KR102333564B1 - A novel synthetic route for the production of optically active diamine derivative and thiazole derivate - Google Patents
A novel synthetic route for the production of optically active diamine derivative and thiazole derivate Download PDFInfo
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Abstract
에독사반의 제조용 중간체의 제조 방법에 관한 것으로, 에독사반 중간체인 광학활성 다이아민 유도체(7번 화합물) 및 티아졸 유도체(10번 화합물)을 고압장비 및 금속 촉매를 사용하지 않고 높은 수율과 순도로 얻을 수 있는 에독사반의 제조용 중간체의 제조 방법에 관한 것이다.It relates to a method for preparing an intermediate for the preparation of edoxaban, which is an optically active diamine derivative (compound 7) and thiazole derivative (compound 10), which are intermediates of edoxaban, without the use of high-pressure equipment and metal catalysts, with high yield and purity It relates to a method for producing an intermediate for the production of edoxaban that can be obtained as
Description
본 발명은 혈액응고 인자 Xa (fXa) 억제제 화합물의 주요 중간체 및 이의 염의 제조방법에 관한 것으로, 더욱 상세하게는 상기 혈액응고인자 억제제는 에독사반이며, 에독사반 중간체인 광학활성 다이아민 유도체(7번 화합물) 및 티아졸 유도체(10번 화합물)을 고압장비 및 금속 촉매를 사용하지 않고 높은 수율과 순도로 얻을 수 있는 에독사반의 제조용 중간체의 제조 방법에 관한 것이다.The present invention relates to a main intermediate of a blood coagulation factor Xa (fXa) inhibitor compound and a method for preparing a salt thereof, and more particularly, the clotting factor inhibitor is edoxaban, and an optically active diamine derivative ( 7) and a thiazole derivative (compound No. 10), which can be obtained in high yield and purity without the use of high-pressure equipment and metal catalysts, and relates to a method for preparing an intermediate for the preparation of edoxaban.
에독사반 및 그의 염 또는 수화물은 하기 “선행기술문헌”에 기재된 특허 문헌 1 내지 8에 개시된 바와 같이 FXa 억제효과를 나타내며, 항응고 인자로 작용한다. 이에 따라 색전질환, 혈전증의 예방 혹은 치료제로 유용하게 사용된다.Edoxaban and its salts or hydrates exhibit FXa inhibitory effects as disclosed in Patent Documents 1 to 8 described in the following “Prior Art Documents”, and act as an anticoagulant. Accordingly, it is usefully used as a preventive or therapeutic agent for embolic diseases and thrombosis.
하기 반응식 1은 에독사반의 일반적인 합성을 나타낸 것으로, 화합물 7 로 표시되는 tert-butyl ((1R,2S,5S)-5-(dimethylcarbamoyl)-2-(1,3-dioxoisoindolin-2-yl)cyclohexyl)carbamate 및 화합물 10으로 표시되는 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid 또는 이의 염은 화합물 11로 표시되는 에독사반을 생성하기 위한 주요 중간체이다.Scheme 1 below shows the general synthesis of edoxaban, tert-butyl ((1R,2S,5S)-5-(dimethylcarbamoyl)-2-(1,3-dioxoisoindolin-2-yl)cyclohexyl represented by compound 7 ) 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid represented by carbamate and compound 10 or a salt thereof to produce edoxaban represented by compound 11 It is a major intermediate.
[반응식 1][Scheme 1]
반응식 2를 참조하면, 특허문헌 6에는 에독사반을 제조하기 위한 주요 중간체 화합물 7의 제조방법이 개시되어 있다. 먼저 mesyloxy 화합물 15로부터 azide화합물 16을 제조하고, 금속으로 인해 환원반응을 통해 화합물 7을 생성한다. 화합물 7을 제조하기 위한 대안적인 방법은 동일한 특허에 개시되어 반응식 3과 같이 나타낸다. Referring to Scheme 2, Patent Document 6 discloses a method for preparing a major intermediate compound 7 for preparing edoxaban. First, azide compound 16 is prepared from mesyloxy compound 15, and compound 7 is produced through a reduction reaction with metal. An alternative method for preparing compound 7 is disclosed in the same patent and is shown in Scheme 3.
[반응식 2][Scheme 2]
[반응식 3][Scheme 3]
반응식 4는 sulfonamide 유도체를 이용한 입체 선택적 분자 내 고리화 반응으로 인해 화합물 7을 제조하는 방법을 나타낸 것으로, 특허문헌 9(WO2014/157653)에 개시되어 있다. Scheme 4 shows a method for preparing compound 7 due to stereoselective intramolecular cyclization using a sulfonamide derivative, and is disclosed in Patent Document 9 (WO2014/157653).
[반응식 4][Scheme 4]
화합물 7의 염의 공정은 특허문헌 6(WO2007/032498)에 개시되어 있다. 하기 반응식 5에서 나타낸 바와 같이, mesyloxy 화합물 26로부터 azide 화합물 27을 제조한 후 환원시키고 benzyl기를 탈보호 시켜 화합물 7을 유도한다. The process of salt of compound 7 is disclosed in Patent Document 6 (WO2007/032498). As shown in Scheme 5 below, azide compound 27 was prepared from mesyloxy compound 26, reduced, and then compound 7 was induced by deprotecting the benzyl group.
[반응식 5][Scheme 5]
화합물 10의 제조방법은 화합물 31로 표기되는 1-methylpiperidine-4-one으로부터 diazotation 반응으로 고리화가 생성되어 bromide유도체가 만들어지고 이것을 carboxylic acid 화합물로 전환시켜 제조하는 방법과 thiazole유도체로의 cyanation에 이어 가수분해로 인해 제조하는 방법으로 특허 문헌 5(WO2005/047296)에 개시되어 있다.The preparation method of compound 10 is a method of producing a bromide derivative by diazotation reaction from 1-methylpiperidine-4-one represented by compound 31, and converting it into a carboxylic acid compound. A method for preparing by decomposition is disclosed in Patent Document 5 (WO2005/047296).
[반응식 6][Scheme 6]
또한 반응식 7과 같이 amine유도체로부터 Sandmayer 유사 반응을 통해 bromide유도체를 만들고 이를 이산화탄소로 친핵성 첨가반응하여 carboxylic acid 염 형태의 10a를 제조하는 방법이 특허문헌 10 (WO2012/017932)에 개시되어있다.In addition, as shown in Scheme 7, a method for preparing a carboxylic acid salt form 10a by making a bromide derivative through a Sandmayer-like reaction from an amine derivative and reacting it with carbon dioxide to nucleophilic acid is disclosed in Patent Document 10 (WO2012/017932).
[반응식 7][Scheme 7]
하지만 상기와 같은 방법들은 주요 중간체를 제조하기 위해서는 고압장비 및 금속 촉매를 사용해야 하여 폭발성을 갖는 수소를 사용하기 때문에 상업적으로 생산할 시 안전성의 우려가 크다.However, since the above methods use high-pressure equipment and a metal catalyst to produce a major intermediate, and use explosive hydrogen, safety concerns are high when commercially produced.
기존의 에독사반 중간체의 제조 방법은 고압장비 및 금속 촉매를 사용해야 하여 폭발성을 갖는 수소를 사용하기 때문에 상업적으로 생산할 시 안전성의 우려가 컸다는 문제점이 있었기 때문에, 본 발명의 연구자들은 FXa 억제제 화합물의 주요 중간체인 화합물 7과 화합물 10 또는 이의 염의 제조방법에서 안전성을 보장하며 높은 수율을 가질 수 있는 새로운 제조방법에 대한 연구를 하여 본 발명에 이르게 되었다.Since the existing method for preparing the edoxaban intermediate uses high-pressure equipment and a metal catalyst, there was a problem that there was a great concern about safety when commercially produced because it uses explosive hydrogen, so the researchers of the present invention The present invention was reached by conducting a study on a new preparation method capable of ensuring safety and having a high yield in the preparation method of compound 7 and compound 10 or a salt thereof, which are major intermediates.
본 발명은 Fxa 억제제 화합물의 주요 중간체인 화학식 7 및 10으로 표시되는 화합물 또는 이의 염의 새로운 제조방법으로 합성이 가능하며, 이는 고압장비, 폭발성 기체 및 금속 촉매를 사용하지 않고 안전하게 고수율로 생산가능한 조건을 제공하는 것이다. The present invention can be synthesized by a new method for preparing the compounds represented by Chemical Formulas 7 and 10 or salts thereof, which are major intermediates of Fxa inhibitor compounds, which can be safely produced in high yield without using high-pressure equipment, explosive gases and metal catalysts. is to provide
상기와 같은 과제를 해결하기 위하여 본 발명은 하기와 같은 다양한 측면의 해결 수단을 제공한다.In order to solve the above problems, the present invention provides means for solving various aspects as follows.
본 발명의 일측면은 하기 화학식 7로 표시되는 에독사반 중간체 화합물의 제조 방법에 있어서, 상기 방법은 하기 화학식 4로 표시되는 화합물을 프탈이미드(pthalimide)와 반응시켜 화학식 6으로 표시되는 화합물을 제조하는 단계; 및 화학식 6으로 표시되는 화합물을 메틸아민(Methyl amine) 또는 하이드라진 하이드레이트(hydrazine hydrate)의 존재 하에 반응시켜 화학식 7로 표시되는 화합물을 제조하는 단계;를 포함하는, 화학식 7로 표시되는 에독사반 중간체 화합물의 제조 방법을 제공한다:In one aspect of the present invention, in the method for preparing an edoxaban intermediate compound represented by the following formula (7), the method comprises reacting the compound represented by the following formula (4) with phthalimide to obtain a compound represented by the formula (6) manufacturing; And reacting the compound represented by Formula 6 in the presence of methylamine or hydrazine hydrate to prepare a compound represented by Formula 7; Edoxaban intermediate represented by Formula 7, including; Methods for preparing the compounds are provided:
[화학식 7][Formula 7]
[화학식 4][Formula 4]
[화학식 6][Formula 6]
본 발명의 일측면에 있어서, 상기 방법은 하기 화학식 3으로 표시되는 화합물을 트리페닐포스파인(triphenylphosphine)과의 반응한 후 디-터트-부틸 디카보네이트 (di-tert-butyl dicarbonate)와 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계를 더 포함하는, 제조 방법을 제공한다:In one aspect of the present invention, in the method, the compound represented by the following formula (3) is reacted with triphenylphosphine and then reacted with di-tert-butyl dicarbonate (di-tert-butyl dicarbonate) It provides a preparation method, further comprising the step of preparing a compound represented by 4:
[화학식 3][Formula 3]
본 발명의 일측면에 있어서, 상기 방법은 하기 화학식 2로 표시되는 화합물을 암모늄클로라이드(Ammonium chloride)의 존재하에서 소듐아자이드(sodium azide)와 반응시켜 화학식 3으로 표시되는 화합물을 제조하는 단계를 더 포함하는, 제조 방법을 제공한다:In one aspect of the present invention, the method further comprises the step of reacting the compound represented by the following formula (2) with sodium azide in the presence of ammonium chloride to prepare a compound represented by the formula (3) There is provided a manufacturing method comprising:
[화학식 2][Formula 2]
본 발명의 일측면에 있어서, 상기 방법은 하기 화학식 1로 표시되는 화합물을 디사이클로헥실카르보이미드(Dicyclohexylcarbodiimide, DCC), 하이드록시벤조트리아졸(Hydroxybenzotriazole, HOBt), 트리에틸아민(triethylamine) 및 디클로로메탄(dichloromethane)의 존재 하에서 디메틸아민하이드로클로라이드(dimethylamine hydrochloride)와 반응시켜 화학식 2로 표시되는 화합물을 제조하는 단계를 더 포함하는, 제조 방법을 제공한다:In one aspect of the present invention, the method is a compound represented by the following formula (1) dicyclohexylcarbodiimide (Dicyclohexylcarbodiimide, DCC), hydroxybenzotriazole (Hydroxybenzotriazole, HOBt), triethylamine (triethylamine) and dichloro It provides a preparation method, further comprising the step of preparing a compound represented by Formula 2 by reacting with dimethylamine hydrochloride in the presence of methane (dichloromethane):
[화학식 1][Formula 1]
본 발명의 일측면에 있어서, 상기 프탈이미드는 화학식 4로 표시되는 화합물을 기준으로 1 당량 내지 3 당량으로 사용되며, 상기 메틸아민은 화학식 6으로 표시되는 화합물을 기준으로 2 당량 내지 8 당량으로 사용되는, 제조 방법을 제공한다.In one aspect of the present invention, the phthalimide is used in 1 to 3 equivalents based on the compound represented by Formula 4, and the methylamine is used in 2 to 8 equivalents based on the compound represented by Formula 6 A manufacturing method is provided.
본 발명의 일측면에 있어서, 상기 트리페닐포스파인은 화학식 3으로 표시되는 화합물을 기준으로 1 당량 내지 6 당량으로 사용되는, 제조 방법을 제공한다.In one aspect of the present invention, the triphenylphosphine is used in an amount of 1 to 6 equivalents based on the compound represented by Formula 3, and provides a preparation method.
본 발명의 일측면에 있어서, 상기 소듐아자이드는 화학식 2로 표시되는 화합물을 기준으로 1 당량 내지 5 당량으로 사용되는, 제조 방법을 제공한다.In one aspect of the present invention, the sodium azide is used in an amount of 1 to 5 equivalents based on the compound represented by Formula 2, to provide a preparation method.
본 발명의 일측면에 있어서, 상기 디사이클로헥실카르보디이미드는 화학식 1로 표시되는 화합물을 기준으로 1 당량 내지 2당량으로 사용되고, 상기 하이드록시벤조트리아졸은 화학식 1로 표시되는 화합물을 기준으로 1 당량 내지 2당량으로 사용되는, 제조 방법을 제공한다.In one aspect of the present invention, the dicyclohexylcarbodiimide is used in 1 to 2 equivalents based on the compound represented by Formula 1, and the hydroxybenzotriazole is 1 based on the compound represented by Formula 1 used in equivalents to 2 equivalents, is provided.
본 발명의 다른 측면은, 하기 화학식 7로 표시되는 에독사반 중간체 화합물의 제조 방법에 있어서, 상기 방법은 하기 화학식 16으로 표시되는 화합물을 triphenylphosphine 및 용매 존재 하에 환원반응시켜 화학식 7로 표시되는 에독사반 중간체 화합물을 제조하는 단계를 포함하는, 제조 방법을 제공한다:In another aspect of the present invention, in the method for preparing an edoxaban intermediate compound represented by the following formula (7), the method is a reduction reaction of the compound represented by the following formula (16) in the presence of triphenylphosphine and a solvent to edoxa represented by the formula (7) A process for preparing a semi-intermediate compound is provided, comprising the steps of:
[화학식 7][Formula 7]
[화학식 16][Formula 16]
본 발명의 다른 측면에 있어서, 상기 용매는 테트라하이드로퓨란 또는 에탄올인, 제조 방법을 제공한다.In another aspect of the present invention, the solvent is tetrahydrofuran or ethanol.
본 발명의 또 다른 측면은, 하기 화학식 10으로 표시되는 에독사반 중간체 화합물 또는 이의 염의 제조 방법에 있어서, 상기 방법은 (a) 하기 화학식 8로 표시되는 화합물을 염기성 조건하에서 디메틸설페이트(dimethylsulfate)와 반응시켜 화학식 9로 표시되는 화합물을 제조하는 단계; 및 (b) 상기 화학식 9로 표시되는 화합물을 소듐 보로하이드라이드와의 반응 및 무기 염기와의 가수분해 반응으로 화학식 10으로 표시되는 화합물을 제조하는 단계;를 포함하는, 제조 방법을 제공한다:In another aspect of the present invention, in the method for preparing an edoxaban intermediate compound or a salt thereof represented by the following formula (10), the method comprises (a) a compound represented by the following formula (8) under basic conditions with dimethylsulfate (dimethylsulfate) and reacting to prepare a compound represented by Formula 9; and (b) preparing a compound represented by Formula 10 by reacting the compound represented by Formula 9 with sodium borohydride and hydrolysis with an inorganic base;
[화학식 10][Formula 10]
[화학식 8][Formula 8]
[화학식 9][Formula 9]
본 발명의 또 다른 측면에 있어서, 상기 방법은 (c) 화학식 10으로 표시되는 에독사반 중간체 화합물을 하이드로클로라이드로 반응시켜 화학식 10으로 표시되는 에독사반 중간체 화합물의 염을 제조하는 단계;를 더 포함하는, 제조 방법을 제공한다.In another aspect of the present invention, the method comprises the steps of (c) reacting the edoxaban intermediate compound represented by Formula 10 with hydrochloride to prepare a salt of the edoxaban intermediate compound represented by Formula 10; It provides a manufacturing method comprising:
본 발명의 또 다른 측면에 있어서, 상기(a) 단계에서 디메틸설페이트는 화학식 8로 표시되는 화합물을 기준으로 1 당량 내지 4 당량으로 사용되며, 상기 염기는 무기 염기이며, 상기 단계는 디메틸포름아마이드(N,N-dimethylformamide), 디클로로메탄(dichloromethane), 클로로폼(chloroform) 및 테트라하이드로퓨란(tetrahydrofuran) 중에서 선택된 용매하에서 반응하는 것인, 제조 방법을 제공한다.In another aspect of the present invention, in step (a), dimethyl sulfate is used in an amount of 1 to 4 equivalents based on the compound represented by Formula 8, the base is an inorganic base, and the step is dimethylformamide ( N,N-dimethylformamide), dichloromethane (dichloromethane), chloroform (chloroform), and tetrahydrofuran (tetrahydrofuran) in the presence of a solvent selected from the reaction, provides a preparation method.
본 발명의 또 다른 측면에 있어서, 상기(b) 단계에서 소듐 보로하이드라이드는 상기 화학식 9로 표시되는 화합물을 기준으로 1 당량 내지 3 당량으로 사용되며, 상기 (b) 단계에서 무기 염기는 상기 화학식 9로 표시되는 화합물을 기준으로 1 당량 내지 5 당량으로 사용되는, 제조 방법을 제공한다.In another aspect of the present invention, in step (b), sodium borohydride is used in an amount of 1 to 3 equivalents based on the compound represented by Formula 9, and the inorganic base in step (b) is represented by the above formula It provides a preparation method, which is used in an amount of 1 to 5 equivalents based on the compound represented by 9.
본 발명의 또 다른 측면에 있어서, 상기 (c) 단계에서, 하이드로클로라이드는 화학식 10으로 표시되는 화합물을 기준으로 1 당량 내지 6 당량으로 사용되는, 제조 방법을 제공한다.In another aspect of the present invention, in step (c), hydrochloride is used in an amount of 1 to 6 equivalents based on the compound represented by Formula 10, to provide a preparation method.
본 발명의 일 측면에 따른 에독사반의 제조용 중간체의 제조 방법에 의하면, 높은 수율과 순도로 에독사반의 제조용 중간체를 대량 생산할 수 있다.According to the manufacturing method of the intermediate for the preparation of edoxaban according to an aspect of the present invention, it is possible to mass-produce the intermediate for the preparation of edoxaban with high yield and purity.
본 발명의 일 측면에 따른 에독사반의 제조용 중간체의 제조 방법에 의하면, 고압장비 및 금속 촉매의 사용 없이도 안전하게 대량 생산이 가능한 에독사반의 제조용 중간체를 대량 생산할 수 있다.According to the manufacturing method of the intermediate for the preparation of edoxaban according to an aspect of the present invention, it is possible to mass-produce an intermediate for the preparation of edoxaban that can be safely mass-produced without the use of high-pressure equipment and a metal catalyst.
이상의 본 발명의 목적들, 다른 목적들, 특징들 및 이점들은 첨부된 도면과 관련된 이하의 바람직한 실시예들을 통해서 쉽게 이해될 것이다. 그러나 본 발명은 여기서 설명되는 실시예들에 한정되지 않고 다른 형태로 구체화될 수도 있다. 오히려, 여기서 소개되는 실시예들은 개시된 내용이 철저하고 완전해질 수 있도록 그리고 통상의 기술자에게 본 발명의 사상이 충분히 전달될 수 있도록 하기 위해 제공되는 것이다.The above objects, other objects, features and advantages of the present invention will be easily understood through the following preferred embodiments in conjunction with the accompanying drawings. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the embodiments introduced herein are provided so that the disclosed content may be thorough and complete, and the spirit of the present invention may be sufficiently conveyed to those skilled in the art.
달리 명시되지 않는 한, 본 명세서에서 사용된 성분, 반응 조건, 성분의 함량을 표현하는 모든 숫자, 값 및/또는 표현은, 이러한 숫자들이 본질적으로 다른 것들 중에서 이러한 값을 얻는 데 발생하는 측정의 다양한 불확실성이 반영된 근사치들이므로, 모든 경우 "약"이라는 용어에 의해 수식되는 것으로 이해되어야 한다. 또한, 본 기재에서 수치범위가 개시되는 경우, 이러한 범위는 연속적이며, 달리 지적되지 않는 한 이러한 범 위의 최소값으로부터 최대값이 포함된 상기 최대값까지의 모든 값을 포함한다. 더 나아가, 이러한 범위가 정수를 지칭하는 경우, 달리 지적되지 않는 한 최소값으로부터 최대값이 포함된 상기 최대값까지를 포함하는 모든 정수가 포함된다.Unless otherwise specified, all numbers, values, and/or expressions expressing ingredients, reaction conditions, and amounts of ingredients used herein refer to a variety of measures that may occur in obtaining such values, among others, in which such numbers are inherently different. Since they are approximations reflecting uncertainty, it should be understood as being modified by the term "about" in all cases. Also, where the disclosure discloses numerical ranges, such ranges are continuous and inclusive of all values from the minimum to the maximum inclusive of the range, unless otherwise indicated. Furthermore, when such ranges refer to integers, all integers inclusive from the minimum to the maximum inclusive are included, unless otherwise indicated.
본 명세서에 있어서, 범위가 변수에 대해 기재되는 경우, 상기 변수는 상기 범위의 기재된 종료점들을 포함하는 기재된 범위 내의 모든 값들을 포함하는 것으로 이해될 것이다. 예를 들면, "5 내지 10"의 범위는 5, 6, 7, 8, 9, 및 10의 값들뿐만 아니라 6 내지 10, 7 내지 10, 6 내지 9, 7 내지 9 등의 임의의 하위 범위를 포함하고, 5.5, 6.5, 7.5, 5.5 내지 8.5 및 6.5 내지 9 등과 같은 기재된 범위의 범주에 타당한 정수들 사이의 임의의 값도 포함하는 것으로 이해될 것이다. 또한 예를 들면, "10% 내지 30%"의 범위는 10%, 11%, 12%, 13% 등의 값들과 30%까지를 포함하는 모든 정수들뿐만 아니라 10% 내지 15%, 12% 내지 18%, 20% 내지 30% 등의 임의의 하위 범위를 포함하고, 10.5%, 15.5%, 25.5% 등과 같이 기재된 범위의 범주 내의 타당한 정수들 사이의 임의의 값도 포함하는 것으로 이해될 것이다.In this specification, when a range is described for a variable, the variable will be understood to include all values within the stated range including the stated endpoints of the range. For example, a range of “5 to 10” includes the values of 5, 6, 7, 8, 9, and 10, as well as any subranges such as 6 to 10, 7 to 10, 6 to 9, 7 to 9, etc. It will be understood to include any value between integers that are appropriate for the scope of the recited range, such as 5.5, 6.5, 7.5, 5.5 to 8.5 and 6.5 to 9, and the like. Also for example, a range of "10% to 30%" includes values such as 10%, 11%, 12%, 13%, and all integers up to and including 30%, as well as 10% to 15%, 12% to It will be understood to include any subrange, such as 18%, 20% to 30%, etc., as well as any value between reasonable integers within the scope of the recited range, such as 10.5%, 15.5%, 25.5%, and the like.
본 출원에서, "포함하다" 또는 "가지다" 등의 용어는 명세서 상에 기재된 특징, 숫자, 단계, 동작, 구성요소, 부품 또는 이들을 조합한 것이 존재함을 지정하려는 것이지, 하나 또는 그 이상의 다른 특징들이나 숫자, 단계, 동작, 구성요소, 부분품 또는 이들을 조합한 것들의 존재 또는 부가 가능성을 미리 배제하지 않는 것으로 이해되어야 한다.In the present application, terms such as “comprise” or “have” are intended to designate that a feature, number, step, operation, component, part, or combination thereof described in the specification exists, but one or more other features It is to be understood that it does not preclude the possibility of the presence or addition of numbers, steps, operations, components, parts, or combinations thereof.
본 명세서에서 “화학식 X로 표시되는 화합물”과 “화합물 X”는 동일한 의미로 사용된다. 일 구현예에서 “화학식 7로 표시되는 화합물”은 “화합물 7”을 의미하며, “화합물 7”은 “화학식 7로 표시되는 화합물”을 의미한다.In the present specification, "a compound represented by Formula X" and "Compound X" are used with the same meaning. In one embodiment, "compound represented by formula 7" means "compound 7", and "compound 7" means "compound represented by formula 7".
본 발명의 실시예에 따른 주요 중간체인 화학식 7 및 10으로 표시되는 화합물 또는 이의 염의 제조방법은 다음과 같은 단계로 설명한다.A method for preparing the compounds represented by Chemical Formulas 7 and 10 or salts thereof, which are major intermediates according to an embodiment of the present invention, will be described in the following steps.
먼저 화합물 7을 제조하기 위해, 화학식 1로 표시 되는 화합물 1로 부터 커플링 시약의 존재 하에서 dimethyl amine hydrochloride와 반응하여 화학식 2로 표시되는 화합물 2를 얻는 단계, 및 sodium azide에 의한 epoxide의 고리열림반응에 의해 화학식 3으로 표시되는 화합물 3을 준비하는 단계, 이어서 triphenylphosphine으로 환원반응을 거친 후 di-tert-butydicarbonate로 보호하여 화학식 4로 표시되는 화합물 4를 제조하는 단계, triphenylphosphine 및 diisopropyl azodicarboxylate, pthalimide의 존재하에서 Mistunobu 반응을 통해 입체화학반전으로 화학식 6으로 표시되는 화합물 6을 제공하는 단계, 마지막으로 알코올 용매, 화합물 6, methylamine 혹은 hydrazine hydrate의 존재하에 화학식 7로 표시되는 화합물 7을 제조하는 단계를 포함한다. First, in order to prepare compound 7, a step of reacting from compound 1 represented by formula 1 with dimethyl amine hydrochloride in the presence of a coupling reagent to obtain compound 2 represented by formula 2, and ring opening reaction of epoxide with sodium azide preparing compound 3 represented by formula 3 by To provide compound 6 represented by formula 6 by stereochemical inversion through Mistunobu reaction under .
또한 본 발명은 triphenylphosphine으로 azide 화합물을 환원시켜 화합물 7을 제조하는 단계를 제공한다. The present invention also provides a step for preparing compound 7 by reducing the azide compound with triphenylphosphine.
화합물 1의 제조공정은 Journal of the American Chemistry Society, 1990, 112, 2993-3017에 보고되어 있고, 화합물 16은 Bioorganic & Medicinal chemistry 17 (2009) 8206-8220에 기술되어 있다. The manufacturing process of compound 1 is reported in Journal of the American Chemistry Society, 1990, 112, 2993-3017, and compound 16 is described in Bioorganic & Medicinal chemistry 17 (2009) 8206-8220.
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 4][Formula 4]
[화학식 6][Formula 6]
[화학식 7][Formula 7]
[화학식 16][Formula 16]
화학식 10으로 표시되는 화합물의 제조방법 단계로는 화학식 8로 표시되는 화합물 8을 염기성 조건 하에서 dimethyl sulfate와의 반응으로 인해 화학식 9로 표시되는 화합물 9를 얻는 단계, 얻어진 화합물 9를 sodium borohydride와의 환원반응 후 무기염기로 가수분해하여 화학식 10으로 표시되는 화합물 10 또는 그의 염을 얻는 단계를 포함한다. The steps of the preparation method of the compound represented by the formula 10 include the steps of obtaining the compound 9 represented by the formula 9 by reacting the compound 8 represented by the formula 8 with dimethyl sulfate under basic conditions, and a reduction reaction of the obtained compound 9 with sodium borohydride. and hydrolyzing with an inorganic base to obtain Compound 10 represented by Formula 10 or a salt thereof.
화합물 8의 제조방법은 Journal of Heterocyclic chemistry, 27, 1990, 563-566, Bioorganic and medicinal chemistry, 2004, 12, 5579-5586에 기술되어 있다.The preparation method of compound 8 is described in Journal of Heterocyclic chemistry, 27, 1990, 563-566, Bioorganic and medicinal chemistry, 2004, 12, 5579-5586.
[화학식 8][Formula 8]
[화학식 9][Formula 9]
[화학식 10][Formula 10]
하기 반응식 8은 화합물 7의 제조방법을 개략적으로 나타낸 반응식을 나타낸 것이다. Scheme 8 below shows a scheme schematically illustrating a method for preparing compound 7.
[반응식 8][Scheme 8]
화합물 2를 제조하는 단계에서, N,N'-dicyclohexylcarbodiimide (DCC)는 화합물 1을 기준으로 1내지 2당량으로 사용되고 바람직하게는 1당량을 사용한다. Hydroxy benzotriazole은 화합물 1을 기준으로 1내지 2당량을 사용하며 바람직하게는 1당량을 사용한다. 염기 및 용매의 사용에는 제한이 없으나 triethylamine과 dichloromethane을 사용한다.In the step of preparing compound 2, N,N'-dicyclohexylcarbodiimide (DCC) is used in 1 to 2 equivalents based on compound 1, preferably 1 equivalent. Hydroxy benzotriazole is used in 1 to 2 equivalents based on Compound 1, preferably 1 equivalent. There are no restrictions on the use of bases and solvents, but triethylamine and dichloromethane are used.
화합물 3을 제조하는 단계에 사용되는 Sodium azide는 1당량 내지 5당량이 사용되지만 바람직하게는 화합물2를 1몰 기준으로 3당량이 적절하다. Ammonium chloride은 1당량 내지 4당량이 사용되고 화합물2를 기준으로 2당량을 사용 하는 것이 바람직하다. 용매로서는 methanol, ethanol, isopropyl alcohol 중 하나를 포함하며 바람직하게는 methanol을 사용한다. 반응조건은 전형적으로 80℃ 내지 95℃ 범위내에서 10시간에서 20시간 교반을 하며 바람직하게는 15시간 동안 교반 한다.Sodium azide used in the step of preparing compound 3 is used in an amount of 1 to 5 equivalents, but preferably 3 equivalents based on 1 mole of compound 2 is appropriate. Ammonium chloride is used in an amount of 1 to 4 equivalents, and it is preferable to use 2 equivalents based on Compound 2. The solvent includes one of methanol, ethanol, and isopropyl alcohol, and preferably methanol is used. The reaction conditions are typically in the range of 80°C to 95°C, stirring for 10 to 20 hours, and preferably stirring for 15 hours.
화합물 4의 제조단계의 triphenylphosphine은 화합물 3을 기준으로 1내지 6당량 사용되지만 바람직하게는2당량을 사용하고, di-tert-butyldicarbonate는 1당량 내지 3당량의 범위 내에서 2당량 사용이 바람직하다. 염기와 용매로서는 제한적이지 않지만 상대적으로 triethylamine, tetrahydrofuran을 사용으로 한다.Triphenylphosphine in the preparation step of compound 4 is used in 1 to 6 equivalents based on compound 3, but preferably 2 equivalents, and di-tert-butyldicarbonate is preferably used in 2 equivalents within the range of 1 to 3 equivalents. The base and solvent are not limited, but relatively triethylamine and tetrahydrofuran are used.
화합물 6의 제조에서의 pthalimide는 화합물 4를 기준으로 1내지 3당량을 사용하지만 바람직하게는 1당량으로 반응을 진행하고, triphenylphosphine은 1내지 2당량의 범위내에서 1.1당량 사용이 바람직하다. Diisopropylazodicarboxylate는 1당량 내지 3당량 내의 범위로 바람직하게는 1.1당량을 사용한다. 용매로는 tetrahydrofuran이 사용되고 반응 조건으로는 상온에서 5시간 내지 20시간까지 반응이 진행이 가능하지만 바람직하게는 10시간이 적절하다. 생성물의 결정화를 위한 정제 용매는 diethylether, diisopropylether, methyl tert-butylether이 사용될 수 있으며 diisopropylether가 바람직하다.In the preparation of compound 6, 1 to 3 equivalents of pthalimide are used based on compound 4, but preferably 1 equivalent is used for the reaction, and 1.1 equivalents of triphenylphosphine is preferably used within the range of 1 to 2 equivalents. Diisopropylazodicarboxylate is preferably used in an amount of 1.1 equivalents in the range of 1 to 3 equivalents. As the solvent, tetrahydrofuran is used, and the reaction can be carried out at room temperature for 5 to 20 hours, but preferably 10 hours is appropriate. As a purification solvent for crystallization of the product, diethylether, diisopropylether, or methyl tert-butylether may be used, and diisopropylether is preferable.
화합물 7을 제조하기 위한 단계에서의 methylamine의 사용은 2당량 내지 8당량 범위내에서 4당량이 적절하다. 용매로서는 methyl alcohol, ethyl alcohol이 사용될 수 있지만 바람직하게는 ethyl alcohol을 사용한다.In the step for preparing compound 7, 4 equivalents of methylamine is appropriate within the range of 2 to 8 equivalents. As the solvent, methyl alcohol or ethyl alcohol may be used, but ethyl alcohol is preferably used.
하기 반응식 9를 참조하면, 화합물 10의 제조방법을 개략적으로 설명한다.Referring to Scheme 9 below, a method for preparing compound 10 will be schematically described.
[반응식 9][Scheme 9]
화합물 9를 제조하는 단계는 염기조건 하에서 반응이 진행되며 dimethylsulfate는 1내지 4당량 범위내에서 2당량이 적절하고, 사용되는 염기로서는 sodium carbonate, potassium carbonate와 같은 무기염기가 사용되지만 potassium carbonate이 적절하다. 용매는 N,N-dimethylformamide, dichloromethane, chloroform, tetrahydrofuran를 포함하며 N,N-dimethylformamide가 적절하다.In the step of preparing compound 9, the reaction proceeds under basic conditions, and 2 equivalents of dimethylsulfate is appropriate within the range of 1 to 4 equivalents. As the base used, inorganic bases such as sodium carbonate and potassium carbonate are used, but potassium carbonate is appropriate. . The solvent includes N,N-dimethylformamide, dichloromethane, chloroform, and tetrahydrofuran, and N,N-dimethylformamide is suitable.
화합물 10 또는 이의 염을 제조하는 단계로는 화합물 9를 기준으로 sodium borohydride 1내지 3당량 사용으로 바람직하게는 1.3당량이 적절하다. 사용되는 염기로는 sodium hydroxide, potassium hydroxide와 같은 무기염기가 사용되지만 바람직하게는 sodium hydroxide가 사용되며, 화합물 9를 기준으로 1내지 5당량 범위내에서 3당량이 적절하다. 화합물 10의 염을 제조하기 위해서는 hydrochloric acid가 사용되는데 이는 1N 내지 6N과 1당량 내지 6당량의 범위내에서 6N의 5eq이 적절하다.In the step of preparing Compound 10 or a salt thereof, 1 to 3 equivalents of sodium borohydride is used based on Compound 9, and preferably 1.3 equivalents is appropriate. As the base used, an inorganic base such as sodium hydroxide or potassium hydroxide is used, but sodium hydroxide is preferably used, and 3 equivalents is appropriate within the range of 1 to 5 equivalents based on compound 9. In order to prepare the salt of compound 10, hydrochloric acid is used, and 5eq of 6N is suitable within the range of 1N to 6N and 1 equivalent to 6 equivalents.
이하, 구체적인 실시예를 통해 본 발명을 보다 구체적으로 설명한다. 하기 실시예는 본 발명의 이해를 돕기 위한 예시에 불과하며, 본 발명의 범위가 이에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through specific examples. The following examples are merely examples to help the understanding of the present invention, and the scope of the present invention is not limited thereto.
실시예 1: (1S,3S,6R)-7-oxabicyclo[4.1.0]heptane-3-carboxylic acid(1)의 제조방법 (Journal of the American Chemical Society, 1990, 112, 2998-3017) Example 1: Preparation of (1S,3S,6R)-7-oxabicyclo[4.1.0]heptane-3-carboxylic acid (1) (Journal of the American Chemical Society, 1990, 112, 2998-3017)
Dichloromethane (100 ml)에 (S)-cyclohex-3-ene-1-carboxylic acid 39 (10.0 g, 0.079 mol)이 용해되어 있는 반응기에 meta-chloroperbenzoic acid (13.6 g, 0.079 mol) in dichloromethane (100 ml)을 천천히 적가한 후 3시간 동안 상온에서 교반하였다. 반응이 종결되면, 0.2M NaOH (100 ml)을 첨가하여 추출하였다. 층 분리 후 수층에 dichloromethane (150 ml)로 추출하고, 층분리를 하였다. 분리된 유기층을 합하여 0.2M NaOH (100 ml), 정제수 (150 ml)로 세척한 후 유기층을 분리한다. 유기층을 Na2SO4으로 수분을 제거하고, 여과, 감압농축을 통해 용매를 제거하였다. 농축된 결과물을 컬럼정제 (MeOH/Dichloromethane)하여 생성물을 얻었다. [9.0 g, 80 %]. 순도 [98.5%].In a reactor in which (S)-cyclohex-3-ene-1-carboxylic acid 39 (10.0 g, 0.079 mol) is dissolved in dichloromethane (100 ml), meta-chloroperbenzoic acid (13.6 g, 0.079 mol) in dichloromethane (100 ml) ) was slowly added dropwise and stirred at room temperature for 3 hours. Upon completion of the reaction, 0.2M NaOH (100 ml) was added to extract. After layer separation, the aqueous layer was extracted with dichloromethane (150 ml), and the layers were separated. The separated organic layers were combined and washed with 0.2M NaOH (100 ml) and purified water (150 ml), and then the organic layer was separated. Moisture was removed from the organic layer with Na2SO4, and the solvent was removed through filtration and concentration under reduced pressure. The concentrated resultant was purified by column (MeOH/Dichloromethane) to obtain a product. [9.0 g, 80%]. Purity [98.5%].
실시예 2: Example 2: (1S,3S,6R)-N,N-dimethyl7-oxabicyclo[4.1.0]heptane-3-carboxamide(2)의 제조방법Preparation of (1S,3S,6R)-N,N-dimethyl7-oxabicyclo[4.1.0]heptane-3-carboxamide (2)
(1S,3S,6R)-7-oxabicyclo[4.1.0]heptane-3-carboxylic acid 1 (15 g, 0.106 mol), dicyclohexylcarbodiimide (21.78 g 0.106 mol), 1-hydroxybenzotriazole (14.26 g, 0.106 mol), triethylamine (10.6 g, 0.117 mol)을 dichloromethane (150 ml)에 녹인 후 상온에서 10분간 교반하였다. 이어서 Dimethylamine hydrochloride (8.5 g, 0.106 mol)을 첨가한 후 상온에서 12시간 동안 교반하였다. 생성된 고체를 여과하고, 여과액에 1N NaOH (50 ml)을 넣어주어 세척하였다. 수층을 dichloromethane (2 x 50 ml)로 추출하고, 유기층을 모두 합한 후, MgSO4로 수분을 건조하고 여과, 농축, silica column 정제 (5% MeOH/CH2Cl2)를 통해 생성물을 얻었다. [16 g, 90%]. 순도 [99%].(1S,3S,6R)-7-oxabicyclo[4.1.0]heptane-3-carboxylic acid 1 (15 g, 0.106 mol), dicyclohexylcarbodiimide (21.78 g 0.106 mol), 1-hydroxybenzotriazole (14.26 g, 0.106 mol), Triethylamine (10.6 g, 0.117 mol) was dissolved in dichloromethane (150 ml) and stirred at room temperature for 10 minutes. Then, dimethylamine hydrochloride (8.5 g, 0.106 mol) was added and stirred at room temperature for 12 hours. The resulting solid was filtered and washed by adding 1N NaOH (50 ml) to the filtrate. The aqueous layer was extracted with dichloromethane (2 x 50 ml), the organic layers were combined, dried over MgSO4, filtered, concentrated, and purified by silica column (5% MeOH/CH2Cl2) to obtain a product. [16 g, 90%]. Purity [99%].
실시예 3: Example 3: (1S,3R,4R)-3-azido-4-hydroxy-N,N-dimethylcyclohexane-10carboxamide(3)의 합성Synthesis of (1S,3R,4R)-3-azido-4-hydroxy-N,N-dimethylcyclohexane-10carboxamide (3)
(1S,3S,6R)-N,N-dimethyl-7-oxoabicyclo[4.1.0]heptane-3-carboxamide 2 (20 g, 0.118 mol)이 Methanol (200 ml)에 녹아 있는 반응기에 ammoniumchloride (12,6 g, 0.236 mol), 정제수 (100 ml) 중 sodium azide (23.0 g, 0.354 mol)를 0℃에서 30분동안 적가한 후, 90℃ 에서 15시간 동안 교반하였다. 반응이 종결되면, 반응 혼합물을 여과하고 상온으로 냉각하고 감압농축을 통해 Methanol을 제거하였다. 정제수 (100ml)과 dichloromethane (200 ml)을 농축 결과물에 넣고 추출을 하였다. 정제수(100 ml x 3)로 유기층을 세척하고 분리된 유기층을 합하여 Na2SO4로 수분을 제거하였다. 수분이 제거된 유기층을 여과하고 여과액을 농축하여 생성물을 얻었다. [21.3 g, 85%]. 순도 [98.2%].(1S,3S,6R)-N,N-dimethyl-7-oxoabicyclo[4.1.0]heptane-3-carboxamide 2 (20 g, 0.118 mol) was dissolved in methanol (200 ml) in a reactor with ammoniumchloride (12, 6 g, 0.236 mol) and sodium azide (23.0 g, 0.354 mol) in purified water (100 ml) were added dropwise at 0° C. for 30 minutes, followed by stirring at 90° C. for 15 hours. Upon completion of the reaction, the reaction mixture was filtered, cooled to room temperature, and concentrated under reduced pressure to remove methanol. Purified water (100 ml) and dichloromethane (200 ml) were added to the concentrated resultant, followed by extraction. The organic layer was washed with purified water (100 ml x 3), the separated organic layers were combined, and moisture was removed with Na2SO4. The organic layer from which moisture was removed was filtered, and the filtrate was concentrated to obtain a product. [21.3 g, 85%]. Purity [98.2%].
실시예 4: Example 4: Tert-butyl ((1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl)carbamate (4)의 합성Synthesis of tert-butyl ((1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl)carbamate (4)
(1S,3S,4R)-3-azido-4-hydroxy-N,N-dimethylcyclohexane-1-carboxamide 3 (15 g, 0.0707 mol)와 THF/H2O (150 ml/5 ml)의 혼합물에 triphenylphosphine (18.5 g, 0.141 mol)을 첨가하고 상온에서 6시간 교반하였다. 추가적으로, THF (50 ml), di-tert-butyl decarbonate (15.4 g, 0.078 mol), triethylamine (7.15 g, 0.141 mol)을 첨가하고 상온에서 4시간 교반하였다. 반응 종결 후, 감압농축으로 인해 THF를 제거하고 dichloromethane (300 ml)을 넣고 추출하였다. 분리된 유기층에 Na2SO4로 수분을 제거한 후 여과하고 여과액은 감압농축으로 용매를 제거하였다. Ethyl acetate (100 ml)로 결정화 하여 생성물을 얻었다. [18.2 g, 90%]. 순도 [99.1%].(1S,3S,4R)-3-azido-4-hydroxy-N,N-dimethylcyclohexane-1-carboxamide 3 (15 g, 0.0707 mol) and triphenylphosphine (18.5 in a mixture of THF/H2O (150 ml/5 ml) g, 0.141 mol) and stirred at room temperature for 6 hours. Additionally, THF (50 ml), di-tert-butyl decarbonate (15.4 g, 0.078 mol), and triethylamine (7.15 g, 0.141 mol) were added and stirred at room temperature for 4 hours. After completion of the reaction, THF was removed by concentration under reduced pressure, dichloromethane (300 ml) was added, and extraction was performed. The separated organic layer was filtered after removing moisture with Na2SO4, and the solvent was removed from the filtrate by concentration under reduced pressure. The product was obtained by crystallization with ethyl acetate (100 ml). [18.2 g, 90%]. Purity [99.1%].
실시예 5: Example 5: Tert-butyl ((1R,2R,5S)-5-(dimethylcarbamoyl)-2-(1,3-dioxoisoindolin-2-yl)cyclohexyl)carbamate (6)Tert-butyl ((1R,2R,5S)-5-(dimethylcarbamoyl)-2-(1,3-dioxoisoindolin-2-yl)cyclohexyl)carbamate (6)
Tert-butyl ((1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl)carbamate 4, phthalimide 5 (15.41 g, 0.105 mol), triphenylphosphine (30.22 g, 0.115 mol), tetrahydrofuran (200 ml)가 담겨있는 반응기에 tetrahydrofuran (100 ml) 중 diisopropylazodicarboxylate (23.31 g, 0.115 mol) 용액을 0℃에서 천천히 적가하고 30분 동안 교반에 이어서 상온에서 10시간 동안 교반하였다. 반응이 완료되면, 과포화 염화나트륨 수용액 (100 ml)을 넣어준 후 ethylacetate (100 ml x 3) 추출하였다. 분리된 유기층을 NaSO4로 수분을 제거하고 여과하여 여과액의 용매를 감압농축으로 제거하였다. 생성된 결정은 ether로 결정을 풀어주어 생성물을 얻었다. [38.3 g, 88%]. 순도 [98.3%].Tert-butyl ((1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl)carbamate 4, phthalimide 5 (15.41 g, 0.105 mol), triphenylphosphine (30.22 g, 0.115 mol), tetrahydrofuran (200 ml) A solution of diisopropylazodicarboxylate (23.31 g, 0.115 mol) in tetrahydrofuran (100 ml) in tetrahydrofuran (100 ml) was slowly added dropwise at 0° C., stirred for 30 minutes, and then stirred at room temperature for 10 hours. Upon completion of the reaction, a supersaturated aqueous sodium chloride solution (100 ml) was added, followed by extraction with ethylacetate (100 ml x 3). The separated organic layer was dried with NaSO4, filtered, and the solvent of the filtrate was removed by concentration under reduced pressure. The formed crystal was released by ether to obtain a product. [38.3 g, 88%]. Purity [98.3%].
실시예 6:Example 6: Tert-butyl ((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate (7)의 합성Synthesis of tert-butyl ((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate (7)
Ethanol (50 ml)에 tert-butyl ((1R,2S,5S)-5-(dimethylcarbamoyl)-2-(1,3-dioxoisoindolin-2-yl)cyclohexyl)carbamate 6 (10 g, 0.024 mol)을 녹인 후 monomethyl amine 수용액 (35 ml)을 25-30℃에서 첨가하였다. 반응물을 3시간 동안 가열환류한 후 농축하여 반응용매를 제거하였다. 정제수와 dichloromethane으로 추출하고 분리된 유기층을 Na2SO4으로 수분을 제거하였다. 유기층을 여과하고 여과액은 감압농축으로 인해 용매가 제거하여 생성물을 얻었다.[5.84 g, 85%]. 순도 [99.8%].Dissolve tert-butyl ((1R,2S,5S)-5-(dimethylcarbamoyl)-2-(1,3-dioxoisoindolin-2-yl)cyclohexyl)carbamate 6 (10 g, 0.024 mol) in ethanol (50 ml) Then, an aqueous solution of monomethyl amine (35 ml) was added at 25-30°C. The reaction mixture was heated to reflux for 3 hours and then concentrated to remove the reaction solvent. After extraction with purified water and dichloromethane, the separated organic layer was dried with Na2SO4. The organic layer was filtered, and the solvent was removed from the filtrate by concentration under reduced pressure to obtain a product [5.84 g, 85%]. Purity [99.8%].
녹는점: 121.7-121.0℃Melting Point: 121.7-121.0℃
실시예 7: Example 7: Tert-butyl((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate (7)의 합성:Synthesis of Tert-butyl((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate (7):
반응기에 tert-butyl((1R,2S,5S)-2-azido-5-(dimethylcarbamoyl)cyclohexyl)carbamate 16 (10 g, 0.032 mol), Methanol/H2O (100 ml/5 ml), triphenylphosphine (25.27 g, 0.096 mol)을 넣고 상온에서 10시간 동안 교반하였다. 반응 종결 후 감압증류로 반응용매를 제거하고 dichloromethane과 정제수를 넣어주어 추출한다. 분리된 유기층의 수분을 제거하고 여과 후 여과액의 용매를 감압농축으로 제거하였다. 농축 결과물은 acetonitrile로 결정화하여 생성물을 얻었다. [7.79 g, 80%]. 순도 [99%].tert-butyl((1R,2S,5S)-2-azido-5-(dimethylcarbamoyl)cyclohexyl)carbamate 16 (10 g, 0.032 mol), Methanol/H2O (100 ml/5 ml), triphenylphosphine (25.27 g , 0.096 mol) and stirred at room temperature for 10 hours. After completion of the reaction, the reaction solvent is removed by distillation under reduced pressure, and dichloromethane and purified water are added for extraction. After removing moisture from the separated organic layer and filtering, the solvent of the filtrate was removed by concentration under reduced pressure. The concentrated product was crystallized with acetonitrile to obtain a product. [7.79 g, 80%]. Purity [99%].
실시예 8: Thiazole[5.4-c]pyridine (33)의 합성 (Journal of Heterocyclic chemistry,27,1990,563-566) Example 8: Synthesis of Thiazole [5.4-c] pyridine (33) (Journal of Heterocyclic chemistry, 27,1990,563-566)
4-aminopyridine-3-thiol 39 (10 g, 0.079 mol), ethanol (90ml), formic acid(10 ml)을 반응기에 넣고 4시간 동안 가열환류하였다. 반응종결 후 정제수 (50 ml)에 부어주고 5N NaOH와 ethyl acetate로 추출하였다. 분리된 유기층의 수분을 제거하고 농축하여 생성물을 얻었다. [9.71 g, 90%]. 순도 [97%].4-aminopyridine-3-thiol 39 (10 g, 0.079 mol), ethanol (90 ml), and formic acid (10 ml) were placed in a reactor and heated to reflux for 4 hours. After completion of the reaction, it was poured into purified water (50 ml) and extracted with 5N NaOH and ethyl acetate. The separated organic layer was removed from moisture and concentrated to obtain a product. [9.71 g, 90%]. Purity [97%].
실시예 9: Thiazole[5,4-c]pyridine-2-carboxylic acid (8)의 합성 (Bioorganic and medicinal chemistry, 2004, 12, 5579-5586) Example 9: Synthesis of Thiazole[5,4-c]pyridine-2-carboxylic acid (8) (Bioorganic and medicinal chemistry, 2004, 12, 5579-5586)
질소 하에서 Tetrahydrofuran (200 ml) 중 thiazole[5,4-c]pyridine 33 (20 g, 0.147 mol)에 n-BuLi (hexanes 중 1.54 M, 0.162 mol)을 -78℃에서 20분 동안 적가하고, CO2 가스를 30분동안 버블링하여 투입시켰다. 반응물을 상온시킨 후 감압농축으로 용매를 제거하여 생성물을 얻었다. [24.3 g, 92%]. 순도 [98.9%].n-BuLi (1.54 M in hexanes, 0.162 mol) was added dropwise to thiazole[5,4-c]pyridine 33 (20 g, 0.147 mol) in Tetrahydrofuran (200 ml) under nitrogen at -78°C for 20 minutes, and CO2 The gas was introduced by bubbling for 30 minutes. After the reaction was allowed to warm to room temperature, the solvent was removed by concentration under reduced pressure to obtain a product. [24.3 g, 92%]. Purity [98.9%].
실시예 10:Example 10: 2-(methoxycarbonyl)-5-methylthiazolo[5.4-c]pyridine-5-ium(9)의 합성Synthesis of 2-(methoxycarbonyl)-5-methylthiazolo[5.4-c]pyridine-5-ium(9)
반응기에 thiazolo[5,4-c]pyridine-2-carboxylic acid 8 (18 g, 0.1 mol), potassium carbonate (27.64 g, 0.2 mol), dimethylformamide (180 ml)을 넣고 65℃로 가열한 후, dimethylsulfate (23.5 g, 0.2 mol)을 30분을 걸쳐 천천히 적가하였다. 반응 혼합물을 80℃에서 1시간동안 교반하고 난 후 얼음물에 부어주었다. 생성된 결정을 여과, 진공건조를 하여 생성물을 얻었다. [18.6 g, 89%]. 순도 [99%].Put thiazolo[5,4-c]pyridine-2-carboxylic acid 8 (18 g, 0.1 mol), potassium carbonate (27.64 g, 0.2 mol), dimethylformamide (180 ml) in a reactor and heat to 65°C, then dimethylsulfate (23.5 g, 0.2 mol) was slowly added dropwise over 30 minutes. The reaction mixture was stirred at 80° C. for 1 hour and then poured into ice water. The resulting crystals were filtered and vacuum dried to obtain a product. [18.6 g, 89%]. Purity [99%].
실시예 11: 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid(10)의 합성Example 11: Synthesis of 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid (10)
2-(methoxycarbonyl)-5-methylthiazolo[5,4-c]pyridine-5-ium 9 (100.0 g, 1.0 eq), methanol (10 V, 1000 ml)을 반응기에 넣고, 상온에서 교반하였다. 10℃로 냉각 후, sodium borohydride (23.5 g, 1.3 당량)을 30분에 3번을 걸쳐 천천히 첨가하였다. 반응 혼합물을 상온에서 5시간 동안 교반하고 NaOH 수용액 (정제수 200 ml 중 수산화나트륨 57.4 g, 3.0 당량)을 10분에 걸쳐 첨가하였다. 75℃에서 2시간 동안 가열환류 한 후, 냉각하여 상온에서 1시간 동안 교반하였다. Acetic acid (100 ml)을 반응 혼합물에 첨가하여 pH 6.5-7로 적정하고 생성된 고체를 여과, 건조를 통해 생성물을 얻었다. [79.5 g, 84%]. 순도[98.7%].2-(methoxycarbonyl)-5-methylthiazolo[5,4-c]pyridine-5-ium 9 (100.0 g, 1.0 eq), methanol (10 V, 1000 ml) was put into a reactor, and the mixture was stirred at room temperature. After cooling to 10° C., sodium borohydride (23.5 g, 1.3 equivalents) was slowly added over 3 times in 30 minutes. The reaction mixture was stirred at room temperature for 5 hours and aqueous NaOH solution (57.4 g of sodium hydroxide in 200 ml of purified water, 3.0 eq.) was added over 10 minutes. After heating to reflux at 75° C. for 2 hours, it was cooled and stirred at room temperature for 1 hour. Acetic acid (100 ml) was added to the reaction mixture, titrated to pH 6.5-7, and the resulting solid was filtered and dried to obtain a product. [79.5 g, 84%]. Purity [98.7%].
실시예 12: 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (10a)의 합성Example 12: Synthesis of 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (10a)
반응기에 2-(methoxycarbonyl)-5-methylthiazolo[5,4-c]pyridine-5-ium 9 (100.0 g, 1.0 당량), methanol (10V, 1000 ml)을 넣고, 10℃로 냉각하였다. Sodium borohydride (23.5 g, 1.3 당량)을 30동안 3번에 걸쳐 적가한 후 상온에서 5시간 동안 교반하였다. 반응기에 NaOH수용액 (정제수 200 ml 중 수산화나트륨 57.4 g, 3.0 당량)을 10분에 걸쳐 첨가하고 75℃에서 2시간 동안 가열환류하였다. 반응이 종료되면, 상온에서 1시간 교반하고 0℃에서 6N HCl (50 ml, 5당량)을 첨가하여 pH 1-2로 적정하였다. 생성된 고체를 여과, 건조하여 생성물을 얻었다. [90.6 g, 81%]. 순도[99%].2-(methoxycarbonyl)-5-methylthiazolo[5,4-c]pyridine-5-ium 9 (100.0 g, 1.0 equiv) and methanol (10V, 1000 ml) were added to the reactor and cooled to 10°C. Sodium borohydride (23.5 g, 1.3 equivalents) was added dropwise over 3 times over 30, followed by stirring at room temperature for 5 hours. An aqueous NaOH solution (57.4 g of sodium hydroxide in 200 ml of purified water, 3.0 equivalents) was added to the reactor over 10 minutes and heated to reflux at 75° C. for 2 hours. Upon completion of the reaction, the mixture was stirred at room temperature for 1 hour and then titrated to pH 1-2 by adding 6N HCl (50 ml, 5 equivalents) at 0°C. The resulting solid was filtered and dried to obtain a product. [90.6 g, 81%]. Purity [99%].
이상, 본 발명의 실시예를 설명하였지만, 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자는 본 발명이 그 기술적 사상이나 필수적인 특징으로 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예는 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.In the above, the embodiments of the present invention have been described, but those of ordinary skill in the art to which the present invention pertains will understand that the present invention may be implemented in other specific forms without changing the technical spirit or essential features. . Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.
Claims (15)
하기 화학식 3으로 표시되는 화합물을 트리페닐포스파인(triphenylphosphine)과의 반응한 후 디-터트-부틸 디카보네이트 (di-tert-butyl dicarbonate)와 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계;
하기 화학식 4로 표시되는 화합물을 프탈이미드(pthalimide)와 반응시켜 화학식 6으로 표시되는 화합물을 제조하는 단계; 및
화학식 6으로 표시되는 화합물을 메틸아민(Methyl amine) 또는 하이드라진 하이드레이트(hydrazine hydrate)의 존재 하에 반응시켜 화학식 7로 표시되는 화합물을 제조하는 단계;를 포함하는,
화학식 7로 표시되는 에독사반 중간체 화합물의 제조 방법:
[화학식 7]
[화학식 3]
[화학식 4]
[화학식 6]
In the method for preparing an intermediate compound of edoxaban represented by the following formula (7), the method comprises:
preparing a compound represented by Formula 4 by reacting the compound represented by the following Chemical Formula 3 with triphenylphosphine and then reacting it with di-tert-butyl dicarbonate;
preparing a compound represented by Formula 6 by reacting the compound represented by Formula 4 with phthalimide; and
Preparing a compound represented by Formula 7 by reacting the compound represented by Formula 6 in the presence of methylamine or hydrazine hydrate; including,
Method for preparing edoxaban intermediate compound represented by Formula 7:
[Formula 7]
[Formula 3]
[Formula 4]
[Formula 6]
상기 방법은 하기 화학식 2로 표시되는 화합물을 암모늄클로라이드(Ammonium chloride)의 존재하에서 소듐아자이드(sodium azide)와 반응시켜 화학식 3으로 표시되는 화합물을 제조하는 단계를 더 포함하는, 제조 방법:
[화학식 2]
The method of claim 1,
The method further comprises the step of reacting the compound represented by the following formula (2) with sodium azide in the presence of ammonium chloride to prepare a compound represented by the formula (3):
[Formula 2]
상기 방법은 하기 화학식 1로 표시되는 화합물을 디사이클로헥실카르보이미드(Dicyclohexylcarbodiimide, DCC), 하이드록시벤조트리아졸(Hydroxybenzotriazole, HOBt), 트리에틸아민(triethylamine) 및 디클로로메탄(dichloromethane)의 존재 하에서 디메틸아민하이드로클로라이드(dimethylamine hydrochloride)와 반응시켜 화학식 2로 표시되는 화합물을 제조하는 단계를 더 포함하는, 제조 방법:
[화학식 1]
4. The method of claim 3,
The method is a compound represented by the following formula (1) dicyclohexylcarbodiimide (Dicyclohexylcarbodiimide, DCC), hydroxybenzotriazole (Hydroxybenzotriazole, HOBt), triethylamine (triethylamine) and dichloromethane (dichloromethane) in the presence of dimethyl Further comprising the step of preparing a compound represented by Formula 2 by reacting with amine hydrochloride (dimethylamine hydrochloride), the preparation method:
[Formula 1]
상기 프탈이미드는 화학식 4로 표시되는 화합물을 기준으로 1 당량 내지 3 당량으로 사용되며,
상기 메틸아민은 화학식 6으로 표시되는 화합물을 기준으로 2 당량 내지 8 당량으로 사용되는, 제조 방법.
The method of claim 1,
The phthalimide is used in an amount of 1 to 3 equivalents based on the compound represented by Formula 4,
The methylamine is used in an amount of 2 to 8 equivalents based on the compound represented by Formula 6.
상기 트리페닐포스파인은 화학식 3으로 표시되는 화합물을 기준으로 1 당량 내지 6 당량으로 사용되는, 제조 방법.
The method of claim 1,
The triphenylphosphine is used in an amount of 1 to 6 equivalents based on the compound represented by Formula 3.
상기 소듐아자이드는 화학식 2로 표시되는 화합물을 기준으로 1 당량 내지 5 당량으로 사용되는, 제조 방법.
4. The method of claim 3,
The sodium azide is used in an amount of 1 to 5 equivalents based on the compound represented by Formula 2, the manufacturing method.
상기 디사이클로헥실카르보디이미드는 화학식 1로 표시되는 화합물을 기준으로 1 당량 내지 2당량으로 사용되고,
상기 하이드록시벤조트리아졸은 화학식 1로 표시되는 화합물을 기준으로 1 당량 내지 2당량으로 사용되는, 제조 방법.
5. The method of claim 4,
The dicyclohexylcarbodiimide is used in an amount of 1 to 2 equivalents based on the compound represented by Formula 1,
The hydroxybenzotriazole is used in an amount of 1 to 2 equivalents based on the compound represented by Formula 1.
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