KR20010026648A - A novel process for preparing N-alkyloxycarbonyl-β-alkylsulfonylvaline - Google Patents

A novel process for preparing N-alkyloxycarbonyl-β-alkylsulfonylvaline Download PDF

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KR20010026648A
KR20010026648A KR1019990038050A KR19990038050A KR20010026648A KR 20010026648 A KR20010026648 A KR 20010026648A KR 1019990038050 A KR1019990038050 A KR 1019990038050A KR 19990038050 A KR19990038050 A KR 19990038050A KR 20010026648 A KR20010026648 A KR 20010026648A
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formula
compound
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cycloalkyl
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신현익
황상열
이규웅
이병한
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성재갑
주식회사 엘지화학
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups

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Abstract

PURPOSE: A new method for preparing the title compound by alkylation of β-mercaptovaline and then N-acylation without separation and purification of an intermediate is provided which does not need a polar solvent such as 1,4-dioxine and a process for removing the polar solvent after the reaction and reduces oxidation time by about 1 hr. CONSTITUTION: N-alkyloxycarbonyl-β-alkylsulfonylvaline of formula 3, salts thereof, hydrates, solvates or isomers thereof are prepared by oxidation reaction of a compound of formula 2 in an organic solvent in the presence of hydrogen peroxide and a catalyst. In formula, R1 and R2 are independently H, lower alkyl, cycloalkyl, aryl or arylalkyl; R3 is lower alkyl, cycloalkyl or arylakyl; X is a reaction leaving group.

Description

Ｎ-알킬옥시카보닐-β-알킬술포닐발린의 신규 제조방법 {A novel process for preparing N-alkyloxycarbonyl-β-alkylsulfonylvaline}A novel process for preparing N-alkyloxycarbonyl-β-alkylsulfonylvaline} N-alkyloxycarbonyl-β-alkylsulfonylvaline

본 발명은 하기 화학식 3의 N-알킬옥시카보닐-β-알킬술포닐발린 화합물의 제조방법에 관한 것이다 :The present invention relates to a method for preparing an N-alkyloxycarbonyl-β-alkylsulfonylvaline compound of formula (3):

[화학식 3][Formula 3]

상기식에서,In the above formula,

R1및 R2는 각각 독립적으로 수소, 저급알킬, 사이클로알킬, 아릴 또는 아릴알킬을 나타내고,R 1 and R 2 each independently represent hydrogen, lower alkyl, cycloalkyl, aryl or arylalkyl,

R3는 저급알킬, 사이클로알킬 또는 아릴알킬을 나타낸다.R 3 represents lower alkyl, cycloalkyl or arylalkyl.

상기 화학식 3의 화합물은 인간 면역결핍 바이러스(HIV)의 프로테아제 억제제의 N-말단 그룹을 구성하는 중요한 부분으로 후천성 면역 결핍증(AIDS)의 치료제 개발에 유용하게 사용되며(참조 : 유럽 특허공보 EP 601,486A1 및 EP 490,667A2), 타치키닌 NK-1 리셉터 연구에서도 유용하게 사용되고 있다(참조 : Joisen et al., J. Med. Chem., 1994, 37, 1586).Compound 3 is an important part of the N-terminal group of protease inhibitors of human immunodeficiency virus (HIV), and is usefully used for the development of a therapeutic agent for AIDS (see, for example, European Patent Publication EP 601,486A1). And EP 490,667 A2), and in the study of tachykinin NK-1 receptors (Joisen et al., J. Med. Chem., 1994, 37, 1586).

따라서 화학식 3의 화합물의 제조방법에 대한 많은 연구가 진행되고 있으며, 이미 국내 출원번호 제 96-49288 호에 제조방법이 개시되어 있다. 이 제조방법에 따르면 하기 화학식 1의 β-메르캅토발린으로부터 하기 화학식 2의 N-알킬옥시카보닐-β-메르캅토발린을 제조하여 정제한 후, 옥손(칼륨 하이드로술페이트)과 같은 산화제을 이용하여 화학식 3의 N-알킬옥시카보닐-β-알킬술포닐발린 화합물을 제조할 수 있으며, 이를 반응도식으로 나타내면 하기 반응식 1과 같다 :Therefore, many studies on the preparation method of the compound of Formula 3 have been conducted, and the preparation method has already been disclosed in Korean Application No. 96-49288. According to this preparation method, N-alkyloxycarbonyl-β-mercaptovaline of formula 2 is purified from β-mercaptovaline of formula 1, and then purified using an oxidizing agent such as oxone (potassium hydrosulfate). An N-alkyloxycarbonyl-β-alkylsulfonylvaline compound of Formula 3 may be prepared, and the reaction scheme is represented by the following Scheme 1:

[화학식 1][Formula 1]

[화학식 2][Formula 2]

[화학식 3][Formula 3]

상기 식에서 R1, R2및 R3는 앞에서 정의한 바와 같고, X 는 반응이탈기이다.Wherein R 1 , R 2 and R 3 are as defined above and X is a reaction leaving group.

그러나 이 제조방법은 화학식 2의 화합물을 분리, 정제한 후 반응를 시켜야 하고, 산화제로서 옥손과 같은, 물에 용해되는 것을 과량 사용해야 하므로 반응 용액의 균질성을 유지하기 위하여 물과 잘 혼합되는 1,4-디옥신과 같은 극성 유기 용매를 사용하여야 하며, 또한 산화 단계의 반응시간이 24시간이나 소요된다. 따라서, 기존의 N-알킬옥시카보닐-β-알킬술포닐발린 화합물의 제조방법은 그 제조·정제 공정이 길고 복잡하였다.However, this preparation method requires reaction after separating and purifying the compound of Formula 2, and using an excessive amount of soluble in water, such as oxone, as an oxidant, so that it is mixed well with water to maintain homogeneity of the reaction solution. Polar organic solvents such as dioxins should be used and the reaction time of the oxidation step is 24 hours. Therefore, the conventional manufacturing method of N-alkyloxycarbonyl- (beta) -alkylsulfonyl valine compound has long and complicated the preparation and purification process.

이에 본 발명자들은 기존의 복잡한 공정보다 간단하고 우수한 제조방법의 개발을 위해 노력하던 중, 반응에서 사용되는 산화제로 과산화수소와 촉매를 사용함으로써 하나의 반응용기에서 중간 화합물을 정제할 필요없이 연속적인 반응으로 N-알킬옥시카보닐-β-알킬술포닐발린 화합물을 제조할 수 있음을 확인하고 본 발명을 완성하게 되었다.Therefore, the present inventors are trying to develop a simple and superior manufacturing method than the existing complex process, and by using hydrogen peroxide and catalyst as the oxidant used in the reaction, it is possible to continuously process the intermediate compound in one reaction vessel without having to purify the intermediate compound. The present invention has been completed by confirming that N-alkyloxycarbonyl-β-alkylsulfonylvaline compounds can be prepared.

본 발명에 따르면 알킬화 및 아실화 단계에서의 반응 용액 그대로 유기층과 수성층의 이상(two phase)용매에서 바로 산화 반응을 수행할 수 있으며, 따라서 이상용매를 혼합시키기 위한 1,4-디옥신과 같은 극성 용매를 사용할 필요성이 없고, 이에 따라 반응 완료후 1,4-디옥신과 같은 용매를 제거하기 위한 공정도 더불어 없어지게 된다. 또한, 산화 반응 시간도 약 1시간 정도로 기존의 24시간에 비해 매우 단축되었다.According to the present invention, the reaction solution in the alkylation and acylation step can be directly subjected to the oxidation reaction in the two phase solvent of the organic layer and the aqueous layer, and thus polarity such as 1,4-dioxin for mixing the ideal solvent. There is no need to use a solvent, thus eliminating the process for removing a solvent such as 1,4-dioxin after the reaction is completed. In addition, the oxidation reaction time was also shortened to about 1 hour compared to the existing 24 hours.

본 발명은 하기 화학식 1의 β-메르캅토발린을 알킬화 반응 및 N-아실화 반응을 시키고 이때 생성되는 중간 화합물(하기 화학식 2의 화합물)을 분리·정제할 필요없이 과산화수소와 촉매를 사용하여 이를 산화시킴으로써 하기 화학식 3의 N-알킬옥시카보닐-β-알킬술포닐발린을 제조하는 방법에 관한 것이다. 본 발명은 동일 반응용기 내에서 반응을 연속적·순차적으로 진행시킬 수 있으며, 이를 반응도식으로 나타내면 하기 반응식 2와 같다.In the present invention, the β-mercaptovaline of Formula 1 is subjected to alkylation and N-acylation reaction and is oxidized using hydrogen peroxide and a catalyst without the need to separate and purify the intermediate compound (compound of Formula 2). It relates to a method for producing N-alkyloxycarbonyl-β-alkylsulfonylvaline of formula (III) by: The present invention can proceed the reaction continuously and sequentially in the same reaction vessel, represented by the reaction scheme shown in Scheme 2 below.

[화학식 1][Formula 1]

[화학식 2][Formula 2]

[화학식 3][Formula 3]

상기식에서,In the above formula,

R1및 R2는 각각 독립적으로 수소, 저급알킬, 사이클로알킬, 아릴 또는 아릴알킬을 나타내고,R 1 and R 2 each independently represent hydrogen, lower alkyl, cycloalkyl, aryl or arylalkyl,

R3는 저급알킬, 사이클로알킬 또는 아릴알킬을 나타내며,R 3 represents lower alkyl, cycloalkyl or arylalkyl,

X 는 반응이탈기로서, 할로겐, -OSO2OR3, -OSO2OH, -SO2OH 또는를 나타낸다.X is a leaving group, halogen, -OSO 2 OR 3 , -OSO 2 OH, -SO 2 OH or Indicates.

또한 본 발명은 상기 화학식 2의 화합물을 과산화수소와 촉매를 사용하여 산화시킴으로써 상기 화학식 3의 N-알킬옥시카보닐-β-알킬술포닐발린을 제조하는 방법을 포함한다.The present invention also includes a method of preparing N-alkyloxycarbonyl-β-alkylsulfonylvaline of Chemical Formula 3 by oxidizing the compound of Chemical Formula 2 using hydrogen peroxide and a catalyst.

본 명세서에서 사용되는 용어 "저급알킬" 은 메틸, 에틸, 이소프로필, 이소부틸, t-부틸을 포함하는 탄소수 1 내지 4개의 직쇄 또는 측쇄 알킬을 의미하고, 용어 "사이클로알킬" 은 사이클로헥실을 포함하는 탄소수 4 내지 8원환형의 알킬을 의미한다. 또한, 용어 "아릴" 은 5 내지 6원환형의 모노사이클로 방향족 또는 9 내지 10원환형의 비사이클로 방향족을 의미하며, 이 때 저급알킬, 카보알콕시, 저급알콕시 또는 할로겐이 치환될 수 있다.The term "lower alkyl" as used herein refers to straight or branched chain alkyl of 1 to 4 carbon atoms, including methyl, ethyl, isopropyl, isobutyl, t-butyl, and the term "cycloalkyl" includes cyclohexyl To 4 to 8 membered cyclic alkyl. In addition, the term "aryl" refers to a 5 to 6 membered monocyclo aromatic or 9 to 10 membered bicyclic aromatic, where lower alkyl, carboalkoxy, lower alkoxy or halogen may be substituted.

본 발명의 제조방법에 따라 화학식 3의 화합물 및 그의 염, 수화물, 용매화물을 제조할 수 있다. 또한 화학식 3의 화합물은 비대칭 탄소 중심을 가질 수 있고, 라세미체, 라세미화합물, 부분 입체 이성체 혼합물 및 개개 부분 입체 이성체로서 존재할 수 있으며, 이들 모든 이성체 형태는 본 발명의 제조방법에 의하여 제조될 수 있다.According to the preparation method of the present invention, a compound of Formula 3 and salts, hydrates, and solvates thereof may be prepared. In addition, the compound of formula 3 may have an asymmetric carbon center and may exist as racemates, racemic compounds, diastereomeric mixtures and individual diastereomers, all of these isomeric forms being prepared by the process of the invention. Can be.

이하 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.

화학식 1의 화합물을 염기성 수용액, 바람직하게는 NaOH 수용액을 용매로 하여 R3X (여기에서, R3및 X 는 상기 정의한 바와 같다)와 반응시킨 후, 다시 유기용매 중의 R1OCOCl (여기에서, R1은 상기 정의한 바와 같다) 과 같은 아실화제를 가하여 반응시키고 이어서, 과산화수소 및 촉매를 사용하여 이 반응용기의 반응용액(유기층과 수층의 이상(two phase)용매)에서 연속적으로 산화 반응을 수행하여 화학식 3의 화합물을 수득할 수 있다.The compound of formula 1 is reacted with R 3 X (wherein R 3 and X are as defined above) using a basic aqueous solution, preferably a NaOH aqueous solution as a solvent, and then R 1 OCOCl in an organic solvent, wherein R 1 is reacted by adding an acylating agent such as defined above, followed by continuous oxidation in a reaction solution of the reaction vessel (two phase solvent of the organic layer and the aqueous layer) using hydrogen peroxide and a catalyst. A compound of formula 3 can be obtained.

본 발명의 산화반응에서의 반응 조건은 다음과 같다.The reaction conditions in the oxidation reaction of the present invention are as follows.

산화 반응에서 산화제로 사용되는 과산화수소는 35% 이하의 묽은 수용액으로 하여 사용하며, 일반적으로 화학식 1의 화합물을 기준으로 하여 2 내지 3 당량을 사용한다.Hydrogen peroxide used as the oxidant in the oxidation reaction is used as a dilute aqueous solution of 35% or less, and generally 2 to 3 equivalents based on the compound of formula (1).

촉매로는 전이금속, 전이금속의 산화물·할로겐산화물, 그의 염 또는 알킬전이금속 등의 일반적인 전이금속류를 다양하게 선택하여 사용할 수 있으며, 바람직하게는 텅스텐산(H2WO4), 텅스텐나트륨(Na2WO4), 산화바나듐 (V2O5), 또는 메틸트리옥소레늄 (CH3ReO3)과 같은 전이금속류을 사용한다. 이때 사용하는 촉매의 양은 0.01 몰퍼센트(mol %) 까지 가능하나, 바람직하게는 0.1몰센트에서 3몰퍼센트를 사용한다.As the catalyst, various transition metals such as transition metals, oxides / halogen oxides of transition metals, salts thereof or alkyl transition metals may be selected and used. Preferably, tungstic acid (H 2 WO 4 ) and tungsten sodium (Na) are used. 2 WO 4 ), vanadium oxide (V 2 O 5 ), or transition metals such as methyltrioxenium (CH 3 ReO 3 ). In this case, the amount of catalyst used may be up to 0.01 mol percent (mol%), but preferably 0.1 mol centigrade to 3 mol percent.

반응용매는 물과 유기 용매의 이상(two phase)용매를 사용한다. 여기서 유기용매는 물과 섞이거나, 섞이지 않아도 된다. 따라서 반드시 극성 유기용매를 사용해야할 필요가 없으며 아세톤과 같은 케톤류의 용매를 제외한 거의 모든 유기용매가 사용 가능하다.The reaction solvent uses a two phase solvent of water and an organic solvent. The organic solvent may or may not be mixed with water. Therefore, it is not necessary to use a polar organic solvent, and almost all organic solvents except for solvents of ketones such as acetone can be used.

반응온도는 30~100℃에서 시킬 수 있으며, 50~80℃에서 반응을 수행하는 것이 특히 바람직하다. 또한, 반응시간은 일반적으로 30분 내지 5시간이 소요되며, 바람직하게는 1 내지 2시간 동안 반응을 수행한다.The reaction temperature can be carried out at 30 ~ 100 ℃, it is particularly preferable to carry out the reaction at 50 ~ 80 ℃. In addition, the reaction time generally takes 30 minutes to 5 hours, preferably 1 to 2 hours.

본 반응이 완결되면 반응용액을 상온으로 냉각하고 남아있는 과산화수소를 제거하기 위하여 아황산나트륨(Na2SO3)을 적가한 후, 에틸아세테이트와 같은 아세트류 또는 디클로메탄과 같은 할로겐 유기 용매로 추출, 농축하여 상기 화학식 3의 N-알킬옥시카보닐-β-알킬술포닐발린 화합물을 얻는다. 또한 상기 화학식 3의 화합물을 염의 형태로 수득할 수 있다.When the reaction is completed, the reaction solution is cooled to room temperature and sodium sulfite (Na 2 SO 3 ) is added dropwise to remove remaining hydrogen peroxide, followed by extraction with acetic acid such as ethyl acetate or halogen organic solvent such as dichloromethane. Concentration yields the N-alkyloxycarbonyl-β-alkylsulfonylvaline compound of Chemical Formula 3. In addition, the compound of Formula 3 may be obtained in the form of a salt.

본 발명은 하기 실시예에 의하여 더욱 구체적으로 설명되나, 본 발명의 범위가 이들에 의하여 어떤 식으로든 제한되는 것은 아니다.The invention is illustrated in more detail by the following examples, although the scope of the invention is not limited in any way by these.

실시예 : N-[(1-메틸에톡시)카보닐]-3-(메틸술포닐)-L-발린 디사이클로헥실아민 염의 제조Example: Preparation of N-[(1-methylethoxy) carbonyl] -3- (methylsulfonyl) -L-valine dicyclohexylamine salt

먼저, (L)-페니실아민을 출발물질로 하여 디메틸술페이트와 반응시켜 메르켑탄에 메틸기를 도입하고, 톨루엔 용액속에 있는 이소프로필클로로포르메이트를 사용하여 화학식 4의 화합물 제조한다. 본 발명에 기술된 제조 방법에 따라, 화학식 4의 화합물을 정제없이 연속적인 공정으로 이상(two phase)반응 용매에서 바로 과산화수소와 전이금속 촉매를 이용하는 산화 반응을 수행함으로써 화학식 5의 화합물을 제조한다. 이렇게 수득한 목적화합물을 보다 깨끗이 정제하고, 다루기 용이한 고체로 수득하기 위하여 디사이클로헥실아민을 이용하여 화학식 6의 N-[(1-메틸에톡시)카보닐]-3-(메틸술포닐)-L-발린 디사이클로헥실아민 염으로 제조한다.First, a (L) -phenyl amine is used as a starting material and reacted with dimethyl sulfate to introduce a methyl group into merpentane, and a compound of Chemical Formula 4 is prepared using isopropylchloroformate in a toluene solution. According to the preparation method described in the present invention, the compound of formula 5 is prepared by subjecting the compound of formula 4 to an oxidation reaction using hydrogen peroxide and a transition metal catalyst directly in a two-phase reaction solvent in a continuous process without purification. The desired compound thus obtained was purified more clearly and was obtained with N-[(1-methylethoxy) carbonyl] -3- (methylsulfonyl) of the formula (6) using dicyclohexylamine in order to obtain a more manageable solid. Prepared with the -L-valine dicyclohexylamine salt.

이를 반응도식으로 나타내면 하기 반응식 3과 같다.This is shown in Scheme 3 and shown in Scheme 3.

실시예 1 : 텅스텐산(H2WO4)을 촉매로 사용한 예Example 1 Example of Using Tungstic Acid (H 2 WO 4 ) as a Catalyst

(N-[(1-메틸에톡시)카보닐]-3-(메틸술포닐)-L-발린 디사이클로헥실아민 염의 제조)(Preparation of N-[(1-methylethoxy) carbonyl] -3- (methylsulfonyl) -L-valine dicyclohexylamine salt)

수산화나트륨 2.7g(67.5mmol)을 물 120g에 용해시킨 후, 출발물질인 (L)-페니실아민10.0g(67.0mmol)을 적가하여 맑은 용액이 될 때까지 교반하였다. 반응용액을 약 10℃로 냉각시키고, 디메틸술페이트[(CH3O)2SO2] 8.9g(70.6mmol)을 적가하였다. 온도를 상온으로 올리고 약 1시간 동안 교반하였다. 6N 수산화나트륨 수용액을 25ml적가한 후, 반응용액의 온도를 약 10℃로 냉각시켰다. 여기에 톨루엔 용매에 용해되어 있는 1N 이소프로필클로로포르메이트 74ml(74mmol)을 약 30분 동안 적가하였다. 모두 적가한 후, 상온으로 온도를 올리고 6N 수산화나트륨 수용액 3ml을 적가하였다. 상온에서 약 1시간 동안 교반한 후, 진한 염산 16ml를 적가하였다. 반응용액에 촉매로서 텅스텐산 17mg(0.068mmol)과 30% 과산화수소수 16.1ml (167.5mmol)를 적가한 후, 60~70℃에서 약 1시간 동안 가열하였다. 상온으로 냉각시킨 후, 아황산나트륨(Na2SO3) 8.5g(67.4mmol)를 적가하여 반응을 끝냈다. 에틸아세테이트(EtOAc) 150ml을 적가, 교반한 후 유기층을 분리하였다. 수층은 다시 에틸아세테이트(EtOAc) 150ml을 적가, 교반하여 유기층을 분리하였다. 유기층을 모아서 감압 농측하고, t-부틸메틸에테르(MTBE) 100ml를 가한 후, 다시 감압 농축하였다. 농축액을 여과하고 t-부틸메틸에테르 60ml로 세척하였다. 여과액을 모두 모아 상기 화학식 5의 화합물을 수득하였으며, 이를 정제하기 위하여 그의 디사이클로헥실아민 염을 제조하였다. 즉, 화학식 5의 화합물이 용해되어 있는 t-부틸메틸에테르 용액에 디사이클로헥실아민 12.1g(66.7mmol)을 상온에서 가하여 1시간 동안 교반하였다. 온도를 0℃로 냉각하여 여과하고, t-부틸메틸에테르 60ml로 세척한 후, 질소로 건조하여 흰색 고체인 표제화합물 23.5g (수율 75.8%)을 수득하였다.After dissolving 2.7 g (67.5 mmol) of sodium hydroxide in 120 g of water, 10.0 g (67.0 mmol) of (L) -phenicylamine as a starting material was added dropwise and stirred until a clear solution was obtained. The reaction solution was cooled to about 10 ° C., and 8.9 g (70.6 mmol) of dimethylsulfate [(CH 3 O) 2 SO 2 ] were added dropwise. The temperature was raised to room temperature and stirred for about 1 hour. After 25 ml of 6N aqueous sodium hydroxide solution was added dropwise, the reaction solution was cooled to about 10 ° C. 74 ml (74 mmol) of 1N isopropylchloroformate dissolved in a toluene solvent were added dropwise thereto for about 30 minutes. After all were added dropwise, the temperature was raised to room temperature and 3 ml of 6N aqueous sodium hydroxide solution was added dropwise. After stirring for about 1 hour at room temperature, 16 ml of concentrated hydrochloric acid was added dropwise. 17 mg (0.068 mmol) of tungstic acid and 16.1 ml (167.5 mmol) of 30% hydrogen peroxide were added dropwise to the reaction solution, followed by heating at 60 to 70 ° C. for about 1 hour. After cooling to room temperature, 8.5 g (67.4 mmol) of sodium sulfite (Na 2 SO 3 ) was added dropwise to complete the reaction. 150 ml of ethyl acetate (EtOAc) was added dropwise and stirred, and then the organic layer was separated. The aqueous layer was added dropwise with 150 ml of ethyl acetate (EtOAc) and stirred to separate the organic layer. The organic layers were collected, concentrated under reduced pressure, 100 ml of t-butyl methyl ether (MTBE) was added, and then concentrated under reduced pressure. The concentrate was filtered off and washed with 60 ml t-butylmethylether. All the filtrates were collected to obtain a compound of Formula 5, to prepare a dicyclohexylamine salt thereof for purification. That is, 12.1 g (66.7 mmol) of dicyclohexylamine was added to a t-butylmethylether solution in which the compound of Formula 5 was dissolved at room temperature, followed by stirring for 1 hour. The temperature was cooled to 0 ° C., filtered, washed with 60 ml of t-butylmethylether, and dried over nitrogen to give 23.5 g (yield 75.8%) of the title compound as a white solid.

1H NMR(CDCl3) δ: 8.70(bs, 2H), 5.63(d, J=8.7Hz, 1H), 4.85(m, 1H), 4.37(d, J=9.6Hz, 1H), 2.97(m, 2H), 2.94(s, 3H), 1.97(d, J=10.6Hz, 4H), 1.78(d, J=13.0Hz, 4H), 1.64~1.12(m, 12H), 1.53(s, 3H), 1.48(s, 3H), 1.21(s, 3H), 1.20(s, 3H) 1 H NMR (CDCl 3 ) δ: 8.70 (bs, 2H), 5.63 (d, J = 8.7 Hz, 1H), 4.85 (m, 1H), 4.37 (d, J = 9.6 Hz, 1H), 2.97 (m , 2H), 2.94 (s, 3H), 1.97 (d, J = 10.6Hz, 4H), 1.78 (d, J = 13.0Hz, 4H), 1.64 ~ 1.12 (m, 12H), 1.53 (s, 3H) , 1.48 (s, 3H), 1.21 (s, 3H), 1.20 (s, 3H)

실시예 2 : 산화바나듐(V2O5)을 촉매로 사용한 예Example 2 Example of Using Vanadium Oxide (V 2 O 5 ) as a Catalyst

(N-[(1-메틸에톡시)카보닐]-3-(메틸술포닐)-L-발린 디사이클로헥실아민 염의 제조)(Preparation of N-[(1-methylethoxy) carbonyl] -3- (methylsulfonyl) -L-valine dicyclohexylamine salt)

(L)-페니실아민 10g을 실시예 1 과 동일한 방법으로 실험을 수행하되, 촉매로서 산화바나듐(V2O5) 0.37g(2.03mmol)을 사용하여 표제화합물 24.8g(수율 80.0%)을 수득하였다.10 g of (L) -phenicylamine was tested in the same manner as in Example 1, except that 24.8 g (yield 80.0%) of the title compound was obtained using 0.37 g (2.03 mmol) of vanadium oxide (V 2 O 5 ) as a catalyst. Obtained.

1H NMR : 실시예 1과 동일 1 H NMR: same as Example 1

실시예 3 : 메틸트리옥시레늄(CH3ReO3)을 촉매로 사용한 예Example 3 Example of Using Methyltrioxyrenium (CH 3 ReO 3 ) as a Catalyst

(N-[(1-메틸에톡시)카보닐]-3-(메틸술포닐)-L-발린 디사이클로헥실아민 염의 제조)(Preparation of N-[(1-methylethoxy) carbonyl] -3- (methylsulfonyl) -L-valine dicyclohexylamine salt)

(L)-페니실아민 10g을 실시예 1 과 동일한 방법으로 실험을 수행하되, 촉매로서 메틸트리옥시레늄(CH3ReO3) 0.5g(2.0mmol)을 사용하여 표제화합물 23.4g (수율 75.5%)을 수득하였다.10 g of (L) -phenicylamine was tested in the same manner as in Example 1, except that 23.4 g of the title compound was used as a catalyst, 0.5 g (2.0 mmol) of methyltrioxyrenium (CH 3 ReO 3 ) (yield 75.5%). ) Was obtained.

1H NMR : 실시예 1과 동일 1 H NMR: same as Example 1

본 발명에 따라 N-알킬옥시카보닐-β-알킬술포닐발린을 제조할 때, 반응 중간에 화학식 2의 화합물을 정제하여 수득한 후 반응을 시킬 필요가 없으며, 전 단계에서의 반응 용액 그대로 유기층과 수층의 이상 (two phase)용매에서 바로 산화 반응을 수행할 수 있음에 따라, 이상용매를 혼합시키기 위한 1,4-디옥신과 같은 극성 용매도 사용할 필요성이 없어진다. 이에 따라 반응 완료후 1,4-디옥신과 같은 용매를 제거하기 위한 공정도 더불어 없어지게 된다. 또한, 산화 반응 시간도 약 1시간 정도로 기존의 24시간에 비해 매우 단축되었다. 화학식 1의 β-메르캅토발린에서부터 시작하여 하나의 반응용기에서 중간 화합물을 정제할 필요없이 연속적인 반응이 가능하므로, 기존의 제조방법보다 간단하고 시간도 단축된다. 사용되는 촉매로는 전이금속류 중에서 다양하게 선택하여 사용할 수 있으며, 또한 그 양은 0.1몰퍼센트이하로도 반응을 수행할 수 있다.When preparing N-alkyloxycarbonyl-β-alkylsulfonyl valine according to the present invention, it is not necessary to carry out the reaction after purifying the compound of the formula (2) in the middle of the reaction, the organic layer as it is the reaction solution in the previous step As the oxidation reaction can be carried out directly in the two phase solvent of the superaqueous layer, there is no need to use a polar solvent such as 1,4-dioxin for mixing the ideal solvent. Accordingly, the process for removing the solvent such as 1,4-dioxin after the completion of the reaction also disappears. In addition, the oxidation reaction time was also shortened to about 1 hour compared to the existing 24 hours. Starting with β-mercaptovaline of formula (1), since it is possible to continuously react without purifying the intermediate compound in one reaction vessel, it is simpler and shorter in time than the conventional manufacturing method. As the catalyst to be used, various transition metals may be selected and used, and the amount thereof may be carried out at 0.1 mole percent or less.

따라서 본 발명은 기존의 제조방법보다 간단하며 우수한 N-알킬옥시카보닐-β-알킬술포닐발린 제조방법을 제공한다.Accordingly, the present invention provides a method for preparing N-alkyloxycarbonyl-β-alkylsulfonylvaline that is simpler than the conventional production method.

Claims (9)

하기 화학식 2의 화합물을 용매중에서 과산화수소와 촉매를 사용하여 산화반응시킴을 특징으로 하여 하기 화학식 3의 화합물, 그의 염, 수화물, 용매화물 또는 이성체를 제조하는 방법 :A process for preparing a compound of formula 3, a salt, a hydrate, a solvate or an isomer thereof, characterized in that the compound of formula 2 is oxidized using hydrogen peroxide and a catalyst in a solvent: [화학식 2][Formula 2] [화학식 3][Formula 3] 상기식에서,In the above formula, R1및 R2는 각각 독립적으로 수소, 저급알킬, 사이클로알킬, 아릴 또는 아릴알킬을 나타내고,R 1 and R 2 each independently represent hydrogen, lower alkyl, cycloalkyl, aryl or arylalkyl, R3는 저급알킬, 사이클로알킬 또는 아릴알킬을 나타낸다.R 3 represents lower alkyl, cycloalkyl or arylalkyl. 하기 화학식 1의 화합물을 하기 화학식 4의 화합물과 반응시킨 후, 유기용매 중의 하기 화학식 5의 화합물을 가하여 반응시키고, 이어서 과산화수소와 촉매를 가하여 산화 반응시킴을 특징으로 하여 하기 화학식 3의 화합물, 그의 염, 수화물, 용매화물 또는 이성체를 제조하는 방법 :The compound of formula 1 is reacted with a compound of formula 4, followed by reaction by adding a compound of formula 5 in an organic solvent, followed by oxidation by addition of hydrogen peroxide and a catalyst. To prepare hydrates, solvates or isomers: [화학식 1][Formula 1] [화학식 3][Formula 3] [화학식 4][Formula 4] R3XR 3 X [화학식 5][Formula 5] R1OCOClR 1 OCOCl 상기식에서,In the above formula, R1및 R2는 각각 독립적으로 수소, 저급알킬, 사이클로알킬, 아릴 또는 아릴알킬을 나타내고,R 1 and R 2 each independently represent hydrogen, lower alkyl, cycloalkyl, aryl or arylalkyl, R3는 저급알킬, 사이클로알킬 또는 아릴알킬을 나타내며,R 3 represents lower alkyl, cycloalkyl or arylalkyl, X 는 반응이탈기를 나타낸다.X represents a reaction leaving group. 제 2 항에 있어서, 과산화수소를 제 2 항에서 정의된 화학식 1의 화합물에 대해 2 내지 3 당량 사용하는 방법.The process of claim 2 wherein hydrogen peroxide is used in the amount of 2 to 3 equivalents relative to the compound of formula 1 as defined in claim 2. 제 1 항 또는 제 2 항에 있어서, 전이금속, 전이금속의 산화물 또는 할로겐산화물, 그의 염 또는 알킬전이금속을 촉매로 사용하는 방법.The process according to claim 1 or 2, wherein a transition metal, an oxide or halogen oxide of the transition metal, a salt thereof, or an alkyl transition metal is used as a catalyst. 제 4 항에 있어서, 텅스텐산(H2WO4), 텅스텐나트륨(Na2WO4), 산화바나듐(V2O5) 및 메틸트리옥소레늄(CH3ReO3) 으로 구성된 군으로부터 선택된 화합물을 촉매로 사용하는 방법.The compound according to claim 4, wherein the compound is selected from the group consisting of tungstic acid (H 2 WO 4 ), sodium tungsten (Na 2 WO 4 ), vanadium oxide (V 2 O 5 ) and methyltrioxorenium (CH 3 ReO 3 ). How to use it as a catalyst. 제 2 항에 있어서, 촉매를 제 2 항에서 정의된 화학식 1의 화합물에 대해 0.001당량 내지 10당량 사용하는 방법.The process of claim 2 wherein the catalyst is used in an amount of 0.001 to 10 equivalents based on the compound of formula 1 as defined in claim 2. 제 1 항 또는 제 2 항에 있어서, 산화 반응을 30~100℃에서 수행하는 방법.The process according to claim 1 or 2, wherein the oxidation reaction is carried out at 30 to 100 ° C. 제 1 항 또는 제 2 항에 있어서, 수층과 유기층의 이상(two phase)용매 중에서 산화 반응을 수행하는 방법.The process according to claim 1 or 2, wherein the oxidation reaction is carried out in a two phase solvent of an aqueous layer and an organic layer. 제 8 항에서 있어서, 케톤류을 제외한, 극성 또는 비극성 용매를 유기용매로 사용하는 방법.The method according to claim 8, wherein a polar or nonpolar solvent is used as the organic solvent except for ketones.
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KR20010050060A (en) * 1999-09-06 2001-06-15 성재갑 A novel process for preparing 1-substituted-5-hydroxymethyl imidazole

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