하기 실시예들은 본 발명을 예시하는 것으로 본 발명의 내용이 실시예에 의해 한정되는 것은 아니다.However, the following examples are illustrative of the present invention, and the content of the present invention is not limited by the examples.
한편, 본 발명의 화합물의 분자구조는 적외선 분광법, 자외선-가시광선 분광법, 핵자기공명 스펙트럼, 질량 분광법과 대표적인 화합물의 원소분석 실측치와 계산치의 비교에 의해 확인하였다.On the other hand, the molecular structure of the compound of the present invention was confirmed by comparison between infrared spectroscopy, ultraviolet-visible light spectroscopy, nuclear magnetic resonance spectra, mass spectroscopy and elemental analysis and calculated values of representative compounds.
<실시예 1> 피페리딘 유도체의 제조Example 1 Preparation of Piperidine Derivatives
(단계 1) 4-디페닐메톡시피페리딘 염산염의 제조(Step 1) Preparation of 4-diphenylmethoxypiperidine hydrochloride
디페닐피랄린(40 g)을 톨루엔(410 g)에 가한 후 트리에틸아민(12.8 g)을 가하고 1 시간동안 교반하였다. 상기 용액에 에틸클로로포르메이트(54.7 g)와 트리에틸아민(12.7 g)을 첨가한 후 10 시간동안 교반하였다. 반응 종료 후 정제수로 세척하고, 묽은 염산 수용액으로 추출하였다. 상기 수용액에 디클로로메탄을 가하여 유기층으로 목적물을 추출한 후 유기층을 감압 농축하였다. 잔사물에 에틸아세테이트를 가한 후 재결정하여 백색 고체의 4-디페닐메톡시피페리딘 염산물(수율 85 %)을 얻었다.Diphenylpyraline (40 g) was added to toluene (410 g), triethylamine (12.8 g) was added and stirred for 1 hour. Ethylchloroformate (54.7 g) and triethylamine (12.7 g) were added to the solution, followed by stirring for 10 hours. After completion of the reaction, the mixture was washed with purified water and extracted with dilute hydrochloric acid aqueous solution. Dichloromethane was added to the aqueous solution to extract the target product into an organic layer, and the organic layer was concentrated under reduced pressure. Ethyl acetate was added to the residue, followed by recrystallization to obtain 4-diphenylmethoxypiperidine hydrochloride (yield 85%) as a white solid.
1H NMR(200 ㎒, CDCl3) δ1.87∼2.15(m, 4H), 3.18(m, 2H), 3.31(m, 2H), 3.75(s, 1H), 5.40(s, 1H), 7.08∼7.48(m, 10H), 9.44(b, 2H). 1 H NMR (200 MHz, CDCl 3 ) δ 1.87 to 2.15 (m, 4H), 3.18 (m, 2H), 3.31 (m, 2H), 3.75 (s, 1H), 5.40 (s, 1H), 7.08 7.48 (m, 10H), 9.44 (b, 2H).
(단계 2) 4-디페닐메톡시-1-(3-클로로프로필)피페리딘의 제조(Step 2) Preparation of 4-diphenylmethoxy-1- (3-chloropropyl) piperidine
30 ㎖의 아세톤에 4-디페닐메톡시피페리딘(2.0 g), 촉매량의 구리, 탄산칼륨(2.0 g), 1-브로모-3-클로로프로판(1.5 ㎖)을 첨가한 후 15 시간동안 환류교반하였다. 반응 종료 후 반응물을 실온으로 냉각하고 여과하였다. 여액에 물과 클로로포름을 가한 후 유기층을 황산나트륨으로 탈수, 여과 및 감압증류하였다. 잔사물을 컬럼크로마토그래피를 수행하여 겔상의 4-디페닐메톡시-1-(3-클로로프로필)피페리딘(수율 85 %)을 얻었다.To 30 ml of acetone, 4-diphenylmethoxypiperidine (2.0 g), catalytic amount of copper, potassium carbonate (2.0 g), 1-bromo-3-chloropropane (1.5 ml) were added and refluxed for 15 hours. Stirred. After the reaction was completed, the reaction was cooled to room temperature and filtered. Water and chloroform were added to the filtrate, and the organic layer was dehydrated with sodium sulfate, filtered, and distilled under reduced pressure. The residue was subjected to column chromatography to give 4-diphenylmethoxy-1- (3-chloropropyl) piperidine (yield 85%) on gels.
TLC : Rf0.3(클로로포름:메탄올=10:1)TLC: R f 0.3 (chloroform: methanol = 10: 1)
IR(KBr) : 2943, 1492, 1453, 1070 ㎝-1 IR (KBr): 2943, 1492, 1453, 1070 cm -1
1H NMR(200 ㎒, CDCl3) δ1.62∼1.99(m, 6H), 2.07∼2.16(m, 2H), 2.44(t, J=14.2 ㎐, 2H), 2.68∼2.78(m, 2H), 3.41∼3.47(m, 1H), 3.56(t, J=13.1 ㎐, 2H), 5.51(s, 1H), 7.40∼7.21(m, 10H). 1 H NMR (200 MHz, CDCl 3 ) δ1.62 to 1.99 (m, 6H), 2.07 to 2.16 (m, 2H), 2.44 (t, J = 14.2 Hz, 2H), 2.68 to 2.78 (m, 2H) , 3.41 to 3.47 (m, 1H), 3.56 (t, J = 13.1 Hz, 2H), 5.51 (s, 1H), 7.40 to 7.21 (m, 10H).
13C NMR(75 ㎒, CDCl3) δ30.1, 31.3, 43.3, 51.1, 55.4, 72.3, 80.1, 127.0, 128.3, 142.8 13 C NMR (75 MHz, CDCl 3 ) δ 30.1, 31.3, 43.3, 51.1, 55.4, 72.3, 80.1, 127.0, 128.3, 142.8
(단계 3) 4-(Step 3) 4- tt -부틸-Butyl NN -메톡시--Methoxy- NN -메틸벤즈아미드의 제조Preparation of Methylbenzamide
10 ㎖의 클로로포름에 4-t-부틸벤조산(1.0 g)을 녹인 후에 1-(3-디메틸아미노프로필)-3-에틸카보디이미드염산염(1.18 g), 4-디메틸아미노피리딘(2.1 g), N,O-디메틸히드록시아민염산염(0.82 g)을 첨가하고 상온에서 2 시간동안 교반하였다.반응 종료 후에 염산 수용액(1 N)을 천천히 가하며 pH 1로 맞춘 후 디클로로메탄으로 추출하고 유기층을 수산화나트륨 수용액(1 N)으로 세척하였다. 유기층을 무수 황산나트륨으로 건조 및 여과하고 감압하에 용매를 제거한 후 컬럼크로마토그래피를 수행하여 백색 고체의 4-t-부틸-N-메톡시-N-메틸벤즈아미드(수율 96 %)를 제조하였다.4- t -butylbenzoic acid (1.0 g) was dissolved in 10 ml of chloroform, followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.18 g), 4-dimethylaminopyridine (2.1 g), N, O-dimethylhydroxyamine hydrochloride (0.82 g) was added and stirred at room temperature for 2 hours. After completion of the reaction, aqueous hydrochloric acid solution (1 N) was slowly added to pH 1, extracted with dichloromethane and the organic layer was extracted with sodium hydroxide. Washed with aqueous solution (IN). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure, followed by column chromatography to prepare 4- t -butyl- N -methoxy- N -methylbenzamide (yield 96%) as a white solid.
녹는점(m.p.) 70∼72℃Melting Point (m.p.) 70 ~ 72 ℃
TLC : Rf0.5(에틸아세테이트:헥산=1:5)TLC: R f 0.5 (ethyl acetate: hexane = 1: 5)
IR(KBr) : 2948, 1627, 1380, 1190 ㎝-1 IR (KBr): 2948, 1627, 1380, 1190 cm -1
1H NMR(200 ㎒, CDCl3) δ1.33(s, 9H), 3.35(s, 3H), 3.58(s, 3H), 7.41(d, J=8.4 ㎐, 2H), 7.63(d, J=8.4 ㎐, 2H). 1 H NMR (200 MHz, CDCl 3 ) δ1.33 (s, 9H), 3.35 (s, 3H), 3.58 (s, 3H), 7.41 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H).
13C NMR(75 ㎒, CDCl3) δ31.1, 33.8, 34.7, 60.9, 124.8, 128.0, 130.9, 153.8, 169.9 13 C NMR (75 MHz, CDCl 3 ) δ 31.1, 33.8, 34.7, 60.9, 124.8, 128.0, 130.9, 153.8, 169.9
(단계 4) 4-디페닐메톡시-1-{3-(4-(Step 4) 4-diphenylmethoxy-1- {3- (4- tt -부틸벤조일)프로필}피페리딘의 제조-Butylbenzoyl) propyl} piperidine
18 ㎖의 테트라히드로퓨란에 4-디페닐메톡시-1-(3-클로로프로필)피페리딘(0.6 g)을 녹인 후에 마그네슘(0.43 g)을 첨가하고, 2 시간동안 상온에서 반응을 시킨 후 4-t-부틸-N-메톡시-N-메틸벤즈아미드(0.1 g)을 첨가하였다. TLC를 이용하여 반응정도를 확인한 후 물로 반응을종결시켰다. 셀라이트로 고체를 제거하고 디클로로메탄으로 추출한 후에 황산나트륨으로 유기층을 건조 및 감압하에 용매를 제거하였다. 잔사물을 컬럼크로마토그래피를 수행하여 얻이진 고체를 에탄올로 재결정하여 백색 고체의 4-디페닐메톡시-1-{3-(4-t-부틸벤조일)프로필}피페리딘(수율 75 %)을 얻었다.After dissolving 4-diphenylmethoxy-1- (3-chloropropyl) piperidine (0.6 g) in 18 ml of tetrahydrofuran, magnesium (0.43 g) was added, followed by reaction at room temperature for 2 hours. 4- t -butyl- N -methoxy- N -methylbenzamide (0.1 g) was added. After confirming the reaction degree using TLC, the reaction was terminated with water. After removing the solid with celite and extracting with dichloromethane, the organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was subjected to column chromatography to give a solid obtained by recrystallization with ethanol to give 4-diphenylmethoxy-1- {3- (4- t -butylbenzoyl) propyl} piperidine as a white solid (yield 75%). Got.
TLC : Rf0.5(클로로포름:메탄올=10:1)TLC: R f 0.5 (chloroform: methanol = 10: 1)
녹는점(m.p.) 84∼86℃Melting Point (m.p.) 84 ~ 86 ℃
1H NMR(200 ㎒, CDCl3) δ1.33(s, 9H), 1.68∼1.75(m, 2H), 1.86∼1.96(m, 4H), 2.08∼2.14(m, 2H), 2.38(t, J=13.7 ㎐, 2H), 2.74∼2.77(m, 2H), 2.98(t, J=13.7 ㎐, 2H), 3.41∼3.44(s, 1H), 5.52(s, 1H), 7.22∼7.40(m, 10H), 7.47(d, J=7.2 ㎐, 2H), 7.91(d, J=7.2 ㎐, 2H). 1 H NMR (200 MHz, CDCl 3 ) δ1.33 (s, 9H), 1.68 to 1.75 (m, 2H), 1.86 to 1.96 (m, 4H), 2.08 to 2.14 (m, 2H), 2.38 (t, J = 13.7 kPa, 2H), 2.74-2.77 (m, 2H), 2.98 (t, J = 13.7 kPa, 2H), 3.41-3.44 (s, 1H), 5.52 (s, 1H), 7.22-7.40 (m , 10H), 7.47 (d, J = 7.2 Hz, 2H), 7.91 (d, J = 7.2 Hz, 2H).
13C NMR(75 ㎒, CDCl3) δ22.3, 31.4, 36.5, 51.3, 58.0, 72.9, 80.3, 125.8, 127.3, 127.6, 128.3, 128.6, 134.9, 143.1, 156.9, 200.2 13 C NMR (75 MHz, CDCl 3 ) δ 22.3, 31.4, 36.5, 51.3, 58.0, 72.9, 80.3, 125.8, 127.3, 127.6, 128.3, 128.6, 134.9, 143.1, 156.9, 200.2
따라서, 반응식 3에서 보는 바와 같이, 화학식 3의 화합물을 마그네슘 존재하에 화학식 2의 화합물과 반응시켜 화학식 1의 피페리딘 유도체를 제조하는 방법은 기존의 피페리딘 유도체의 제조방법에 비해 제조공정이 단순하며, 저가의 출발 물질을 사용하여 고수율로 제조할 수 있어 역가가 높은 선택적인 히스타민 수용체차단 활성 및 칼슘 길항작용을 나타내는 피페리딘 유도체 및 그의 약학적으로 허용가능한 염을 경제적으로 얻을 수 있다.Therefore, as shown in Scheme 3, a method of preparing a piperidine derivative of Formula 1 by reacting a compound of Formula 3 with a compound of Formula 2 in the presence of magnesium is more efficient than a conventional method of preparing a piperidine derivative. Simple, low-cost starting materials can be prepared in high yield to economically obtain piperidine derivatives and pharmaceutically acceptable salts thereof that exhibit high titers of selective histamine receptor blocking activity and calcium antagonism .
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