KR100192150B1 - Preparation method of bis-triazole derivatives - Google Patents

Preparation method of bis-triazole derivatives Download PDF

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KR100192150B1
KR100192150B1 KR1019950044711A KR19950044711A KR100192150B1 KR 100192150 B1 KR100192150 B1 KR 100192150B1 KR 1019950044711 A KR1019950044711 A KR 1019950044711A KR 19950044711 A KR19950044711 A KR 19950044711A KR 100192150 B1 KR100192150 B1 KR 100192150B1
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triazole
bis
present
difluorophenyl
mol
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KR970027072A (en
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백우현
김지한
박윤영
김형근
이준광
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조생현
보령제약주식회사
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
    • B01J20/04—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of alkali metals, alkaline earth metals or magnesium
    • B01J20/046—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of alkali metals, alkaline earth metals or magnesium containing halogens, e.g. halides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

본 발명에 따르면, 옥시란(Ⅱ)과 1H-1,2,4-트리아졸(Ⅲ)을 금속 할라이드 또는 유기아민염(Ⅳ) 촉매 존재 하에서 반응시키는 것을 특징으로 하는 플루코나졸의 제조 방법이 제공된다. 본 발명의 방법은 항진균 작용을 가진 목적 화합물을 보다 높은 수율로 생산할 수 있게 하므로, 공정 경제상 매우 유리하다.According to the present invention, there is provided a method for producing fluconazole, characterized in that an oxirane (II) is reacted with 1H-1,2,4-triazole (III) in the presence of a metal halide or organic amine salt (IV) catalyst. . The process of the present invention enables the production of the desired compound with antifungal action in higher yield, which is very advantageous in process economy.

Description

비스-트리아졸 유도체의 제조방법Method for preparing bis-triazole derivative

본 발명의 항진균 작용을 가진 구조식(Ⅰ)의 비스-트리아졸의 신규 제조방법에 관한 것이다.It relates to a novel process for preparing bis-triazole of formula (I) having an antifungal action of the present invention.

상기 화합물(Ⅰ)은 일반명 플루코나졸로 잘 알려져 있으며, 그 제조 방법으로서 영국 특허 제2,099,818호에 1-[2-(2,4-디플루오로페닐)-2,3,-에폭시프로필]-1H-1,2,4-트리아졸(Ⅱ)과 1H-1,2,4-트리아졸(Ⅲ)의 반응에 의해 비스-트리아졸을 제조하는 방법이 기재되어 있다.The compound (I) is well known by the common name fluconazole, and 1- [2- (2,4-difluorophenyl) -2,3, -epoxypropyl] -1H is disclosed in British Patent No. 2,099,818 as a preparation method thereof. A process for preparing bis-triazoles by reaction of -1,2,4-triazole (II) with 1H-1,2,4-triazole (III) is described.

그러나, 이 방법은 과량의 트리아졸을 사용해야 하고, 수율이 44％(상기 특허 실시예 D)에 불과한 단점을 가지고 있다.However, this method has the disadvantage of using an excess of triazole and having a yield of only 44% (Patent Example D above).

따라서, 본 발명은 선행기술의 문제점을 개선하여 트리아졸과의 반응성을 증대시킴으로써 공업적으로 고수율의 목적 화합물을 제조하고 경제성을 높이는데 목적이 있다.Accordingly, the present invention aims to produce high yield industrial target compounds and increase economics by improving the reactivity with triazoles by improving the problems of the prior art.

본 발명자들은 상기와 같은 목적을 성취하고자 연구를 거듭하여, 하기 반응도식에 나타난 바와 같이, 옥시란 화합물(Ⅱ)을 금속 할라이드 및 유기아민염에서 선택된 촉매를 사용하여 트리아졸(Ⅲ)과 반응시킬 경우 목적 화합물(Ⅰ)을 높은 수율로 수득할 수 있음을 발견하여 본 발명을 완성하였다.In order to achieve the above object, the present inventors have studied and reacted oxirane compound (II) with triazole (III) using a catalyst selected from metal halides and organic amine salts, as shown in the following scheme. The present invention was completed by the discovery that the desired compound (I) can be obtained in high yield.

즉, 본 발명의 방법에 따르면, 칼륨 요오다이드, 칼륨 브로마이드, 나트륨 요오다이드, 나트륨 브로마이드와 같은 금속 할라이드; 및 테트라부틸암모늄 할라이드, 테트라프로필암모늄 할라이드, 테트라에틸암모늄 할라이드, 벤질트리부틸암모늄 할라이드 등을 포함하는 하기 식(Ⅳ)으로 표시되는 유기아민염에서 선택된 촉매를 사용함으로써, 트리아졸과의 반응성을 증가시켜 1단계 반응으로 향상된 수율의 목적물의 수득할 수 있다.That is, according to the method of the present invention, a metal halide such as potassium iodide, potassium bromide, sodium iodide, sodium bromide; And by using a catalyst selected from organic amine salts represented by the following formula (IV) including tetrabutylammonium halide, tetrapropylammonium halide, tetraethylammonium halide, benzyltributylammonium halide and the like, thereby increasing the reactivity with triazole To obtain an improved yield of the desired product in a one step reaction.

(식중, R1, R2, R3, 및 R4는 각각 서로 같거나 다른 C1- C4의 알킬, 저급아릴 알킬 또는 아릴이고, X는 Br 또는 I이다.)Wherein R 1 , R 2 , R 3 , and R 4 are each the same or different C 1 -C 4 alkyl, lower aryl alkyl, or aryl, and X is Br or I.

본 발명에 따르는 반응에서 사용되는 촉매량은 0.05내지 1당량을 사용하며, 바람직하게는 0.05내지 0.1당량이 적당하다.The amount of catalyst used in the reaction according to the present invention is 0.05 to 1 equivalent, preferably 0.05 to 0.1 equivalent.

반응 온도는 50내지 150℃이며, 75-100℃가 바람직하다.Reaction temperature is 50-150 degreeC, and 75-100 degreeC is preferable.

본 발명에서 사용되는 용매로서는 C1- C3알코올, 아세토니트릴, 아세톤, N,N -디메틸포름아미드 등이 바람직하다.As the solvent used in the present invention, C 1 -C 3 alcohol, acetonitrile, acetone, N, N-dimethylformamide and the like are preferable.

본 발명의 방법에 따르면, 금속 할라이드 또는 유기 아민염을 촉매로 사용하여 옥시란과 트리아졸의 반응성을 증가시키므로, 당량의 트리아졸만을 사용하고 비등점이 낮은 회수가능한 용매를 사용하는 경제적인 공정을 수행하여 선행 기술보다 20％이상 수율을 향상시켜 목적 화합물인 비스-트리아졸을 제조할 수 있다.According to the method of the present invention, the metal halide or organic amine salt is used as a catalyst to increase the reactivity of the oxirane and triazole, thereby performing an economical process using only an equivalent of triazole and a low boiling point recoverable solvent. By improving the yield by 20% or more compared to the prior art, the desired compound bis-triazole can be prepared.

본 발명을 하기 실시예에 의해 더 상세히 설명하는바, 본 발명은 하기의 실시예에 국한되는 것은 아니다.The present invention is explained in more detail by the following examples, which are not intended to limit the present invention.

[실시예 1]Example 1

2-(2,4-디플루오로페닐)-1,3,-비스(1H-1,2,4,-트리아졸-1-일)-2-프로판올2- (2,4-difluorophenyl) -1,3, -bis (1H-1,2,4, -triazol-1-yl) -2-propanol

1-[2-(2,4-디플루오로페닐)-2,3-에폭시프로필]-1H-1,2,4-트리아졸 메탄설포네이트(229.5g, 0.69mol), 탄산칼륨(210.0g, 1.52mol), 칼륨 요오다이드(5.7g), 1H-1,2,4-트리아졸(52.3g, 0.75mol)을 에탄올(2L)중에서 3시간 동안 환류시킨다. 에탄올을 감압제거한 다음, 잔사물에 포화 탄산수소나트륨 수용액(2.5L)을 가하여 디클로로메탄(2.5L)으로 추출하고 포화 탄산수소나트륨 수용액(2.5L 씩 2회)으로 세척한다. 물층을 디클로로메탄(2.5L)으로 추출하고 포화 탄산수소나트륨 수용액(2.5L 씩 2회)으로 세척한다. 합한 유기층을 무수 마그네슘 설페이트로 건조시키고 용매를 감압제거한다. 이 잔사물(177.2g)을 이소프로필 알코올(400㎖)에서 재결정하여 표제 화합물 131.6g(62.4％)을 수득한다. 그 여액을 감압농축한 후 이소프로필 알코올에서 결정화하면 6.2g(2.94％)이 추가 수득된다.1- [2- (2,4-difluorophenyl) -2,3-epoxypropyl] -1H-1,2,4-triazole methanesulfonate (229.5 g, 0.69 mol), potassium carbonate (210.0 g , 1.52 mol), potassium iodide (5.7 g), 1H-1,2,4-triazole (52.3 g, 0.75 mol) are refluxed in ethanol (2 L) for 3 hours. After ethanol was removed under reduced pressure, the residue was added with saturated aqueous sodium hydrogen carbonate solution (2.5 L), extracted with dichloromethane (2.5 L), and washed with saturated aqueous sodium hydrogen carbonate solution (2 times 2.5 L each). The water layer is extracted with dichloromethane (2.5 L) and washed with saturated aqueous sodium hydrogen carbonate solution (2 times 2.5 L each). The combined organic layers are dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure. This residue (177.2 g) was recrystallized in isopropyl alcohol (400 mL) to give 131.6 g (62.4%) of the title compound. The filtrate was concentrated under reduced pressure and crystallized in isopropyl alcohol to yield 6.2 g (2.94%).

[실시예 2]Example 2

2-(2,4,-디플루오로페닐)-1,3-비스(1H-1,2,4-트리아졸-1-일)-2-프로판올2- (2,4, -difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) -2-propanol

1-[2-(2,4-디플루오로페닐)-2,3,-에폭시프로필]-1H-1,2,4-트리아졸 메탄설포네이트(22.95g, 0.069mol), 탄산칼륨(21.0g, 0.152mol), 칼륨 브로마이드(0.41g), 1H-1,2,4-트리아졸(5.23g, 0.075mol)을 에탄올(200㎖)중에서 3시간 동안 환류시킨 후 실시예 1과 동일한 과정으로 처리하면 실시예 1과 동일한 표제 화합물 12.9g(61.2％)이 수득된다.1- [2- (2,4-difluorophenyl) -2,3, -epoxypropyl] -1H-1,2,4-triazole methanesulfonate (22.95 g, 0.069 mol), potassium carbonate (21.0 g, 0.152 mol), potassium bromide (0.41 g), 1H-1,2,4-triazole (5.23 g, 0.075 mol) were refluxed in ethanol (200 mL) for 3 hours and then the same procedure as in Example 1 Treatment yields 12.9 g (61.2%) of the same title compound as in Example 1.

[실시예 3]Example 3

2-(2,4,-디플루오로페닐)-1,3-비스(1H-1,2,4-트리아졸-1-일)-2-프로판올2- (2,4, -difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) -2-propanol

1-[2-(2,4-디플루오로페닐)-2,3,-에폭시프로필]-1H-1,2,4-트리아졸 메탄설포네이트(22.95g, 0.069mol), 탄산칼륨(21.0g, 0.152mol), 테트라부틸암모늄 요오다이드(1.27g), 1H-1,2,4-트리아졸(5.23g, 0.075mol)을 에탄올(200㎖)중에서 3시간 동안 환류시킨 후 실시예 1과 동일한 과정으로 처리하면 실시예 1과 동일한 표제 화합물 13.2g(62.6％)이 수득된다.1- [2- (2,4-difluorophenyl) -2,3, -epoxypropyl] -1H-1,2,4-triazole methanesulfonate (22.95 g, 0.069 mol), potassium carbonate (21.0 g, 0.152 mol), tetrabutylammonium iodide (1.27 g), 1H-1,2,4-triazole (5.23 g, 0.075 mol) were refluxed in ethanol (200 mL) for 3 hours, followed by Example 1 13.2 g (62.6%) of the same title compound as in Example 1 was obtained by the same procedure as in.

[실시예 4]Example 4

2-(2,4,-디플루오로페닐)-1,3-비스(1H-1,2,4-트리아졸-1-일)-2-프로판올2- (2,4, -difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) -2-propanol

1-[2-(2,4-디플루오로페닐)-2,3,-에폭시프로필]-1H-1,2,4-트리아졸(11.3g, 47.6mmol), 탄산칼륨(7.2g, 52.1mmol), 칼륨 요오다이드(0.4g), 1H-1,2,4,-트라이졸(3.6g, 52.2mmol)을 에탄올(20㎖)중에서 3시간 동안 환류시킨 후, 실시예 1과 동일한 과정으로 처리하면 실시예 1과 동일한 표제 화합물 9.4g(64.4％)이 수득된다.1- [2- (2,4-difluorophenyl) -2,3, -epoxypropyl] -1H-1,2,4-triazole (11.3 g, 47.6 mmol), potassium carbonate (7.2 g, 52.1 mmol), potassium iodide (0.4 g), 1H-1,2,4, -triazole (3.6 g, 52.2 mmol) were refluxed in ethanol (20 mL) for 3 hours, and then the same procedure as in Example 1 was performed. Treatment yielded 9.4 g (64.4%) of the same title compound as in Example 1.

Claims (2)

하기 구조식(Ⅱ)의 옥시란과 하기 구조식(Ⅲ)의 1H-1,2,4-트라이졸을 반응시켜 하기 구조식(Ⅰ)의 화합물을 제조하는 방법에 있어서, 하기 구조식(Ⅱ) 의 옥시란과 하기 구조식(Ⅲ)의 1H-1,2,4-트라이졸을 금속할라이드 촉매 존재하에서 반응시켜 하기 구조식(Ⅰ)의 화합물을 제조하는 방법.Oxylan of the following structural formula (II) in the method of preparing the compound of the following structural formula (I) by making the oxirane of the following structural formula (II) react with the 1H-1,2,4-triazole of the following structural formula (III). And 1H-1,2,4-triazole of formula (III) below in the presence of a metal halide catalyst to prepare a compound of formula (I). 제1항에 있어서, 금속할라이드 촉매가 칼륨요오다이드 또는 칼륨브로마이드인 것을 특징으로 하는 방법.The method of claim 1 wherein the metal halide catalyst is potassium iodide or potassium bromide.
KR1019950044711A 1995-11-29 1995-11-29 Preparation method of bis-triazole derivatives KR100192150B1 (en)

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