KR20160044117A - Method for preparation of optically active 3-amino-arylpropan-1-ol derivatives from 3-chloro-1-arylpropan-1-ol derivatives - Google Patents

Method for preparation of optically active 3-amino-arylpropan-1-ol derivatives from 3-chloro-1-arylpropan-1-ol derivatives Download PDF

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KR20160044117A
KR20160044117A KR1020140138278A KR20140138278A KR20160044117A KR 20160044117 A KR20160044117 A KR 20160044117A KR 1020140138278 A KR1020140138278 A KR 1020140138278A KR 20140138278 A KR20140138278 A KR 20140138278A KR 20160044117 A KR20160044117 A KR 20160044117A
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arylpropan
amino
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이기인
이선아
황인택
허정희
임석태
허재현
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한국화학연구원
(주) 파마젠
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    • C07C209/02—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of hydrogen atoms by amino groups
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    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
    • C07C209/32—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups
    • C07C209/36—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst
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Abstract

The present invention relates to a method for preparing an optically active 3-amino-1-arylpropan-1-ol derivative, including the step of making an optically active 3-chloro-1-arylpropan-1-ol compound react with an amine derivative. The method according to the present invention allows direct amination of an optically active 3-chloro-1-arylpropan-1-ol derivative through a single-step reaction. Thus, it is possible to provide a compound functioning as a key intermediate of various optically active molecules through a simple process with high yield, while maintaining the optical purity of the reactant. Therefore, the method may be used for preparing medicines, such as (S)-Duloxetin, (R)-Fluoxetine, (R)- Tomoxetine or (R)- Nisoxetine, with high optical purity by combining the method for preparing an optically active 3-chloro-1-arylpropan-1-ol derivative as a reactant of the method with an additional substitution reaction.

Description

광학 활성 3-클로로-1-아릴프로판-1-올 유도체로부터 3-아미노-1-아릴프로판-1-올 유도체의 제조방법{Method for preparation of optically active 3-amino-arylpropan-1-ol derivatives from 3-chloro-1-arylpropan-1-ol derivatives}Method for preparing 3-amino-1-arylpropan-1-ol derivative from optically active 3-chloro-1-arylpropan-1-ol derivative 3-chloro-1-arylpropan-1-ol derivatives}

본 발명은 요오드화합물 존재 하에 광학 활성 3-클로로-1-아릴프로판-1-올 화합물을 아민 유도체와 반응시키는 단계를 포함하는, 광학 활성 3-아미노-1-아릴프로판-1-올 유도체의 제조방법에 관한 것이다.
The present invention relates to a process for the preparation of an optically active 3-amino-1-arylpropan-1-ol derivative which comprises reacting an optically active 3-chloro-1-arylpropan-1-ol compound with an amine derivative in the presence of an iodine compound ≪ / RTI >

자연 발생하는 아미노산이나 당류를 비롯한 생물에서 생산 및/또는 사용되는 많은 분자들은 광학적 비대칭성(카이랄성; chilarity)을 갖는다. 생체에서 사용되는 화합물은 대부분 같은 카이랄성을 나타낸다. 예컨대, 대부분의 아미노산은 L형, 당류는 D형이다. 효소 역시 카이랄성을 지니며, 카이랄성을 지닌 기질의 두 거울상 이성질체를 구분할 수 있다. 예컨대, 주머니와 같은 형태로 기질을 감싸안는 효소를 가정할 때, 주머니가 비대칭적 구조를 가질 때, 기질의 형태에 따라 하나의 이성질체는 효소의 비대칭적 주머니 구조에 맞아 들어가는 반면, 다른 이성질체는 상이한 구조로 인해 들어가지 못한다.Many molecules produced and / or used in living organisms including naturally occurring amino acids and sugars have optical asymmetry (chirality). Most of the compounds used in vivo show the same chiral properties. For example, most amino acids are of the L type and the sugars are of the D type. Enzymes also have chiral properties and can distinguish two enantiomers of a substrate with chiral properties. For example, supposing an enzyme that envelops the substrate in the form of a bag, when the pouch has an asymmetric structure, depending on the type of substrate, one isomer fits into the asymmetric pocket structure of the enzyme, while the other isomer Due to the structure, it can not enter.

일반적으로 D형 아미노산은 단맛이 나며, L형은 무미하다. 스피어민트 잎과 캐러웨이 씨앗은 각각 다른 향을 갖는 L-카르본과 D-카르본을 지니고 있다. 상기 두 가지 이성질체 분자가 서로 다른 향을 내는 이유는 인간의 후각기관이 거울상 이성질체에 서로 다르게 반응하는 카이랄성 분자로 이루어져 있기 때문이다.Generally, D-type amino acids are sweet and L-type is tasteless. Spearmint leaves and caraway seeds have L-Carbone and D-Carbone with different fragrances. The reason why the two isomeric molecules give different fragrances is because the human nose is composed of chiral molecules that react differently to enantiomers.

이러한 분자의 카이랄성은 의약품에서도 중요한 요소이다. 카이랄성을 지니는 의약품에서 하나의 이성질체는 특정한 약효를 갖는 한편, 다른 이성질체는 효과를 나타내지 못하여 약효를 반감시키거나, 심한 경우 독성을 나타내는 경우도 있다. 예컨대, 탈리도마이드는 라세미 혼합물로서, 하나의 거울상 이성질체는 조증에 효과가 있는 반면, 다른 거울상 이성질체는 기형아를 유발한다. 에탐부톨은 하나의 이성질체는 결핵에 효과가 있는 반면, 다른 이성질체는 실명을 유발한다. 나프록센은 하나의 이성질체는 관절염 등에 진통효과를 나타내는 반면, 다른 종류는 진통효과가 없으며 간에 독성을 유발한다. 또한 스테로이드 수용체나, 페니실린의 작용은 입체 선택성을 나타낸다. 따라서, 거울상 이성질체의 혼합으로 인한 잠재적인 부작용을 방지하기 위해서는 높은 순도로 제공되어야 한다. 그러나, 거울상 이성질체는 광학적 특성을 제외하고는 분자량, 극성 등 물리화학적 성질이 같아 분리가 매우 어려우므로 선택적으로 하나의 이성질체를 주로 생산할 수 있는 합성 방법을 발굴하는 것이 무엇보다도 중요하다.The chiral nature of these molecules is also important in pharmaceuticals. In pharmaceuticals with chiral properties, one isomer has a specific drug effect, while the other isomer has no effect, thus halving the drug efficacy, or even toxic if severe. For example, as thalidomide is a racemic mixture, one enantiomer is effective for mania, while the other enantiomer induces a deformity. While ethambutol is effective on one isomer of tuberculosis, other isomers cause blindness. While naproxen has an analgesic effect on one isomer such as arthritis, the other has no analgesic effect and causes liver toxicity. The action of steroid receptors or penicillin also exhibits stereoselectivity. Therefore, it must be provided with high purity to prevent potential side effects due to mixing of the enantiomers. However, since the enantiomers have the same physicochemical properties such as molecular weight and polarity except for their optical properties, separation is very difficult. Therefore, it is most important to find a synthesis method capable of selectively producing one isomer.

광학 활성을 갖는 3-아미노-1-프로판올 유도체는 다양한 의약품 중간체, 정밀화학제품, 또는 생리활성물질의 합성을 위한 빌딩블럭(building block)으로 사용되고 있다. 예컨대, 둘록세틴(duloxetine)이나 플록세틴(Fluoxetine), 니속세틴(Nisoxetine), 토목세틴(Tomoxetine) 등은 핵심중간체로 3-아미노-1-프로판올을 공통으로 포함한다(도 1).The optically active 3-amino-1-propanol derivatives are used as building blocks for the synthesis of various pharmaceutical intermediates, fine chemical products, or physiologically active substances. For example, duloxetine, fluoxetine, Nisoxetine, and Tomoxetine are common core intermediates and include 3-amino-1-propanol (FIG. 1).

(S)-3-할로-1-(2-티에닐)-1-프로판올이나 (S)-3-아미노-1-(2-티에닐)-1-프로판올은 우울증이나 요실금 치료에 사용되는 (S)-메틸-[3-(1-나프탈레닐옥시)-3-(2-티에닐)프로필]아민 즉, 둘록세틴의 합성에 필요한 핵심중간체이다(Huiling et al. Chirality 2000, 12, 26-29; Sorbera et al. Drugs of the Future 2000, 25 (9) 907-916). 우울증과 범불안장애 치료에 사용되는 둘록세틴은 당뇨병성 신경병증에 의해 유발되는 통증과 저린 증상에도 또한 사용되고 있는 선택적 세로토닌 및 노에피네프린 재흡수차단제 계열에 속하는 약물이다. 이같은 둘록세틴(duloxetine)은 뇌 속 세로토닌이나 노에피네프린 농도를 높여 작용하는바 이 같은 성분들은 정신균형을 유지하고 통증 신호를 차단하는 역할을 한다 (미국등록특허 제7,435,563호; 한국공개특허 제10-2007-0104942호).( S ) -3-amino-1- (2-thienyl) -1-propanol and ( S ) -3-halo-1- S ) -methyl- [3- (1-naphthalenyloxy) -3- (2-thienyl) propyl] amine or duloxetine (Huiling et al. Chirality 2000, 12, 26 -29; Sorbera et al. Drugs of the Future 2000, 25 (9) 907-916). Duloxetine, used in the treatment of depression and generalized anxiety, is a drug belonging to the family of selective serotonin and norepinephrine reuptake inhibitors, which is also used for pain and hypersensitivity reactions caused by diabetic neuropathy. Such duloxetine acts to increase the concentration of serotonin or norepinephrine in the brain, which acts to maintain mental balance and block pain signals (U.S. Patent No. 7,435,563; Korean Patent Laid- 2007-0104942).

둘록세틴이라 불리는 N-메틸-3-(1-나프탈레닐옥시)-3-(2-티에닐)프로판아민은 이중 세로토닌 및 노르에피네프린 재흡수 저해제이다. 특히 (+)-둘록세틴(a.k.a. (S)-둘록세틴)은 항우울제로서 특별한 치료학적 유용성을 가진다. 둘록세틴 및 이의 제조는 미국등록특허 제5,023,269호, 미국등록특허 제4,956,388호 및 테트라히드론 레터스(Tetrahedron Letters, 1990, 31(49): 7101-04)에 기재되어 있다. 7가지 상이한 경로를 통한 합성 또한 논문 상에 개시되어 있다(Drugs of the Future, 2000, 25(9): 907-916). 상기 합성은 주요 중간체의 분해(resolution) 또는 케톤기의 알코올로의 입체 특이적 환원을 포함한다.N-methyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propanamine, called duloxetine, is a dual serotonin and norepinephrine reuptake inhibitor. In particular, (+) - duloxetine (aka ( S ) -duloxetine) has particular therapeutic utility as an antidepressant. Duloxetine and its preparation are described in U.S. Patent No. 5,023,269, U.S. Patent No. 4,956,388 and Tetrahedron Letters, 1990, 31 (49): 7101-04. Synthesis via seven different pathways is also described in the paper (Drugs of the Future, 2000, 25 (9): 907-916). The synthesis involves resolution of the main intermediate or stereospecific reduction of the ketone group to the alcohol.

상기 약물들의 핵심중간체인 광학 활성 3-아미노프로판올 유도체, 예컨대, 토목세틴, 니속세틴 및 플록세틴 등의 합성에서 중간체로 사용되는 3-아미노-1-페닐프로판-1-올 및 이의 유도체를 합성하기 위하여 다양한 합성방법이 공지되어 있다(미국등록특허 제5,708,035호; Y. Gao and K. B. Sharpless, J. Org . Chem ., 1988, 53: 4081-4084; E. J. Corey and G. A. Reichard, Tetrahedron Lett ., 1989, 30: 5207-5210). 이 중에서도 아토목세틴이라 불리는 토목세틴의 (R)-이성질체는 이의 (S)-이성질체에 비해 9배 이상의 약효를 갖는 것으로 확인되었으며, 염산염의 형태로 스트라테라(Strattera™)라는 상표명으로 시판되고 있다.Amino-1-phenylpropan-1-ol and its derivatives, which are used as intermediates in the synthesis of optically active 3-aminopropanol derivatives such as cis-sitethine, nisuetetine and fluoxetine, there are a variety of synthetic methods are known to (United States Patent No. 5,708,035 call; Y. Gao and KB Sharpless, J. Org Chem, 1988, 53:.. 4081-4084; EJ Corey and GA Reichard, Tetrahedron Lett . , ≪ / RTI > 1989,30: 5207-5210). Among these, the ( R ) -isomer of the covalent cytine, called asomomycetin, has been found to have a 9-fold more potent activity than the ( S ) -isomer thereof and is commercially available under the trade name Strattera (TM) in the hydrochloride form .

또한, 플록세틴이나 니속세틴의 경우 (R)-형 이성질체가 보다 우수한 효과를 나타내는 것으로 알려져 있음에도 불구하고 이를 고순도로 제조하는데 어려움이 있어 현재까지도 라세믹체의 형태로 사용되고 있다. 따라서, 이들 약물의 고순도 광학 활성체로의 전환은 매우 시급하다.
In addition, although it is known that the ( R ) -form isomer exhibits more excellent effects in the case of flocetin or nisan cetin, it is difficult to produce it in a high purity, and thus it is still used in the form of racemic form. Therefore, conversion of these drugs into highly pure optically active substances is very urgent.

본 발명자들은 (S)-둘록세틴, (R)-플록세틴, (R)-토목세틴 또는 (R)-니속세틴과 같이 특정 입체 이성질체가 우수한 약리활성을 나타내어 높은 광학 순도로 제공할 필요가 있는 약물의 제조에 있어서 핵심 중간체로 사용되는 광학 활성을 갖는 3-아미노-1-아릴프로판-1-올 유도체를 제조할 때, 3-클로로-1-아릴프로판-1-올 화합물을 소량의 요오드화합물을 존재 하에 아민 유도체와 반응시키면, 직접 아민화할 수 있으므로 단일 반응으로 높은 광학 순도를 유지하면서 높은 수율로 표제 화합물을 합성할 수 있음을 확인하고 본 발명을 완성하였다.
The present inventors have found that certain stereoisomers such as ( S ) -duloxetine, ( R ) -floxetin, ( R ) -conjugated sitin or ( R ) Amino-1-arylpropan-1-ol derivative having an optically active 3-amino-1-arylpropan-1-ol derivative, which is used as a core intermediate in the production of a drug, , The title compound can be synthesized with high yield while maintaining high optical purity by a single reaction. The present invention has been completed based on this finding.

본 발명은 하기 반응식 1에 따른 요오드화합물 존재 하에 광학 활성 3-클로로-1-아릴프로판-1-올 화합물을 아민 유도체와 반응시키는 단계를 포함하는, 광학 활성 3-아미노-1-아릴프로판-1-올 유도체의 제조방법을 제공한다:The present invention relates to a process for the preparation of optically active 3-amino-1-arylpropane-1-ol comprising reacting an optically active 3-chloro-1-arylpropan-1-ol compound with an amine derivative in the presence of an iodine compound according to the following reaction scheme 1 - < / RTI >

[반응식 1][Reaction Scheme 1]

Figure pat00001
Figure pat00001

상기 식에서,In this formula,

Ar은 C5-10 아릴 또는 헤테로아릴이고;Ar is C5-10 aryl or heteroaryl;

Figure pat00002
는
Figure pat00003
또는
Figure pat00004
로서 반응 전과 후에서 동일하며;
Figure pat00002
The
Figure pat00003
or
Figure pat00004
The same as before and after the reaction;

R1 및 R2는 각각 독립적으로 수소, C1 -4 알킬, C7 -10 아랄킬, C5 -10 아릴, 피롤리디닐, 피페리디닐 또는 모르포리닐이고;R 1 and R 2 are each independently hydrogen, C 1 -4 alkyl, C 7 -10 aralkyl, C 5 -10 aryl, pyrrolidinyl, piperidinyl or know a forest carbonyl;

상기 C5 -10 아릴 또는 헤테로아릴은 각각 독립적으로 비치환되거나, 할로겐, 히드록시, 니트로, 시아노, C1-4 알킬, 아미노, (C1-4 알킬)아미노 및 디(C1-4 알킬)아미노로 구성된 군으로부터 선택되는 하나 이상의 작용기로 치환되거나, C5-10 아릴 또는 C5 -10 헤테로아릴로부터 선택되는 2개 이상이 융합된(fused) 다환고리 형태일 수 있다.
The C 5 -10 aryl or heteroaryl are each independently unsubstituted or substituted, halogen, hydroxy, nitro, cyano, C 1-4 alkyl, amino, (C 1-4 alkyl) amino and di (C 1-4 alkyl) or substituted with with at least one functional group selected from the group consisting of amino, may be a C 5-10 aryl or C 5 -10 the two or more selected from heteroaryl fusion (fused) polycyclic ring form.

둘록세틴, 플록세틴, 토목세틴 또는 니속세틴 등의 다양한 카이랄성 의약품을 제조하기 위한 핵심 중간체로서, 광학 활성을 갖는 3-아미노-1-아릴프로판-1-올 유도체를 통해 합성할 수 있으며, 상기 광학 활성을 갖는 3-아미노-1-아릴프로판-1-올 유도체는 광학 활성을 갖는 3-클로로-1-아릴프로판-1-올 유도체로부터 제조할 수 있다.
Amino-1-arylpropan-1-ol derivatives as optically active core intermediates for the preparation of various chiral drugs such as duloxetine, fluoxetine, cynomolgus catechin or nisuccine, The optically active 3-amino-1-arylpropan-1-ol derivative can be prepared from an optically active 3-chloro-1-arylpropan-1-ol derivative.

상기 광학 활성을 갖는 3-아미노-1-아릴프로판-1-올 유도체의 제조에 사용되는 반응물인 3-클로로-1-아릴프로판-1-올 유도체는 3-클로로-1-아릴프로판-1-온 유도체의 비대칭 환원에 의해 제공될 수 있다. 이와 같은 비대칭 환원의 경우 기질로서 클로로케톤을 사용하는 경우 가장 우수한 광학 활성을 나타낸다. 즉, 클로로케톤을 사용하여 비대칭 환원반응을 수행하는 경우 다른 유사 화합물에 비해 높은 광학 순도로 예컨대, (R)-형 또는 (S)-형 화합물 중 어느 하나로 주로 구성되는 생성물을 수득할 수 있다.The 3-chloro-1-arylpropan-1-ol derivative, which is a reactant used in the production of the optically active 3-amino-1-arylpropan- Can be provided by asymmetric reduction of the < RTI ID = 0.0 > Such asymmetric reduction shows the best optical activity when chloro ketone is used as a substrate. That is, when an asymmetric reduction reaction is carried out using chloro ketone, it is possible to obtain a product mainly composed of, for example, ( R ) -type or ( S ) -type compound with higher optical purity than other similar compounds.

종래 3-클로로-1-아릴프로판-1-올 유도체로부터 3-아미노-1-아릴프로판-1-올 유도체를 제조하는 방법은 상기 3-클로로-1-아릴프로판-1-올 유도체를 포화 NaI 용액에서 환류하여 클로로기를 우수한 이탈기인 요오드기로 전환한 후, 아민 유도체와 반응시키는 2단계의 공정을 통해 수행된다. 그러나, 상기 방법은 고가의 NaI를 과량(반응물에 대해 7 내지 10 당량)으로 사용해야하는 단점이 있다. 또한, 상기 요오드화 반응은 발열반응이므로 폭발과 화제의 위험성을 내포하고 있어 까다로운 실험 조건을 요구한다.A process for preparing 3-amino-1-arylpropan-1-ol derivatives from 3-chloro-1-arylpropan-1-ol derivatives is a method for preparing 3-chloro-1- A step of converting the chloro group into an iodine group having a good leaving group and then reacting with an amine derivative. However, this method has a disadvantage in that an excess amount of expensive NaI (7 to 10 equivalents based on the reactant) is used. In addition, since the iodination reaction is an exothermic reaction, it involves explosion and danger of a subject, which requires severe experimental conditions.

이외에 J. Sanderson 등은 아민 용액을 이용한 직접 아민화 반응에 의해 3-아미노-1-아릴프로판-1-올 유도체를 제조하는 방법을 개시하였으나(Org. Biomol. Chem., 2011, 9: 3854), 상기 방법은 고도로 많은 양의 아민 화합물을 필요로 하며(반응물에 대해 최소 50 당량) 140℃ 이상의 고온에서 반응을 수행해야 하는 단점이 있다.In addition, J. Sanderson et al. Have disclosed a method for producing 3-amino-1-arylpropan-1-ol derivatives by direct amination reaction using an amine solution (Org. Biomol. Chem., 2011, 9: 3854) , The process requires a very high amount of amine compound (at least 50 equivalents to the reactants) and the reaction must be carried out at a high temperature above 140 ° C.

이들 방법과 비교하여 본 발명의 제조방법은 다량의 아민 화합물이나 고가의 요오드화합물을 필요로 하지 않으면서도 3-클로로-1-아릴프로판-1-올 유도체, 아민 유도체 용액, 용매 및 소량의 요오드화합물만을 이용하여 단일 단계의 반응을 수행함으로써 표제 화합물인 3-아미노-1-아릴프로판-1-올 유도체를 제공할 수 있는 방법이다.
Compared with these processes, the production process of the present invention is free from the need for a large amount of an amine compound or an expensive iodine compound, but also a 3-chloro-1-arylpropan-1-ol derivative, an amine derivative solution, a solvent and a small amount of iodine compound Amino-1-arylpropan-1-ol derivative can be obtained by carrying out a single-step reaction using only the above-mentioned compound.

바람직하게, 상기 요오드화합물로는 KI, NaI, CuI, n-Bu4NII(tetrabutylammonium iodide), I2 또는 TMSI(tetramethylsilyl iodide)을 사용할 수 있으나, 이에 제한되지 않는다.
Preferably, the iodine compound may be KI, NaI, CuI, n-Bu 4 NII (tetrabutylammonium iodide), I 2 or tetramethylsilyl iodide (TMSI).

바람직하게, 상기 식에서 Ar은 페닐, 플루오로페닐, 나프틸, 티에닐, 퓨릴, 벤조퓨릴 또는 벤조티에닐일 수 있다.
Preferably, where Ar is phenyl, fluorophenyl, naphthyl, thienyl, furyl, benzofuryl or benzothienyl.

바람직하게, R1 및 R2는 각각 독립적으로 수소, 메틸, 에틸, 이소프로필, 터트-부틸 및 벤질로 구성된 군으로부터 선택되는 것일 수 있다.Preferably, R 1 and R 2 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl and benzyl.

또한, R1 및 R2 중 적어도 하나는 수소 이외의 치환기를 갖는 것일 수 있다.Also, at least one of R 1 and R 2 may have a substituent other than hydrogen.

보다 바람직하게, R1 및 R2 중 하나는 수소이고 다른 하나는 메틸일 수 있으나, 이에 제한되지 않는다.
More preferably, one of R < 1 > and R < 2 > may be hydrogen and the other may be methyl, but is not limited thereto.

바람직하게, 상기 아민 유도체는 3-클로로-1-아릴프로판-1-올 화합물의 사용량에 대해 5 내지 15배의 몰비로 반응시킬 수 있다. 아민 유도체의 비등점이 낮음을 고려할 때, 아민 유도체의 사용량이 상기 범위 미만으로 낮은 경우 반응온도에서 소실되어 수율이 낮아질 수 있다. 한편, 아민 유도체는 약 15배 몰비이면 반응을 완성하는 데에 충분하므로 이를 초과하여 사용하는 경우 불필요하게 반응물을 낭비할 수 있다.
Preferably, the amine derivative can be reacted at a molar ratio of 5 to 15 times the amount of the 3-chloro-1-arylpropan-1-ol compound. Considering that the boiling point of the amine derivative is low, when the amount of the amine derivative used is less than the above range, it may disappear at the reaction temperature and the yield may be lowered. On the other hand, when the amine derivative is used at a molar ratio of about 15 times, it is sufficient to complete the reaction. Therefore, when the amine derivative is used in excess, the reactant may be unnecessarily wasted.

바람직하게, 상기 반응은 C1 -4 저급 알콜 또는 테트라하이드로퓨란 등의 용매에서, 보다 바람직하게는 메탄올 또는 테트라하이드로퓨란에서 수행될 수 있으나, 이에 제한되지 않는다.
Preferably, the reaction can be carried out in a solvent such as C 1 -4 lower alcohol or tetrahydrofuran, more preferably in methanol or tetrahydrofuran, but is not limited thereto.

바람직하게, 상기 요오드화합물을 3-클로로-1-아릴프로판-1-올 화합물의 사용량에 대해 0.05 내지 0.2배의 몰비로 사용할 수 있으나, 이에 제한되지 않는다. 예컨대, 종래에 클로로기를 요오드화한 후 다시 아민화하는 2단계의 반응과는 달리 단일 단계의 반응을 통해 직접 아민화하므로 상기 요오드화합물은 촉매와 같이 작용하므로 많은 양을 사용하지 않아도 무방하다.
Preferably, the iodine compound may be used in a molar ratio of 0.05 to 0.2 times the amount of 3-chloro-1-arylpropan-1-ol compound, but is not limited thereto. For example, unlike the conventional two-step reaction in which a chloro group is iodinated and then aminated again, the iodine compound directly acts as a catalyst, so that a large amount of the iodine compound may not be used.

바람직하게, 상기 반응은 80 내지 120℃ 온도로 가열 환류하여 수행할 수 있다. 바람직하게, 상기 반응은 6 내지 12시간 동안 수행할 수 있으나, 이에 제한되지 않는다.
Preferably, the reaction can be carried out by heating to reflux at a temperature of 80 to 120 < 0 > C. Preferably, the reaction can be carried out for 6 to 12 hours, but is not limited thereto.

바람직하게, 본 발명의 제조방법은 생성물을 분리 및/또는 정제하기 위하여 상기 아민화 반응 후 용매를 제거하는 단계, 유기 용매로 추출하는 단계, 건조하는 단계, 농축하는 단계, 정제하는 단계 또는 이들의 조합을 추가로 수행할 수 있다.Preferably, the production process of the present invention is carried out by removing the solvent after the amination reaction in order to separate and / or purify the product, extracting with an organic solvent, drying, concentrating, Combinations can be performed additionally.

예컨대, 본 발명의 구체적인 실시예에서는, 반응을 완료한 후 용매인 메탄올을 제거하였다. 그 결과로 남은 잔유물은 1N NaOH 수용액을 가한 후 유기 용매로서 에틸아세테이트를 이용하여 추출하고 유기층을 회수하였다. 회수한 유기층은 황산나트륨으로 건조시킨 후 농축하였다. 농축시킨 생성물은 최종적으로 실리카 컬럼 크로마토그래피로 정제하여 고순도의 생성물을 수득하였다. 상기 크로마토그래피는 디클로로메탄, 메탄올, 수산화암모늄을 40:10:1로 혼합한 용매를 이용하여 수행하였으나, 이에 제한되지 않는다.
For example, in a specific embodiment of the present invention, methanol was removed after the reaction was completed. The resulting residue was extracted with 1N NaOH aqueous solution, extracted with ethyl acetate as an organic solvent, and the organic layer was recovered. The recovered organic layer was dried over sodium sulfate and concentrated. The concentrated product was finally purified by silica column chromatography to obtain a high purity product. The chromatography was performed using a solvent in which dichloromethane, methanol, and ammonium hydroxide were mixed in a ratio of 40: 10: 1, but the present invention is not limited thereto.

바람직하게, 본 발명의 제조방법은 반응물 또는 생성물이 80% 이상의 거울상 이성질체 잉여율(enantiomeric excess; ee)의 광학 활성을 갖는 것이 특징이다. 구체적으로, 80% 이상의 ee의 광학 활성을 갖는 반응물을 이용하여 80% 이상으로 ee가 유지되는 생성물을 수득할 수 있다. 즉, 본 발명의 제조방법은 아민화 과정 동안 반응물의 광학 활성을 유지할 수 있다.Preferably, the process of the invention is characterized in that the reactants or products have an optical activity of an enantiomeric excess ( ee ) of at least 80%. Specifically, to 80% or more by using a reagent having an optical activity of at least 80% ee can be obtained a product which remains ee. That is, the process of the present invention can maintain the optical activity of the reactants during the amination process.

본 발명에서 용어, "거울상 이성질체 잉여율(enantiomeric excess; ee)"은 광학 이성질체 혼합물에서 이성질체의 광학적 순도를 나타내는 변수로, 각 광학 이성질체의 몰분율 차이의 절대값으로 나타난다. 예컨대, R형 이성질체 80몰과 S형 이성질체 20몰이 혼합된 혼합물에서 R형 이성질체의 거울상 이성질체 잉여율은 |80-20|=60%이다. 따라서, 80% 이상의 ee 값을 갖는다는 것은 이성질체 혼합물 중 원하는 이성질체를 90% 이상 포함함을 의미한다.
The term "enantiomeric excess (ee)" in the present invention is a variable representing the optical purity of an isomer in an optical isomer mixture, expressed as an absolute value of the difference in mole fraction of each optical isomer. For example, the enantiomeric excess of the R -isomer in a mixture of 80 mol of the R -isomer and 20 mol of the S -isomer is | 80-20 | = 60%. Thus, having an ee value of 80% or greater means that it contains at least 90% of the desired isomer in the isomer mixture.

바람직하게, 상기 제조방법은 (S)-둘록세틴, (R)-플록세틴, (R)-토목세틴 또는 (R)-니속세틴의 제조를 위한 중간체를 제공할 수 있다. 그러나, 이에 제한되는 것은 아니며, 그 골격에 3-아미노-1-아릴프로판-1-올 유도체 또는 상기 유도체의 히드록시기의 수소 자리에 추가로 치환기를 포함하는 화합물에 있어서, 상기 히드록시기 또는 이의 수소 자리가 치환된 치환기가 결합된 탄소가 입체중심으로 작용하여 해당 위치에서 높은 광학 순도를 갖는 화합물의 제조에 제한없이 사용될 수 있다.
Preferably, the process can provide an intermediate for the preparation of ( S ) -duloxetine, ( R ) -floxetin, ( R ) -cindustin or ( R ) -ninitetetine. However, the present invention is not limited thereto, and a compound having a 3-amino-1-arylpropan-1-ol derivative or a substituent in the hydrogen position of the hydroxy group of the derivative in the skeleton thereof, The carbon to which the substituted substituent is bonded acts as the stereocenter and can be used without limitation in the production of a compound having high optical purity at the corresponding position.

본 발명의 제조방법은 단일 단계의 반응으로 광학 활성 3-클로로-1-아릴프로판-1-올 유도체를 직접 아민화하여 3-아미노-1-아릴프로판-1-올 유도체로 전환하므로 반응물의 광학 순도를 유지하면서 간단한 공정을 통해 높은 수율로 다양한 광학 활성 분자의 핵심 중간체가 되는 화합물을 제공할 수 있다. 따라서, 상기 제조방법을 높은 광학 순도로 본 발명의 제조방법에서 반응물로 사용되는 광학 활성 3-클로로-1-아릴프로판-1-올 유도체를 제조하는 방법 및 추가적인 치환반응과 조합함으로써 높은 광학 순도로 (S)-둘록세틴, (R)-플록세틴, (R)-토목세틴 또는 (R)-니속세틴 등의 약물을 제조하는 데 유용하게 사용될 수 있다.
The production method of the present invention converts an optically active 3-chloro-1-arylpropan-1-ol derivative directly into a 3-amino-1-arylpropan-1-ol derivative in a single step reaction, It is possible to provide a compound which becomes a core intermediate of various optically active molecules with a high yield through a simple process while maintaining purity. Thus, the above process can be combined with a method for producing an optically active 3-chloro-1-arylpropan-1-ol derivative used as a reactant in the production method of the present invention with high optical purity and a further substitution reaction, ( S ) -duloxetine, ( R ) -floxetine, ( R ) -cindustine or ( R ) -nixantetine.

도 1은 둘록세틴(duloxetine), 플록세틴(Fluoxetine), 니속세틴(Nisoxetine) 및 토목세틴(Tomoxetine)의 핵심중간체인 광학 활성을 갖는 3-아미노-1-프로판올 잔기를 나타낸 개요도이다.1 is a schematic diagram showing an optically active 3-amino-1-propanol residue as a core intermediate of duloxetine, fluoxetine, nisoxetine and tomoxetine.

이하, 실시예를 통하여 본 발명의 구성 및 효과를 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위가 이들 실시예에 의해 한정되는 것은 아니다.
Hereinafter, the constitution and effects of the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.

제조예Manufacturing example 1: 촉매의 제조 1: Preparation of catalyst

1.1. 1.1. catcat -1의 제조-1 production

Figure pat00005
Figure pat00005

격막과 N2 흐름을 구비한 둥근 바닥 플라스크에 무수 에틸렌글리콜(2.5 mmol, 140 ㎕)을 첨가하였다. 이후, 트리이소프로필보레이트(triisopropylborate; 2.55 mmol, 0.58 ㎖)에 이어 건조 톨루엔(7 ㎖)을 첨가하였다. 반응 혼합물을 조심스럽게 가열하여 균질한 무색의 용액이 형성될 때까지 환류하였다. 건조 톨루엔(5 ㎖)에 녹인 (R)-(+)-α,α-디페닐-2-피롤리딘메탄올((R)-(+)-α,α-diphenyl-2-pyrrolidinemethanol; 2.49 mmol, 633 mg) 용액을 반응 혼합물에 첨가하였다. 상기 첨가과정 동안 흰색 침전이 관찰되었다. 반응 혼합물을 80℃에서 1시간 동안 교반하였다. 생성된 흰색 결정성 고체를 여과하고, 고진공하에 건조시켜 표적 화합물을 수득하였다.Of anhydrous ethylene glycol (2.5 mmol, 140 ㎕) was added to a round bottom flask equipped with a septum and N 2 flow. Triisopropylborate (2.55 mmol, 0.58 mL) was then added followed by dry toluene (7 mL). The reaction mixture was carefully heated to reflux until a homogeneous, colorless solution formed. To a solution of ( R ) - (+) -, alpha -diphenyl-2-pyrrolidine methanol (( R ) - (+) - alpha, alpha-diphenyl-2-pyrrolidineemethanol dissolved in dry toluene , 633 mg) was added to the reaction mixture. A white precipitate was observed during the addition process. The reaction mixture was stirred at 80 < 0 > C for 1 hour. The resulting white crystalline solid was filtered and dried under high vacuum to give the target compound.

Yield: 1.13 g (90%);Yield: 1.13 g (90%);

mp: 270℃;mp: 270 DEG C;

[α]25 D = 158.4 (c 0.12 , CHCl3); [α] 25 D = 158.4 ( c 0.12, CHCl 3);

1H NMR (300 MHz, DMSO-d 6 ) δ 7.72 (d, J = 7.2 Hz, 2H), 7.52 (d, J = 7.2 Hz, 2H), 7.06-7.28 (m, 6H), 6.69 (t, 1H, NH), 4.54 (m, 1H), 3.67-3.79 (m, 2H), 3.55-3.63 (m, 2H), 3.02-3.11 (m, 1H), 2.86-2.97 (m, 1H) 1.56-1.83 (m, 3H), 1.31 (m, 1H); 1 H NMR (300 MHz, DMSO- d 6) δ 7.72 (d, J = 7.2 Hz, 2H), 7.52 (d, J = 7.2 Hz, 2H), 7.06-7.28 (m, 6H), 6.69 (t, 1H), 4.54 (m, 1H), 3.67-3.79 (m, 2H), 3.55-3.63 (m, 2H), 3.02-3.11 (m, 3 H), 1.31 (m, 1 H);

13C NMR (75 MHz, DMSO-d 6 ) δ 148.5, 147.1, 128.2, 128.2, 126.7, 125.8, 78.0, 64.3, 63.2, 47.4, 27.1, 26.2; 13 C NMR (75 MHz, DMSO- d 6 )? 148.5, 147.1, 128.2, 128.2, 126.7, 125.8, 78.0, 64.3, 63.2, 47.4, 27.1, 26.2;

HRMS (EI): m/z calcd for C19H22BNO3 323.1693; found: 323.1691.
 HRMS (EI): m / z calcd for C 19 H 22 BNO 3 323.1693; found: 323.1691.

1.2. 1.2. catcat -2의 제조-2 production

Figure pat00006
Figure pat00006

격막과 N2 흐름을 구비한 둥근 바닥 플라스크에 무수 에틸렌글리콜(2.5 mmol, 140 ㎕)을 첨가하였다. 이후, 트리이소프로필보레이트(triisopropylborate; 2.55 mmol, 0.58 ㎖)에 이어 건조 톨루엔(7 ㎖)을 첨가하였다. 반응 혼합물을 조심스럽게 가열하여 균질한 무색의 용액이 형성될 때까지 환류하였다. 건조 톨루엔(5 ㎖)에 녹인 (S)-(-)-α,α-디페닐-2-피롤리딘메탄올((S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol; 2.49 mmol, 633 mg) 용액을 반응 혼합물에 첨가하였다. 상기 첨가과정 동안 흰색 침전이 관찰되었다. 반응 혼합물을 80℃에서 1시간 동안 교반하였다. 생성된 흰색 결정성 고체를 여과하고, 고진공하에 건조시켜 표적 화합물을 수득하였다.
Of anhydrous ethylene glycol (2.5 mmol, 140 ㎕) was added to a round bottom flask equipped with a septum and N 2 flow. Triisopropylborate (2.55 mmol, 0.58 mL) was then added followed by dry toluene (7 mL). The reaction mixture was carefully heated to reflux until a homogeneous, colorless solution formed. It was dissolved in dry toluene (5 ㎖) (S) - (-) - α, α- diphenyl-2-pyrrolidine methanol ((S) - (-) - α, α-diphenyl-2-pyrrolidinemethanol; 2.49 mmol , 633 mg) was added to the reaction mixture. A white precipitate was observed during the addition process. The reaction mixture was stirred at 80 < 0 > C for 1 hour. The resulting white crystalline solid was filtered and dried under high vacuum to give the target compound.

제조예Manufacturing example 2: 촉매를 이용한 비대칭 환원 2: Asymmetric reduction using catalyst

2.1. (2.1. ( SS )-3-) -3- 클로로Chloro -1-(2--1- (2- 티에닐Thienyl )-1-)-One- 프로판올의Propanol 제조 Produce

Figure pat00007
Figure pat00007

상기 제조예 1.1.에 따라 제조한 cat-1(0.1 mmol, 33 mg)을 2 ㎖의 THF에 용해시키고, BH3·DMS(0.80 mmol, 0.08 ㎖)을 첨가한 후, 7분 정도 교반하였다. 상기 반응 혼합물에 1-(2-티에닐)-3-클로로프로판-1-온(1.2 mmol, 210 mg)을 0.45 ㎖ THF에 용해시킨 용액을 5분에 걸쳐 한방울씩 적하하여 첨가하였다. 2시간 동안 실온에서 반응시킨 후, 메탄올을 첨가하여 반응을 종결시켰다. 용매를 제거한 후, 에틸아세테이트와 물을 첨가하여 유기층을 분리하였다. 분리된 수용액층에 에틸아세테이트를 가하여 한번 더 추출하였다. 유기층을 합하여 Na2SO4로 건조시킨 후 여과하였다. 수득한 여과액을 농축하고 컬럼 크로마토그래피로 정제하여 액상의 (S)-3-클로로-1-(2-티에닐)-1-프로판올(수율 92%, 95% ee)을 얻었다.Cat-1 (0.1 mmol, 33 mg) prepared in Preparation 1.1 was dissolved in 2 mL of THF, BH 3. DMS (0.80 mmol, 0.08 mL) was added, and the mixture was stirred for about 7 minutes. A solution of 1- (2-thienyl) -3-chloropropan-1-one (1.2 mmol, 210 mg) in 0.45 ml of THF was added dropwise to the reaction mixture dropwise over 5 minutes. After 2 hours of reaction at room temperature, methanol was added to terminate the reaction. After removal of the solvent, ethyl acetate and water were added to separate the organic layer. Ethyl acetate was added to the separated aqueous layer to further extract it. The organic layers were combined, dried over Na 2 SO 4 and filtered. The obtained filtrate was concentrated and purified by column chromatography to obtain ( S ) -3-chloro-1- (2-thienyl) -1-propanol as a liquid (yield: 92%, 95% ee ).

[α]25 D = -5.60 (c 1.2 , MeOH); [α] 25 D = -5.60 ( c 1.2, MeOH);

1H NMR (300 MHz, CDCl3) δ 7.28 (dd, 1H, J = 4.9, 1.3 Hz), 7.00 (m, 2H), 5.18 (m, 1H), 3.75 (m, 1H), 3.58 (m, 1H), 2.39-2.14 (m, 3H); 1 H NMR (300 MHz, CDCl 3) δ 7.28 (dd, 1H, J = 4.9, 1.3 Hz), 7.00 (m, 2H), 5.18 (m, 1H), 3.75 (m, 1H), 3.58 (m, 1H), 2.39-2. 14 (m, 3H);

13C NMR (75 MHz, CDCl3) δ 147.4, 126.8, 124.9, 124.1, 67.2, 41.5, 41.4; 13 C NMR (75 MHz, CDCl 3) δ 147.4, 126.8, 124.9, 124.1, 67.2, 41.5, 41.4;

HRMS (EI): m/z calcd for C7H9ClOS 176.0063; found: 176.0041;HRMS (EI): m / z calcd for C 7 H 9 ClOS 176.0063; found: 176.0041;

GC analysis: CP-Chirasil-Dex CB (25 m, 0.25 mm, 0.25 m), Injector: 280℃, Oven:70℃ for 3 min to 210℃ at 10℃/min hold 3 min, FID: 280℃; t1 = 69.9 min (R), t2 = 70.3 min (S); ee = 95%.
GC analysis: CP-Chirasil-Dex CB (25 m, 0.25 mm, 0.25 m), Injector: 280 캜, Oven: 70 캜 for 3 min to 210 캜 at 10 캜 / min hold 3 min, FID: 280 캜; t 1 = 69.9 min ( R ), t 2 = 70.3 min ( S ); ee = 95%.

2.2. (2.2. ( SS )-3-) -3- 클로로Chloro -1--One- 페닐프로판Phenylpropane -1-올의 제조-1-ol

Figure pat00008
Figure pat00008

상기 제조예 1.1.에 따라 제조한 cat-1(1.78 mmol, 575 mg)을 25 ㎖의 THF에 용해시키고, BH3·DMS(12.5 mmol, 1.18 ㎖)을 첨가한 후, 7분 정도 교반하였다. 상기 반응 혼합물에 3-클로로프로피오페논(17.8 mmol, 3.0 g)을 6 ㎖ THF에 용해시킨 용액을 10분에 걸쳐 한방울씩 적하하여 첨가하였다. 2시간 동안 실온에서 반응시킨 후, 메탄올을 첨가하여 반응을 종결시켰다. 용매를 제거한 후, 에틸아세테이트와 물을 첨가하여 유기층을 분리하였다. 분리된 수용액층에 에틸아세테이트를 가하여 한번 더 추출하였다. 유기층을 합하여 Na2SO4로 건조시킨 후 여과하였다. 수득한 여과액을 농축하고 컬럼 크로마토그래피(헥산:에틸아세테이트 = 3:1)로 정제하여 고체상의 (S)-3-클로로-1-페닐프로판-1-올(수율 94%, 90% ee)을 얻었다.Cat-1 (1.78 mmol, 575 mg) prepared in Preparation 1.1 was dissolved in 25 mL of THF, BH 3. DMS (12.5 mmol, 1.18 mL) was added, and the mixture was stirred for about 7 minutes. A solution of 3-chloropropiophenone (17.8 mmol, 3.0 g) in 6 mL of THF was added dropwise to the reaction mixture dropwise over 10 minutes. After 2 hours of reaction at room temperature, methanol was added to terminate the reaction. After removal of the solvent, ethyl acetate and water were added to separate the organic layer. Ethyl acetate was added to the separated aqueous layer to further extract it. The organic layers were combined, dried over Na 2 SO 4 and filtered. Concentrated to a filtrate obtained which was purified by column chromatography (hexane: ethyl acetate = 3: 1) to provide (S) -3- chloro-1-phenylpropan-1-ol of solid (yield 94%, 90% ee) ≪ / RTI >

상기 화합물을 핵산에서 재결정하여 99% ee의 (S)-3-클로로-1-페닐프로판-1-올(84% 회수율)을 수득하였다.The above compound was recrystallized in a nucleic acid to obtain ( S ) -3-chloro-1-phenylpropan-1-ol (84% recovery) with 99% ee .

1H NMR (300 MHz, CDCl3) δ 7.36-7.25 (m, 5H), 4.93 (dd, J = 8.25 Hz, 1H), 3.77-2.68 (m, 1H), 3.58-3.51 (m, 1H), 2.28-2.17 (m, 1H), 2.13-2.02 (m, 2H); 1 H NMR (300 MHz, CDCl 3 )? 7.36-7.25 (m, 5H), 4.93 (dd, J = 8.25 Hz, 1H), 3.77-2.68 2.28-2.17 (m, 1 H), 2.13-2.02 (m, 2 H);

HPLC (Chiralcel OB-H column, i-PrOH/Hexane 20/80, 0.8 ㎖/min): t1 = 6.95 min (S), t2 = 8.36 min (R).
HPLC (Chiralcel OB-H column, i- PrOH / Hexane 20/80, 0.8 ml / min): t 1 = 6.95 min ( S ), t 2 = 8.36 min ( R ).

2.3. (2.3. ( RR )-3-) -3- 클로로Chloro -1--One- 페닐프로판Phenylpropane -1-올의 제조-1-ol

Figure pat00009
Figure pat00009

상기 제조예 1.2.에 따라 제조한 cat-2(1.78 mmol, 575 mg)를 25 ㎖의 THF에 용해시키고, BH3·DMS(12.5 mmol, 1.18 ㎖)을 첨가한 후, 7분 정도 교반하였다. 상기 반응 혼합물에 3-클로로프로피오페논(17.8 mmol, 3.0 g)을 6 ㎖ THF에 용해시킨 용액을 10분에 걸쳐 한방울씩 적하하여 첨가하였다. 2시간 동안 실온에서 반응시킨 후, 메탄올을 첨가하여 반응을 종결시켰다. 상기 제조예 2.2.와 동일한 방법으로 정제하여 고상의 (R)-3-클로로-1-페닐프로판-1-올(수율 95%, 93% ee)을 얻었다.Cat-2 (1.78 mmol, 575 mg) prepared in Preparation Example 1.2 was dissolved in 25 mL of THF, and BH 3. DMS (12.5 mmol, 1.18 mL) was added thereto, followed by stirring for about 7 minutes. A solution of 3-chloropropiophenone (17.8 mmol, 3.0 g) in 6 mL of THF was added dropwise to the reaction mixture dropwise over 10 minutes. After 2 hours of reaction at room temperature, methanol was added to terminate the reaction. ( R ) -3-chloro-1-phenylpropan-1-ol (yield: 95%, 93% ee ) was obtained in the same manner as in Preparation Example 2.2.

상기 화합물을 핵산에서 재결정하여 99% ee의 (R)-3-클로로-1-페닐프로판-1-올(86% 회수율)을 수득하였다.The above compound was recrystallized in a nucleic acid to obtain ( R ) -3-chloro-1-phenylpropan-1-ol (86% recovery) with 99% ee .

HPLC (Chiralcel OB-H column, i-PrOH/Hexane 20/80, 0.8 ㎖/min): t1 = 7.0 min (S), t2 = 8.2 min (R).
HPLC (Chiralcel OB-H column, i- PrOH / Hexane 20/80, 0.8 ml / min): t 1 = 7.0 min ( S ), t 2 = 8.2 min ( R ).

비교예Comparative Example 1: 요오드화 과정을 포함하는 ( 1: containing the iodination process ( SS )-3-) -3- 메틸아미노Methyl amino -1-(2--1- (2- 티에닐Thienyl )-1-)-One- 프로판올의Propanol 제조 Produce

Figure pat00010

Figure pat00010

(S)-3-클로로-1-(2-티에닐)-1-프로판올(2 g, 11.3 mmol)을 NaI가 포화된 아세톤(100 ㎖; NaI의 양은 약 300 내지 500 몰% 즉, 35 내지 57 mmol)에 첨가하고, 상기 반응 혼합물을 빛으로부터 보호하면서 70℃에서 18시간 동안 환류시켰다. 반응 후 생성된 침전물 NaCl을 여과하여 제거하고 여과액은 농축시켰다. 농축된 잔여물을 물에 부은 후, Et2O로 추출하였다. 추출액을 NaCl 포화용액으로 세척한 후 MgSO4로 건조하고 여과 및 농축하여 잔유물로써 (S)-3-아이오도-1-(2-티에닐)-1-프로판올을 수득하였다[1H NMR δ 7.29 (1H, dd, J =1.3 and 4.9, thienyl H-5), 7.00 (2H, m, thienyl H-3 and H-4), 5.07 (1H, ddd, J =4.5 and 8.6), 3.35 and 3.14 (1H each, m, CH2I), 2.38-2.16 (2H, 1H, m, CH2, OH)]. 상기 화합물은 더 이상의 정제 없이 이후 반응에 직접 사용하였다. (S) -3- chloro-1- (2-thienyl) -1-propanol (2 g, 11.3 mmol), NaI a saturated acetone (100 ㎖ a; amount of NaI or about 300 to 500 mol%, and 35 to 57 mmol) and the reaction mixture was refluxed at 70 < 0 > C for 18 h with protection from light. After the reaction, the resulting precipitate NaCl was removed by filtration and the filtrate was concentrated. After the concentrated residue was poured into water, and extracted with Et 2 O. The extract was washed with saturated NaCl solution, dried over MgSO 4 , filtered and concentrated to give ( S ) -3-iodo-1- (2-thienyl) -1-propanol as a residue [ 1 H NMR δ 7.29 (2H, m, thienyl H-3 and H-4), 5.07 (1H, ddd, J = 4.5 and 8.6), 3.35 and 3.14 (1H, dd, J = 1.3 and 4.9, thienyl H- 1H each, m, CH 2 I), 2.38-2.16 (2H, 1H, m, CH 2 , OH)]. The compound was used directly in subsequent reactions without further purification.

상기 수득한 (S)-3-아이오도-1-(2-티에닐)-1-프로판올을 THF(17 ㎖)에 녹인 용액에 메틸아민(40% 수용액, 8.5 ㎖, 100 mmol)을 첨가하였다. 상기 혼합물을 실온에서 18시간 동안 교반하였다. 반응물을 5N NaOH(3 ㎖)로 처리한 후 농축하였다. 농축한 잔여물에 물을 가하고, Et2O로 수차례 추출하였다. 추출액을 NaCl 포화용액으로 세척하고 Na2SO4로 건조시켜 여과하였다.여과액을 농축하고 컬럼 크로마토그래피(실리카겔, 디클로로메탄:메탄올:수산화암모늄=40:10:1)로 정제하여 액상의 (S)-3-메틸아미노-1-(2-티에닐)-1-프로판올(수율 71%)을 얻었다.Methylamine (40% aqueous solution, 8.5 ml, 100 mmol) was added to a solution of the thus obtained ( S ) -3-iodo-1- (2-thienyl) -1-propanol in THF . The mixture was stirred at room temperature for 18 hours. The reaction was treated with 5 N NaOH (3 mL) and then concentrated. Water was added to the concentrated residue, and extracted several times with Et 2 O. Washing the extract with saturated NaCl solution and was filtered and dried with Na 2 SO 4 The filtrate was concentrated and purified by column chromatography (silica gel, dichloromethane: methanol: ammonium hydroxide = 40: 10: 1) to obtain a liquid with (S ) -3-methylamino-1- (2-thienyl) -1-propanol (yield: 71%).

[α]20 D = -10.8 (c 0.52 , MeOH); [α] 20 D = -10.8 ( c 0.52, MeOH);

1H NMR (300 MHz, CDCl3) δ 7.29 (1H, d, J = 4.9 Hz, thienyl H-5), 6.98-6.91 (2H, m, thienyl H-3 and H-4), 5.18 (1H, dd, J =3.0 and 8.1), 3.38 (2H, brs, OH, NH), 3.01-2.83 (2H, m, CH2N), 2.43 (3H, s, NCH3), 2.04-1.83 (2H, m, CH2).
 1 H NMR (300 MHz, CDCl 3) δ 7.29 (1H, d, J = 4.9 Hz, thienyl H-5), 6.98-6.91 (2H, m, thienyl H-3 and H-4), 5.18 (1H, dd, J = 3.0 and 8.1) , 3.38 (2H, brs, OH, NH), 3.01-2.83 (2H, m, CH 2 N), 2.43 (3H, s, NCH 3), 2.04-1.83 (2H, m , CH 2 ).

비교예Comparative Example 2: 촉매를 사용하지 않는 ( 2: catalyst-free ( SS )-3-) -3- 메틸아미노Methyl amino -1-(2--1- (2- 티에닐Thienyl )-1-)-One- 프로판올의Propanol 제조 Produce

Figure pat00011

Figure pat00011

(S)-3-클로로-1-(2-티에닐)-1-프로판올(206 ㎎, 1.17 mmol), 40% 메틸아민 수용액(1 ㎖, 11.5 mmol), 메탄올(2 ㎖)을 혼합하고 80℃에서 8시간 동안 가열 환류하였다. 반응이 완료되면, 메탄올을 제거하고 남은 잔유물을 에틸아세테이트(3 ㎖)로 추출하였다. 추출한 유기층을 황산나트륨으로 건조시켜 농축하였다. 농축시킨 반응물을 실리카 컬럼 크로마토그래피(디클로로메탄:메탄올:수산화암모늄=40:10:1)로 정제하여 오일상의 (S)-3-메틸아미노-1-(2-티에닐)-1-프로판올(126 ㎎, 61%)을 얻었다.
 (S) -3- chloro-1- (2-thienyl) -1-propanol (206 ㎎, 1.17 mmol), 40% methylamine aqueous solution (1 ㎖, 11.5 mmol), methanol (2 ㎖) and the mixture 80 Lt; 0 > C for 8 hours. When the reaction was complete, the methanol was removed and the remaining residue was extracted with ethyl acetate (3 mL). The extracted organic layer was dried with sodium sulfate and concentrated. The concentrated reaction product was purified by silica column chromatography (dichloromethane: methanol: ammonium hydroxide = 40: 10: 1) to obtain ( S ) -3-methylamino-1- (2-thienyl) 126 mg, 61%).

실시예Example 1: 촉매로서  1: as a catalyst KIKI 를 사용하는 (To use SS )-3-) -3- 메틸아미노Methyl amino -1-(2--1- (2- 티에닐Thienyl )-1-)-One- 프로판올의Propanol 제조 Produce

Figure pat00012

Figure pat00012

(S)-3-클로로-1-(2-티에닐)-1-프로판올(200 ㎎, 1.13 mmol), 40% 메틸아민 수용액(1.4 ㎖, 16 mmol), 메탄올(2 ㎖)의 혼합 용액에 KI(19 ㎎, 0.1 mmol)를 첨가한 후, 80℃에서 8시간 동안 가열 환류하였다. 반응이 완료되면, 메탄올을 제거하고 남은 잔유물을 에틸아세테이트(3 ㎖)로 추출하였다. 추출한 유기층을 황산나트륨으로 건조시켜 농축하였다. 농축시킨 반응물을 실리카 컬럼 크로마토그래피(디클로로메탄:메탄올:수산화암모늄=40:10:1)로 정제하여 고체상의 (S)-3-메틸아미노-1-(2-티에닐)-1-프로판올(157 ㎎, 81%)을 얻었다.To a mixed solution of ( S ) -3-chloro-1- (2-thienyl) -1-propanol (200 mg, 1.13 mmol), 40% methylamine aqueous solution (1.4 ml, 16 mmol) and methanol KI (19 mg, 0.1 mmol) was added thereto, and the mixture was refluxed at 80 ° C for 8 hours. When the reaction was complete, the methanol was removed and the remaining residue was extracted with ethyl acetate (3 mL). The extracted organic layer was dried with sodium sulfate and concentrated. The concentrated reaction product was purified by silica column chromatography (dichloromethane: methanol: ammonium hydroxide = 40: 10: 1) to obtain solid ( S ) -3-methylamino-1- (2-thienyl) 157 mg, 81%).

HPLC analysis: (Chiralcel OD-H column, Hex:IPA:DEA = 97:2:1, 0.5 ㎖/min): t1 = 66.2 min (R), t2 = 70.7 min (S); ee = 95%.
HPLC analysis: (Chiralcel OD-H column, Hex: IPA: DEA = 97: 2: 1, 0.5 ml / min): t 1 = 66.2 min ( R ), t 2 = 70.7 min ( S ); ee = 95%.

실시예Example 2: 촉매로서 Na 2: Na II 를 사용하는 (To use SS )-3-) -3- 메틸아미노Methyl amino -1-(2--1- (2- 티에닐Thienyl )-1-)-One- 프로판Propane 올의 제조Manufacturing

(S)-3-클로로-1-(2-티에닐)-1-프로판올(200 ㎎, 1.13 mmol), 40% 메틸아민 수용액(1.4 ㎖, 16 mmol), 메탄올(2 ㎖)의 혼합 용액에 NaI(17 ㎎, 0.1 mmol)를 첨가한 후, 80℃에서 8시간 동안 가열 환류하였다. 반응이 완료되면, 메탄올을 제거하고 남은 잔유물을 에틸아세테이트(3 ㎖)로 추출하였다. 추출한 유기층을 황산나트륨으로 건조시켜 농축하였다. 농축시킨 반응물을 실리카 컬럼 크로마토그래피(디클로로메탄:메탄올:수산화암모늄=40:10:1)로 정제하여 고체상의 (S)-3-메틸아미노-1-(2-티에닐)-1-프로판올(161 ㎎, 82%)을 얻었다.
To a mixed solution of ( S ) -3-chloro-1- (2-thienyl) -1-propanol (200 mg, 1.13 mmol), 40% methylamine aqueous solution (1.4 ml, 16 mmol) and methanol NaI (17 mg, 0.1 mmol) was added thereto, and the mixture was heated to reflux at 80 占 폚 for 8 hours. When the reaction was complete, the methanol was removed and the remaining residue was extracted with ethyl acetate (3 mL). The extracted organic layer was dried with sodium sulfate and concentrated. The concentrated reaction product was purified by silica column chromatography (dichloromethane: methanol: ammonium hydroxide = 40: 10: 1) to obtain solid ( S ) -3-methylamino-1- (2-thienyl) 161 mg, 82%).

실시예Example 3: 촉매로서  3: as catalyst CuICuI 를 사용하는 (To use SS )-3-) -3- 메틸아미노Methyl amino -1-(2--1- (2- 티에닐Thienyl )-1-)-One- 프로판올의Propanol 제조 Produce

(S)-3-클로로-1-(2-티에닐)-1-프로판올(200 ㎎, 1.13 mmol), 40% 메틸아민 수용액(1.4 ㎖, 16 mmol), 메탄올(2 ㎖)의 혼합 용액에 CuI(22 ㎎, 0.1 mmol)를 첨가한 후, 80℃에서 8시간 동안 가열 환류하였다. 반응이 완료되면, 메탄올을 제거하고 남은 잔유물을 에틸아세테이트(3 ㎖)로 추출하였다. 추출한 유기층을 황산나트륨으로 건조시켜 농축하였다. 농축시킨 반응물을 실리카 컬럼 크로마토그래피(디클로로메탄:메탄올:수산화암모늄=40:10:1)로 정제하여 고체상의 (S)-3-메틸아미노-1-(2-티에닐)-1-프로판올(141 ㎎, 73%)을 얻었다.
To a mixed solution of ( S ) -3-chloro-1- (2-thienyl) -1-propanol (200 mg, 1.13 mmol), 40% methylamine aqueous solution (1.4 ml, 16 mmol) and methanol CuI (22 mg, 0.1 mmol) was added thereto, and the mixture was heated to reflux at 80 占 폚 for 8 hours. When the reaction was complete, the methanol was removed and the remaining residue was extracted with ethyl acetate (3 mL). The extracted organic layer was dried with sodium sulfate and concentrated. The concentrated reaction product was purified by silica column chromatography (dichloromethane: methanol: ammonium hydroxide = 40: 10: 1) to obtain solid ( S ) -3-methylamino-1- (2-thienyl) 141 mg, 73%).

실시예Example 4: 촉매로서 n- 4: n- BuThis 44 NIINII 를 사용하는 (To use SS )-3-) -3- 메틸아미노Methyl amino -1-(2--1- (2- 티에닐Thienyl )-1-프로판올의 제조) -1-propanol

(S)-3-클로로-1-(2-티에닐)-1-프로판올(200 ㎎, 1.13 mmol), 40% 메틸아민 수용액(1.4 ㎖, 16 mmol), 메탄올(2 ㎖)의 혼합 용액에 n-Bu4NII(tetrabutylammonium iodide; 42 ㎎, 0.1 mmol)를 첨가한 후, 80℃에서 8시간 동안 가열 환류하였다. 반응이 완료되면, 메탄올을 제거하고 남은 잔유물을 에틸아세테이트(3 ㎖)로 추출하였다. 추출한 유기층을 황산나트륨으로 건조시켜 농축하였다. 농축시킨 반응물을 실리카 컬럼 크로마토그래피(디클로로메탄:메탄올:수산화암모늄=40:10:1)로 정제하여 고체상의 (S)-3-메틸아미노-1-(2-티에닐)-1-프로판올(151 ㎎, 78%)을 얻었다.
To a mixed solution of ( S ) -3-chloro-1- (2-thienyl) -1-propanol (200 mg, 1.13 mmol), 40% methylamine aqueous solution (1.4 ml, 16 mmol) and methanol n-Bu 4 NII (tetrabutylammonium iodide; 42 mg, 0.1 mmol) was added thereto, and the mixture was refluxed at 80 ° C for 8 hours. When the reaction was complete, the methanol was removed and the remaining residue was extracted with ethyl acetate (3 mL). The extracted organic layer was dried with sodium sulfate and concentrated. The concentrated reaction product was purified by silica column chromatography (dichloromethane: methanol: ammonium hydroxide = 40: 10: 1) to obtain solid ( S ) -3-methylamino-1- (2-thienyl) 151 mg, 78%).

실시예Example 5: 촉매로서  5: as catalyst II 22 를 사용하는 (To use SS )-3-) -3- 메틸아미노Methyl amino -1-(2--1- (2- 티에닐Thienyl )-1-)-One- 프로판올의Propanol 제조 Produce

(S)-3-클로로-1-(2-티에닐)-1-프로판올(200 ㎎, 1.13 mmol), 40% 메틸아민 수용액(1.4 ㎖, 16 mmol), 메탄올(2 ㎖)의 혼합 용액에 I2(29 ㎎, 0.1 mmol)를 첨가한 후, 80℃에서 8시간 동안 가열 환류하였다. 반응이 완료되면, 메탄올을 제거하고 남은 잔유물을 에틸아세테이트(3 ㎖)로 추출하였다. 추출한 유기층을 황산나트륨으로 건조시켜 농축하였다. 농축시킨 반응물을 실리카 컬럼 크로마토그래피(디클로로메탄:메탄올:수산화암모늄=40:10:1)로 정제하여 고체상의 (S)-3-메틸아미노-1-(2-티에닐)-1-프로판올(143 ㎎, 73%)을 얻었다.
To a mixed solution of ( S ) -3-chloro-1- (2-thienyl) -1-propanol (200 mg, 1.13 mmol), 40% methylamine aqueous solution (1.4 ml, 16 mmol) and methanol I 2 (29 mg, 0.1 mmol) was added thereto, and the mixture was refluxed at 80 ° C for 8 hours. When the reaction was complete, the methanol was removed and the remaining residue was extracted with ethyl acetate (3 mL). The extracted organic layer was dried with sodium sulfate and concentrated. The concentrated reaction product was purified by silica column chromatography (dichloromethane: methanol: ammonium hydroxide = 40: 10: 1) to obtain solid ( S ) -3-methylamino-1- (2-thienyl) 143 mg, 73%).

실시예Example 6: 촉매로서  6: as catalyst TMSITMSI 를 사용하는 (To use SS )-3-) -3- 메틸아미노Methyl amino -1-(2--1- (2- 티에닐Thienyl )-1-)-One- 프로판올의Propanol 제조 Produce

(S)-3-클로로-1-(2-티에닐)-1-프로판올(200 ㎎, 1.13 mmol), 40% 메틸아민 수용액(1.4 ㎖, 16 mmol), 메탄올(2 ㎖)의 혼합 용액에 TMSI(tetramethylsilyl iodide; 23 ㎎, 0.1 mmol)를 첨가한 후, 80℃에서 8시간 동안 가열 환류하였다. 반응이 완료되면, 메탄올을 제거하고 남은 잔유물을 에틸아세테이트(3 ㎖)로 추출하였다. 추출한 유기층을 황산나트륨으로 건조시켜 농축하였다. 농축시킨 반응물을 실리카 컬럼 크로마토그래피(디클로로메탄:메탄올:수산화암모늄=40:10:1)로 정제하여 고체상의 (S)-3-메틸아미노-1-(2-티에닐)-1-프로판올(166 ㎎, 85%)을 얻었다.
To a mixed solution of ( S ) -3-chloro-1- (2-thienyl) -1-propanol (200 mg, 1.13 mmol), 40% methylamine aqueous solution (1.4 ml, 16 mmol) and methanol TMSI (tetramethylsilyl iodide; 23 mg, 0.1 mmol) was added thereto, and the mixture was refluxed at 80 ° C for 8 hours. When the reaction was complete, the methanol was removed and the remaining residue was extracted with ethyl acetate (3 mL). The extracted organic layer was dried with sodium sulfate and concentrated. The concentrated reaction product was purified by silica column chromatography (dichloromethane: methanol: ammonium hydroxide = 40: 10: 1) to obtain solid ( S ) -3-methylamino-1- (2-thienyl) 166 mg, 85%).

실시예Example 7: 촉매로서  7: as catalyst KIKI 를 사용하는 (To use SS )-3-디메틸아미노-1-(2-) -3-dimethylamino-1- (2- 티에닐Thienyl )-1-)-One- 프로판올의Propanol 제조 Produce

Figure pat00013

Figure pat00013

(S)-3-클로로-1-(2-티에닐)-1-프로판올(200 ㎎, 1.13 mmol), 50% 디메틸아민 수용액(1.7 ㎖, 18 mmol), 메탄올(2 ㎖)의 혼합 용액에 KI(19 ㎎, 0.1 mmol)를 첨가한 후, 80℃에서 8시간 동안 가열 환류하였다. 반응이 완료되면, 메탄올을 제거하고 남은 잔유물에 1N NaOH 수용액(2 ㎖)을 가한 후, 에틸아세테이트(3 ㎖)로 추출하였다. 추출한 유기층을 황산나트륨으로 건조시켜 농축하였다. 농축시킨 반응물을 실리카 컬럼 크로마토그래피(헥산:에틸아세테이트=3:1)로 정제하여 고체상의 (S)-3-디메틸아미노-1-(2-티에닐)-1-프로판올(187 ㎎, 89%)을 얻었다.To a mixed solution of ( S ) -3-chloro-1- (2-thienyl) -1-propanol (200 mg, 1.13 mmol), 50% dimethylamine aqueous solution (1.7 ml, 18 mmol) and methanol KI (19 mg, 0.1 mmol) was added thereto, and the mixture was refluxed at 80 ° C for 8 hours. When the reaction was completed, the methanol was removed, and the residue was added with 1 N aqueous NaOH solution (2 mL), followed by extraction with ethyl acetate (3 mL). The extracted organic layer was dried with sodium sulfate and concentrated. The concentrated reaction product was purified by silica column chromatography (hexane: ethyl acetate = 3: 1) to obtain 187 mg of ( S ) -3-dimethylamino-1- (2-thienyl) ).

[α]30 D = -7.22 (c 0.48 , MeOH);[?] 30 D = -7.22 ( c 0.48, MeOH);

1H NMR δ 7.20 (1H, dd, J =1.5 and 4.9, thienyl H-5), 6.94 (2H, m, thienyl H-3 and H-4), 6.20 (1H, br), 5.18 (1H, m), 2.61 (2H, m), 2.29 (6H, s, CH3), 1.94 (2H, m); 1 H NMR δ 7.20 (1H, dd, J = 1.5 and 4.9, thienyl H-5), 6.94 (2H, m, thienyl H-3 and H-4), 6.20 (1H, br), 5.18 (1H, m ), 2.61 (2H, m) , 2.29 (6H, s, CH 3), 1.94 (2H, m);

HPLC analysis: (Chiralcel OD-H column, Hex:IPA:DEA = 97:2:1, 0.5 ㎖/min): t1 = 22.6 min (R), t2 = 25.0 min (S); ee = 94%.
HPLC analysis: (Chiralcel OD-H column, Hex: IPA: DEA = 97: 2: 1, 0.5 ml / min): t 1 = 22.6 min ( R ), t 2 = 25.0 min ( S ); ee = 94%.

실시예Example 8: 촉매로서  8: as catalyst KIKI 를 사용하는 (To use RR )-3-) -3- 메틸아미노Methyl amino -1--One- 페닐Phenyl -1--One- 프로판올의Propanol 제조 Produce

Figure pat00014

Figure pat00014

(R)-3-클로로-1-페닐-프로판올(400 ㎎, 2.34 mmol), 40% 메틸아민 수용액(2.8 ㎖, 32.2 mmol), 메탄올(7 ㎖)의 혼합 용액에 KI(38 ㎎, 0.23 mmol)를 첨가한 후, 80℃에서 8시간 동안 가열 환류하였다. 반응이 완료되면, 메탄올을 제거하고 남은 잔유물에 1N NaOH 수용액(2 ㎖)을 가한 후, 에틸아세테이트(3 ㎖)로 추출하였다. 추출한 유기층을 황산나트륨으로 건조시켜 농축하였다. 농축시킨 반응물을 실리카 컬럼 크로마토그래피(디클로로메탄:메탄올:수산화암모늄=40:10:1)로 정제하여 오일상의 (R)-3-메틸아미노-1-페닐-1-프로판올(352 ㎎, 72%)을 얻었다.(38 mg, 0.23 mmol) was added to a mixed solution of ( R ) -3-chloro-1-phenyl-propanol (400 mg, 2.34 mmol), 40% methylamine aqueous solution (2.8 ml, 32.2 mmol) ) Was added, and the mixture was heated to reflux at 80 DEG C for 8 hours. When the reaction was completed, the methanol was removed, and the residue was added with 1 N aqueous NaOH solution (2 mL), followed by extraction with ethyl acetate (3 mL). The extracted organic layer was dried with sodium sulfate and concentrated. The concentrated reaction product was purified by silica column chromatography (dichloromethane: methanol: ammonium hydroxide = 40: 10: 1) to obtain 352 mg of ( R ) -3-methylamino- ).

[α]30 D = -7.22 (c 0.48 , MeOH);[?] 30 D = -7.22 ( c 0.48, MeOH);

1H NMR (300 MHz, CDCl3) δ 7.40-7.34 (m, 4H), 7.28-7.25 (m, 1H), 4.98-7.96 (dd, J = 3.0 and 8.7, 1H), 3.36 (s, br, 1H), 20.97-2.87 (m, 2H), 2.49 (s, 3H), 1.95-1.90 (m, 1H), 1.86-1.79 (m, 1H); 1 H NMR (300 MHz, CDCl 3) δ 7.40-7.34 (m, 4H), 7.28-7.25 (m, 1H), 4.98-7.96 (dd, J = 3.0 and 8.7, 1H), 3.36 (s, br, 1H), 20.97-2.87 (m, 2H), 2.49 (s, 3H), 1.95-1.90 (m, 1H), 1.86-1.79 (m, 1H);

13C NMR (75 MHz, CDCl3) 144.9, 128.2, 126.9, 125.6, 75.4, 50.3, 36.6, 35.8; 13 C NMR (75 MHz, CDCl 3 ) 144.9, 128.2, 126.9, 125.6, 75.4, 50.3, 36.6, 35.8;

HPLC analysis: (Chiralcel OD-H column, Hex:IPA:DEA = 97:2:1, 0.5 ㎖/min): t1 = 53.7 min (R), t2 = 63.3 min (S); ee ≥ 99%.
HPLC analysis: (Chiralcel OD-H column, Hex: IPA: DEA = 97: 2: 1, 0.5 ml / min): t 1 = 53.7 min ( R ), t 2 = 63.3 min ( S ); ee ≥ 99%.

실시예Example 9: 촉매로서  9: as a catalyst KIKI 를 사용하는 (To use SS )-3-) -3- 메틸아미노Methyl amino -1--One- 페닐Phenyl -1--One- 프로판올의Propanol 제조 Produce

Figure pat00015

Figure pat00015

(S)-3-클로로-1-페닐-프로판올(400 ㎎, 2.34 mmol), 40% 메틸아민 수용액(2.8 ㎖, 32.2 mmol), 메탄올(7 ㎖)의 혼합 용액에 KI(38 ㎎, 0.23 mmol)를 첨가한 후, 80℃에서 8시간 동안 가열 환류하였다. 반응이 완료되면, 메탄올을 제거하고 남은 잔유물에 1N NaOH 수용액(2 ㎖)을 가한 후, 에틸아세테이트(3 ㎖)로 추출하였다. 추출한 유기층을 황산나트륨으로 건조시켜 농축하였다. 농축시킨 반응물을 실리카 컬럼 크로마토그래피(디클로로메탄:메탄올:수산화암모늄=40:10:1)로 정제하여 오일상의 (S)-3-메틸아미노-1-페닐-1-프로판올(367 ㎎, 75%)을 얻었다.
(38 mg, 0.23 mmol) was added to a mixed solution of ( S ) -3-chloro-1-phenyl-propanol (400 mg, 2.34 mmol), 40% methylamine aqueous solution (2.8 ml, 32.2 mmol) ) Was added, and the mixture was heated to reflux at 80 DEG C for 8 hours. When the reaction was completed, the methanol was removed, and the residue was added with 1 N aqueous NaOH solution (2 mL), followed by extraction with ethyl acetate (3 mL). The extracted organic layer was dried with sodium sulfate and concentrated. The concentrated reaction product was purified by silica column chromatography (dichloromethane: methanol: ammonium hydroxide = 40: 10: 1) to obtain 367 mg of ( S ) -3-methylamino- ).

종합적으로, 3-클로로-1-아릴프로판-1-올 유도체를 요오드화한 후 아민화하는 2단계의 공정을 수행함으로써 달성되는 비교예 1의 방법과 비교하여 단일 단계 반응에 의해 달성되는 실시예 1 내지 9의 방법은 현저히 적은 양의 요오드화합물(반응물 대비 비교예 1에서 3 내지 5배 몰비 대 실시예 1 내지 9에서 0.1배 몰비로 사용) 즉, 1/30 내지 1/50 정도의 요오드화합물만을 사용하고도 동등 이상의 수율 예컨대, 적게는 1% 많게는 20% 가까이 향상된 수율로 표제 화합물을 수득할 수 있음을 확인하였다. 구체적으로 비교예 1의 방법과 비교하여 실시예의 방법은 2단계의 공정을 단일 단계로 구현하여 반응 시간을 단축하고 반응의 편의성을 향상시켰으며, 폭발성 물질인 요오드화합물 예컨대, NaI 등의 사용량을 현저하게 감소시킴으로써 암실에서 반응시켜야 하는 등의 번거로운 조건을 필요로 하지 않았다. 뿐만 아니라 상기 요오드화합물들이 고가임을 고려할 때, 이의 사용량을 현저히 감소시킴으로써 경제적인 대량 생산이 가능하게 되었음을 시사한다. 한편, 실시예와 동일한 반응 조건으로 수행하되 촉매량의 요오드화합물을 사용하지 않는 비교예 2와 비교하여서는 10 내지 30%의 수율 증가를 나타내었다. 이는 본 발명의 제조방법이 고가의 요오드화합물을 촉매량으로 사용하면서도 단일 단계의 간단한 방법으로 종래의 2단계 공정에 의해 3-아미노-1-아릴프로판-1-올 유도체를 제조하는 방법에 비해 동등 이상의 수율로 3-아미노-1-아릴프로판-1-올 유도체를 제공할 수 있으므로, 이를 중간체로 포함하는 광학 활성 약물을 대량생산에 유용하게 사용될 수 있음을 나타내는 것이다.Comprehensively, Example 1, which is achieved by a single stage reaction as compared to the method of Comparative Example 1 which is achieved by carrying out the two-step process of iodination of the 3-chloro-1-arylpropan- The method of Examples 1 to 9 is characterized in that only a very small amount of iodine compound (used in a molar ratio of 3 to 5 times in Comparative Example 1 to a reactant in a ratio of 0.1 times in Examples 1 to 9) It was confirmed that the title compound can be obtained even at a yield of at least equivalent, for example, less than 1% and as much as 20%. Specifically, in comparison with the method of Comparative Example 1, the method of the present embodiment implements the two-step process in a single step to shorten the reaction time and improve the convenience of the reaction. The amount of the iodine compound such as NaI, which is an explosive substance, And the reaction was required in the dark room. In addition, considering that the iodine compounds are expensive, it is possible to economically mass-produce them by significantly reducing the amount of the iodine compounds used. On the other hand, the yield was increased by 10 to 30% as compared with Comparative Example 2 in which the catalytic amount of iodine compound was not used in the same reaction conditions as those of Example. This is because the production method of the present invention is superior to the conventional method of producing a 3-amino-1-arylpropan-1-ol derivative by a simple two-step process using a high-priced iodine compound in a catalytic amount, 3-amino-1-arylpropan-1-ol derivatives can be provided in the yields, indicating that optically active drugs containing them as intermediates can be useful for mass production.

Claims (12)

하기 반응식 1에 따른 요오드화합물 존재 하에 광학 활성 3-클로로-1-아릴프로판-1-올 화합물을 아민 유도체와 반응시키는 단계를 포함하는, 광학 활성 3-아미노-1-아릴프로판-1-올 유도체의 제조방법:
[반응식 1]
Figure pat00016

상기 식에서,
Ar은 C5 -10 아릴 또는 헤테로아릴이고;
Figure pat00017
는
Figure pat00018
또는
Figure pat00019
로서 반응 전과 후에서 동일하며;
R1 및 R2는 각각 독립적으로 수소, C1 -4 알킬, C7 -10 아랄킬, C5 -10 아릴, 피롤리디닐, 피페리디닐 또는 모르포리닐이고;
상기 C5 -10 아릴 또는 헤테로아릴은 각각 독립적으로 비치환되거나, 할로겐, 히드록시, 니트로, 시아노, C1 -4 알킬, 아미노, (C1 -4 알킬)아미노 및 디(C1-4 알킬)아미노로 구성된 군으로부터 선택되는 하나 이상의 작용기로 치환되거나, C5 -10 아릴 또는 C5 -10 헤테로아릴로부터 선택되는 2개 이상이 융합된(fused) 다환고리 형태일 수 있다.
Claims 1. An optically active 3-amino-1-arylpropan-1-ol derivative comprising reacting an optically active 3-chloro-1-arylpropan-1-ol compound with an amine derivative in the presence of an iodine compound according to Scheme 1 below : ≪
[Reaction Scheme 1]
Figure pat00016

In this formula,
Ar is C 5 -10 aryl or heteroaryl;
Figure pat00017
The
Figure pat00018
or
Figure pat00019
The same as before and after the reaction;
R 1 and R 2 are each independently hydrogen, C 1 -4 alkyl, C 7 -10 aralkyl, C 5 -10 aryl, pyrrolidinyl, piperidinyl or know a forest carbonyl;
The C 5 -10 aryl or heteroaryl are each independently unsubstituted or substituted, halogen, hydroxy, nitro, cyano, C 1 -4 alkyl, amino, (C 1 -4 alkyl) amino and di (C 1-4 Alkyl) amino, or a fused polycyclic ring form in which two or more selected from C 5 -10 aryl or C 5 -10 heteroaryl are fused.
제1항에 있어서,
상기 요오드화합물은 KI, NaI, CuI, n-Bu4NII(tetrabutylammonium iodide), I2 또는 TMSI(tetramethylsilyl iodide)인 것인 광학 활성 3-아미노-1-아릴프로판-1-올 유도체의 제조방법.
The method according to claim 1,
The method of the iodine compound is KI, NaI, CuI, n- Bu 4 NII (tetrabutylammonium iodide), I 2 or TMSI (tetramethylsilyl iodide) to the optically active 3-amino-1-aryl-1-ol derivatives.
제1항에 있어서,
Ar은 페닐, 플루오로페닐, 나프틸, 티에닐, 퓨릴, 벤조퓨릴 또는 벤조티에닐인 것인 광학 활성 3-아미노-1-아릴프로판-1-올 유도체의 제조방법.
The method according to claim 1,
Wherein Ar is phenyl, fluorophenyl, naphthyl, thienyl, furyl, benzofuryl or benzothienyl. 3. A process for the preparation of optically active 3-amino-1-arylpropan-1-ol derivatives.
제1항에 있어서,
R1 및 R2는 각각 독립적으로 수소, 메틸, 에틸, 이소프로필, 터트-부틸 및 벤질로 구성된 군으로부터 선택되는 것인 광학 활성 3-아미노-1-아릴프로판-1-올 유도체의 제조방법.
The method according to claim 1,
Wherein R 1 and R 2 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl and benzyl.
제4항에 있어서,
R1 및 R2 중 적어도 하나는 수소 이외의 치환기를 갖는 것인 광학 활성 3-아미노-1-아릴프로판-1-올 유도체의 제조방법.
5. The method of claim 4,
Amino-1-arylpropan-1-ol derivative wherein at least one of R 1 and R 2 has a substituent other than hydrogen.
제1항에 있어서,
상기 아민 유도체는 3-클로로-1-아릴프로판-1-올 화합물의 사용량에 대해 10 내지 20배의 몰비로 반응시키는 것인 광학 활성 3-아미노-1-아릴프로판-1-올 유도체의 제조방법.
The method according to claim 1,
Amino-1-arylpropan-1-ol derivative wherein the amine derivative is reacted at a molar ratio of 10 to 20 times the amount of 3-chloro-1-arylpropan- .
제1항에 있어서,
상기 반응은 C1 -4 저급 알콜 또는 테트라하이드로퓨란 용매에서 수행되는 것인 광학 활성 3-아미노-1-아릴프로판-1-올 유도체의 제조방법.
The method according to claim 1,
Wherein the reaction is carried out in a C 1 -4 lower alcohol or in a tetrahydrofuran solvent.
제1항에 있어서,
상기 요오드화합물을 3-클로로-1-아릴프로판-1-올 화합물의 사용량에 대해 0.05 내지 0.2배의 몰비로 사용하는 것인 광학 활성 3-아미노-1-아릴프로판-1-올 유도체의 제조방법.
The method according to claim 1,
Amino-1-arylpropan-1-ol derivative wherein the iodine compound is used in a molar ratio of 0.05 to 0.2 times the amount of 3-chloro-1-arylpropan- .
제1항에 있어서,
상기 반응은 80 내지 120℃ 온도로 가열 환류하여 수행하는 것인 광학 활성 3-아미노-1-아릴프로판-1-올 유도체의 제조방법.
The method according to claim 1,
Amino-1-arylpropan-1-ol derivative wherein the reaction is carried out by heating to reflux at a temperature of 80 to 120 ° C.
제1항에 있어서,
용매를 제거하는 단계, 유기 용매로 추출하는 단계, 건조하는 단계, 농축하는 단계, 정제하는 단계 또는 이들의 조합을 추가로 수행하는 것인 광학 활성 3-아미노-1-아릴프로판-1-올 유도체의 제조방법.
The method according to claim 1,
An optically active 3-amino-1-arylpropan-1-ol derivative, which further comprises a step of removing the solvent, extracting with an organic solvent, drying, concentrating, purifying or a combination thereof ≪ / RTI >
제1항에 있어서,
반응물 또는 생성물이 80% 이상의 거울상 이성질체 잉여율(enantiomeric excess; ee)의 광학 활성을 갖는 것인 광학 활성 3-아미노-1-아릴프로판-1-올 유도체의 제조방법.
The method according to claim 1,
Amino-1-arylpropan-1-ol derivative wherein the reactant or product has an optical activity of an enantiomeric excess ( ee ) of 80% or more.
제1항에 있어서,
상기 제조방법은 (S)-둘록세틴, (R)-플록세틴, (R)-토목세틴 또는 (R)-니속세틴의 제조를 위한 중간체를 제공하는 것인 광학 활성 3-아미노-1-아릴프로판-1-올 유도체의 제조방법.
The method according to claim 1,
The process is characterized in that it provides an intermediate for the preparation of ( S ) -duloxetine, ( R ) -floxetin, ( R ) -cindustine or ( R ) Ol or a propane-1-ol derivative.
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Publication number Priority date Publication date Assignee Title
KR20060127402A (en) * 2003-12-08 2006-12-12 와이어쓰 Process for preparation of substituted aminoalcohols

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Title
SUN-AH LEE 등, A Practical Synthesis of the Antidepressant (S)-Duloxetine, Bull. Korean Chem. Soc., 2014, Vol. 35, No. 6, pp. 1894-1896 *

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