KR100696187B1 - Preparation method of 2-2-aminoethyl-1-methylpyrrolidine - Google Patents

Preparation method of 2-2-aminoethyl-1-methylpyrrolidine Download PDF

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KR100696187B1
KR100696187B1 KR1020050037236A KR20050037236A KR100696187B1 KR 100696187 B1 KR100696187 B1 KR 100696187B1 KR 1020050037236 A KR1020050037236 A KR 1020050037236A KR 20050037236 A KR20050037236 A KR 20050037236A KR 100696187 B1 KR100696187 B1 KR 100696187B1
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formula
acid
methylpyrrolidine
aminoethyl
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KR20060114985A (en
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유태희
윤흥식
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(주)리드젠
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
    • B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
    • B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
    • B01J23/42—Platinum
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
    • B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
    • B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
    • B01J23/44—Palladium

Abstract

본 발명은 2-(2-아미노에틸)-1-메틸피롤리딘 제조방법에 관한 것으로, 본 발명은 상업적으로 저가로 구할 수 있는 1-메틸-2-피롤리디논을 출발물질로 사용하고, 제조과정에서 생성되는 중간 물질인 (1-메틸피롤리딘-2-일리덴)-아세토니트릴의 산염을 효과적으로 수소화 반응시키는 단계를 포함하는 것을 특징으로 하여 2-(2-아미노에틸)-1-메틸피롤리딘을 고수율, 고순도로 제조할 수 있는 경제적인 합성방법을 제공한다.The present invention relates to a method for preparing 2- (2-aminoethyl) -1-methylpyrrolidine. The present invention uses 1-methyl-2-pyrrolidinone, which is commercially available at low cost, as a starting material, It is characterized in that it comprises the step of effectively hydrogenating the acid salt of (1-methylpyrrolidin-2-ylidene) -acetonitrile, which is an intermediate produced in the manufacturing process, characterized in that 2- (2-aminoethyl) -1- Provides an economical synthesis method for producing methylpyrrolidine in high yield and high purity.

1-메틸-2피롤리디논, 2-(2-아미노에틸)-1-메틸피롤리딘, (1-메틸피롤리딘-2-일리덴)-아세토니트릴, 수소화 반응 1-methyl-2pyrrolidinone, 2- (2-aminoethyl) -1-methylpyrrolidine, (1-methylpyrrolidin-2-ylidene) -acetonitrile, hydrogenation reaction

Description

2-(2-아미노에틸)-1-메틸피롤리딘의 제조방법{PREPARATION METHOD OF 2-(2-AMINOETHYL)-1-METHYLPYRROLIDINE}Production method of 2- (2-aminoethyl) -1-methylpyrrolidine {PREPARATION METHOD OF 2- (2-AMINOETHYL) -1-METHYLPYRROLIDINE}

본 발명은 2-(2-아미노에틸)-1-메틸피롤리딘 제조방법에 관한 것으로, 보다 상세하게는 하기 화학식 4의 아세토니트릴계 화합물과 산을 반응시켜 하기 화학식 5의 산염을 제조하는 단계 및 상기 화학식 5의 산염을 수소화 반응시키는 단계를 포함하는 화학식 1의 2-(2-아미노에틸)-1-메틸피롤리딘 제조방법에 관한 것이다. The present invention relates to a method for preparing 2- (2-aminoethyl) -1-methylpyrrolidine, and more particularly, to preparing an acid salt of formula 5 by reacting an acetonitrile compound of formula 4 with an acid. And it relates to a method for producing 2- (2-aminoethyl) -1-methylpyrrolidine of the formula (1) comprising the step of hydrogenating the acid salt of the formula (5).

[화학식 1][Formula 1]

Figure 112005023410010-pat00001
Figure 112005023410010-pat00001

[화학식 4][Formula 4]

Figure 112005023410010-pat00002
Figure 112005023410010-pat00002

[화학식 5][Formula 5]

Figure 112005023410010-pat00003
Figure 112005023410010-pat00003

최근 유전공학분야의 눈부신 발전으로, 암 등의 많은 질환의 병리학적 원인이 단백질 또는 유전자 발현 등의 세포수준으로 초점이 맞추어지면서, 단백질의 기능을 변형시킴으로써 그러한 질환을 치료하기 위한 약물로서 아미노산으로 구성되는 폴리펩티드가 관심을 받고 있다. 종래의 화학합성 약물에 대한 대체물 또는 신약으로서 이러한 폴리펩티드는 생체독성이 낮으면서 치료 효능이 높은 것으로 알려져 있지만, 생체내로의 흡수 효율이 낮고, 생체 내에 존재하는 각종 효소에 의해 분해 되기 쉬운 등의 아직 해결해야할 많은 문제가 존재한다. 이러한 문제를 해결하기 위해서, 대체 약물로서 폴리펩티드를 구성하는 아미노산 중 일부를 천연에 존재하는 아미노산에서 천연에 존재하지 않는 합성된 아미노산으로 대체하고자 하는 많은 시도가 이루어지고 있다.Recent remarkable developments in the field of genetic engineering have focused on the pathological causes of many diseases, such as cancer, at the cellular level, such as protein or gene expression, and composed of amino acids as drugs to treat such diseases by modifying their function. The polypeptide of interest is of interest. As a substitute or a new drug for a conventional chemical synthesis drug, such a polypeptide is known to have low biotoxicity and high therapeutic efficacy, but has yet to be solved such as low absorption efficiency in vivo and easy degradation by various enzymes present in the living body. There are many problems to do. In order to solve this problem, many attempts have been made to replace some of the amino acids constituting the polypeptide as an alternative drug from amino acids existing in nature to synthesized amino acids not present in nature.

이러한 관점에서 새로운 폴리펩티드 약물의 개발은 다음과 같은 절차에 의해서 수행되고 있다. 우선, 질환의 치료에 유용할 것으로 예상되는 단백질의 종류 및 구조를 먼저 밝혀내고, 그 단백질의 기능에 영향을 미치는 폴리펩티드를 스크리닝(Screening)한 다음, 이를 자연에서 발생하는 아미노산들을 이용하여 알라닌 스캐닝 등의 방법으로 단백질의 아미노산들을 변형시키면서 각각의 아미노산들의 중요성을 검증함으로써 약물로서 사용될 수 있는 최적의 아미노산 서열을 찾아낸다. 그 다음 단계로, 천연에 존재하지 않는 아미노산 형태를 사용하여, 인체 내에 존재하는 여러 가지 효소들에 의해 분해되지 않게 하거나 신체 흡수율을 높이는 등의 방법을 통해 생체 이용율을 높인다. 이러한 접근 방법은 하이쓰루풋 스크리닝(HIGH THROUGHPUT SCREENING)을 통한 선도 물질의 발굴 및 그 선도 물질을 최적화하는 방법과 더불어 신약 개발을 위한 전형적인 방법으로서 당업계에서 인식되고 있다.In this respect, the development of a new polypeptide drug is carried out by the following procedure. First, the types and structures of proteins that are expected to be useful for the treatment of diseases are first identified, followed by screening for polypeptides that affect the function of the proteins, followed by alanine scanning using naturally occurring amino acids. By examining the importance of each amino acid while modifying the amino acids of the protein, the method finds the optimal amino acid sequence that can be used as a drug. The next step is to increase the bioavailability by using amino acid forms that do not exist in nature to prevent degradation by various enzymes present in the human body or to increase body absorption. This approach is recognized in the art as a typical method for new drug development, along with methods of optimizing the lead material and optimizing the lead material through HIGH THROUGHPUT SCREENING.

따라서 이러한 폴리펩티드의 신약 물질의 개발을 위해서는, 천연 존재 아미노산을 모방한 빌딩 블록으로서 사용될 수 있는 천연에 존재하지 않는 아미노산 및 그 유도체를 고순도 및 고수율로 제조하는 것이 요구되고 있다. 천연에 존재하지 않는 아미노산중에서도 호모-프롤린 유도체의 일종인 2-(2-아미노에틸)-1-메틸피롤리딘은 여러 의약품 등의 유도체화에 많이 쓰이고 있는 물질로서 경제적으로 제조하는 방법은 매우 중요한 과제라 하겠다.Therefore, for the development of a new drug substance of such a polypeptide, it is required to produce amino acids and derivatives thereof which are not present in nature that can be used as building blocks that mimic natural amino acids with high purity and high yield. Among the amino acids which do not exist in nature, 2- (2-aminoethyl) -1-methylpyrrolidine, a kind of homo-proline derivative, is widely used for derivatization of various medicines, and the method of economic preparation is very important. It's a task.

2-(2-아미노에틸)-1-메틸피롤리딘을 제조하는 기존의 방법으로는 다음과 같은 것들이 있으며, 제조에 있어서 각각 방법에 따른 제조 반응식과 대량으로 제조할 경우 그에 따른 문제점을 내포함을 알 수 있다. Conventional methods for preparing 2- (2-aminoethyl) -1-methylpyrrolidine include the followings, and include manufacturing schemes according to the respective methods in manufacturing and problems associated with the preparation in large quantities. It can be seen.

(1) 프롤린으로부터 호몰로게이션을 통해 탄소 수 하나를 늘린 다음 몇 단계를 거쳐 아민을 만드는 방법으로 반응을 도식화하면 반응식 1로 표현된다.(1) Schematically formulating the reaction by increasing the number of carbons from the proline through homologation and then making the amine in several steps.

[반응식 1]Scheme 1

Figure 112005023410010-pat00004
Figure 112005023410010-pat00004

그러나, 호몰로게이션 자체가 디아조메탄을 사용하는 등의 매우 위험한 과정을 포함하고 있으며, 뒷부분인 아민 제조 단계 또한 여러 단계를 거쳐야하는 번거로움이 있다(Tetrahedron Lett. 1997, 38, 3609.).However, the homologation itself involves a very dangerous process, such as the use of diazomethane, and the later stages of amine preparation are also cumbersome ( Tetrahedron Lett. 1997 , 38 , 3609.).

(2) N-메틸피롤리딘으로 부터 제조하는 방법이 있는 데, 반응을 도식화하면 반응식 2로 표현된다.(2) There is a method for preparing from N-methylpyrrolidine, which is represented by Scheme 2 when the reaction is schematic.

[반응식 2]Scheme 2

Figure 112005023410010-pat00005
Figure 112005023410010-pat00005

상기 반응은 반응 단계는 짧지만, 첫 반응이 광반응으로 대량 생산에는 적합하지 않다(Tetrahedron Lett. 1999, 40, 3169.).The reaction is short in reaction stage, but the first reaction is photoreaction and not suitable for mass production ( Tetrahedron Lett. 1999 , 40, 3169.).

(3) 1-메틸-2-피롤리디논으로 부터 제조하는 방법이 있는 데, 반응을 도식화하면 반응식 3으로 표현된다.(3) There is a method for producing from 1-methyl-2-pyrrolidinone, and when the reaction is schematic, it is represented by Scheme 3.

[반응식 3]Scheme 3

Figure 112005023410010-pat00006
Figure 112005023410010-pat00006

그러나, 상기 반응은 에스테르 화합물을 제조하기 위하여 3단계를 진행한 후 에스테르 화합물로부터 화학식 1의 아민 제조를 위해 여러 단계를 거쳐야하고 반응 중간체의 분리 또는 정제작업 등으로 효율성이 저하되는 단점을 가지고 있다(Heterocycles 1986, 24, 1825.).However, the reaction has to go through three steps to prepare the ester compound and then several steps for the preparation of the amine of the formula (1) from the ester compound has the disadvantage that the efficiency is reduced by the separation or purification of the reaction intermediate ( Heterocycles 1986 , 24, 1825.).

이에, 본 발명자들은 화학식 1로 표현되는 2-(2-아미노에틸)-1-메틸피롤리딘을 보다 효율적이고 산업적 이용 가능성을 높일 수 있는 제조방법을 찾기 위하여 많은 연구를 수행하였으며, 그 결과 저가의 출발 물질인 1-메틸-2-피롤리디논으로부터 고수율 및 고순도의 화학식 1의 화합물인 2-(2-아미노에틸)-1-메틸피롤리딘을 효율적으로 제조할 수 있음을 발견하였고, 따라서 본 발명의 기술적 과제는 2-(2-아미노에틸)-1-메틸피롤리딘의 효율적인 제조 방법을 제공하는 것이다.Thus, the present inventors have conducted a lot of research to find a method for producing a more efficient and industrial availability of 2- (2-aminoethyl) -1-methylpyrrolidine represented by Formula 1, and as a result, It was found that 2- (2-aminoethyl) -1-methylpyrrolidin, which is a compound of formula (I) of high yield and purity, can be efficiently prepared from 1-methyl-2-pyrrolidinone which is a starting material of Accordingly, the technical problem of the present invention is to provide an efficient method for preparing 2- (2-aminoethyl) -1-methylpyrrolidine.

상기 기술적 과제를 달성하기 위해서, 본 발명은 하기 화학식 4의 아세토니트릴계 화합물과 산을 반응시켜 하기 화학식 5의 산염을 제조하는 단계 및 상기 화학식 5의 산염을 수소화 반응시키는 단계를 포함하는 화학식 1의 2-(2-아미노에틸)-1-메틸피롤리딘 제조방법을 제공한다. In order to achieve the above technical problem, the present invention comprises the steps of preparing an acid salt of the formula (5) by reacting the acetonitrile-based compound of the formula (4) with an acid and the hydrogenation of the acid salt of the formula (5) Provided is a method for preparing 2- (2-aminoethyl) -1-methylpyrrolidine.

[화학식 1][Formula 1]

Figure 112005023410010-pat00007
Figure 112005023410010-pat00007

[화학식 4] [화학식 5][Formula 4] [Formula 5]

Figure 112005023410010-pat00008
Figure 112005023410010-pat00009
Figure 112005023410010-pat00008
Figure 112005023410010-pat00009

상기 화학식 중 HA는 무기산 또는 유기산HA in the above formula is an inorganic acid or an organic acid

또한, 본 발명은 상기 화학식 4의 아세토니트릴계 화합물이, ⅰ) 1-메틸-2-피롤리디논과 디메틸설페이트를 반응시켜 중간체인 화학식 2의 화합물을 제조하는 단계; ⅱ) 상기 화학식 2를 유리하지 않은 상태에서 메틸시아노아세테이트와 반응시켜 화학식 3의 에스테르 화합물을 제조하는 단계 및; ⅲ) 상기 화학식 3의 에스테르 화합물을 탈카르복실화 하는 단계를 거쳐 제조된 것을 특징으로 하는 화학식 1의 2-(2-아미노에틸)-1-메틸피롤리딘 제조방법을 제공한다. In addition, the present invention comprises the steps of preparing a compound of formula (2), wherein the acetonitrile compound of formula (4), i) reacting 1-methyl-2-pyrrolidinone with dimethylsulfate; Ii) reacting Formula 2 with methylcyanoacetate in an unfavorable state to produce an ester compound of Formula 3; Iii) a method of preparing 2- (2-aminoethyl) -1-methylpyrrolidine of formula 1, which is prepared by decarboxylating the ester compound of formula 3;

[화학식 2] [화학식 3][Formula 2] [Formula 3]

Figure 112005023410010-pat00010
Figure 112005023410010-pat00011
Figure 112005023410010-pat00010
Figure 112005023410010-pat00011

또한, 본 발명은 상기 산이 염산, 황산, 인산 및 질산으로 구성된 군으로부터 선택된 하나 이상의 무기산 또는 하기 화학식의 유기산 중 하나인 것을 특징으로 하는 화학식 1의 2-(2-아미노에틸)-1-메틸피롤리딘 제조방법을 제공한다. In addition, the present invention is 2- (2-aminoethyl) -1-methylpi of Formula 1, characterized in that the acid is one of at least one inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid or an organic acid of the formula Provided is a method for preparing lollidine.

Figure 112005023410010-pat00012
Figure 112005023410010-pat00012

화학식 중, R1 및 R2 는 각각 독립적으로 수소, 탄소수 1 내지 10 의 저급 알킬,; 아릴기로 치환된 탄소수 1 내지 10 의 저급 알킬; 또는 분자구조내에 산소 또는 질소를 1 내지 3개 포함하는 탄소수 1 내지 10 의 저급 알킬.In the formula, R1 and R2 are each independently hydrogen, lower alkyl having 1 to 10 carbon atoms; Lower alkyl having 1 to 10 carbon atoms substituted with an aryl group; Or lower alkyl having 1 to 10 carbon atoms containing 1 to 3 oxygen or nitrogen in the molecular structure.

또한, 본 발명은 상기 수소화 반응이 Pd/C, Pd(OH)2/C, Pt, PtO2 및 Raney Ni로 구성된 군으로부터 선택된 하나 이상의 금속촉매와 1 내지 100기압의 수소 분위기하에서 수행되는 것을 특징으로 하는 2-(2-아미노에틸)-1-메틸피롤리딘의 제조방법을 제공한다.In addition, the present invention is characterized in that the hydrogenation reaction is carried out in a hydrogen atmosphere of 1 to 100 atm and at least one metal catalyst selected from the group consisting of Pd / C, Pd (OH) 2 / C, Pt, PtO 2 and Raney Ni A method for producing 2- (2-aminoethyl) -1-methylpyrrolidine is provided.

이하에서 본 발명에 대해 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail.

본 발명은 화학식 4의 아세토니트릴계 화합물과 산을 반응시켜 하기 화학식 5의 산염을 제조하는 단계 및 상기 화학식 5의 산염을 수소화 반응시키는 단계를 포함하는 화학식 1의 2-(2-아미노에틸)-1-메틸피롤리딘 제조방법을 제공한다. The present invention comprises reacting an acetonitrile-based compound of Formula 4 with an acid to prepare an acid salt of Formula 5 below, and hydrogenating the acid salt of Formula 5 to 2- (2-aminoethyl)- Provided is a method for preparing 1-methylpyrrolidine.

[화학식 1][Formula 1]

Figure 112005023410010-pat00013
Figure 112005023410010-pat00013

[화학식 4] [화학식 5][Formula 4] [Formula 5]

Figure 112005023410010-pat00014
Figure 112005023410010-pat00015
Figure 112005023410010-pat00014
Figure 112005023410010-pat00015

상기 화학식 4의 아세토니트릴계 화합물은 수소화 반응 이전에 산과 반응시켜 산염의 형태로 미리 활성화하는 단계를 거친다. 화학식 4의 아세토니트릴계 화합물을 제조하는 과정을 포함한 2-(2-아미노에틸)-1-메틸피롤리딘 제조방법의 구체적인 반응을 도식화하면 하기 반응식 4로 표현된다.The acetonitrile-based compound of Chemical Formula 4 is reacted with an acid prior to the hydrogenation reaction in advance to activate in the form of an acid salt. A schematic reaction of the method for preparing 2- (2-aminoethyl) -1-methylpyrrolidine including a process of preparing an acetonitrile compound of Formula 4 is represented by the following Scheme 4.

[반응식 4]Scheme 4

Figure 112005023410010-pat00016
Figure 112005023410010-pat00016

상기 화학식 5의 화합물에서 HA, 즉 산은 염산, 황산, 인산 및 질산으로 구성된 군으로부터 선택된 하나 이상의 무기산 또는 하기 화학식의 유기산 중 하나인 것이 바람직하다. In the compound of Formula 5, HA, that is, the acid is preferably at least one inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid, or an organic acid of the following formula.

Figure 112005023410010-pat00017
Figure 112005023410010-pat00017

상기 화학식 중, R1 및 R2 는 각각 독립적으로 수소, 탄소수 1 내지 10 의 저급 알킬,; 아릴기로 치환된 탄소수 1 내지 10 의 저급 알킬; 또는 분자구조내에 산소 또는 질소를 1 내지 3개 포함하는 탄소수 1 내지 10 의 저급 알킬인 것이 바람직하다.In the formula, R1 and R2 are each independently hydrogen, lower alkyl having 1 to 10 carbon atoms; Lower alkyl having 1 to 10 carbon atoms substituted with an aryl group; Or lower alkyl having 1 to 10 carbon atoms containing 1 to 3 oxygen or nitrogen in the molecular structure.

또한, 상기 수소화 반응은 수소화 촉매의 존재하에 수행되는 것이 바람직하다. 상기 수소화 반응의 촉매로서 사용될 수 있는 것으로는 공지의 금속촉매 모두 사용가능하며, 바람직하게는 Pd/C, Pd(OH)2/C, Pt, PtO2 및 Raney Ni로 구성된 군으로부터 선택된 하나 이상의 금속촉매를 사용하는 것이 바람직하고, 수소화 반응시 1 내지 100기압 범위의 수소분위기하에서 수행하는 것이 바람직하다. 본 발명의 2-(2-아미노에틸)-1-메틸피롤리딘 제조방법은 상기 반응 외에 필요에 따라 별도의 정제과정이 수행될 수 있음은 물론이다.In addition, the hydrogenation reaction is preferably carried out in the presence of a hydrogenation catalyst. Any known metal catalyst may be used as the catalyst for the hydrogenation reaction, and preferably at least one metal selected from the group consisting of Pd / C, Pd (OH) 2 / C, Pt, PtO 2 and Raney Ni It is preferable to use a catalyst, and it is preferable to carry out under hydrogen atmosphere in the range of 1 to 100 atm in the hydrogenation reaction. 2- (2-aminoethyl) -1-methylpyrrolidine production method of the present invention, of course, in addition to the above reaction may be carried out a separate purification process if necessary.

상기 화학식 4의 아세토니트릴계 화합물은 상업적으로 저가로 구할 수 있는 1-메틸-2-피롤리디논을 출발물질로 사용하여 디메틸썰페이트와 반응시켜 하기 화학식 2의 화합물을 제조하고, 이어서 메틸시아노아세테이트를 반응시켜 하기 화학식 3의 화합물을 제조한 후 탈카르복실화(decarboxylation)하여 제조된다. 상기 탈카르복실화 반응은 염기와 반응시킴으로 수행될 수 있으며, 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에게는 상식에 속하는 내용이므로 본 명세서에서는 더 이상의 설명은 하지 않기로 한다.The acetonitrile-based compound of Formula 4 may be reacted with dimethylsulfate using 1-methyl-2-pyrrolidinone, which is commercially available at low cost, to prepare a compound of Formula 2, followed by methylcyano Acetate is reacted to prepare a compound of Formula 3, followed by decarboxylation. The decarboxylation reaction may be carried out by reacting with a base, and thus it will not be described further herein because it belongs to common sense to those skilled in the art.

[화학식 2] [화학식 3][Formula 2] [Formula 3]

Figure 112005023410010-pat00018
Figure 112005023410010-pat00019
Figure 112005023410010-pat00018
Figure 112005023410010-pat00019

상기 화학식 4의 아세토니트릴계 화합물을 제조하는 과정을 포함한 2-(2-아미노에틸)-1-메틸피롤리딘 제조방법을 도식화하면 반응식 5로 표현된다.Schematic of the preparation method of 2- (2-aminoethyl) -1-methylpyrrolidine including the process of preparing the acetonitrile-based compound of Formula 4 is represented by Scheme 5.

[반응식 5]Scheme 5

Figure 112005023410010-pat00020
Figure 112005023410010-pat00020

상기 반응식 5로 도식화되는 본 발명에 따라 1-메틸-2-피롤리디논을 출발물질로 하여 화학식 1의 화합물 2-(2-아미노에틸)-1-메틸피롤리딘을 합성하는 새로운 제조방법이 제공된다. According to the present invention illustrated in Scheme 5, a new preparation method for synthesizing compound 2- (2-aminoethyl) -1-methylpyrrolidine of Formula 1 using 1-methyl-2-pyrrolidinone as a starting material is provided. Is provided.

상기 반응식 2는 화학식 4의 아세토니트릴계 화합물로부터 화학식 1의 화합물을 제조하는 반응공정을 포함하고 있으며, 본 발명의 2-(2-아미노에틸)-1-메틸피롤리딘을 제조하기 위한 수소화 반응의 출발물질로서 상기 화학식 4의 아세토니트릴계 화합물의 3차 아민은, 적절한 산염인 상기 화학식 5의 화합물을 만들어 활성화함으로써 효과적으로 수소화 반응을 시킬 수 있다.Scheme 2 includes a reaction process for preparing a compound of Formula 1 from an acetonitrile compound of Formula 4, and a hydrogenation reaction for preparing 2- (2-aminoethyl) -1-methylpyrrolidine of the present invention. As a starting material of the tertiary amine of the acetonitrile compound of formula (4), it is possible to effectively hydrogenate the reaction by forming and activating the compound of formula (5), which is a suitable acid.

하기 실시예에 의하여 본 발명을 더욱 구체적으로 설명한다. 하기 실시예는 본 발명의 내용을 예시하는 것일 뿐 발명의 범위가 실시예에 의해 한정되는 것은 아니다. The present invention is explained in more detail by the following examples. The following examples are merely illustrative of the content of the present invention, but the scope of the invention is not limited by the examples.

실시예 1-1: 1-메틸-2-(시아노카보메톡시메틸렌)-피롤리딘(화학식 3)의 합성 Example 1-1: Synthesis of 1-methyl-2- (cyanocarbomethoxymethylene) -pyrrolidine (Formula 3)

1-메틸-2-피롤리디논 30.0kg (303mol)와 디메틸썰페이트 46kg(35L, 364mol)을 넣고 상온에서 1시간 정도 교반시켰다. 교반시 발열로 인해 온도가 약 50oC 정도까지 상승하였다. 온도의 상승이 멈추면 온도를 60oC로 가온하고 12시간 정도 교반하였다. 그 다음, 톨루엔 121L를 넣고, 트리에틸아민 92kg, 메틸시아노아세테이트 33kg을 넣고 4시간 동안 80oC로 가열하였다. 반응이 종결되면, 상온으로 냉각하고, 물 200L를 넣어 교반 시킨 후 디클로로메탄 200L로 두 번 추출하였다. 유기층을 20kg의 황산나트륨(sodium sulfate)을 넣어 건조하고 여과한 후, 감압증류로 용매를 제거하였다. 용매제거 후 얻은 고체의 화합물에 이소프로필에테르 121L를 넣고 세차게 30분간 교반시켰다. 교반 후 여과 하고, 건조하여 39kg의 표제 화합물 을 얻었다 1H NMR (400 MHz, CDCl3) d : 3.72(3H, s), 3.62(2H, t, J=7.6 Hz), 3.44(3H, s), 3.30(2H, t, J=8.0Hz), 2.01(2H, dt, J=7.2, 8.0Hz). 30.0 kg (303 mol) of 1-methyl-2-pyrrolidinone and 46 kg (35 L, 364 mol) of dimethylsulfate were added thereto, followed by stirring at room temperature for 1 hour. The temperature rose to about 50 o C due to the exotherm upon stirring. When the increase in temperature stopped, the temperature was warmed to 60 ° C. and stirred for about 12 hours. Then, 121 L of toluene was added, 92 kg of triethylamine and 33 kg of methylcyanoacetate were added and heated to 80 ° C. for 4 hours. After the reaction was terminated, the mixture was cooled to room temperature, stirred with 200 L of water, and extracted twice with 200 L of dichloromethane. The organic layer was dried with 20 kg of sodium sulfate and filtered, and then the solvent was removed by distillation under reduced pressure. 121L of isopropyl ether was added to the solid compound obtained after solvent removal, and it stirred for 30 minutes. After stirring, filtered and dried to obtain 39 kg of the title compound 1H NMR (400 MHz, CDCl 3) d: 3.72 (3H, s), 3.62 (2H, t, J = 7.6 Hz), 3.44 (3H, s), 3.30 (2H, t, J = 8.0 Hz), 2.01 (2H, dt, J = 7.2, 8.0 Hz).

실시예 1-2: (1-메틸피롤리딘-2-일리덴)-아세토니트릴(화학식 4)의 합성 Example 1-2: Synthesis of (1-methylpyrrolidin-2-ylidene) -acetonitrile (Formula 4)

우선, 물 380Kg을 넣고 수산화나트륨 17.7Kg을 넣어 용해시켜 수산화나트륨 용액을 준비하였다. 이 용액에 상기 실시예 1-1에서 수득한 1-메틸-2-(시아노카보메톡시메틸렌)-피롤리딘 38kg(211 mol)을 넣고 온도를 100oC로 승온시킨 후 2시간 동안 반응시켰다. TLC로 반응 종결 확인 후, 20oC로 급냉시켰다. 이 용액을 디클로로메탄 250kg으로 추출하였다. 추출한 유기층을 감압증류로 1/2 정도의 용매를 제거한 후, 물 125kg으로 4번 세정하고 황산나트륨으로 건조한 다음, 여과 후 용매를 감압증류로 제거하여 액체형태의 8.24kg의 표제 화합물을 얻었다 1H NMR (400 MHz, CDCl3) d : 3.59(1H, s), 3.44(2H, t, J=7.2Hz), 2.86(2H, t, J=8.0Hz), 2.77(3H, s), 1.99(2H, dt, J=7.2, 8.0Hz). First, 380 Kg of water was added thereto, and 17.7 Kg of sodium hydroxide was dissolved therein to prepare a sodium hydroxide solution. 38 kg (211 mol) of 1-methyl-2- (cyanocarbomethoxymethylene) -pyrrolidine obtained in Example 1-1 was added to this solution, and the temperature was raised to 100 ° C., followed by reaction for 2 hours. . After confirming the completion of the reaction by TLC, it was quenched to 20 ° C. This solution was extracted with 250 kg of dichloromethane. The extracted organic layer was removed by distillation under reduced pressure, about 1/2 of the solvent was washed 4 times with 125 kg of water, dried over sodium sulfate, and then filtered and the solvent was removed by distillation under reduced pressure to obtain 8.24 kg of the title compound in liquid form. 1 H NMR (400 MHz, CDCl 3 ) d: 3.59 (1H, s), 3.44 (2H, t, J = 7.2 Hz), 2.86 (2H, t, J = 8.0 Hz), 2.77 (3H, s), 1.99 (2H , dt, J = 7.2, 8.0 Hz).

실시예 2: 2-(2-아미노에틸)-1-메틸피롤리딘의 합성Example 2: Synthesis of 2- (2-aminoethyl) -1-methylpyrrolidine

실시예 1-2에서 수득한 (1-메틸피롤리딘-2-일리덴)-아세토니트릴 20g(0.164 mol)을 넣고 메탄올 79g에 녹인 후, 파라톨루엔술포닉산 63g을 넣고 교반시키면서 완전히 용해시킨 후, Pd(OH)2/C 2.0g을 넣고 수소를 18bar를 유지하면 상온에서 5시 간 반응시켰다. TLC로 반응 종결을 확인하고, Pd(OH)2/C를 여과한 후, 감압증류로 여액의 MeOH을 제거하고, 이소프로필에테르 145g을 넣고 세차게 교반시키면서 50% 수산화나트륨 용액 61g을 넣고 30분 동안 유지하였다. 생성된 고체를 여과하고, 여액을 층분리한 후, 물층을 이소프로필에테르 73g으로 한 번 더 추출하였다. 모아진 유기층을 황산나트륨으로 건조하고, 여과 후 용매를 감압증류로 제거한 다음, 감압 분별 증류(bp: 156 oC, 75~85 oC / 20~30 mmHg) 에 의해 13.85g의 표제 화합물을 얻었다 1H NMR (400 MHz, CDCl3) d : 3.10-3.01(1H, m), 2.80-2.62(2H, m), 2.31(3H, s), 2.15-2.00(2H, m), 1.97-1.63(4H, m), 1.51-1.35(4H, m).After 20 g (0.164 mol) of (1-methylpyrrolidin-2-ylidene) -acetonitrile obtained in Example 1-2 was dissolved in 79 g of methanol, 63 g of paratoluene sulfonic acid was added thereto, followed by complete dissolution with stirring. , Pd (OH) 2 / C 2.0g was added and the hydrogen was maintained at 18bar and reacted at room temperature for 5 hours. Check the reaction by TLC, filter Pd (OH) 2 / C, remove MeOH from the filtrate by distillation under reduced pressure, add 145 g of isopropyl ether and add 61 g of 50% sodium hydroxide solution with vigorous stirring for 30 minutes. Maintained. The resulting solid was filtered, the filtrate was separated and the water layer was extracted once more with 73 g of isopropyl ether. The combined organic layer was dried over sodium sulfate and, after filtration to remove the solvent by distillation under reduced pressure, then under reduced pressure fractional distillation (bp: 156 o C, 75 ~ 85 o C / 20 ~ 30 mmHg) by 13.85g of the title compound 1 H NMR (400 MHz, CDCl 3 ) d: 3.10-3.01 (1H, m), 2.80-2.62 (2H, m), 2.31 (3H, s), 2.15-2.00 (2H, m), 1.97-1.63 (4H, m), 1.51-1.35 (4H, m).

이상에서 살펴본 바와 같이, 본 발명에 따른 방법은 상업적으로 저가로 구할 수 있는 1-메틸-2-피롤리디논을 출발물질로 사용하고, 제조과정에서 생성되는 중간 물질인 (1-메틸피롤리딘-2-일리덴)-아세토니트릴의 산염을 효과적으로 수소화 반응시키는 단계를 포함하는 것을 특징으로 하여 2-(2-아미노에틸)-1-메틸피롤리딘을 고수율, 고순도로 제조할 수 있는 경제적인 방법을 제공한다.As described above, the method according to the present invention uses 1-methyl-2-pyrrolidinone, which is commercially available at low cost, as a starting material, and (1-methylpyrrolidine, which is an intermediate produced in the manufacturing process). A method for producing 2- (2-aminoethyl) -1-methylpyrrolidine in high yield and high purity, comprising the step of effectively hydrogenating an acid salt of 2-ylidene) -acetonitrile. To provide a way.

앞에서 설명된 본 발명의 일실시예는 본 발명의 기술적 사상을 한정하는 것으로 해석되어서는 안 된다. 본 발명의 보호범위는 청구범위에 기재된 사항에 의하여만 제한되고, 본 발명의 기술분야에서 통상의 지식을 가진 자는 본 발명의 기술적 사상을 다양한 형태로 개량 변경하는 것이 가능하다. 따라서 이러한 개량 및 변경은 통상의 지식을 가진 자에게 자명한 것인 한 본 발명의 보호범위에 속하게 될 것이다.One embodiment of the present invention described above should not be construed as limiting the technical spirit of the present invention. The protection scope of the present invention is limited only by the matters described in the claims, and those skilled in the art can change and change the technical idea of the present invention in various forms. Therefore, such improvements and modifications will fall within the protection scope of the present invention, as will be apparent to those skilled in the art.

Claims (4)

하기 화학식 4의 아세토니트릴계 화합물과 산을 반응시켜 하기 화학식 5의 산염을 제조하는 단계 및 상기 화학식 5의 산염을 수소화 촉매 및 수소 분위기 하에서 수소화 반응시키는 단계를 포함하는 화학식 1의 2-(2-아미노에틸)-1-메틸피롤리딘 제조방법. To prepare an acid salt of the formula (5) by reacting the acetonitrile-based compound of the formula (4) with an acid and the hydrogenation of the acid salt of the formula (5) under a hydrogenation catalyst and hydrogen atmosphere (2- Aminoethyl) -1-methylpyrrolidine preparation method. [화학식 1][Formula 1]
Figure 112006063145638-pat00021
Figure 112006063145638-pat00021
 [화학식 4][Formula 4]
Figure 112006063145638-pat00022
Figure 112006063145638-pat00022
 [화학식 5][Formula 5]
Figure 112006063145638-pat00023
Figure 112006063145638-pat00023
 상기 화학식 중 HA는 무기산 또는 유기산HA in the above formula is an inorganic acid or an organic acid 삭제delete 제1항에 있어서,The method of claim 1, 상기 산은 염산, 황산, 인산 및 질산으로 구성된 군으로부터 선택된 하나 이상의 무기산 또는 하기 화학식의 유기산 중 하나인 것을 특징으로 하는 화학식 1의 2-(2-아미노에틸)-1-메틸피롤리딘 제조방법. Said acid is at least one inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid, or one of the organic acids of the formula (2-) 2-methylethyl 1-methylpyrrolidine.
Figure 112006063145638-pat00026
Figure 112006063145638-pat00026
 화학식 중, R1 및 R2 는 각각 독립적으로 수소, 탄소수 1 내지 10의 저급 알킬,; 탄소수 6내지 20의 아릴기로 치환된 탄소수 1 내지 10의 저급 알킬; 또는 분자구조내에 산소 또는 질소를 1 내지 3개 포함하는 탄소수 1 내지 10의 저급 알킬.In the formula, R1 and R2 are each independently hydrogen, lower alkyl having 1 to 10 carbon atoms; Lower alkyl having 1 to 10 carbon atoms substituted with an aryl group having 6 to 20 carbon atoms; Or lower alkyl having 1 to 10 carbon atoms containing 1 to 3 oxygen or nitrogen in the molecular structure. 제1항에 있어서, The method of claim 1, 상기 수소화 반응은 Pd/C, Pd(OH)2/C, Pt, PtO2 및 Raney Ni로 구성된 군으로부터 선택된 하나 이상의 금속 수소화 촉매와 1 내지 100기압의 수소 분위기하에서 수행되는 것을 특징으로 하는 2-(2-아미노에틸)-1-메틸피롤리딘의 제조방법.The hydrogenation reaction is carried out under a hydrogen atmosphere of 1 to 100 atm and at least one metal hydrogenation catalyst selected from the group consisting of Pd / C, Pd (OH) 2 / C, Pt, PtO 2 and Raney Ni. Method for preparing (2-aminoethyl) -1-methylpyrrolidine.
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JPS5359662A (en) 1976-11-08 1978-05-29 Kyowa Hakko Kogyo Co Ltd Novel acetonitriles and process for preparation of the same
WO1997009040A1 (en) 1995-09-08 1997-03-13 Novo Nordisk A/S 2-alkylpyrrolidines

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JPS5359662A (en) 1976-11-08 1978-05-29 Kyowa Hakko Kogyo Co Ltd Novel acetonitriles and process for preparation of the same
WO1997009040A1 (en) 1995-09-08 1997-03-13 Novo Nordisk A/S 2-alkylpyrrolidines

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101325589B1 (en) * 2012-07-26 2013-11-06 동인화학 주식회사 Process for the preparation of 1-alkyl-2-(2-aminoethyl)pyrrolidines

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