KR20120110682A - Production method of (3s)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl-2-butanol using by sodiumborohydride - Google Patents

Production method of (3s)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl-2-butanol using by sodiumborohydride Download PDF

Info

Publication number
KR20120110682A
KR20120110682A KR1020110028701A KR20110028701A KR20120110682A KR 20120110682 A KR20120110682 A KR 20120110682A KR 1020110028701 A KR1020110028701 A KR 1020110028701A KR 20110028701 A KR20110028701 A KR 20110028701A KR 20120110682 A KR20120110682 A KR 20120110682A
Authority
KR
South Korea
Prior art keywords
tert
amino
butoxycarbonyl
chloro
phenyl
Prior art date
Application number
KR1020110028701A
Other languages
Korean (ko)
Other versions
KR101299972B1 (en
Inventor
김대영
강영구
서기형
권대길
Original Assignee
순천향대학교 산학협력단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 순천향대학교 산학협력단 filed Critical 순천향대학교 산학협력단
Priority to KR1020110028701A priority Critical patent/KR101299972B1/en
Publication of KR20120110682A publication Critical patent/KR20120110682A/en
Application granted granted Critical
Publication of KR101299972B1 publication Critical patent/KR101299972B1/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B55/00—Racemisation; Complete or partial inversion
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/18—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Materials Engineering (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Emergency Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

PURPOSE: A manufacturing method of (3S)-3-(tert-butoxycaronyl)amino-1-chloro-4-phenyl-(2S)-butanol is provided to generate a target product with high yield and stereoselectivity. CONSTITUTION: A manufacturing method of (3S)-3-(tert-butoxycaronyl)amino-1-chloro-4-phenyl-(2S)-butanol in chemical formula 2 comprises: a step of solving (3S)-3-(tert-butoxycaronyl)amino-1-chloro-4-phenyl-(2S)-butanone with a reactive solvent; a step of conducting a mixing by putting a reducing agent into a solution; and a step of crystallization by a crystallization solvent. In chemical formulas, halogen atom is chlorine and the amine-protective group is selected from a tert- butoxycarbonyl group.

Description

수소화붕소나트륨을 이용한 (3Ｓ)-3-(ｔｅｒｔ-부톡시카르보닐)아미노-1-클로로-4-페닐-(2Ｓ)-부탄올의 제조방법{Production method of (3S)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl-2-butanol using by sodiumborohydride}Method for producing (3S) -3- (tetrebute-butoxycarbonyl) amino-1-chloro-4-phenyl- (2S) -butanol using sodium borohydride {Production method of (3S) -3- (tert- butoxycarbonyl) amino-1-chloro-4-phenyl-2-butanol using by sodiumborohydride}

본 발명은 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올{(3S)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl-(2S)-butanol}의 제조방법에 관한 것으로서, 좀더 상세히 설명하면, 5~10℃에서 메탄올을 반응용매로 사용하여 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-2-부탄온{(3S)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl-2-butanone}을 환원제인 수소화붕소나트륨(NaBH4)과 반응시켜 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올을 99%이상의 dr(부분입체이성질체비율(diastereomeric ratio)) 값으로 제조하는 방법에 관한 것이다. (3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl- (2S) -butanol {(3S) -3- (tert-butoxycarbonyl) amino-1-chloro- 4-phenyl- (2S) -butanol}, and more specifically, (3S) -3- (tert-butoxycarbonyl) amino- using methanol as a reaction solvent at 5-10 ° C. Reaction of 1-chloro-4-phenyl-2-butanone {(3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl-2-butanone} with sodium borohydride (NaBH 4 ) as a reducing agent To prepare (3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl- (2S) -butanol with a dr (diastereomeric ratio) value of 99% or more It is about.

또한 본 발명은 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올의 제조 후, 정제과정 없이 KOH와의 반응으로 쉽게 고리화되어 약제학적으로 유용한 (2S,3S)-1,2-에폭시-3-(tert-부톡시카르보닐)아미노-4-페닐부탄{(2S,3S)-1,2-epoxy-3-(tert-butoxycarbonyl)amino-4-phenylbutane}을 제조하는 방법에 관한 것이다.
In addition, the present invention, after the preparation of (3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl- (2S) -butanol, is easily cyclized by reaction with KOH without purification and pharmaceutical (2S, 3S) -1,2-epoxy-3- (tert-butoxycarbonyl) amino-4-phenylbutane {(2S, 3S) -1,2-epoxy-3- (tert-butoxycarbonyl) amino-4-phenylbutane}.

사람의 면역 결핍 바이러스(HIV:Human Immunodeficiency Virus)는 기회성 감염에 수반하는 감수성 및 면역 체계, 구체적으로 CD4 + T-세포의 파괴를 특징으로 하는 질병인 후천성면역결핍증후군(AIDS:Acquired Immune Deficiency Syndrome) 및 지속적인 일반화된 럼프절증, 열병 및 체중 감소와 같은 징후를 특징으로 하는 증후군인 AIDS 관련 전구 증후군(ARC)의 원인이 된다.Human Immunodeficiency Virus (HIV) is an Immune Deficiency (AIDS) disease, a disease characterized by the destruction of the susceptibility and immune system associated with opportunistic infections, specifically CD 4 + T-cells. Syndrome) and AIDS-related prognostic syndrome (ARC), a syndrome characterized by persistent generalized lump nodules, fever and weight loss.

하기 화학식 1에서 화학식(Ⅲ)으로 표시되는 (2S,3S)-1,2-에폭시-3-(tert-부톡시카르보닐)아미노-4-페닐부탄은 AIDS의 치료제로 개발된 프로테아제 억제인자(protease Inhibitor)의 핵심 중간체로써 여러 HIV 프로테아제 억제인자의 변화가 쉽다.(2S, 3S) -1,2-epoxy-3- (tert-butoxycarbonyl) amino-4-phenylbutane represented by Formula (III) in Formula 1 is a protease inhibitor developed as a therapeutic agent for AIDS ( As a key intermediate of the protease inhibitor, it is easy to change several HIV protease inhibitors.

Figure pat00001
Figure pat00001

지금까지 알려진 화학식(Ⅲ)의 합성방법은 대표적으로 아스코르브산(ascorbic acid)을 사용하는 방법(J. Org. Chem. (1988), 53, 2598-2602.), 주석산(tartric acid)을 사용하는 방법(J. Chem. Soc., Chem. Commun. (1992), 273-274.), 페닐알라닌(phenylalanine)을 사용하는 방법(J. Org. Chem. (1994), 59, 3650-3664.), 키랄 보조기를 사용하는 방법(J. Org. Chem. (1997), 62, 6080-6082)으로 나뉜다. Synthesis of the formula (III) known so far is typically used ascorbic acid (J. Org. Chem. (1988), 53, 2598-2602.), Tartaric acid (tartric acid) Method (J. Chem. Soc., Chem. Commun. (1992), 273-274.), Method using phenylalanine (J. Org. Chem. (1994), 59, 3650-3664.), Chiral braces (J. Org. Chem. (1997), 62, 6080-6082).

그러나 이러한 방법들은 장단점은 있으나, 전체적으로 반응단계가 길며 수율이 낮아 그 효율성이 떨어지고, 값비싼 원료를 사용함으로 해서 상업적으로 큰 이득이 없다는 문제가 있었다.However, these methods have advantages and disadvantages, but overall, the reaction stage is long, the yield is low, the efficiency is low, and there is a problem in that there is no commercial advantage by using expensive raw materials.

또한, 하기 화학식 2에서 키랄 촉매를 사용한 화학식(I)의 환원반응이 알려져 있는데(J. Org. Chem.(2004), 69, 7391.), 다양한 유도체에서 높은 입체선택성으로 2-할로케톤의 환원반응을 하여 높은 입체선택성으로 제품을 합성하였으나, 사용하는 촉매들이 상당히 비싸기 때문에 상업적으로 유용하지 않다.In addition, a reduction reaction of Formula (I) using a chiral catalyst in Formula 2 is known (J. Org. Chem. (2004), 69, 7391.), reduction of 2-haloketone with high stereoselectivity in various derivatives The product was synthesized with high stereoselectivity by reaction, but it is not commercially useful because the catalysts used are quite expensive.

Figure pat00002
Figure pat00002

화학식(I)을 이용하여 여러 가지 방법으로 화학식 (Ⅱ)를 제조하였는데 대표적으로 방법이 하기 화학식 3과 같이, LiAlH(OtBu)3, LiAlH4, Al(O i Pr)3를 사용하는 방법이다(J. Org. Chem., (1995), 60, 6697., J. Org. Chem., (2006), 840., US5684176(1997), Org. Syn. (2007) 84, 58.).Formula (II) was prepared by various methods using Formula (I). Typically, the method uses LiAlH (O t Bu) 3 , LiAlH 4 , Al (O i Pr) 3 as in Formula 3 below. (J. Org. Chem., (1995), 60, 6697., J. Org. Chem., (2006), 840., US5684176 (1997), Org. Syn. (2007) 84, 58.).

Figure pat00003
Figure pat00003

그러나 환원제를 사용하는 반응들은 대부분 -15℃이하의 극저온에서 반응하여 반응조건이 까다롭고 상기 환원제들이 폭발가능성이 있어 상업적으로 위험하기 때문에 상업적으로 유용하지 않다.However, most of the reactions using reducing agents are not commercially useful because they are reacted at cryogenic temperatures of -15 ° C. or lower, and the reaction conditions are difficult and the reducing agents are explosive and commercially dangerous.

또한 하기 화학식 4와 같이, NaBH4를 사용한 방법도 많이 알려져 있으나 이 역시 -15℃에서 반응을 하여 반응조건이 까다롭다. 또한 입체선택성이 매우 떨어져 재처리를 하여야 한다는 단점이 있으며 수율이 떨어져 상업적으로 유용하지 않다(J. Med. Chem. (1994) 37, 1758., TL(1995) 36, 5453., J. Med. Chem. (1991) 34, 3267. Org. Biomol. Chem. (2004), 2, 2061., CN101037403, J. Org. Chem.,(2001), 66, 5790.).In addition, as shown in the following formula (4), many methods using NaBH 4 is also known, but this is also difficult to react by reaction at -15 ℃. In addition, there is a disadvantage that the reselection is very poor due to the stereoselectivity and the yield is not commercially useful (J. Med. Chem. (1994) 37, 1758., TL (1995) 36, 5453., J. Med. Chem. (1991) 34, 3267. Org Biomol. Chem. (2004), 2, 2061., CN101037403, J. Org. Chem., (2001), 66, 5790.).

Figure pat00004
Figure pat00004

또한 하기 화학식 5에서와 같이, 화학식(I)에서 할로겐원소가 염소, 아민보호기가 tert-부톡시카르보닐 그룹인 화합물을 이용하여 NaBH4로 환원시킨 반응도 알려져 있으나(J. Med. Chem. (1991) 34, 3267.) 반응 수율이 매우 떨어지고 입체선택성도 좋지 않다.In addition, as shown in Chemical Formula 5, a reaction in which the halogen element is reduced to NaBH 4 using a compound in which the halogen element is chlorine and the amine protecting group is tert-butoxycarbonyl group is also known (J. Med. Chem. (1991). 34, 3267.) Poor reaction yield and poor stereoselectivity.

Figure pat00005
Figure pat00005

본 발명의 목적은 상술한 바와 같은 종래 기술의 문제점을 해결하기 위해 이루어진 것으로서, 실행이 용이하고, 높은 수율과 입체선택성으로 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올을 생성하는 제조방법을 제공하는 것이다.An object of the present invention is to solve the problems of the prior art as described above, it is easy to implement, (3S) -3- (tert-butoxycarbonyl) amino-1-chloro with high yield and stereoselectivity It is to provide a process for producing 4-phenyl- (2S) -butanol.

본 발명의 다른 목적은 비용이 저렴하고, 공업적 규모에 적합화될 수 있는 (2S,3S)-1,2-에폭시-3-(tert-부톡시카르보닐)아미노-4-페닐부탄의 제조방법을 제공하는 것이다.
Another object of the present invention is to prepare (2S, 3S) -1,2-epoxy-3- (tert-butoxycarbonyl) amino-4-phenylbutane, which is inexpensive and can be adapted to industrial scale. To provide a way.

상기 목적을 달성하기 위해 본 발명에 따른 하기 화학식(Ⅱ)의 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올의 제조방법은 In order to achieve the above object, a process for preparing (3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl- (2S) -butanol of the following general formula (II)

(a) 하기 화학식(I)의 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-2-부탄온을 반응 용매로 녹이는 단계, (b) 상기 (a) 단계의 용액에 환원제를 넣어 교반하는 단계, (c) 상기 (b) 단계에서의 반응 종료 후 결정화 용매로 결정화하는 단계를 포함하는 것을 특징으로 한다.(a) dissolving (3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl-2-butanone of formula (I) with a reaction solvent, (b) (a) And stirring the reducing agent into the solution of step 1), and (c) crystallizing with a crystallization solvent after completion of the reaction in step (b).

Figure pat00006
Figure pat00006

(여기서, 할로겐원소는 염소, 아민 보호기는 tert-부톡시카르보닐 그룹으로 선택).Wherein the halogen element is chlorine and the amine protecting group is selected as the tert-butoxycarbonyl group.

또 본 발명에 따른 3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올의 제조방법에 있어서, 상기 (a) 단계는 5~10℃의 상태에서 실행되며, 상기 반응용매는 메탄올이고, 상기 환원제는 수소화붕소나트륨(NaBH4)인 것을 특징으로 한다.In addition, in the method for preparing 3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl- (2S) -butanol according to the present invention, the step (a) is performed at 5 to 10 ° C. The reaction solvent is methanol, and the reducing agent is sodium borohydride (NaBH 4 ).

또 본 발명에 따른 3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올의 제조방법에 있어서, 상기 결정화 용매는 디이소프로필에테르(diisopropyl ether)인 것을 특징으로 한다.In the method for preparing 3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl- (2S) -butanol according to the present invention, the crystallization solvent is diisopropyl ether (diisopropyl ether). It is characterized by the).

또한 상기 목적을 달성하기 위해 본 발명에 따른 화학식(Ⅲ)의 (2S,3S)-1,2-에폭시-3-(tert-부톡시카르보닐)아미노-4-페닐부탄의 제조 방법은 (a) 하기 화학식(I)의 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-2-부탄온을 메탄올에 녹이고 온도를 5~10℃로 내리는 단계, (b) 상기 (a) 단계의 용액에 NaBH4를 넣어 교반하는 단계, (c) 상기 (b) 단계에서의 반응 종료 후 이를 디이소프로필에테르로 결정화하는 단계, (d) 상기 (c) 단계에서 형성된 하기 화학식(Ⅱ)의 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올을 KOH와 같이 에탄올에 녹여 고리화하는 단계를 포함하는 것을 특징으로 한다.In addition, in order to achieve the above object, a method for preparing (2S, 3S) -1,2-epoxy-3- (tert-butoxycarbonyl) amino-4-phenylbutane of formula (III) according to the present invention is (a ) Dissolving (3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl-2-butanone of formula (I) in methanol and lowering the temperature to 5-10 占 폚, ( b) stirring NaBH 4 into the solution of step (a), (c) crystallizing it with diisopropyl ether after completion of the reaction in step (b), and (d) in step (c) Dissolving (3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl- (2S) -butanol of the following formula (II) in ethanol such as KOH to cyclize It is characterized by.

Figure pat00007

Figure pat00007

본 발명에 따르면, 실행이 용이하고, 높은 수율과 입체선택성으로 화학식(Ⅱ)의 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올을 생성할 수 있다는 효과가 얻어진다.According to the present invention, (3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl- (2S) -butanol of formula (II) is easy to carry out and has high yield and stereoselectivity. The effect that can be produced is obtained.

또 본 발명에 따르면, 비용이 저렴하고, 재처리과정 없이 공업적 규모에 적합화될 수 있는 화학식(Ⅲ)의 (2S,3S)-1,2-에폭시-3-(tert-부톡시카르보닐)아미노-4-페닐부탄을 제조할 수 있다는 효과가 얻어진다.
In addition, according to the present invention, (2S, 3S) -1,2-epoxy-3- (tert-butoxycarbonyl) of formula (III) which is inexpensive and can be adapted to industrial scale without reprocessing The effect that amino-4-phenylbutane can be manufactured is obtained.

도 1 및 도 2는 각각 화학식(Ⅱ)~화학식(Ⅲ)의 HPLC데이터를 나타내는 도면.
도 3 및 도 4는 화학식 (Ⅱ)와 화학식 (Ⅲ)의 핵자기공명데이터를 나타내는 도면.1 and 2 show HPLC data of Formulas (II) to (III), respectively.
3 and 4 show nuclear magnetic resonance data of formulas (II) and (III).

본 발명의 상기 및 그 밖의 목적과 새로운 특징은 본 명세서의 실시 예의 설명 부분 및 첨부 도면에 의해 더욱 명확하게 될 것이다.The above and other objects and novel features of the present invention will become more apparent from the following description of the embodiments of the present specification and the accompanying drawings.

이하 본 발명의 바람직한 실시 예를 첨부된 상세하게 설명하면 다음과 같다.Hereinafter, described in detail with reference to the preferred embodiment of the present invention.

[실시 예 1][Example 1]

본 발명에 따른 실시 예 1은 하기 화학식(Ⅱ)의 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올의 제조 방법에 관한 것이다.Example 1 according to the present invention relates to a process for preparing (3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl- (2S) -butanol of the formula (II).

Figure pat00008
Figure pat00008

먼저 하기 화학식(I)의 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-2-부탄온 2.97g을 용기 내에서 메탄올 45㎖에 녹인 후 교반한다. First, 2.97 g of (3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl-2-butanone of the formula (I) is dissolved in 45 ml of methanol in a vessel, followed by stirring.

Figure pat00009
Figure pat00009

그리고 나서 온도를 0℃로 내린다. Then the temperature is lowered to 0 ° C.

다음에 5℃로 교반하면서 NaBH4를 상기 용기에 천천히 투입한다. 5℃에서 한 시간 교반한다. Next, NaBH 4 is slowly introduced into the vessel while stirring at 5 ° C. Stir at 5 ° C. for one hour.

계속해서 TLC(thin layer chromatography)로 반응진행상황을 확인하고 반응이 종료가 되면, 0.5N HCl로 중성화시킨 후 여과하여 생성된 B(OH)3를 제거시켜준다. Subsequently, the reaction progress is confirmed by TLC (thin layer chromatography), and when the reaction is completed, the resultant is neutralized with 0.5N HCl and filtered to remove B (OH) 3 .

그 후, 여액을 농축시킨 후 에틸아세테이트 30㎖와 정제수 30㎖를 넣고 추출해준다. 물 층을 제거하고 유기층을 무수 황산나트륨으로 잔류한 물을 제거하고 여과한다. After concentrating the filtrate, 30 ml of ethyl acetate and 30 ml of purified water are extracted. The water layer is removed and the organic layer is removed with anhydrous sodium sulfate and filtered.

다시, 여액을 농축한 후 디이소프로필에테르(diisopropyl ether)로 결정화하여 96% 수율과 99.4% dr값으로 상기 화학식(Ⅱ)의 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올 (2.87g)을 얻었다.Again, the filtrate was concentrated and crystallized with diisopropyl ether to give (3S) -3- (tert-butoxycarbonyl) amino-1 of formula (II) in 96% yield and 99.4% dr. -Chloro-4-phenyl- (2S) -butanol (2.87 g) was obtained.

상기 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올에 대한 기기분석 데이터는 다음과 같다.Instrument analysis data for the (3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl- (2S) -butanol are as follows.

1H NMR(200Mz, DMSO-d 6) d 7.27-7.12(m, 5H), 6.71-6.67(d, J=8, 1H), 5.43-5.41(d, J=4, 1H), 3.68-3.43(m, 4H), 3.03-2.96(d, J=14, 1H), 2.61-2.54(m, 1H), 1.25(s, 9H); Rt HPLC(90:10, n-hexane:i-PrOH, 220 nm, 1.0 mL/min), Chiralpak OD column, 7.6 min(minor), 8.7 min(major).
 1 H NMR (200Mz, DMSO- d 6 ) d 7.27-7.12 (m, 5H), 6.71-6.67 (d, J = 8, 1H), 5.43-5.41 (d, J = 4, 1H), 3.68-3.43 (m, 4H), 3.03-2.96 (d, J = 14, 1H), 2.61-2.54 (m, 1H), 1.25 (s, 9H); Rt HPLC (90:10, n-hexane: i-PrOH, 220 nm, 1.0 mL / min), Chiralpak OD column, 7.6 min (minor), 8.7 min (major).

[실시 예 2][Example 2]

본 발명에 따른 실시 예 2는 하기 화학식(Ⅲ)의 (2S,3S)-1,2-에폭시-3-(tert-부톡시카르보닐)아미노-4-페닐부탄의 제조 방법에 관한 것이다.Example 2 according to the present invention relates to a process for preparing (2S, 3S) -1,2-epoxy-3- (tert-butoxycarbonyl) amino-4-phenylbutane of formula (III).

Figure pat00010
Figure pat00010

용기 내에 KOH 0.42g을 메탄올 10㎖에 녹인 후 교반한다. 이때 온도는 상온으로 유지한다. 0.42 g of KOH was dissolved in 10 ml of methanol and stirred in a vessel. At this time, the temperature is maintained at room temperature.

다음에 상기 실시 예 1에 의해 생성된 상기 화학식 (Ⅱ)의 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올 2.99g을 상기 용기에 천천히 투입한다. Next, 2.99 g of (3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl- (2S) -butanol of the formula (II) produced by Example 1 was added to the vessel. Slowly inject into.

그리고, 상온에서 3시간 교반한다. And it stirred at room temperature for 3 hours.

TLC로 반응진행상황을 확인하고 반응이 종료되면, 1N HCl로 중성화시킨 후 에틸아세테이트 50㎖, 물 50㎖로 추출해준다. Check the reaction progress by TLC, and when the reaction is completed, neutralize with 1N HCl, and then extract with 50 ml of ethyl acetate and 50 ml of water.

다음에 물 층을 제거하고 유기층을 무수 황산나트륨으로 잔류한 물을 제거하고 여과한다. The water layer is then removed and the organic layer is removed with anhydrous sodium sulfate and filtered.

여액을 농축한 후 헥산으로 결정화하여 95% 수율로 상기 화학식(Ⅲ)의 (2S,3S)-1,2-에폭시-3-(tert-부톡시카르보닐)아미노-4-페닐부탄(2.48g)을 얻었다.The filtrate was concentrated and crystallized with hexane to give (2S, 3S) -1,2-epoxy-3- (tert-butoxycarbonyl) amino-4-phenylbutane (2.48 g) in 95% yield. )

상기 (2S,3S)-1,2-에폭시-3-(tert-부톡시카르보닐)아미노-4-페닐부탄에 대한 기기분석 데이터는 다음과 같다.Instrumental analysis data for the (2S, 3S) -1,2-epoxy-3- (tert-butoxycarbonyl) amino-4-phenylbutane are as follows.

1H NMR(200Mz, CDCl3) d 7.35-7.20(m, 5H), 4.50-4.47(d, J=6, 1H), 3.71-3.65(m, 1H), 3.02-2.72(m, 5H), 1.37(s, 9H); Rt HPLC(90:10, n-hexane:i-PrOH, 220 nm, 1.0 mL/min), Chiralpak OD column, 6.5 min(minor), 7.2 min(major).
1 H NMR (200Mz, CDCl 3 ) d 7.35-7.20 (m, 5H), 4.50-4.47 (d, J = 6, 1H), 3.71-3.65 (m, 1H), 3.02-2.72 (m, 5H), 1.37 (s, 9 H); Rt HPLC (90:10, n-hexane: i-PrOH, 220 nm, 1.0 mL / min), Chiralpak OD column, 6.5 min (minor), 7.2 min (major).

도 1 및 도 2에 도시된 데이터는 Agilent technologies 1200 infinity HPLC(High Pressure Liquid Chromatography) 시스템을 이용하여 측정한 데이터이다.
1 and 2 are data measured using an Agilent technologies 1200 infinity High Pressure Liquid Chromatography (HPLC) system.

분석조건 Chiralpak OD (90:10, n-hexane:i-PrOH, 220 nm, 1.0 mL/min)Analytical conditions Chiralpak OD (90:10, n-hexane: i-PrOH, 220 nm, 1.0 mL / min)

Figure pat00011
Figure pat00011

화학식(Ⅱ)의 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올 Rt = 8.7min(3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl- (2S) -butanol Rt = 8.7 min of formula (II)

화학식(Ⅲ)의 (2S,3S)-1,2-에폭시-3-(tert-부톡시카르보닐)아미노-4-페닐butane Rt = 7.2min(2S, 3S) -1,2-epoxy-3- (tert-butoxycarbonyl) amino-4-phenylbutane Rt = 7.2 min of formula (III)

화학식(Ⅳ)의 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2R)-부탄올 Rt = 7.6min(3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl- (2R) -butanol Rt = 7.6 min of formula (IV)

화학식(V)의 (2R,3S)-1,2-에폭시-3-(tert-부톡시카르보닐)아미노-4-페닐butane Rt = 6.5min
(2R, 3S) -1,2-epoxy-3- (tert-butoxycarbonyl) amino-4-phenylbutane Rt of formula (V) = 6.5 min

도 3 및 도 4에 도시된 데이터는 Bruker AC NMR 200의 장비로 측정한 데이터이다.
3 and 4 is data measured by the equipment of Bruker AC NMR 200.

이상 본 발명자에 의해서 이루어진 발명을 상기 실시 예에 따라 구체적으로 설명하였지만, 본 발명은 상기 실시 예는 실험을 위해 실행된 것이며, 이에 한정되는 것은 아니고, 그 요지를 이탈하지 않는 범위에서 여러 가지로 변경 가능한 것은 물론이다.
Although the invention made by the present inventors has been described in detail according to the above embodiments, the present invention has been carried out for the experiment, and the present invention is not limited thereto, and various modifications can be made without departing from the gist of the invention. Of course it is possible.

본 발명에 따른 수소화붕소나트륨을 이용한 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올의 제조방법은 AIDS의 치료제에 이용된다.The method for preparing (3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl- (2S) -butanol using sodium borohydride according to the present invention is used for the treatment of AIDS.

Claims (4)

하기 화학식(Ⅱ)의 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올의 제조방법으로서,
(a) 하기 화학식(I)의 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-2-부탄온을 반응 용매로 녹이는 단계,
(b) 상기 (a) 단계의 용액에 환원제를 넣어 교반하는 단계,
(c) 상기 (b) 단계에서의 반응 종료 후 결정화 용매로 결정화하는 단계를 포함하는 것을 특징으로 하는 3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올의 제조방법.
Figure pat00012

(여기서, 할로겐원소는 염소, 아민 보호기는 tert-부톡시카르보닐 그룹으로 선택).As a method for producing (3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl- (2S) -butanol of the formula (II),
(a) dissolving (3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl-2-butanone of formula (I) with a reaction solvent,
(b) adding a reducing agent to the solution of step (a) and stirring the solution;
(c) 3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl- (characterized in that it comprises crystallizing with a crystallization solvent after completion of the reaction in step (b). 2S) -Butanol.
Figure pat00012

Wherein the halogen element is chlorine and the amine protecting group is selected as the tert-butoxycarbonyl group. 제1항에 있어서,
상기 (a) 단계는 5~10℃의 상태에서 실행되며,
상기 반응용매는 메탄올이고, 상기 환원제는 수소화붕소나트륨(NaBH4)인 것을 특징으로 하는 3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올의 제조방법.The method of claim 1,
The step (a) is carried out in a state of 5 ~ 10 ℃,
The reaction solvent is methanol, and the reducing agent is sodium borohydride (NaBH 4 ). 3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl- (2S) -butanol Manufacturing method. 제1항 있어서,
상기 결정화 용매는 디이소프로필에테르(diisopropyl ether)인 것을 특징으로 하는 3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올의 제조방법.The method of claim 1,
The crystallization solvent is diisopropyl ether (diisopropyl ether), characterized in that 3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl- (2S) -butanol. 하기 화학식(Ⅲ)의 (2S,3S)-1,2-에폭시-3-(tert-부톡시카르보닐)아미노-4-페닐부탄의 제조 방법으로서,
(a) 하기 화학식(I)의 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-2-부탄온을 메탄올에 녹이고 온도를 5~10℃로 내리는 단계,
(b) 상기 (a) 단계의 용액에 NaBH4를 넣어 교반하는 단계,
(c) 상기 (b) 단계에서의 반응 종료 후 이를 디이소프로필에테르로 결정화하는 단계,
(d) 상기 (c) 단계에서 형성된 하기 화학식(Ⅱ)의 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올을 KOH와 같이 에탄올에 녹여 고리화하는 단계를 포함하는 것을 특징으로 하는 (2S,3S)-1,2-에폭시-3-(tert-부톡시카르보닐)아미노-4-페닐부탄의 제조 방법.
Figure pat00013
As a method for producing (2S, 3S) -1,2-epoxy-3- (tert-butoxycarbonyl) amino-4-phenylbutane of formula (III),
(a) dissolving (3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl-2-butanone of formula (I) in methanol and lowering the temperature to 5-10 占 폚; ,
(b) adding NaBH 4 to the solution of step (a) and stirring the solution;
(c) crystallizing it with diisopropyl ether after completion of the reaction in step (b),
(d) (3S) -3- (tert-butoxycarbonyl) amino-1-chloro-4-phenyl- (2S) -butanol of the following formula (II) formed in step (c) is ethanol, such as KOH. Method for producing (2S, 3S) -1,2-epoxy-3- (tert-butoxycarbonyl) amino-4-phenylbutane, comprising the step of dissolving in cyclization.
Figure pat00013
KR1020110028701A 2011-03-30 2011-03-30 Production method of (3S)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl-2-butanol using by sodiumborohydride KR101299972B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1020110028701A KR101299972B1 (en) 2011-03-30 2011-03-30 Production method of (3S)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl-2-butanol using by sodiumborohydride

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
KR1020110028701A KR101299972B1 (en) 2011-03-30 2011-03-30 Production method of (3S)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl-2-butanol using by sodiumborohydride

Publications (2)

Publication Number Publication Date
KR20120110682A true KR20120110682A (en) 2012-10-10
KR101299972B1 KR101299972B1 (en) 2013-08-26

Family

ID=47281484

Family Applications (1)

Application Number Title Priority Date Filing Date
KR1020110028701A KR101299972B1 (en) 2011-03-30 2011-03-30 Production method of (3S)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl-2-butanol using by sodiumborohydride

Country Status (1)

Country Link
KR (1) KR101299972B1 (en)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5481011A (en) * 1994-12-13 1996-01-02 Bristol-Myers Squibb Company Process for preparing N-protected amino acid α-halomethyl ketones and alcohols from N-protected amino acid esters
JP4482783B2 (en) * 1999-01-28 2010-06-16 味の素株式会社 Process for producing α-amino ketones
EP1346979A4 (en) * 2000-11-30 2005-11-09 Ajinomoto Kk Processes for preparation of n-protected- -amino alcohols and n-protected- -amino epoxides

Also Published As

Publication number Publication date
KR101299972B1 (en) 2013-08-26

Similar Documents

Publication Publication Date Title
CN107474107B (en) Process for the preparation of GLYX-13 and compounds useful for the preparation of GLYX-13
JP2021504418A (en) Method for producing 2- (5-methoxyisochroman-1-yl) -4,5-dihydro-1H-imidazole and its hydrogen sulfate
EP2914574B1 (en) New process
JPH0776209B2 (en) Process for producing optically active 3-hydroxypyrrolidine derivative
US8912345B2 (en) Method for preparing optically pure (−)-clausenamide compound
HUE031138T2 (en) Process for producing Lacosamide
CN104837817B (en) Synthetic route for preparation of 3-amino-piperidine compounds
CN109456253B (en) Method for synthesizing (S) -3- (4-bromophenyl) -piperidine or salt thereof through chiral induction
CN110092786B (en) Method for preparing evodiamine
AU2017333054B2 (en) Method for preparing phenylalanine compound
KR20120110682A (en) Production method of (3s)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl-2-butanol using by sodiumborohydride
JP2014156493A (en) Production intermediate of tetrahydropyran compound
CN114014864A (en) Preparation process of traasiril compound
JPWO2014051077A1 (en) Method for producing high purity nitrogen-containing heterocyclic compound
WO2004110972A1 (en) Process for producing (2r)-2-propyloctanoic acid and intermediate therefor
KR20140028433A (en) Proces for purifying fluvoxamine free base and process for preparing high purity fluvoxamine maleate using the same
CN109400629B (en) Indole spirooxazine heterocyclic compound and preparation method thereof
WO2020213714A1 (en) Method for producing cis-(-)-fluocino piperidol
JP2020070296A (en) Method for producing linagliptin
CN117164586B (en) Preparation method of spiro diamine
JP5397706B2 (en) Method for producing high purity 1-benzyl-3-aminopyrrolidine
CN112824381B (en) Preparation method of piperidine amine
CN115322106A (en) Synthesis method of trans-3-azido-1-methylcyclobutanol and trans-3-amino-1-methylcyclobutanol
CN116947867A (en) Preparation method of important intermediate of pyrimidine-4 (3H) -ketone heterocyclic compound
KR101298046B1 (en) Efficient process of solifenacin and it's salt

Legal Events

Date Code Title Description
A201 Request for examination
E902 Notification of reason for refusal
E701 Decision to grant or registration of patent right
GRNT Written decision to grant
FPAY Annual fee payment

Payment date: 20160822

Year of fee payment: 4

FPAY Annual fee payment

Payment date: 20170822

Year of fee payment: 5

FPAY Annual fee payment

Payment date: 20180821

Year of fee payment: 6

FPAY Annual fee payment

Payment date: 20190821

Year of fee payment: 7