KR101299972B1 - 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

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KR101299972B1
KR101299972B1 KR1020110028701A KR20110028701A KR101299972B1 KR 101299972 B1 KR101299972 B1 KR 101299972B1 KR 1020110028701 A KR1020110028701 A KR 1020110028701A KR 20110028701 A KR20110028701 A KR 20110028701A KR 101299972 B1 KR101299972 B1 KR 101299972B1
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amino
butoxycarbonyl
phenyl
chloro
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김대영
강영구
서기형
권대길
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순천향대학교 산학협력단
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Abstract

(3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올{(3S)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl-(2S)-butanol}의 제조방법 및 2S,3S)-1,2-에폭시-3-(tert-부톡시카르보닐)아미노-4-페닐부탄의 제조 방법에 관한 것으로, (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.

Figure 112011023120813-pat00014

상기와 같은 제조방법을 이용하는 것에 의해 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 있다,(3S)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl-(2S)-butanol{(3S)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl -(2S)-butanol} and 2S,3S)-1,2-epoxy-3-(tert-butoxycarbonyl)amino-4-phenylbutane. Dissolving (3S)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl-2-butanone of (I) in methanol and lowering the temperature to 5-10°C, (b) above (a) adding NaBH 4 to the solution of step and stirring, (c) after the reaction in step (b), crystallizing it with diisopropyl ether, (d) the following formula formed in step (c) (II) (3S)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl-(2S)-butanol is dissolved in ethanol, such as KOH, and cyclized. do.
Figure 112011023120813-pat00014

(2S,3S)-1,2-epoxy-3-(tert-part of formula (III), which is inexpensive by using the above-described manufacturing method and can be adapted to industrial scale without reprocessing. Oxycarbonyl)amino-4-phenylbutane can be prepared,

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}(Production method of (3S)-3-(tert-) of (3S)-3-(Terr-butoxycarbonyl)amino-1-chloro-4-phenyl-(2S)-butanol using sodium borohydride 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. The present invention is (3S)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl-(2S)-butanol{(3S)-3-(tert-butoxycarbonyl)amino-1-chloro- 4-phenyl-(2S)-butanol}, and in more detail, (3S)-3-(tert-butoxycarbonyl)amino- using methanol at 5~10℃ as a reaction solvent. 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 at least 99%. 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 thus pharmaceutical Useful as (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 AIDS (Acquired Immune Deficiency), a disease characterized by susceptibility and immune system accompanying opportunistic infections, specifically CD 4 + T-cell destruction. Syndrome) and AIDS-related prodromal syndrome (ARC), a syndrome characterized by symptoms such as persistent generalized lumpectomy, 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 below is a protease inhibitor developed as a therapeutic agent for AIDS ( Protease Inhibitor) is a key intermediate, and various HIV protease inhibitors are easy to change.

Figure 112011023120813-pat00001
Figure 112011023120813-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 method of the formula (III) known so far is typically using ascorbic acid (ascorbic acid) (J. Org. Chem. (1988), 53, 2598-2602.), tartaric acid (tartric acid) using Method (J. Chem. Soc., Chem. Commun. (1992), 273-274.), Method using phenylalanine (J. Org. Chem. (1994), 59, 3650-3664.), It is divided into a method using a chiral auxiliary (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 the overall reaction step is long, the yield is low, the efficiency is low, and there is a problem that there is no great 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, the reduction reaction of the formula (I) using a chiral catalyst in the following formula 2 is known (J. Org. Chem. (2004), 69, 7391.), the 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 112011023120813-pat00002
Figure 112011023120813-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 in various ways using Formula (I). Representatively, the method uses LiAlH(O t Bu) 3 , LiAlH 4 , and Al(O i Pr) 3 as shown in Formula 3 below. (J. Org. Chem., (1995), 60, 6697., J. Org. Chem., (2006), 840., US5684176 (1997), Org. Syn. (2007) 84, 58.).

Figure 112011023120813-pat00003
Figure 112011023120813-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 a reducing agent are not commercially useful because they react at an extremely low temperature of -15°C or lower, and the reaction conditions are difficult and the reducing agents are commercially dangerous due to the possibility of explosion.

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), a method using NaBH 4 is also known, but this also reacts at -15°C, which makes the reaction conditions difficult. In addition, there is a disadvantage in that the stereoselectivity is very poor and re-treatment is required, and the yield is poor, and 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 112011023120813-pat00004
Figure 112011023120813-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 the following Chemical Formula 5, a reaction in which a halogen element is reduced to NaBH 4 using a compound in which a halogen element is chlorine and an amine protecting group is a tert-butoxycarbonyl group is also known (J. Med. Chem. (1991) ) 34, 3267.) The reaction yield is very poor and the stereoselectivity is also poor.

Figure 112011023120813-pat00005
Figure 112011023120813-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.The object of the present invention is to solve the problems of the prior art as described above, easy to implement, and high yield and stereoselectivity (3S)-3-(tert-butoxycarbonyl)amino-1-chloro It provides a method 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 the production of (2S,3S)-1,2-epoxy-3-(tert-butoxycarbonyl)amino-4-phenylbutane, which is inexpensive and can be adapted to industrial scale. Is 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 (a) 하기 화학식(I)의 (3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-2-부탄온을 5 ~ 10℃에서 메탄올로 녹이는 단계, (b) 상기 (a) 단계의 용액에 수소화붕소나트륨(NaBH4)를 넣어 교반하는 단계, (c) 상기 (b) 단계에서의 반응 종료 후 디이소프로필에테르(diisopropyl ether) 용매로 결정화하는 단계를 포함하는 것을 특징으로 한다.

Figure 112013026488680-pat00018

In order to achieve the above object, a method for preparing (3S)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl-(2S)-butanol of the following formula (II) according to the present invention is ( a) Dissolving (3S)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl-2-butanone of the following formula (I) with methanol at 5-10° C., (b) In the solution of step (a), sodium borohydride (NaBH 4 ) is added and stirred, and (c) crystallization with a diisopropyl ether solvent after the reaction in step (b) is completed. It is characterized by.
Figure 112013026488680-pat00018

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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, it is easy to implement, and (3S)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl-(2S)-butanol of formula (II) with high yield and stereoselectivity. The effect that can produce.

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 produced 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 are diagrams showing HPLC data of formulas (II) to (III), respectively.
3 and 4 are views showing nuclear magnetic resonance data of the 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 new features of the present invention will become more apparent by the description of the embodiments of the present specification and the accompanying drawings.

이하 본 발명의 바람직한 실시 예를 첨부된 상세하게 설명하면 다음과 같다.Hereinafter, preferred embodiments of the present invention will be described in detail as follows.

[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 method for preparing (3S)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl-(2S)-butanol of the following formula (II).

Figure 112011023120813-pat00008
Figure 112011023120813-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 following formula (I) is dissolved in 45 ml of methanol in a container and stirred.

Figure 112011023120813-pat00009
Figure 112011023120813-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 was slowly added to the container while stirring at 5°C. Stir at 5°C for 1 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 checked by thin layer chromatography (TLC), and when the reaction is complete, neutralization with 0.5N HCl and filtration removes the resulting 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 that, the filtrate was concentrated, and 30 ml of ethyl acetate and 30 ml of purified water were added and extracted. The water layer was removed, and the organic layer was 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 value. -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.Instrumental analysis data for (3S)-3-(tert-butoxycarbonyl)amino-1-chloro-4-phenyl-(2S)-butanol is 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 method for preparing (2S,3S)-1,2-epoxy-3-(tert-butoxycarbonyl)amino-4-phenylbutane of the following formula (III).

Figure 112011023120813-pat00010
Figure 112011023120813-pat00010

용기 내에 KOH 0.42g을 메탄올 10㎖에 녹인 후 교반한다. 이때 온도는 상온으로 유지한다. In a container, 0.42 g of KOH was dissolved in 10 ml of methanol and stirred. 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 container. Slowly put in.

그리고, 상온에서 3시간 교반한다. Then, the mixture was stirred at room temperature for 3 hours.

TLC로 반응진행상황을 확인하고 반응이 종료되면, 1N HCl로 중성화시킨 후 에틸아세테이트 50㎖, 물 50㎖로 추출해준다. After confirming the progress of the reaction by TLC and when the reaction is complete, neutralize with 1N HCl and 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 was then removed, and the organic layer was 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 yield (2S,3S)-1,2-epoxy-3-(tert-butoxycarbonyl)amino-4-phenylbutane (2.48g) of the formula (III) 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 is 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)Analysis conditions Chiralpak OD (90:10, n-hexane:i-PrOH, 220 nm, 1.0 mL/min)

Figure 112011023120813-pat00011
Figure 112011023120813-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 = 8.7min 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 of formula (III) = 7.2min

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 of formula (IV) = 7.6 min

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) = 6.5min

도 3 및 도 4에 도시된 데이터는 Bruker AC NMR 200의 장비로 측정한 데이터이다.
The data shown in FIGS. 3 and 4 are data measured with 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.
The invention made by the present inventors has been described in detail according to the above embodiment, but the present invention has been implemented for experiments, but is not limited thereto, and is modified in various ways without departing from the gist thereof. 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 5 ~ 10℃에서 메탄올로 녹이는 단계,
(b) 상기 (a) 단계의 용액에 수소화붕소나트륨(NaBH4)를 넣어 교반하는 단계,
(c) 상기 (b) 단계에서의 반응 종료 후 디이소프로필에테르(diisopropyl ether) 용매로 결정화하는 단계를 포함하는 것을 특징으로 하는 3S)-3-(tert-부톡시카르보닐)아미노-1-클로로-4-페닐-(2S)-부탄올의 제조방법.
Figure 112013026488680-pat00019

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) below with methanol at 5-10° C.,
(b) adding sodium borohydride (NaBH 4 ) to the solution of step (a) and stirring,
(c) 3S)-3-(tert-butoxycarbonyl)amino-1- characterized in that it comprises the step of crystallizing with a diisopropyl ether solvent after the reaction in step (b) is completed. Method for preparing chloro-4-phenyl-(2S)-butanol.
Figure 112013026488680-pat00019

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR960022492A (en) * 1994-12-13 1996-07-18 니콜라스 피. 말라테스티닠 Method for preparing N-protected amino acid alpha-halomethylketone and alcohol from N-protected amino acid ester
EP1148046A1 (en) * 1999-01-28 2001-10-24 Ajinomoto Co., Inc. Process for the preparation of alpha-aminoketones
EP1346979A1 (en) * 2000-11-30 2003-09-24 Ajinomoto Co., Inc. Processes for preparation of n-protected- -amino alcohols and n-protected- -amino epoxides

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR960022492A (en) * 1994-12-13 1996-07-18 니콜라스 피. 말라테스티닠 Method for preparing N-protected amino acid alpha-halomethylketone and alcohol from N-protected amino acid ester
EP1148046A1 (en) * 1999-01-28 2001-10-24 Ajinomoto Co., Inc. Process for the preparation of alpha-aminoketones
EP1346979A1 (en) * 2000-11-30 2003-09-24 Ajinomoto Co., Inc. Processes for preparation of n-protected- -amino alcohols and n-protected- -amino epoxides

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