KR100893756B1 - Process for preparing useful in synthesis of montelukast - Google Patents

Process for preparing useful in synthesis of montelukast Download PDF

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KR100893756B1
KR100893756B1 KR1020090002910A KR20090002910A KR100893756B1 KR 100893756 B1 KR100893756 B1 KR 100893756B1 KR 1020090002910 A KR1020090002910 A KR 1020090002910A KR 20090002910 A KR20090002910 A KR 20090002910A KR 100893756 B1 KR100893756 B1 KR 100893756B1
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reaction
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montelukast
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권윤자
조동옥
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주식회사 메디켐코리아
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/18—Halogen atoms or nitro radicals

Abstract

Provided is a method for mass production of montelukast having leukotriene antagonism, which can treat asthma disease, diseases related to immunity, and respiratory disease such as allergic rhinitis. A method for mass production of montelukast represented by the formula 1 comprises the following steps of: reacting a (S)-diol compound represented by the formula 2 through a Mitsnobu reaction to prepare a (S)-phosphine oxo-compound wherein sec-alcohol groups are activated, represented by the formula 3 in the presence of a phosphine compound; and coupling the (S)-phosphine oxo-compound with 1-(mercaptomethyl) cyclopropane acetic acid represented by the formula 4a.

Description

몬테루카스트의 효율적 제조방법{Process for preparing useful in synthesis of montelukast}Process for preparing useful in synthesis of montelukast

본 발명은 류코트리엔 길항작용이 우수하여 천식질환, 면역관련 질환, 알레르기 비염과 같은 호흡기 질환의 치료제로 사용되고 있는 몬테루카스트(montelukast) 또는 이의 약제학적으로 허용 가능한 염을 효율적으로 제조하는 방법에 관한 것이다.The present invention relates to a method for efficiently preparing montelukast or a pharmaceutically acceptable salt thereof, which has excellent leukotriene antagonism and is used as a therapeutic agent for respiratory diseases such as asthma disease, immune related diseases and allergic rhinitis.

몬테루카스트(montelukast) 또는 이의 약제학적으로 허용 가능한 염은 류코트리엔(Leukotriene)의 작용을 차단하여 천식 질환 치료제로는 물론이고, 면역관련 질환, 알레르기 비염과 같은 호흡기 질병 치료에 매우 효과적인 구강 투여제로 개발되고 있다.Montelukast or a pharmaceutically acceptable salt thereof has been developed as an effective oral agent for the treatment of respiratory diseases such as immune related diseases and allergic rhinitis, as well as treating asthma diseases by blocking the action of leukotriene. .

천식 및 알레르기 질환의 발병이 최근 20년 사이에 2∼3배 이상의 빠른 증가세를 보이고 있다. 특히 소아의 경우 유병률이 15%로 높고, 대부분이 만성질환 형태로 전환되는 경향이 있어 집중적인 치료가 요구되고 있다. 기존 치료방법 은 단순히 기관지 확장제 또는 먹는 스테로이드제로 한정되었으나, 염증치료제와 흡입제 위주의 국제치료 기준에 맞도록 바뀌면서 몬테루카스트 제제의 시장은 매우 확대되어 가고 있다.The incidence of asthma and allergic diseases has increased more than 2-3 times in recent 20 years. In particular, children have a high prevalence of 15%, and most of them tend to be converted into chronic diseases, so intensive treatment is required. Existing treatment methods have been limited to bronchodilators or steroids, but the market for montelukast products is expanding as they change to meet international treatment standards based on inflammation and inhalants.

몬테루카스트(montelukast)의 일반적인 제조방법으로서, 하기 화학식 2로 표시되는 (S)-다이알콜 화합물을 출발물질로 사용하여 몬테루카스트를 합성하는 방법을 간략히 설명하면 하기와 같다.As a general manufacturing method of montelukast, a method of synthesizing montelukast using the (S) -dialcohol compound represented by the following Chemical Formula 2 as a starting material is briefly described.

유럽특허 제480,717호에는 하기 반응식 1에 나타낸 바와 같이, 하기 화학식 2로 표시되는 (S)-다이알콜 화합물을 출발물질로 사용하여 몬테루카스트를 제조하는 방법이 개시되어 있다. European Patent No. 480,717 discloses a process for preparing montelukast using the (S) -dialcohol compound represented by the following formula (2) as a starting material, as shown in Scheme 1 below.

Figure 112009002334207-pat00002
Figure 112009002334207-pat00002

상기 반응식 1에 따른 일반적 제조방법에서는, 상기 화학식 2로 표시되는 광 학활성 (S)-다이알콜 화합물의 sec-알콜기를 메실레이트(mesylate)로 활성화하고, tert-알콜기는 테트라하이드로피란(THP)으로 보호화하여 상기 화학식 Ⅳ로 표시되는 화합물을 제조한다. 그런 다음, 상기 화학식 Ⅳ로 표시되는 화합물을 메틸 1-(머캅토메틸)사이클로프로판아세테이트와 커플링 반응하여 상기 화학식 Ⅴ로 표시되는 화합물을 제조한다. 그런 다음, 상기 화학식 Ⅴ로 표시되는 화합물의 tert-알콜 보호기를 탈보호하고 다시 가수분해 반응하여, 목적하는 상기 화학식 1로 표시되는 몬테루카스트 또는 이의 소디움염을 제조하였다. In the general preparation method according to Scheme 1, the sec -alcohol group of the optically active (S) -dialcohol compound represented by Chemical Formula 2 is activated with mesylate, and the tert -alcohol group is tetrahydropyran (THP) It is protected by to prepare a compound represented by the formula (IV). Then, the compound represented by Chemical Formula V is prepared by coupling the compound represented by Chemical Formula IV with methyl 1- (mercaptomethyl) cyclopropane acetate. Then, the tert -alcohol protecting group of the compound represented by the above formula (V) was deprotected and hydrolyzed again to prepare the desired montelukast or its sodium salt represented by the above formula (1).

그러나, 상기 반응식 1에 따른 공지 방법에서는 sec-알콜기를 메실레이트(mesylate)로 활성화하고 있으나, 메실레이트기가 도입된 상기 화학식 Ⅱ로 표시되는 화합물은 실온에서의 안정성이 열악하여 몬테루카스트의 대량 생산을 위한 중간체 화합물로서 이용하기에는 한계가 있다. 또한, 상기 반응식 1에 따른 제조방법은 tert-알콜기의 보호화 및 탈보호화 반응을 수행하고 있고, 보호화제로서는 고가원료를 사용하고 있는 등 전체적인 제조공정이 경제성면에서 열악한 문제가 있다.However, in the known method according to Scheme 1, the sec -alcohol group is activated with mesylate, but the compound represented by Formula II in which the mesylate group is introduced has poor stability at room temperature, so that the mass production of montelukast is poor. There is a limit to use as an intermediate compound. In addition, the manufacturing method according to the reaction formula 1 is a tert -alcoholization and deprotection of the reaction, and the overall manufacturing process, such as using a high-cost raw material as a protective agent has a poor economical problem.

또한, 미국공개특허 제2007-028177호에는 상기 반응식 1에 나타낸 공지 제조방법을 개선시킨 몬테루카스트의 제조방법이 개시되어 있다. In addition, US Patent Publication No. 2007-028177 discloses a method for producing montelukast, which is an improvement of the known production method shown in Scheme 1.

Figure 112009002334207-pat00003
Figure 112009002334207-pat00003

상기 반응식 2에 따른 제조방법에서는, 상기 화학식 2로 표시되는 광학활성 (S)-다이알콜 화합물의 sec-알콜기를 메실레이트(mesylate)로 활성화한 후에, NaOH와 같은 강염기 존재하에서 상기 화학식 4a로 표시되는 1-(머캅토메틸)사이클로프로판아세트산과 커플링 반응하여 상기 화학식 1로 표시되는 몬테루카스트를 제조하였다. 상기 반응식 2에 따른 제조방법은, 상기 반응식 1의 제조방법을 비롯하여 기존방법에 비교하여 제조공정을 크게 단축시킨 점에서 개선효과는 있다. 그러나, 상기 반응식 2에 따른 공지 방법 역시 sec-알콜기를 메실레이트(mesylate)로 활성화하고 있고, 메실레이트기가 도입된 상기 화학식 Ⅱ로 표시되는 화합물은 실온에서의 안정성이 열악하여 몬테루카스트의 대량 생산을 위한 중간체 화합물로서 이용하기에는 한계가 있다.In the preparation method according to Scheme 2, after activating the sec -alcohol group of the optically active (S) -dialcohol compound represented by Chemical Formula 2 with mesylate, it is represented by Chemical Formula 4a in the presence of a strong base such as NaOH. Coupling reaction with 1- (mercaptomethyl) cyclopropane acetic acid to prepare montelukast represented by the formula (1). The manufacturing method according to Scheme 2 has an improvement effect in that the manufacturing process is greatly shortened compared to the existing method including the manufacturing method of Scheme 1 above. However, the well-known method according to Scheme 2 also activates the sec -alcohol group as mesylate, and the compound represented by Formula II in which the mesylate group is introduced has poor stability at room temperature, so that the mass production of montelukast is poor. There is a limit to use as an intermediate compound.

또한, 미국특허 제5,614,632호는 tert-알콜기의 보호 및 탈보호 반응을 생략시킨 개선된 제조방법이 개시되어 있다. 즉, 하기 반응식 3에 나타낸 바와 같 이 강염기(BuLi)의 존재 하에서 하기 화학식 2로 표시되는 광학활성 (S)-다이알콜 화합물을 1-(머캅토메틸)사이클로프로판아세트산과 커플링 반응하여 하기 화학식 1로 표시되는 몬테루카스트를 제조하였다. U. S. Patent No. 5,614, 632 also discloses an improved process for the elimination of the protection and deprotection of tert -alcohol groups. That is, as shown in Scheme 3, the optically active (S) -dialcohol compound represented by the following Chemical Formula 2 in the presence of a strong base (BuLi) is subjected to a coupling reaction with 1- (mercaptomethyl) cyclopropaneacetic acid A montelukast represented by 1 was prepared.

Figure 112009002334207-pat00004
Figure 112009002334207-pat00004

그러나, 상기 반응식 3에 따른 제조방법은 tert-알콜기의 보호 및 탈보호 반응을 생략한 공정 개선의 효과는 있지만, 몬테루카스트의 대량생산 방법으로서는 여전히 개선의 여지가 있다. 즉, 상기 화학식 2로 표시되는 화합물과 상기 화학식 4a로 표시되는 화합물 간의 커플링 반응시킬 때, 상기 화학식 4a로 표시되는 1-(머캅토메틸)사이클로프로판아세트산은 2 당량 이상의 n-BuLi 존재 하에서 상기 화학식 Ⅵ으로 표시되는 다이리튬(Dilithium) 화합물로 전환시켜 커플링 반응에 사용한다. 이때, 사용된 n-BuLi의 강염기는 폭발성이 매우 큰 화합물로 온도와 수분에 매우 민감하므로, 실험실에서도 숙련된 연구원만 사용하는 화합물이다. 이런 이유로, n-BuLi을 사용하는 화학공정은 산업에 적용하기는 많은 어려움이 있다. 또한, 상기 화학식 Ⅵ으로 표시되는 다이리튬(Dilithium) 화합물 역시 수분과 온도에 따른 폭발성 때문에 수분과 공기가 철저히 차단된 -40℃ 이하의 극저온에서 매우 신속하게 수행해야만 하는 어려움이 있다. 따라서, 상기 반응식 2 에 따른 제조방법 역시 몬테루카스트의 대량생산 방법으로 적용하기에는 여전히 어려움이 있다.However, although the production method according to Scheme 3 has the effect of improving the process of omitting the protection and deprotection reaction of the tert -alcohol group, there is still room for improvement as a mass production method of montelukast. That is, in the coupling reaction between the compound represented by Formula 2 and the compound represented by Formula 4a, the 1- (mercaptomethyl) cyclopropaneacetic acid represented by Formula 4a is present in the presence of at least 2 equivalents of n-BuLi. It is converted to a dilithium compound represented by the formula (VI) and used for the coupling reaction. At this time, the strong base of the n-BuLi used is a compound with a very explosive compound is very sensitive to temperature and moisture, it is a compound used only by skilled researchers in the laboratory. For this reason, chemical processes using n-BuLi have many difficulties in industrial application. In addition, the dilithium compound represented by Chemical Formula VI also has a difficulty in being performed very quickly at a cryogenic temperature of −40 ° C. or less, in which moisture and air are completely blocked because of explosiveness according to moisture and temperature. Therefore, there is still a difficulty in applying the production method according to Scheme 2 as a mass production method of montelukast.

이상에서 살펴본 바와 같이, 천식 및 알레르기 등의 호흡기 질환 치료제로서 유효한 상기 화학식 1로 표시되는 몬테루카스트 및 이의 약제학적으로 허용 가능한 염을 손쉽게 대량 생산이 가능한 개선된 제조방법의 개발이 절실히 요구되고 있다.As described above, there is an urgent need for the development of an improved manufacturing method capable of easily mass-producing montelukast represented by Formula 1 and its pharmaceutically acceptable salts, which are effective as agents for treating respiratory diseases such as asthma and allergies.

본 발명은 상기 화학식 2로 표시되는 (S)-다이올 화합물의 sec-알콜기를 활성화하기 위하여 미츠노부 반응(Mitsnobu reaction)을 수행하여 신규 중간체 화합물을 경유하는, 새로운 몬테루카스트 및 이의 약제학적으로 허용 가능한 염의 제조방법을 제공하는데 그 목적이 있다.The present invention is a new montelukast and its pharmaceutically acceptable through a novel intermediate compound by performing a Mitsnobu reaction to activate the sec -alcohol group of the (S) -diol compound represented by Formula 2 It is an object to provide a method for preparing a salt.

또한, 본 발명은 공정 단축 및 제조수율 향상 등에 의해 몬테루카스트 및 이의 약제학적으로 허용 가능한 염의 대량 생산에 유용한 개선된 제조방법을 제공하는데 그 목적이 있다.It is also an object of the present invention to provide an improved manufacturing method useful for mass production of montelukast and its pharmaceutically acceptable salts by shortening the process and improving production yield.

또한, 본 발명은 미츠노부 반응(Mitsnobu reaction)을 수행하여 제조된 신규 중간체 화합물을 제공하는데 그 목적이 있다.It is also an object of the present invention to provide a novel intermediate compound prepared by performing the Mitsnobu reaction.

본 발명은 하기 화학식 2로 표시되는 (S)-다이올 화합물을 미츠노부 반 응(Mitsnobu reaction)시켜 sec-알콜 그룹을 활성화 한 후에, 하기 화학식 4a로 표시되는 1-(머캅토메틸)사이클로프로판아세트산과 커플링 반응시켜 하기 화학식 1로 표시되는 몬테루카스트를 제조하는 단계; 를 포함하여 이루어지는 몬테루카스트 및 이의 약제학적으로 허용 가능한 염의 제조방법을 그 특징으로 한다.The present invention is a 1- (mercaptomethyl) cyclopropane represented by the following formula (4a) after activating the sec -alcohol group by Mitsnobu reaction of the (S) -diol compound represented by the formula (2) Coupling a reaction with acetic acid to produce montelukast represented by the following Chemical Formula 1; Characterized in that the manufacturing method of montelukast and its pharmaceutically acceptable salt comprising a.

Figure 112009002334207-pat00005
Figure 112009002334207-pat00005

또한, 본 발명은 하기 화학식 2로 표시되는 (S)-다이올 화합물을 미츠노부 반응(Mitsnobu reaction)시켜 sec-알콜 그룹을 활성화 한 후에, 하기 화학식 4b로 표시되는 1-(머캅토메틸)사이클로프로판아세트산 알킬 에스테르와 커플링 반응시켜, 하기 화학식 5로 표시되는 몬테루카스트 알킬 에스테르 화합물을 제조하는 단계; 및 하기 화학식 5로 표시되는 몬테루카스트 알킬 에스테르 화합물을 가수분해하여 상기 화학식 1로 표시되는 몬테루카스트를 제조하는 단계; 를 포함하여 이루어지는 몬테루카스트 및 이의 약제학적으로 허용 가능한 염의 제조방법을 그 특징으로 한다.In addition, the present invention is a 1- (mercaptomethyl) cyclo represented by the following formula (4b) after activating the sec -alcohol group by the Mitsnobu reaction (S) -diol compound represented by the formula (2) Coupling reaction with a propane acetic acid alkyl ester to prepare a montelukast alkyl ester compound represented by Formula 5; And hydrolyzing the montelukast alkyl ester compound represented by Formula 5 to produce montelukast represented by Formula 1; Characterized in that the manufacturing method of montelukast and its pharmaceutically acceptable salt comprising a.

Figure 112009002334207-pat00006
Figure 112009002334207-pat00006

상기 반응식 5에서, R2는 C1∼C6의 알킬기를 나타낸다.In the above reaction scheme 5, R 2 represents an alkyl group of C 1 ~C 6.

또한, 본 발명의 제조방법에서는 상기한 미츠노부 반응(Mitsnobu reaction)시켜 sec-알콜 그룹이 활성화 된 중간체 화합물이, 하기 화학식 3으로 표시되는 (S)-포스핀옥소 화합물임을 그 특징으로 한다.In addition, the method of the present invention is characterized in that the intermediate compound in which the sec -alcohol group is activated by the above Mitsnobu reaction is an (S) -phosphinoxo compound represented by the following formula (3).

Figure 112009002334207-pat00007
Figure 112009002334207-pat00007

상기 화학식 3에서, R1은 C1-C4 알킬기, C1-C4 알콕시기, 또는 페닐기를 나타내고, Y는 할로겐원자 또는 에틸아조다이카르복실레이트를 나타낸다.In Formula 3, R 1 represents a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, or a phenyl group, and Y represents a halogen atom or ethyl azodicarboxylate.

본 발명이 특징으로 하는 상기 화학식 1로 표시되는 몬테루카스트 또는 이의 약제학적으로 허용 가능한 염의 제조방법을 각 과정별로 보다 구체적으로 설명하면 하기와 같다.Hereinafter, a method for preparing montelukast represented by the general formula (1) or a pharmaceutically acceptable salt thereof according to the present invention will be described in detail for each process.

먼저, 상기 화학식 2로 표시되는 (S)-다이올 화합물의 sec-알콜기를 활성화하여 상기 화학식 3으로 표시되는 (S)-포스핀옥소 화합물을 제조한다.First, the sec -alcohol group of the (S) -diol compound represented by Chemical Formula 2 is activated to prepare the (S) -phosphinoxo compound represented by Chemical Formula 3.

상기 활성화 반응은 일명, 미츠노부 반응(Mitsnobu reaction)으로 진행된다. 미츠노부 반응은 할로겐화제 또는 다이에틸아조다이카르복실레이트(DEAD)와, (R1)3P로 표시되는 포스핀 화합물의 존재 하에서, -20℃ 내지 40℃의 온도범위에서 바람직하기로는 -5 내지 0℃의 온화한 반응조건하에 진행된다. 상기 할로겐화제로는 N-브로모숙신이미드(NBS), N-클로로숙신이미드(NCS), N-요오드숙신이미드(NIS), 염소(Cl2), 브롬(Br2), 요오도(I2), 알칼리금속 할라이드를 사용할 수 있다. 상기 포스핀 화합물로는 트리메틸포스핀, 트리에틸포스핀과 같은 트리(C1-C6 알킬)포스핀, 트리메톡시포스핀, 트리에톡시포스핀과 같은 트리(C1-C6 알콕시)포스핀, 또는 트리페닐포스핀이 사용될 수 있다. 그리고, 반응용매로는 반응에 영향을 주지 않는 불활성 유기용매라면 모두 사용될 수 있으며, 구체적으로는 다이메틸포름아마이드(DMF), N,N-다이메틸아세타아마이드(DMAC), 다이메틸설폭사이드(DMSO), 테트라하이드로퓨란(THF), 다이에틸에테르, 메틸렌클로라이드, 에틸아세 테이트, 아세톤, 아세토니트릴 등이 사용될 수 있다.The activation reaction is a so-called Mitsnobu reaction (Mitsnobu reaction) proceeds. The Mitsunobu reaction is preferably in the temperature range of -20 ° C to 40 ° C in the presence of a halogenating agent or diethylazodicarboxylate (DEAD) and a phosphine compound represented by (R 1 ) 3 P. To mild reaction conditions of 0 to 0 캜. The halogenating agent is N- bromosuccinimide (NBS), N- chloro-succinimide (NCS), the N- iodine succinic imide (NIS), chlorine (Cl 2), bromine (Br 2), iodo ( I 2 ), alkali metal halides may be used. Examples of the phosphine compound include tri (C 1 -C 6 alkyl) phosphine such as trimethylphosphine and triethylphosphine, tri (C 1 -C 6 alkoxy) such as trimethoxyphosphine and triethoxyphosphine. Phosphine, or triphenylphosphine can be used. As the reaction solvent, any inert organic solvent which does not affect the reaction may be used. Specifically, dimethylformamide (DMF), N, N -dimethylacetamide (DMAC), and dimethyl sulfoxide ( DMSO), tetrahydrofuran (THF), diethyl ether, methylene chloride, ethyl acetate, acetone, acetonitrile and the like can be used.

상기한 미츠노부 반응을 통해 제조된 상기 화학식 3으로 표시되는 (S)-포스핀옥소 화합물은, 통상의 분리 정제과정을 수행하여 분리하여 다음 반응에 사용할 수 있겠으나, 공정의 편의성을 도모하기 위해서는 별도의 분리 정제 없이 연속적으로 다음 반응에 직접 사용하는 것이 바람직하다. 상기 화학식 3으로 표시되는 화합물의 안정성을 알아보기 위해, 상기 미츠노부 반응에 사용된 용매에 용해시킨 용액상태로 상온 이하의 온도 구체적으로는 -20℃ 내지 20℃ 온도에서 2일 동안 보관하였다. TLC(Thin-layer chromatography) 분석 등을 통해 확인한 결과, 상기 화학식 3으로 표시되는 화합물은 상업적으로 이용하기에 적합한 정도로 안정성이 확보된 중간체 화합물임을 알 수 있었다.The (S) -phosphinoxo compound represented by Chemical Formula 3 prepared through the Mitsunobu reaction may be separated by performing a conventional separation and purification process, and may be used in the following reaction, but for the convenience of the process It is preferred to use directly in the next reaction continuously without separate separation purification. In order to determine the stability of the compound represented by Chemical Formula 3, the solution was dissolved in the solvent used in the Mitsunobu reaction and stored at a temperature below room temperature, specifically, at -20 ° C to 20 ° C for 2 days. As a result of TLC (Thin-layer Chromatography) analysis and the like, it was found that the compound represented by Chemical Formula 3 is an intermediate compound having a stable degree to be suitable for commercial use.

그런 다음, 본 발명에 따른 제조방법에서는 (S)-sec-알콜기가 활성화된 상기 화학식 3으로 표시되는 (S)-포스핀옥소 화합물을 상기 화학식 4a로 표시되는 1-(머캅토메틸)사이클로프로판아세트산와 커플링 반응시켜, 목적하는 상기 화학식 1로 표시되는 몬테루카스트를 직접 제조할 수 있다.Then, in the preparation method according to the present invention, the (S) -phosphinoxo compound represented by Chemical Formula 3 in which the (S) -sec -alcohol group is activated is 1- (mercaptomethyl) cyclopropane represented by Chemical Formula 4a. By coupling reaction with acetic acid, the desired montelukast represented by the formula (1) can be prepared directly.

또한, 본 발명에 따른 제조방법에서는 (S)-sec-알콜기가 활성화된 상기 화학식 3으로 표시되는 (S)-포스핀옥소 화합물을 상기 화학식 4b로 표시되는 1-(머캅토메틸)사이클로프로판아세트산 알킬 에스테르와 커플링 반응시켜 상기 화학식 5로 표시되는 몬테루카스트 알킬 에스테르 화합물을 제조한 후에, 이 화합물을 통상의 가수분해 반응을 수행하여 목적하는 상기 화학식 1로 표시되는 몬테루카스트를 제조할 수 있다.In addition, in the preparation method according to the present invention, the (S) -phosphinoxo compound represented by Chemical Formula 3 in which the (S) -sec -alcohol group is activated is 1- (mercaptomethyl) cyclopropane acetic acid represented by Chemical Formula 4b. After coupling reaction with an alkyl ester to prepare a montelukast alkyl ester compound represented by Chemical Formula 5, the compound may be subjected to a conventional hydrolysis reaction to prepare a desired montelukast represented by Chemical Formula 1.

본 발명이 수행하는 커플링 반응은 염기 존재하에서 -20℃ 내지 40℃의 온도조건에서 교반하면 커플링 반응은 짧은 시간 내에 완료된다. 이때 염기는 수산화나트륨(NaOH), 수소화나트륨(NaH), 수산화칼륨(KOH), 메톡시나트륨(NaOMe), 칼륨 tert-부톡사이드(tert-BuOK) 등을 포함하는 알칼리금속염 화합물 중에서 선택하여 1 내지 3 당량 범위로 사용한다. 상기 커플링 반응에 사용되는 용매는 커플링 반응에 영향을 주지 않는 불활성 유기용매라면 모두 사용될 수 있으며, 구체적으로는 다이메틸포름아마이드(DMF), N,N-다이메틸아세트아마이드(DMAC), 다이메틸설폭사이드(DMSO), 테트라하이드로퓨란(THF), 다이에틸에테르, 메틸렌클로라이드, 에틸아세테이트, 아세톤, 아세토니트릴 등이 사용될 수 있다.When the coupling reaction carried out by the present invention is stirred at a temperature condition of -20 ° C to 40 ° C in the presence of a base, the coupling reaction is completed in a short time. In this case, the base is selected from alkali metal salt compounds including sodium hydroxide (NaOH), sodium hydride (NaH), potassium hydroxide (KOH), methoxy sodium (NaOMe), potassium tert -butoxide ( tert- BuOK), and the like. It is used in 3 equivalent range. Any solvent used in the coupling reaction may be used as long as it is an inert organic solvent that does not affect the coupling reaction. Specifically, dimethylformamide (DMF), N, N -dimethylacetamide (DMAC), and die Methyl sulfoxide (DMSO), tetrahydrofuran (THF), diethyl ether, methylene chloride, ethyl acetate, acetone, acetonitrile and the like can be used.

또한, 상기 화학식 5로 표시되는 몬테루카스트 알킬 에스테르 화합물의 가수분해 반응하여 상기 화학식 1로 표시되는 몬테루카스트를 제조한다. 가수분해 반응은 알칼리금속 하이드록사이드의 무기 염기를 사용하는 조건에서 수행한다. 보다 구체적으로 설명하면, 상기 가수분해 반응은 소디움하이드록사이드(NaOH), 리튬하이드록사이드(LiOH) 및 칼륨하이드록사이드(KOH) 중에서 선택된 무기 염기를 사용하여 -20℃ 내지 30℃ 온도 조건에서 수행한다. 특히 좋기로는 1 내지 3 당량의 소디움 하이드록사이드(NaOH)를 물에 용해시켜 제조된 20 내지 70% 농도의 염기 수용액을 사용하여, 실온에서 교반하면 가수분해 반응은 거의 정량적으로 진행되어 고순도의 몬테루카스트를 제조할 수 있다. 상기 가수분해 반응이 완결되면, 반응액을 염산, 황산과 같은 산 용액으로 중화하여 상기 화학식 1로 표시되는 유리산(free acid) 형태의 몬테루카스트를 제조하며, 간단한 용매 추출을 통해 몬테루카스트의 유리산은 쉽게 분리가 가능하다.In addition, a hydrolysis reaction of the montelukast alkyl ester compound represented by the formula (5) to prepare a montelukast represented by the formula (1). The hydrolysis reaction is carried out under conditions using an inorganic base of alkali metal hydroxide. More specifically, the hydrolysis reaction is performed at -20 ° C to 30 ° C using an inorganic base selected from sodium hydroxide (NaOH), lithium hydroxide (LiOH) and potassium hydroxide (KOH). To perform. Particularly preferably, when the mixture is stirred at room temperature using a 20 to 70% concentration of an aqueous base solution prepared by dissolving 1 to 3 equivalents of sodium hydroxide (NaOH) in water, the hydrolysis reaction proceeds almost quantitatively to obtain high purity. Montelukast can be prepared. When the hydrolysis reaction is completed, the reaction solution is neutralized with an acid solution such as hydrochloric acid and sulfuric acid to prepare montelukast in the form of free acid represented by Chemical Formula 1, and the free acid of montelukast is easily obtained through simple solvent extraction. It can be separated.

또한, 본 발명에서는 상기 가수분해 반응을 수행함에 있어 상기 커플링 반응하여 제조된 상기 화학식 5로 표시되는 몬테루카스트 알킬 에스테르 화합물을 분리 정제하여 수득한 이후에 가수분해 반응을 진행할 수도 있지만, 커플링 반응이 완결된 반응액 내에서 일용기 반응(one-pot reaction)으로 직접 가수분해 반응을 진행할 수도 있다. 공정 단축을 통한 상업적 유용성을 고려한다면, 커플링 반응과 가수분해 반응은 일용기 반응(one-pot reaction)으로 연속적으로 수행하는 것이 보다 바람직하다.In addition, in the present invention, the hydrolysis reaction may be performed after the separation and purification of the montelukast alkyl ester compound represented by Chemical Formula 5 prepared by the coupling reaction in carrying out the hydrolysis reaction. The hydrolysis reaction may be carried out directly in a one-pot reaction in the completed reaction solution. In consideration of commercial utility through process shortening, the coupling reaction and the hydrolysis reaction are more preferably carried out continuously in a one-pot reaction.

한편, 본 발명은 상기 화학식 1로 표시되는 몬테루카스트를 약제학적으로 허용 가능한 염으로 형태로 얻을 수도 있는 바, 약제학적으로 허용 가능한 염의 제조방법은 의약품 합성분야에서 일반적으로 알려진 통상의 방법이다. 본 발명에서의 약제학적으로 허용 가능한 염은 나트륨, 칼륨 등의 알칼리금속과의 금속염, 또는 암모늄 이온과의 염 일 수 있다. 예를 들면, 상기 화학식 1로 표시되는 몬테루카스트의 나트륨염을 제조하기 위해서는, 몬테루카스트 유리산(free acid)을 알콜 수용액에 녹인 후에 1 당량의 알칼리금속 수산화물을 첨가하여 몬테루카스트의 나트륨염으로 전환시켜 얻을 수 있다. 고 순도의 몬테루카스트의 나트륨염을 얻기 위해서는, 용매 결정화 방법을 통해서 결정성 화합물로서 얻을 수도 있다.On the other hand, the present invention can obtain the montelukast represented by the formula (1) in the form of a pharmaceutically acceptable salt, a method for preparing a pharmaceutically acceptable salt is a conventional method generally known in the field of pharmaceutical synthesis. The pharmaceutically acceptable salt in the present invention may be a metal salt with an alkali metal such as sodium or potassium, or a salt with ammonium ion. For example, in order to prepare the sodium salt of montelukast represented by the formula (1), the montelukast free acid can be obtained by dissolving montelukast free acid in an aqueous alcohol solution and then adding an equivalent of alkali metal hydroxide to the sodium salt of montelukast. have. In order to obtain the high purity montelukast sodium salt, it can also be obtained as a crystalline compound through a solvent crystallization method.

이상에서 설명한 바와 같이, 본 발명에서는 상기 화학식 3으로 표시되는 신규 중간체 화합물을 합성 경유함으로써 목적하는 상기 화학식 1로 표시되는 몬테루카스트 또는 이의 약제학적으로 허용 가능한 염을 고 순도 및 고 수율로 합성할 수 있었다. 또한, 본 발명에 따른 일련의 제조방법에서 사용되는 반응물질 및 중간체 화합물들은 상업적으로 이용하기에 적합할 정도로 안정성이 확보되어 있다. 따라서, 본 발명의 제조방법은 몬테루카스트 또는 이의 약제학적으로 허용 가능한 염의 대량 생산을 위한 상업적인 제조방법으로서 유용하다.As described above, in the present invention, through the synthesis of the novel intermediate compound represented by Formula 3, the desired montelukast represented by Formula 1 or a pharmaceutically acceptable salt thereof could be synthesized in high purity and high yield. . In addition, the reactants and intermediate compounds used in the series of preparation methods according to the present invention are secured to a degree suitable for commercial use. Thus, the process of the present invention is useful as a commercial process for the mass production of montelukast or its pharmaceutically acceptable salts.

이와 같은 본 발명은 다음의 실시예를 통하여 보다 상세히 설명하겠는 바, 본 발명이 이들 실시예에 의해 한정되는 것은 아니다.Such a present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

[실시예]EXAMPLE

실시예 1. 몬테루카스트 (화학식 1)의 제조Example 1 Preparation of Montelukast (Formula 1)

2-(2-(3-(S)-(3-(2-(7-클로로-2-퀴놀리닐)-에테닐)페닐)-3-하이드록시프로필)페닐)-2-프로판올(화학식 2; 1 g, 2.18 mmol)을 다이메틸포름아마이드(DMF) 10 mL에 녹이고, 0℃로 냉각하였다. N-브로모숙신이미드(NBS) 0.78 g(4.37 mmol)과 트리페닐포스핀(PPh3) 1.14 g(4.37 mmol)을 서서히 가한 후 온도를 유지하면서 30분 교반하였다. 반응물을 소량 산처리 분리하여 TLC로 출발물질이 완전히 소모됨을 확인하였다. 한편 다른 반응용기에 1-(머캅토메틸)사이클로프로판아세트산(화학식 4a) 0.38 g(2.47 mmol)을 다이메틸포름아마이드(DMF) 5 mL에 녹이고 10℃로 냉각한 후, 47% NaOH 수용액 0.38 mL를 서서히 가하고, 30분 교반한 후, 위 반응액에 서서히 부가하였다. 10℃에서 30분 교반한 후, 반응물을 실온으로 승 온한 후 4시간 더 교반하였다. 반응물에 메틸렌클로라이드 20 mL와 0.5N HCl 수용액 30 mL을 가하여 추출하였다. 유기층을 정제수 30 mL로 2번 세척한 후 포화 소금물로 세척한 후 유기층을 황산마그네슘으로 건조하고 감압 농축하여 실리카겔 컬럼 크로마토분리를 통해 표제 화합물을 1.13 g(1.94 mmol, 89%) 얻었다. 2- (2- (3- (S)-(3- (2- (7-chloro-2-quinolinyl) -ethenyl) phenyl) -3-hydroxypropyl) phenyl) -2-propanol 2; 1 g, 2.18 mmol) was dissolved in 10 mL of dimethylformamide (DMF) and cooled to 0 ° C. 0.78 g (4.37 mmol) of N -bromosuccinimide (NBS) and 1.14 g (4.37 mmol) of triphenylphosphine (PPh 3 ) were added slowly, followed by stirring for 30 minutes while maintaining the temperature. The reaction was separated by a small amount of acid treatment to confirm complete consumption of the starting material by TLC. Meanwhile, 0.38 g (2.47 mmol) of 1- (mercaptomethyl) cyclopropane acetic acid (Formula 4a) was dissolved in 5 mL of dimethylformamide (DMF) in another reaction vessel, cooled to 10 ° C., and 0.38 mL of 47% aqueous NaOH solution. Was added slowly, stirred for 30 minutes, and then slowly added to the reaction solution. After 30 min stirring at 10 ° C., the reaction was warmed to room temperature and stirred for further 4 h. 20 mL of methylene chloride and 30 mL of 0.5N HCl aqueous solution were added to the reaction. The organic layer was washed twice with 30 mL of purified water, washed with saturated brine, and then the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 1.13 g (1.94 mmol, 89%) of the title compound through silica gel column chromatography.

1H NMR(300MHz, CDCl3) δ 8.09(d, 2H), 7.73-7.62(m, 4H), 7.51-7.34(m, 6H), 7.17-7.09(m, 3H), 3.94(t, 1H), 3.13-3.07(m, 1H), 2.82-2.78(m, 1H), 2.50(s, 2H), 2.38(s, 2H), 2.20-2.16(m, 2H), 1.60(d, 6H), 0.57-0.32(m, 4H) 1 H NMR (300 MHz, CDCl 3 ) δ 8.09 (d, 2H), 7.73-7.62 (m, 4H), 7.51-7.34 (m, 6H), 7.17-7.09 (m, 3H), 3.94 (t, 1H) , 3.13-3.07 (m, 1H), 2.82-2.78 (m, 1H), 2.50 (s, 2H), 2.38 (s, 2H), 2.20-2.16 (m, 2H), 1.60 (d, 6H), 0.57 -0.32 (m, 4H)

실시예 2. 몬테루카스트 (화학식 1)의 제조Example 2. Preparation of Montelukast (Formula 1)

2-(2-(3-(S)-(3-(2-(7-클로로-2-퀴놀리닐)-에테닐)페닐)-3-하이드록시프로필)페닐)-2-프로판올(화학식 2; 1 g, 2.18 mmol)을 다이메틸포름아마이드(DMF) 10 mL에 녹이고, 0℃로 냉각하였다. N-브로모숙신이미드(NBS) 0.78 g(4.37 mmol)과 트리에틸포스핀(P(C2H5)3) 0.52 g(4.37 mmol)을 서서히 가한 후 온도를 유지하면서 30분 교반하였다. 반응물을 소량 산처리 분리하여 TLC로 출발물질이 완전히 소모됨을 확인하였다. 한편 다른 반응용기에 1-(머캅토메틸)사이클로프로판아세트산(화학식 4a) 0.38 g(2.47 mmol)을 다이메틸포름아마이드(DMF) 5 mL에 녹이고 10℃로 냉각한 후, 47% NaOH 수용액 0.38 mL를 서서히 가하고, 30분 교반한 후, 위 반응액에 서서히 부가하였다. 10℃에서 30분 교반한 후, 반응물을 실온으로 승온한 후 4시간 더 교반하였다. 반응물에 메틸렌클로라이드 20 mL와 0.5N HCl 수용액 30 mL을 가하여 추출하였다. 유기층을 정제수 30 mL로 2번 세척한 후 포화 소금물로 세척한 후 유기층을 황산마그네슘으로 건조하고 감압 농축하여 실리카겔 컬럼 크로마토분리를 통해 표제 화합물을 0.79 g(1.35 mmol, 62%) 얻었다. 2- (2- (3- (S)-(3- (2- (7-chloro-2-quinolinyl) -ethenyl) phenyl) -3-hydroxypropyl) phenyl) -2-propanol 2; 1 g, 2.18 mmol) was dissolved in 10 mL of dimethylformamide (DMF) and cooled to 0 ° C. 0.78 g (4.37 mmol) of N -bromosuccinimide (NBS) and 0.52 g (4.37 mmol) of triethylphosphine (P (C 2 H 5 ) 3 ) were added slowly, followed by stirring for 30 minutes while maintaining the temperature. The reaction was separated by a small amount of acid treatment to confirm complete consumption of the starting material by TLC. Meanwhile, 0.38 g (2.47 mmol) of 1- (mercaptomethyl) cyclopropane acetic acid (Formula 4a) was dissolved in 5 mL of dimethylformamide (DMF) in another reaction vessel, cooled to 10 ° C., and 0.38 mL of 47% aqueous NaOH solution. Was added slowly, stirred for 30 minutes, and then slowly added to the reaction solution. After 30 minutes of stirring at 10 ° C., the reaction was allowed to warm to room temperature and then further stirred for 4 hours. 20 mL of methylene chloride and 30 mL of 0.5N HCl aqueous solution were added to the reaction. The organic layer was washed twice with 30 mL of purified water and then with saturated brine, and then the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 0.79 g (1.35 mmol, 62%) of the title compound through silica gel column chromatography.

1H NMR(300MHz, CDCl3) δ 8.09(d, 2H), 7.73-7.62(m, 4H), 7.51-7.34(m, 6H), 7.17-7.09(m, 3H), 3.94(t, 1H), 3.13-3.07(m, 1H), 2.82-2.78(m, 1H), 2.50(s, 2H), 2.38(s, 2H), 2.20-2.16(m, 2H), 1.60(d, 6H), 0.57-0.32(m, 4H) 1 H NMR (300 MHz, CDCl 3 ) δ 8.09 (d, 2H), 7.73-7.62 (m, 4H), 7.51-7.34 (m, 6H), 7.17-7.09 (m, 3H), 3.94 (t, 1H) , 3.13-3.07 (m, 1H), 2.82-2.78 (m, 1H), 2.50 (s, 2H), 2.38 (s, 2H), 2.20-2.16 (m, 2H), 1.60 (d, 6H), 0.57 -0.32 (m, 4H)

실시예 3. 몬테루카스트 (화학식 1)의 제조Example 3. Preparation of Montelukast (Formula 1)

2-(2-(3-(S)-(3-(2-(7-클로로-2-퀴놀리닐)-에테닐)페닐)-3-하이드록시프로필)페닐)-2-프로판올(화학식 2; 1.5 g, 3.27 mmol)을 다이메틸포름아마이드(DMF) 15 mL에 녹이고, 0℃로 냉각하였다. N-브로모숙신이미드(NBS) 1.17 g(6.55 mmol)과 트리페닐포스핀(PPh3) 1.71 g(6.55 mmol)을 서서히 가한 후 온도를 유지하면서 30분 교반하였다. 반응물을 소량 산처리 분리하여 TLC로 출발물질이 완전히 소모됨을 확인하였다. 한편 다른 반응용기에 1-(머캅토메틸)사이클로프로판아세트산(화학식 4a) 1.24 g을 DMF 10 mL에 녹이고 0℃로 냉각한 후, NaH 0.18 g(4.44 mmol)을 가하고, 10℃로 반응온도를 유기하며 30분 교반한 후, 위 반응액에 서서히 부가하였다. 10℃에서 30분 교반한 후, 반응물을 실온으로 승온한 후 4시간 더 교반하였다. 반응물에 메틸렌클로라이드 20 mL와 0.5N HCl 수용액 30 mL을 가하여 추출하였다. 유기층을 정제수 50 mL로 2번 세척한 후 포화 소금물 로 세척한 후 유기층을 황산마그네슘으로 건조하고 감압 농축하여 실리카겔 컬럼 크로마토분리를 통해 표제 화합물을 1.49 g(2.55 mmol, 78%) 얻었다. 2- (2- (3- (S)-(3- (2- (7-chloro-2-quinolinyl) -ethenyl) phenyl) -3-hydroxypropyl) phenyl) -2-propanol 2; 1.5 g, 3.27 mmol) was dissolved in 15 mL of dimethylformamide (DMF) and cooled to 0 ° C. 1.17 g (6.55 mmol) of N -bromosuccinimide (NBS) and 1.71 g (6.55 mmol) of triphenylphosphine (PPh 3 ) were added slowly, followed by stirring for 30 minutes while maintaining the temperature. The reaction was separated by a small amount of acid treatment to confirm complete consumption of the starting material by TLC. Meanwhile, 1.24 g of 1- (mercaptomethyl) cyclopropane acetic acid (Formula 4a) was dissolved in 10 mL of DMF, cooled to 0 ° C., and 0.18 g (4.44 mmol) of NaH was added thereto. After stirring for 30 minutes, and slowly added to the reaction solution. After 30 minutes of stirring at 10 ° C., the reaction was allowed to warm to room temperature and then further stirred for 4 hours. 20 mL of methylene chloride and 30 mL of 0.5N HCl aqueous solution were added to the reaction. The organic layer was washed twice with 50 mL of purified water, washed with saturated brine, and then the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 1.49 g (2.55 mmol, 78%) of the title compound through silica gel column chromatography.

1H NMR(300MHz, CDCl3) δ 8.09(d, 2H), 7.73-7.62(m, 4H), 7.51-7.34(m, 6H), 7.17-7.09(m, 3H), 3.94(t, 1H), 3.13-3.07(m, 1H), 2.82-2.78(m, 1H), 2.50(s, 2H), 2.38(s, 2H), 2.20-2.16(m, 2H), 1.60(d, 6H), 0.57-0.32(m, 4H) 1 H NMR (300 MHz, CDCl 3 ) δ 8.09 (d, 2H), 7.73-7.62 (m, 4H), 7.51-7.34 (m, 6H), 7.17-7.09 (m, 3H), 3.94 (t, 1H) , 3.13-3.07 (m, 1H), 2.82-2.78 (m, 1H), 2.50 (s, 2H), 2.38 (s, 2H), 2.20-2.16 (m, 2H), 1.60 (d, 6H), 0.57 -0.32 (m, 4H)

실시예 4. 몬테루카스트 (화학식 1)의 제조Example 4 Preparation of Montelukast (Formula 1)

2-(2-(3-(S)-(3-(2-(7-클로로-2-퀴놀리닐)-에테닐)페닐)-3-하이드록시프로필)페닐)-2-프로판올(화학식 2; 1 g, 2.18 mmol)을 다이메틸포름아마이드(DMF) 10 mL에 녹이고, 0℃로 냉각하였다. N-브로모숙신이미드(NBS) 0.78 g(4.37 mmol)과 트리페닐포스핀(PPh3) 1.14 g(4.37 mmol)을 서서히 가한 후 온도를 유지하면서 30분 교반하였다. 반응물을 소량 산처리 분리하여 TLC로 출발물질이 완전히 소모됨을 확인하였다. 한편 다른 반응용기에 1-(머캅토메틸)사이클로프로판아세트산(화학식 4a) 0.38 g(2.47 mmol)을 다이메틸포름아마이드(DMF) 5 mL에 녹이고 10℃로 냉각한 후, KOH 용액 0.42 mL를 서서히 가하고, 30분 교반한 후, 위 반응액에 서서히 부가하였다. 10℃에서 30분 교반한 후, 반응물을 실온으로 승온한 후 4시간 더 교반하였다. 반응물에 메틸렌클로라이드 20 mL와 0.5N HCl 수용액 30 mL을 가하여 추출하였다. 유기층을 정제수 30 mL로 2번 세척한 후 포화 소금물로 세척한 후 유기층을 황산마그네슘으로 건조하고 감압 농축하여 실리카겔 컬 럼 크로마토분리를 통해 표제 화합물을 0.71 g(62.1%) 얻었다. 2- (2- (3- (S)-(3- (2- (7-chloro-2-quinolinyl) -ethenyl) phenyl) -3-hydroxypropyl) phenyl) -2-propanol 2; 1 g, 2.18 mmol) was dissolved in 10 mL of dimethylformamide (DMF) and cooled to 0 ° C. 0.78 g (4.37 mmol) of N -bromosuccinimide (NBS) and 1.14 g (4.37 mmol) of triphenylphosphine (PPh 3 ) were added slowly, followed by stirring for 30 minutes while maintaining the temperature. The reaction was separated by a small amount of acid treatment to confirm complete consumption of the starting material by TLC. Meanwhile, 0.38 g (2.47 mmol) of 1- (mercaptomethyl) cyclopropane acetic acid (Formula 4a) was dissolved in 5 mL of dimethylformamide (DMF) in another reaction vessel, and cooled to 10 ° C. After the addition, the mixture was stirred for 30 minutes, and then slowly added to the reaction solution. After 30 minutes of stirring at 10 ° C., the reaction was allowed to warm to room temperature and then further stirred for 4 hours. 20 mL of methylene chloride and 30 mL of 0.5N HCl aqueous solution were added to the reaction. The organic layer was washed twice with 30 mL of purified water, washed with saturated brine, and then dried over magnesium sulfate and concentrated under reduced pressure to obtain 0.71 g (62.1%) of the title compound through silica gel column chromatography.

1H NMR(300MHz, CDCl3) δ 8.09(d, 2H), 7.73-7.62(m, 4H), 7.51-7.34(m, 6H), 7.17-7.09(m, 3H), 3.94(t, 1H), 3.13-3.07(m, 1H), 2.82-2.78(m, 1H), 2.50(s, 2H), 2.38(s, 2H), 2.20-2.16(m, 2H), 1.60(d, 6H), 0.57-0.32(m, 4H) 1 H NMR (300 MHz, CDCl 3 ) δ 8.09 (d, 2H), 7.73-7.62 (m, 4H), 7.51-7.34 (m, 6H), 7.17-7.09 (m, 3H), 3.94 (t, 1H) , 3.13-3.07 (m, 1H), 2.82-2.78 (m, 1H), 2.50 (s, 2H), 2.38 (s, 2H), 2.20-2.16 (m, 2H), 1.60 (d, 6H), 0.57 -0.32 (m, 4H)

실시예 5. 몬테루카스트 (화학식 1)의 제조Example 5. Preparation of Montelukast (Formula 1)

2-(2-(3-(S)-(3-(2-(7-클로로-2-퀴놀리닐)-에테닐)페닐)-3-하이드록시프로필)페닐)-2-프로판올(화학식 2; 1 g, 2.18 mmol)을 다이메틸포름아마이드(DMF) 10 mL에 녹이고, 0℃로 냉각하였다. N-브로모숙신이미드(NBS) 0.78 g(4.37 mmol)과 트리페닐포스핀(PPh3) 1.14 g(4.37 mmol)을 서서히 가한 후 온도를 유지하면서 30분 교반하였다. 반응물을 소량 산처리 분리하여 TLC로 출발물질이 완전히 소모됨을 확인하였다. 한편 다른 반응용기에 1-(머캅토메틸)사이클로프로판아세트산(화학식 4a), 0.38 g(2.47 mmol)을 다이메틸포름아마이드(DMF) 5 mL에 녹이고 10℃로 냉각한 후, 칼륨 tert-부톡사이드(tert-BuOK) 0.61 g을 서서히 가하고, 30분 교반한 후, 위 반응액에 서서히 부가하였다. 10℃에서 30분 교반한 후, 반응물을 실온으로 승온한 후 4시간 더 교반하였다. 반응물에 메틸렌클로라이드 20 mL와 0.5N HCl 수용액 30 mL을 가하여 추출하였다. 유기층을 정제수 30 mL로 2번 세척한 후 포화 소금물로 세척한 후 유기층을 황산마그네슘으로 건조하고 감압 농축하여 실리카겔 컬럼 크로마토분리를 통해 표제 화합물을 1.0 g(78.2%) 얻 었다. 2- (2- (3- (S)-(3- (2- (7-chloro-2-quinolinyl) -ethenyl) phenyl) -3-hydroxypropyl) phenyl) -2-propanol 2; 1 g, 2.18 mmol) was dissolved in 10 mL of dimethylformamide (DMF) and cooled to 0 ° C. 0.78 g (4.37 mmol) of N -bromosuccinimide (NBS) and 1.14 g (4.37 mmol) of triphenylphosphine (PPh 3 ) were added slowly, followed by stirring for 30 minutes while maintaining the temperature. The reaction was separated by a small amount of acid treatment to confirm complete consumption of the starting material by TLC. Meanwhile, 0.38 g (2.47 mmol) of 1- (mercaptomethyl) cyclopropane acetic acid (Formula 4a) in another reaction vessel was dissolved in 5 mL of dimethylformamide (DMF) and cooled to 10 ° C., followed by potassium tert -butoxide. 0.61 g of ( tert- BuOK) was added slowly, stirred for 30 minutes, and then slowly added to the reaction solution. After 30 minutes of stirring at 10 ° C., the reaction was allowed to warm to room temperature and then further stirred for 4 hours. 20 mL of methylene chloride and 30 mL of 0.5N HCl aqueous solution were added to the reaction. The organic layer was washed twice with 30 mL of purified water, washed with saturated brine, and then dried over magnesium sulfate and concentrated under reduced pressure to obtain 1.0 g (78.2%) of the title compound through silica gel column chromatography.

1H NMR(300MHz, CDCl3) δ 8.09(d, 2H), 7.73-7.62(m, 4H), 7.51-7.34(m, 6H), 7.17-7.09(m, 3H), 3.94(t, 1H), 3.13-3.07(m, 1H), 2.82-2.78(m, 1H), 2.50(s, 2H), 2.38(s, 2H), 2.20-2.16(m, 2H), 1.60(d, 6H), 0.57-0.32(m, 4H) 1 H NMR (300 MHz, CDCl 3 ) δ 8.09 (d, 2H), 7.73-7.62 (m, 4H), 7.51-7.34 (m, 6H), 7.17-7.09 (m, 3H), 3.94 (t, 1H) , 3.13-3.07 (m, 1H), 2.82-2.78 (m, 1H), 2.50 (s, 2H), 2.38 (s, 2H), 2.20-2.16 (m, 2H), 1.60 (d, 6H), 0.57 -0.32 (m, 4H)

실시예 6. 몬테루카스트 (화학식 1)의 제조Example 6 Preparation of Montelukast (Formula 1)

2-(2-(3-(S)-(3-(2-(7-클로로-2-퀴놀리닐)-에테닐)페닐)-3-하이드록시프로필)페닐)-2-프로판올(화학식 2; 1 g, 2.18 mmol)을 다이메틸포름아마이드(DMF) 10 mL에 녹이고, 0℃로 냉각하였다. N-클로로숙신이미드(NCS) 0.78 g(4.37 mmol)과 트리페닐포스핀(PPh3) 1.14 g(4.37 mmol)을 서서히 가한 후 온도를 유지하면서 30분 교반하였다. 반응물을 소량 산처리 분리하여 TLC로 출발물질이 완전히 소모됨을 확인하였다. 한편 다른 반응용기에 1-(머캅토메틸)사이클로프로판아세트산(화학식 4a) 0.38 g(2.47 mmol)을 다이메틸포름아마이드(DMF) 5 mL에 녹이고 10℃로 냉각한 후, 47% NaOH 수용액 0.38 mL를 서서히 가하고, 30분 교반한 후, 위 반응액에 서서히 부가하였다. 10℃에서 30분 교반한 후, 반응물을 실온으로 승온한 후 4시간 더 교반하였다. 반응물에 메틸렌클로라이드 20 mL와 0.5N HCl 수용액 30 mL를 가하여 추출하였다. 유기층을 정제수 30 mL로 2번 세척한 후 포화 소금물로 세척한 후 유기층을 황산마그네슘으로 건조하고 감압 농축하여 실리카겔 컬럼 크로마토분리를 통해 표제 화합물을 0.96 g(1.65 mmol, 76%) 얻었다. 2- (2- (3- (S)-(3- (2- (7-chloro-2-quinolinyl) -ethenyl) phenyl) -3-hydroxypropyl) phenyl) -2-propanol 2; 1 g, 2.18 mmol) was dissolved in 10 mL of dimethylformamide (DMF) and cooled to 0 ° C. 0.78 g (4.37 mmol) of N -chlorosuccinimide (NCS) and 1.14 g (4.37 mmol) of triphenylphosphine (PPh 3 ) were added slowly, followed by stirring for 30 minutes while maintaining the temperature. The reaction was separated by a small amount of acid treatment to confirm complete consumption of the starting material by TLC. Meanwhile, 0.38 g (2.47 mmol) of 1- (mercaptomethyl) cyclopropane acetic acid (Formula 4a) was dissolved in 5 mL of dimethylformamide (DMF) in another reaction vessel, cooled to 10 ° C., and 0.38 mL of 47% aqueous NaOH solution. Was added slowly, stirred for 30 minutes, and then slowly added to the reaction solution. After 30 minutes of stirring at 10 ° C., the reaction was allowed to warm to room temperature and then further stirred for 4 hours. 20 mL of methylene chloride and 30 mL of 0.5N HCl aqueous solution were added to the reaction. The organic layer was washed twice with 30 mL of purified water, washed with saturated brine, and then the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 0.96 g (1.65 mmol, 76%) of the title compound through silica gel column chromatography.

1H NMR(300MHz, CDCl3) δ 8.09(d, 2H), 7.73-7.62(m, 4H), 7.51-7.34(m, 6H), 7.17-7.09(m, 3H), 3.94(t, 1H), 3.13-3.07(m, 1H), 2.82-2.78(m, 1H), 2.50(s, 2H), 2.38(s, 2H), 2.20-2.16(m, 2H), 1.60(d, 6H), 0.57-0.32(m, 4H) 1 H NMR (300 MHz, CDCl 3 ) δ 8.09 (d, 2H), 7.73-7.62 (m, 4H), 7.51-7.34 (m, 6H), 7.17-7.09 (m, 3H), 3.94 (t, 1H) , 3.13-3.07 (m, 1H), 2.82-2.78 (m, 1H), 2.50 (s, 2H), 2.38 (s, 2H), 2.20-2.16 (m, 2H), 1.60 (d, 6H), 0.57 -0.32 (m, 4H)

실시예 7. 몬테루카스트 메틸 에스테르 (화학식 5)의 제조Example 7 Preparation of Montelukast Methyl Ester (Formula 5)

2-(2-(3-(S)-(3-(2-(7-클로로-2-퀴놀리닐)-에테닐)페닐)-3-하이드록시프로필)페닐)-2-프로판올(화학식 2; 1 g, 2.18 mmol)을 다이메틸포름아마이드(DMF) 10 mL에 녹이고, 0℃로 냉각하였다. N-브로모숙신이미드(NBS) 0.78 g(4.37 mmol)과 트리페닐포스핀(PPh3) 1.14 g(4.37 mmol)을 서서히 가한 후 온도를 유지하면서 30분 교반하였다. 반응물을 소량 산처리 분리하여 TLC로 출발물질이 완전히 소모됨을 확인하였다. 한편 다른 반응용기에 메틸 1-(머캅토메틸)사이클로프로판아세테이트(화학식 4b) 0.38 g(2.47 mmol)을 다이메틸포름아마이드(DMF) 5 mL에 녹이고 10℃로 냉각한 후, NaH 0.12 g(2.96 mmol)을 가하고, 30분 교반한 후, 위 반응액에 서서히 부가하였다. 10℃에서 30분 교반한 후, 반응물을 실온으로 승온한 후 4시간 더 교반하였다. 반응물에 메틸렌클로라이드 20 mL와 0.5N HCl 수용액 30 mL를 가하여 추출하였다. 유기층을 정제수 30 mL로 2번 세척한 후 포화 소금물로 세척한 후 유기층을 황산마그네슘으로 건조하고 감압 농축하여 실리카겔 컬럼 크로마토분리를 통해 표제 화합물을 0.90 g(1.50 mmol, 69%) 얻었다. 2- (2- (3- (S)-(3- (2- (7-chloro-2-quinolinyl) -ethenyl) phenyl) -3-hydroxypropyl) phenyl) -2-propanol 2; 1 g, 2.18 mmol) was dissolved in 10 mL of dimethylformamide (DMF) and cooled to 0 ° C. 0.78 g (4.37 mmol) of N -bromosuccinimide (NBS) and 1.14 g (4.37 mmol) of triphenylphosphine (PPh 3 ) were added slowly, followed by stirring for 30 minutes while maintaining the temperature. The reaction was separated by a small amount of acid treatment to confirm complete consumption of the starting material by TLC. Meanwhile, 0.38 g (2.47 mmol) of methyl 1- (mercaptomethyl) cyclopropane acetate (Formula 4b) was dissolved in 5 mL of dimethylformamide (DMF) in another reaction vessel, and cooled to 10 ° C., followed by 0.12 g of NaH (2.96). mmol) was added, stirred for 30 minutes, and then slowly added to the reaction solution. After 30 minutes of stirring at 10 ° C., the reaction was allowed to warm to room temperature and then further stirred for 4 hours. 20 mL of methylene chloride and 30 mL of 0.5N HCl aqueous solution were added to the reaction. The organic layer was washed twice with 30 mL of purified water and then with saturated brine, and then the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 0.90 g (1.50 mmol, 69%) of the title compound through silica gel column chromatography.

1H NMR(300MHz, CDCl3) δ 8.09(d, 2H), 7.73-7.62(m, 4H), 7.51-7.34(m, 6H), 7.17-7.09(m, 3H), 3.94(t, 1H), 3.59(s, 3H), 3.14-3.12(m, 1H), 2.89-2.85(m, 1H), 2.5-2.19(m, 2H), 2.07(s, 2H), 1.60(d, 6H), 0.50-0.38(m, 4H) 1 H NMR (300 MHz, CDCl 3 ) δ 8.09 (d, 2H), 7.73-7.62 (m, 4H), 7.51-7.34 (m, 6H), 7.17-7.09 (m, 3H), 3.94 (t, 1H) , 3.59 (s, 3H), 3.14-3.12 (m, 1H), 2.89-2.85 (m, 1H), 2.5-2.19 (m, 2H), 2.07 (s, 2H), 1.60 (d, 6H), 0.50 -0.38 (m, 4H)

실시예 8. 2-(2-(3-(S)-(3-(2-(7-클로로-2-퀴놀리닐)-에테닐)페닐)-3-브로모트리페닐포스핀옥시프로필)페닐)-2-프로판올 (화학식 3)의 제조Example 8. 2- (2- (3- (S)-(3- (2- (7-chloro-2-quinolinyl) -ethenyl) phenyl) -3-bromotriphenylphosphineoxypropyl ) Phenyl) -2-propanol (Formula 3)

2-(2-(3-(S)-(3-(2-(7-클로로-2-퀴놀리닐)-에테닐)페닐)-3-하이드록시프로필)페닐)-2-프로판올(화학식 2; 4 g, 8.72 mmol)을 메틸렌클로라드 40 mL에 녹이고, -5℃ 내지 0℃로 냉각하였다. N-브로모숙신이미드(NBS) 3.12 g(17.48 mmol)과 트리페닐포스핀(PPh3) 4.48 g(17.48 mmol)을 서서히 가한 후 온도를 유지하면서 30분 교반하였다. TLC로 출발물질이 완전히 소모됨을 확인한 후, 저온에서 용매를 제거하고, 에틸아세테이트 50 mL으로 추출하여 노란색 고체로 표제 화합물을 6.81 g(8.51 mmol) 얻었다. 2- (2- (3- (S)-(3- (2- (7-chloro-2-quinolinyl) -ethenyl) phenyl) -3-hydroxypropyl) phenyl) -2-propanol 2; 4 g, 8.72 mmol) was dissolved in 40 mL of methylene chloride and cooled to -5 ° C to 0 ° C. 3.12 g (17.48 mmol) of N -bromosuccinimide (NBS) and 4.48 g (17.48 mmol) of triphenylphosphine (PPh 3 ) were added slowly, followed by stirring for 30 minutes while maintaining the temperature. After confirming that the starting material was completely consumed by TLC, the solvent was removed at low temperature, and extracted with 50 mL of ethyl acetate to give 6.81 g (8.51 mmol) of the title compound as a yellow solid.

1H NMR(300MHz, CDCl3) δ 8.91(s, 2H), 8.70(m, 2H), 7.91-8.21(m, 7H), 7.42-7.68(m, 5H), 7.08-7.34(m, 15H), 5.00(t, 1H), 3.55(m, 1H), 2.23-2.89(m, 3H), 1.66(d, 6H), 0.57-0.32(m, 4H) 1 H NMR (300 MHz, CDCl 3 ) δ 8.91 (s, 2H), 8.70 (m, 2H), 7.91-8.21 (m, 7H), 7.42-7.68 (m, 5H), 7.08-7.34 (m, 15H) , 5.00 (t, 1H), 3.55 (m, 1H), 2.23-2.89 (m, 3H), 1.66 (d, 6H), 0.57-0.32 (m, 4H)

FT-IR(KBr, cm-1) ν 3411, 3045, 2978, 2931, 1706, 1626, 1600, 1483, 1386, 1159 , 1074, 972, 761, 696FT-IR (KBr, cm -1 ) ν 3411, 3045, 2978, 2931, 1706, 1626, 1600, 1483, 1386, 1159, 1074, 972, 761, 696

실시예 9. 몬테루카스트 (화학식 1)의 제조Example 9 Preparation of Montelukast (Formula 1)

실시예 8을 통해 얻은 2-(2-(3-(S)-(3-(2-(7-클로로-2-퀴놀리닐)-에테닐)페닐)-3-브로모트리페닐포스핀옥시프로필)페닐)-2-프로판올(화학식 3) 3.40 g(4.25 mmol)을 다이메틸포름아마이드(DMF) 20 mL에 녹이고 0℃로 냉각하여 교반하였다. 한편 다른 반응용기에 1-(머캅토메틸)사이클로프로판아세테이트(화학식 4a) 0.93 g(6.37 mmol)을 다이메틸포름아마이드(DMF) 10 mL에 녹이고 10℃로 냉각한 후, 47% NaOH 수용액 0.93 mL를 가하고, 30분 교반한 후, 위 반응액에 서서히 부가하였다. 10℃에서 30분 교반한 후, 반응물을 실온으로 승온한 후 4시간 더 교반하였다. 반응물에 메틸렌클로라이드 20 mL와 0.5N HCl 수용액 30 mL을 가하여 추출하였다. 유기층을 정제수 30 mL로 2번 세척한 후 포화 소금물로 세척한 후 유기층을 황산마그네슘으로 건조하고 감압 농축하여 실리카겔 컬럼 크로마토분리를 통해 표제 화합물을 1.71 g(2.93 mmol, 69%) 얻었다. 2- (2- (3- (S)-(3- (2- (7-chloro-2-quinolinyl) -ethenyl) phenyl) -3-bromotriphenylphosphine obtained through Example 8 3.40 g (4.25 mmol) of oxypropyl) phenyl) -2-propanol (Formula 3) was dissolved in 20 mL of dimethylformamide (DMF), cooled to 0 ° C., and stirred. In another reaction vessel, 0.93 g (6.37 mmol) of 1- (mercaptomethyl) cyclopropane acetate (Formula 4a) was dissolved in 10 mL of dimethylformamide (DMF), cooled to 10 ° C, and then 0.93 mL of an aqueous 47% NaOH solution. Was added and stirred for 30 minutes, and then slowly added to the reaction solution. After 30 minutes of stirring at 10 ° C., the reaction was allowed to warm to room temperature and then further stirred for 4 hours. 20 mL of methylene chloride and 30 mL of 0.5N HCl aqueous solution were added to the reaction. The organic layer was washed twice with 30 mL of purified water, washed with saturated brine, and then dried over magnesium sulfate and concentrated under reduced pressure to obtain 1.71 g (2.93 mmol, 69%) of the title compound through silica gel column chromatography.

1H NMR(300MHz, CDCl3) δ 8.09(d, 2H), 7.73-7.62(m, 4H), 7.51-7.34(m, 6H), 7.17-7.09(m, 3H), 3.94(t, 1H), 3.59(s, 3H), 3.14-3.12(m, 1H), 2.89-2.85(m, 1H), 2.5-2.19(m, 2H), 2.07(s, 2H), 1.60(d, 6H), 0.50-0.38(m, 4H) 1 H NMR (300 MHz, CDCl 3 ) δ 8.09 (d, 2H), 7.73-7.62 (m, 4H), 7.51-7.34 (m, 6H), 7.17-7.09 (m, 3H), 3.94 (t, 1H) , 3.59 (s, 3H), 3.14-3.12 (m, 1H), 2.89-2.85 (m, 1H), 2.5-2.19 (m, 2H), 2.07 (s, 2H), 1.60 (d, 6H), 0.50 -0.38 (m, 4H)

실시예 10. 몬테루카스트 메틸 에스테르 (화학식 5)의 제조Example 10 Preparation of Montelukast Methyl Ester (Formula 5)

실시예 8를 통해 얻은 2-(2-(3-(S)-(3-(2-(7-클로로-2-퀴놀리닐)-에테닐)페 닐)-3-브로모트리페닐포스핀옥시프로필)페닐)-2-프로판올(화학식 3) 3.40 g (4.25 mmol)을 다이메틸포름아마이드(DMF) 20 mL에 녹이고 0℃로 냉각하여 교반하였다. 한편 다른 반응용기에 메틸 1-(머캅토메틸)사이클로프로판아세테이트(화학식 4b) 1.02 g(6.37 mmol)을 THF 15 mL에 녹이고 10℃로 냉각한 후, NaH 0.31 g (7.64mmol)를 서서히 가하고, 30분 교반한 후, 위 반응액에 서서히 부가하였다. 10℃에서 30분 교반한 후, 반응물을 실온으로 승온한 후 4시간 더 교반하였다. 반응물에 메틸렌클로라이드 50 mL와 0.5N HCl 수용액 60 mL을 가하여 추출하였다. 유기층을 정제수 50 mL로 2번 세척한 후 포화 소금물로 세척한 후 유기층을 황산마그네슘으로 건조하고 감압 농축하여 실리카겔 컬럼 크로마토분리를 통해 표제 화합물을 1.65 g(2.76 mmol, 65%) 얻었다. 2- (2- (3- (S)-(3- (2- (7-chloro-2-quinolinyl) -ethenyl) phenyl) -3-bromotriphenylforce obtained through Example 8 3.40 g (4.25 mmol) of pinoxypropyl) phenyl) -2-propanol (Formula 3) were dissolved in 20 mL of dimethylformamide (DMF), cooled to 0 ° C., and stirred. Meanwhile, 1.02 g (6.37 mmol) of methyl 1- (mercaptomethyl) cyclopropane acetate (Formula 4b) was dissolved in 15 mL of THF, cooled to 10 ° C, and 0.31 g (7.64 mmol) of NaH was gradually added thereto. After stirring for 30 minutes, the reaction solution was slowly added. After 30 minutes of stirring at 10 ° C., the reaction was allowed to warm to room temperature and then further stirred for 4 hours. 50 mL of methylene chloride and 60 mL of 0.5N HCl aqueous solution were added to the reaction. The organic layer was washed twice with 50 mL of purified water and then with saturated brine, and then the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 1.65 g (2.76 mmol, 65%) of the title compound through silica gel column chromatography.

1H NMR(300MHz, CDCl3) δ 8.09(d, 2H), 7.73-7.62(m, 4H), 7.51-7.34(m, 6H), 7.17-7.09(m, 3H), 3.94(t, 1H), 3.59(s, 3H), 3.14-3.12(m, 1H), 2.89-2.85(m, 1H), 2.5-2.19(m, 2H), 2.07(s, 2H), 1.60(d, 6H), 0.50-0.38(m, 4H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.09 (d, 2H), 7.73-7.62 (m, 4H), 7.51-7.34 (m, 6H), 7.17-7.09 (m, 3H), 3.94 (t, 1H) , 3.59 (s, 3H), 3.14-3.12 (m, 1H), 2.89-2.85 (m, 1H), 2.5-2.19 (m, 2H), 2.07 (s, 2H), 1.60 (d, 6H), 0.50 -0.38 (m, 4 H).

실시예 11. 몬테루카스트 (화학식 1)의 제조Example 11 Preparation of Montelukast (Formula 1)

실시예 10을 통해 얻은 몬테르카스트 메틸 에스테르 (화학식 5) 0.90 g을 메탄올 5 mL에 녹이고, 47% NaOH 수용액 0.1 mL를 가하고 상온에서 4시간을 교반한 후, TLC를 통해 반응의 완결을 확인하고, 0.5N HCL 15 mL와 메틸렌클로라이드 20 mL를 가하여 추출하였다. 유기층을 정제수 20 mL로 2번 세척한 후 포화 소금물 로 세척한 후 유기층을 황산마그네슘으로 건조하고 감압 농축하여 실리카겔 컬럼 크로마토분리를 통해 표제 화합물을 0.84 g(1.43 mmol, 95%) 얻었다.Dissolve 0.90 g of montecaste methyl ester (Formula 5) obtained in Example 10 in 5 mL of methanol, add 0.1 mL of 47% NaOH aqueous solution, and stir at room temperature for 4 hours, and confirm the completion of the reaction by TLC. 15 mL of 0.5N HCL and 20 mL of methylene chloride were added for extraction. The organic layer was washed twice with 20 mL of purified water, washed with saturated brine, and then the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 0.84 g (1.43 mmol, 95%) of the title compound through silica gel column chromatography.

1H NMR(300MHz, CDCl3) δ 8.09(d, 2H), 7.73-7.62(m, 4H), 7.51-7.34(m, 6H), 7.17-7.09(m, 3H), 3.94(t, 1H), 3.13-3.07(m, 1H), 2.82-2.78(m, 1H), 2.50(s, 2H), 2.38(s, 2H), 2.20-2.16(m, 2H), 1.60(d, 6H), 0.57-0.32(m, 4H) 1 H NMR (300 MHz, CDCl 3 ) δ 8.09 (d, 2H), 7.73-7.62 (m, 4H), 7.51-7.34 (m, 6H), 7.17-7.09 (m, 3H), 3.94 (t, 1H) , 3.13-3.07 (m, 1H), 2.82-2.78 (m, 1H), 2.50 (s, 2H), 2.38 (s, 2H), 2.20-2.16 (m, 2H), 1.60 (d, 6H), 0.57 -0.32 (m, 4H)

실시예 12. 몬테루카스트 메틸 에스테르 (화학식 1)의 제조Example 12. Preparation of Montelukast Methyl Ester (Formula 1)

2-(2-(3-(S)-(3-(2-(7-클로로-2-퀴놀리닐)-에테닐)페닐)-3-하이드록시프로필)페닐)-2-프로판올(화학식 2; 1.5 g, 3.27 mmol)을 다이메틸포름아마이드(DMF) 15 mL에 녹이고, 0℃로 냉각하였다. N-클로로숙신이미드(NCS) 1.17 g(6.55 mmol)과 트리페닐포스핀(PPh3) 1.71 g(6.55 mmol)을 서서히 가한 후 온도를 유지하면서 30분 교반하였다. 반응물을 소량 산처리 분리하여 TLC로 출발물질이 완전히 소모됨을 확인하였다. 한편 다른 반응용기에 메틸 1-(머캅토메틸)사이클로프로판아세테이트(화학식 4b), 0.59 g(3.70 mmol)을 다이메틸포름아마이드(DMF) 8 mL에 녹이고 10℃로 냉각한 후, 47% NaOH 수용액 0.59 mL를 서서히 가하고, 30분 교반한 후, 위 반응액에 서서히 부가하였다. 10℃에서 30분 교반한 후, 반응물을 실온으로 승온한 후 4시간 더 교반하고 TLC를 통해 화합물 5의 완결을 확인하였다. 반응물을 0℃로 냉각한 후, 47% NaOH 수용액 0.30 mL를 가하고 서서히 반응물의 온도를 상승시켜 상온에서 8시간을 교반하여 메틸에스터를 가수분해하였다. 반응물에 메틸렌클로라이드 30 mL와 0.5N HCl 수용액 40 mL을 가하여 추출하였다. 유기층을 정제수 40 mL로 2번 세척한 후 포화 소금물로 세척한 후 유기층을 황산마그네슘으로 건조하고 감압 농축하여 실리카겔 컬럼 크로마토분리를 통해 표제 화합물을 1.39 g(2.38 mmol, 73%) 얻었다. 2- (2- (3- (S)-(3- (2- (7-chloro-2-quinolinyl) -ethenyl) phenyl) -3-hydroxypropyl) phenyl) -2-propanol 2; 1.5 g, 3.27 mmol) was dissolved in 15 mL of dimethylformamide (DMF) and cooled to 0 ° C. 1.17 g (6.55 mmol) of N -chlorosuccinimide (NCS) and 1.71 g (6.55 mmol) of triphenylphosphine (PPh 3 ) were added slowly, followed by stirring for 30 minutes while maintaining the temperature. The reaction was separated by a small amount of acid treatment to confirm complete consumption of the starting material by TLC. Meanwhile, 0.59 g (3.70 mmol) of methyl 1- (mercaptomethyl) cyclopropane acetate (Formula 4b) was dissolved in 8 mL of dimethylformamide (DMF) in another reaction vessel, and cooled to 10 ° C., followed by 47% aqueous NaOH solution. 0.59 mL was slowly added, stirred for 30 minutes, and then slowly added to the reaction solution. After stirring at 10 ° C. for 30 minutes, the reaction was allowed to warm up to room temperature and then stirred for another 4 hours to confirm completion of compound 5 via TLC. After the reaction was cooled to 0 ° C., 0.30 mL of an aqueous 47% NaOH solution was added thereto, and the temperature of the reaction product was gradually raised, followed by stirring at room temperature for 8 hours to hydrolyze the methyl ester. 30 mL of methylene chloride and 40 mL of 0.5N HCl aqueous solution were added to the reaction. The organic layer was washed twice with 40 mL of purified water, washed with saturated brine, and then the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 1.39 g (2.38 mmol, 73%) of the title compound through silica gel column chromatography.

1H NMR(300MHz, CDCl3) δ 8.09(d, 2H), 7.73-7.62(m, 4H), 7.51-7.34(m, 6H), 7.17-7.09(m, 3H), 3.94(t, 1H), 3.13-3.07(m, 1H), 2.82-2.78(m, 1H), 2.50(s, 2H), 2.38(s, 2H), 2.20-2.16(m, 2H), 1.60(d, 6H), 0.57-0.32(m, 4H) 1 H NMR (300 MHz, CDCl 3 ) δ 8.09 (d, 2H), 7.73-7.62 (m, 4H), 7.51-7.34 (m, 6H), 7.17-7.09 (m, 3H), 3.94 (t, 1H) , 3.13-3.07 (m, 1H), 2.82-2.78 (m, 1H), 2.50 (s, 2H), 2.38 (s, 2H), 2.20-2.16 (m, 2H), 1.60 (d, 6H), 0.57 -0.32 (m, 4H)

실시예 13. 몬테루카스트의 나트륨염 (화학식 1)의 제조Example 13. Preparation of Sodium Salt of Montelukast (Formula 1)

몬테루카스트 3.5 g을 무수 톨루엔 10 mL를 가하고, 별도의 용기에서 에탄올 10 mL에 NaOH 0.24 g을 완전히 녹인 용액을 상온에서 앞서 녹여놓은 톨루엔 용액에 서서히 부가하며 30분을 교반하였다. 상온에서 용액을 감압 제거하고, 35 ℃ 정도로 약간 승온한 상태에서 농축액에 에틸아세테이트 50 mL를 서서히 부가하며, 미리 얻어놓은 결정 20 mg을 시딩하여 결정성을 확립하고, 1시간 이상 교반하여 미백색 고체로 표제 화합물을 35.2 g(98%) 얻었다. 10 g of anhydrous toluene was added to 3.5 g of montelukast, and a solution obtained by completely dissolving 0.24 g of NaOH in 10 mL of ethanol in a separate container was slowly added to the previously dissolved toluene solution at room temperature and stirred for 30 minutes. The solution was removed under reduced pressure at room temperature, and 50 mL of ethyl acetate was slowly added to the concentrated solution at a slightly elevated temperature of about 35 ° C., 20 mg of the obtained crystal was seeded to establish crystallinity, and stirred for 1 hour or more to yield a white white solid. 35.2 g (98%) of the title compound were obtained.

1H NMR(300MHz, CDCl3) δ 7.93(d, 2H), 7.59-7.11(m, 11H), 7.05-6.90(m, 3H), 3.92(m, 1H), 3.24(m, 1H), 2.65-2.03(m, 7H), 1.50(d, 6H), 0.37-0.10(m, 4H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.93 (d, 2H), 7.59-7.11 (m, 11H), 7.05-6.90 (m, 3H), 3.92 (m, 1H), 3.24 (m, 1H), 2.65 -2.03 (m, 7H), 1.50 (d, 6H), 0.37-0.10 (m, 4H).

본 발명의 몬테루카스트 제조방법은 종래의 방법에서 합성경로를 크게 단축시켜 공정상 이로울 뿐만 아니라, 경제성이 있는 산업적 제조방법이라 할 수 있다. 또한, 본 발명의 제조방법에서 중간체로 합성되는 상기 화학식 3으로 표시되는 (S)-포스핀옥소 화합물은 신규 화합물이며, 이 중간체 화합물의 분리 정제없이 일용기 반응으로 커플링 반응을 수행하더라도 고수율 및 고순도로 몬테루카스트를 합성할 수 있어, 종래방법에서 지적된 다단계공정과 수율, 순도의 문제를 해결할 수 있는 유용한 제조기술이다. The montelukast manufacturing method of the present invention can be referred to as an industrial manufacturing method that is economically advantageous as well as the process by greatly shortening the synthesis path in the conventional method. In addition, the (S) -phosphinoxo compound represented by the formula (3) synthesized as an intermediate in the preparation method of the present invention is a novel compound, even if the coupling reaction is carried out in a one-group reaction without separation and purification of the intermediate compound, high yield. And it is possible to synthesize montelukast with high purity, it is a useful manufacturing technology that can solve the problems of the multi-step process, yield, purity pointed out in the conventional method.

따라서, 본 발명의 제조방법은 몬테루카스트의 상업적인 대량생산 공정으로 적용되어서도 충분히 경쟁력이 있다.Therefore, the production method of the present invention is sufficiently competitive even if applied to the commercial mass production process of montelukast.

Claims (11)

할로겐화제 또는 다이에틸아조다이카르복실레이트(DEAD)와, (R1)3P (이때, R1은 C1-C4 알킬기, C1-C4 알콕시기, 또는 페닐기를 나타냄)로 표시되는 포스핀 화합물의 존재 하에서, 하기 화학식 2로 표시되는 (S)-다이올 화합물을 미츠노부 반응(Mitsnobu reaction)시켜 sec-알콜 그룹이 활성화 된 하기 화학식 3으로 표시되는 (S)-포스핀옥소 화합물을 제조하고; Represented by a halogenating agent or diethylazodicarboxylate (DEAD) and (R 1 ) 3 P, wherein R 1 represents a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, or a phenyl group In the presence of a phosphine compound, a (S) -phosphinoxo compound represented by the following formula (3) in which a sec -alcohol group is activated by a Mitsnobu reaction of the (S) -diol compound represented by the following formula (2) To prepare;
Figure 112009019731554-pat00013
Figure 112009019731554-pat00013
 상기 반응식에서, R1은 C1-C4 알킬기, C1-C4 알콕시기, 또는 페닐기를 나타내고, Y는 할로겐원자 또는 에틸아조다이카르복실레이트를 나타내고,In the above scheme, R 1 represents a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, or a phenyl group, Y represents a halogen atom or ethyl azodicarboxylate, 하기 화학식 3으로 표시되는 (S)-포스핀옥소 화합물과 하기 화학식 4a로 표시되는 1-(머캅토메틸)사이클로프로판아세트산을 커플링 반응시켜 하기 화학식 1로 표시되는 몬테루카스트를 제조하는 단계;Preparing a montelukast represented by the following Chemical Formula 1 by coupling a (S) -phosphinoxo compound represented by the following Chemical Formula 3 with 1- (mercaptomethyl) cyclopropaneacetic acid represented by the following Chemical Formula 4a;
Figure 112009019731554-pat00014
Figure 112009019731554-pat00014
 상기 반응식에서, R1 및 Y는 상기에서 정의한 바와 같고,In the above scheme, R 1 and Y are as defined above, 를 포함하여 이루어지는 것을 특징으로 하는 몬테루카스트 또는 이의 약제학적으로 허용 가능한 염의 제조방법.Method for producing montelukast or a pharmaceutically acceptable salt thereof, characterized in that comprising a. 할로겐화제 또는 다이에틸아조다이카르복실레이트(DEAD)와, (R1)3P (이때, R1은 C1-C4 알킬기, C1-C4 알콕시기, 또는 페닐기를 나타냄)로 표시되는 포스핀 화합물의 존재 하에서, 하기 화학식 2로 표시되는 (S)-다이올 화합물을 미츠노부 반응(Mitsnobu reaction)시켜 sec-알콜 그룹이 활성화 된 하기 화학식 3으로 표시되는 (S)-포스핀옥소 화합물을 제조하고; Represented by a halogenating agent or diethylazodicarboxylate (DEAD) and (R 1 ) 3 P, wherein R 1 represents a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, or a phenyl group In the presence of a phosphine compound, a (S) -phosphinoxo compound represented by the following formula (3) in which a sec -alcohol group is activated by a Mitsnobu reaction of the (S) -diol compound represented by the following formula (2) To prepare;
Figure 112009019731554-pat00015
Figure 112009019731554-pat00015
 상기 반응식에서, R1은 C1-C4 알킬기, C1-C4 알콕시기, 또는 페닐기를 나타내고, Y는 할로겐원자 또는 에틸아조다이카르복실레이트를 나타내고,In the above scheme, R 1 represents a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, or a phenyl group, Y represents a halogen atom or ethyl azodicarboxylate, 하기 화학식 3으로 표시되는 (S)-포스핀옥소 화합물과 하기 화학식 4b로 표시되는 1-(머캅토메틸)사이클로프로판아세트산 알킬 에스테르와 커플링 반응시켜, 하기 화학식 5로 표시되는 몬테루카스트 알킬 에스테르 화합물을 제조하고;The montelukast alkyl ester compound represented by the following formula (5) is subjected to a coupling reaction with the (S) -phosphinoxo compound represented by the following formula (3) and the 1- (mercaptomethyl) cyclopropane acetic acid alkyl ester represented by the following formula (4b) To manufacture;
Figure 112009019731554-pat00016
Figure 112009019731554-pat00016
 상기 반응식에서, R1 및 Y는 상기에서 정의한 바와 같고, R2는 C1∼C6의 알킬기를 나타내고,In the above scheme, R 1 and Y are as defined above, R 2 represents an alkyl group of C 1 to C 6 , 하기 화학식 5로 표시되는 몬테루카스트 알킬 에스테르 화합물을 가수분해하여 하기 화학식 1로 표시되는 몬테루카스트를 제조하는 단계; Preparing a montelukast represented by the following Formula 1 by hydrolyzing a montelukast alkyl ester compound represented by the following Formula 5;
Figure 112009019731554-pat00017
Figure 112009019731554-pat00017
 상기 반응식에서, R2는 상기에서 정의한 바와 같고,In the above scheme, R 2 is as defined above, 를 포함하여 이루어지는 것을 특징으로 하는 몬테루카스트 또는 이의 약제학적으로 허용 가능한 염의 제조방법.Method for producing montelukast or a pharmaceutically acceptable salt thereof, characterized in that comprising a. 삭제delete 삭제delete 제 1 항 또는 제 2 항에 있어서, The method according to claim 1 or 2, 상기 미츠노부 반응(Mitsnobu reaction) 온도범위가 -20℃ 내지 40℃인 것을 특징으로 하는 제조방법.The Mitsnobu reaction temperature range of -20 ℃ to 40 ℃ characterized in that the manufacturing method. 제 1 항 또는 제 2 항에 있어서, The method according to claim 1 or 2, 상기 할로겐화제는 N-브로모숙신이미드(NBS), N-클로로숙신이미드(NCS), N-요오드숙신이미드(NIS), 염소(Cl2), 브롬(Br2), 요오도(I2), 및 알칼리금속 할라이드 중에서 선택되는 것을 특징으로 하는 제조방법.The halogenating agent is N -bromosuccinimide (NBS), N -chlorosuccinimide (NCS), N- iodine succinimide (NIS), chlorine (Cl 2 ), bromine (Br 2 ), iodo ( I 2 ), and an alkali metal halide. 제 1 항 또는 제 2 항에 있어서, The method according to claim 1 or 2, 상기 포스핀 화합물은 트리(C1-C6 알킬)포스핀, 트리(C1-C6 알콕시)포스핀, 및 트리페닐포스핀 중에서 선택되는 것을 특징으로 하는 제조방법.Said phosphine compound is selected from tri (C 1 -C 6 alkyl) phosphine, tri (C 1 -C 6 alkoxy) phosphine, and triphenylphosphine. 제 1 항 또는 제 2 항에 있어서, The method according to claim 1 or 2, 상기 커플링 반응은 LiOH, NaOH, NaH, KOH, NaOMe, 및 tert-BuOK 중에서 선택된 알칼리 금속염의 염기 존재하에서 수행하는 것을 특징으로 하는 제조방법.The coupling reaction is carried out in the presence of a base of an alkali metal salt selected from LiOH, NaOH, NaH, KOH, NaOMe, and tert- BuOK. 제 1 항 또는 제 2 항에 있어서, The method according to claim 1 or 2, 상기 커플링 반응 온도범위가 -20℃ 내지 40℃인 것을 특징으로 하는 제조방 법.The coupling reaction temperature range is -20 ℃ to 40 ℃ characterized in that the manufacturing method. 제 2 항에 있어서, The method of claim 2, 상기 커플링 반응이 완결된 반응액 내에서 일용기 반응(one-pot reaction)으로 직접 가수분해 반응을 수행하는 것을 특징으로 하는 제조방법.The method of claim 1, characterized in that the hydrolysis reaction is carried out directly by a one-pot reaction in the reaction solution in which the coupling reaction is completed. 하기 화학식 3으로 표시되는 (S)-포스핀옥소 화합물 :(S) -phosphinoxo compound represented by the following general formula (3): [화학식 3][Formula 3]
Figure 112009019731554-pat00012
Figure 112009019731554-pat00012
 상기 화학식 3에서, R1은 C1-C4 알킬기, C1-C4 알콕시기, 또는 페닐기를 나타내고, Y는 할로겐원자 또는 에틸아조다이카르복실레이트를 나타낸다.In Formula 3, R 1 represents a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, or a phenyl group, and Y represents a halogen atom or ethyl azodicarboxylate.
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KR101323664B1 (en) 2011-05-18 2013-11-06 한국유나이티드제약 주식회사 A process for preparation of montelukast and its intermediates

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