KR20020042888A - Process for optically active (S)-2-(6'-methoxy-2'-naphthyl) propionic acid and derivatives thereof - Google Patents

Process for optically active (S)-2-(6'-methoxy-2'-naphthyl) propionic acid and derivatives thereof Download PDF

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KR20020042888A
KR20020042888A KR1020000072231A KR20000072231A KR20020042888A KR 20020042888 A KR20020042888 A KR 20020042888A KR 1020000072231 A KR1020000072231 A KR 1020000072231A KR 20000072231 A KR20000072231 A KR 20000072231A KR 20020042888 A KR20020042888 A KR 20020042888A
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methoxy
chloride
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naphthyl
propionic acid
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박형준
조은정
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구광시
주식회사 코오롱
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings

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Abstract

PURPOSE: Provided is a method for preparing higher purity (S)-2-(6'-methoxy-2'-naphthyl)propionic acid in higher yields than existing method. CONSTITUTION: The method, which is for preparing optical pure (S)-2-(6'-methoxy-2'-naphthyl)propionic acid of formula 3 and its derivative, comprises Grignard reacting a compound of formula 1 with a compound of formula 2. In the formulae, X represents halogen such as bromine, iodine, and chlorine, or -SO2R'(wherein, R' represents a methyl, an ethyl, paratoluene, benzene, paranitrobenzene); and L represents a methyl, or an ethyl; or sodium or potassium. The reaction temperature is -30 to 100 deg.C.

Description

광학활성을 지닌 (Ｓ)-2-(6'-메톡시-2'-나프틸)프로피온산 및 그 유도체의 신규한 제조방법{Process for optically active (S)-2-(6'-methoxy-2'-naphthyl) propionic acid and derivatives thereof}Novel process for preparing (S) -2- (6'-methoxy-2'-naphthyl) propionic acid and its derivatives having optical activity {Process for optically active (S) -2- (6'-methoxy-2 '-naphthyl) propionic acid and derivatives

본 발명은 하기의 화학식(1)의 (S)-2-(6'-메톡시-2'-나프틸)프로피온산 (나프록센, Naproxen)의 제조에 있어서, 최종 산물이 광학활성을 지니도록 제조할 수 있는 방법에 관한 것이다.In the preparation of (S) -2- (6'-methoxy-2'-naphthyl) propionic acid (naproxen, Naproxen) of the formula (1) below, the final product may be prepared to have optical activity. It is about how it can be.

비스테로이드성 소염진통제로 널리 쓰이고 있는 방향족 프로피온산계 소염진통제는 키랄탄소를 가진 광학이성질체로 존재하며 두 가지 이성질체의 소염진통효과는 매우 차이가 크다. 나프록센의 경우에는 광학적으로 순수한 (S)-이성질체만으로 시장이 형성되어 있는 상태이며, 다른 방향족 프로피온산계 소염진통제들의 경우도 점차 한가지 이성질체의 형태로 개발 및 판매되는 추세에 있어, 이에 대한제조방법에 관하여 많은 연구가 이루어지고 있다.Aromatic propionic acid-based anti-inflammatory drugs, widely used as nonsteroidal anti-inflammatory drugs, exist as optical isomers with chiral carbon, and the anti-inflammatory effects of the two isomers are very different. In the case of naproxen, the market is formed only with optically pure (S) -isomer, and other aromatic propionic acid anti-inflammatory drugs are gradually developed and sold in the form of one isomer. Much research is being done.

미국 특허 제3,904,683호에서는 디히드로아비에틸아민을 이용한 재결정법으로 라세믹 나프록센에서 광학순도 98∼99%의 (S)-나프록센을 얻었으나 그 수율이 17%정도여서, 경제성확보에 불리하며, 미국 특허 제4,723,033호에 의하면, 광학활성촉매 하에서 비대칭적 그린야드 반응을 통해 최고 수율 50%정도로 나프록센을 제조하는 방법이 알려져 있다. 그러나, 이 방법의 경우, 전이금속촉매의 비용 및 부틸리튬을 사용하는 격렬한 반응으로 공정화가 쉽지 않으며, 70% 이상의 광학순도를 얻을 수 없어 재결정법을 도입해야 하는 단점이 있다.U.S. Patent No. 3,904,683 obtains (S) -naproxen having an optical purity of 98-99% from racemic naproxen by recrystallization with dihydroabiethylamine, but the yield is about 17%, which is disadvantageous for securing economic efficiency. According to Patent No. 4,723,033, a method of producing naproxen with a maximum yield of about 50% through an asymmetric green yard reaction under an optically active catalyst is known. However, this method is not easy to process due to the cost of the transition metal catalyst and violent reaction using butyllithium, and has the disadvantage of introducing a recrystallization method because an optical purity of 70% or more cannot be obtained.

또한, 미국 특허 제5,233,084호에 의하면, 2-(6'-메톡시-2'나프틸)프로펜산으로부터 광학활성 금속촉매를 사용한 수소화 반응을 통해 나프록센을 제조하는 방법을 제시하고 있으나, 이 경우 역시, 2-(6'-메톡시-2'-나프틸)프로펜산을 제조하기 위해 전기화학적으로 이산화탄소를 도입하는 반응 등 여러단계의 반응이 필요하며, 고가 금속촉매 사용 및 가압반응으로 인한 공정화 어려움의 단점이 있다.In addition, US Pat. No. 5,233,084 discloses a method for preparing naproxen from a hydrogenation reaction using an optically active metal catalyst from 2- (6'-methoxy-2'naphthyl) propenoic acid. To prepare 2- (6'-methoxy-2'-naphthyl) propenoic acid, several stages of reactions are required, such as the introduction of carbon dioxide electrochemically, and it is difficult to process due to the use of expensive metal catalysts and pressurization. There are disadvantages.

이러한 이유로 상기의 공지의 방법들을 보다 개선한 공정개발이 요구되어 왔다.For this reason, there is a need for process development that further improves the above known methods.

이에 본 발명자는 오랫동안 지속적인 연구를 수행한 결과, 저가의 광학활성 단분자체를 이용하여 광학활성을 지닌 2-(6'-메톡시-2'-나프틸)프로피온산을 고순도, 고수율로 제조함으로써 전술한 종래기술의 문제점을 효과적으로 극복할 수 있는 본 발명을 완성하였다.Accordingly, the present inventors have conducted a long-time continuous research, by using a low-cost optically active monomolecular body to prepare 2- (6'-methoxy-2'-naphthyl) propionic acid having high optical activity in high purity, high yield The present invention has been completed to effectively overcome the problems of the prior art.

따라서, 본 발명은 기존의 제조방법보다 순도 및 수율이 높은 2-(6'-메톡시 -2'-나프틸)프로피온산의 신규한 제조방법을 제공하는 것을 목적으로 한다.Accordingly, an object of the present invention is to provide a novel method for preparing 2- (6'-methoxy-2'-naphthyl) propionic acid, which is higher in purity and yield than conventional methods.

본 발명은 광학활성 단분자체인 (S)-2-할로프로피온산 내지 (S)-2-알킬(아릴)설폰옥시프로피온산의 금속염 또는 에스테르로서의 하기 화학식 (1)의 화합물과, 하기 화학식(2)의 화합물을 그린야드반응시켜 광학적으로 순수한 하기 화학식(3)의 (S)-2-(6'-메톡시-2'-나프틸) 프로피온산 및 그 유도체를 제조하는 방법에 관한 것이다.The present invention relates to a compound of formula (1) as a metal salt or ester of (S) -2-halopropionic acid to (S) -2-alkyl (aryl) sulfoneoxypropionic acid, which is an optically active monomer, and The present invention relates to a method for preparing optically pure (S) -2- (6'-methoxy-2'-naphthyl) propionic acid and its derivatives by green yard reaction of a compound.

상기 식에서 X는 브롬, 요오드, 염소 등의 할로겐이거나 -OSO2R'(여기서 R'는 메틸, 에틸, 파라톨루엔, 벤젠, 파라니트로벤젠이다)이고; L은 메틸, 에틸이거나 나트륨, 칼륨이다.In which X is halogen, such as bromine, iodine, chlorine, or -OSO 2 R 'wherein R' is methyl, ethyl, paratoluene, benzene, paranitrobenzene; L is methyl, ethyl or sodium, potassium.

본 발명에서 사용한 (S)-2-할로프로피온산의 금속염 또는 에스테르는 포도당을 발효시켜 (R)-젖산 및 이의 금속염 또는 에스테르를 대량으로 제조한 후, 염화티오닐(SOCl2)을 사용하여 그것의 히드록시기를 염소로 치환시켜 제조하며, (S)-2-알킬(아릴)설폰옥시프로피온산의 금속염 또는 에스테르 역시 포도당을 발효시켜 (S)-젖산 및 이의 금속염 또는 에스테르를 대량으로 제조한 후, 그것의 히드록시기를 메탄설포닐 클로라이드(메실클로라이드), 에탄설포닐 클로라이드, 파라톨루엔설포닐 클로라이드, 벤젠설포닐 클로라이드 또는 파라니트로벤젠설포닐 클로라이드 와 반응시켜 알킬설폰 또는 아릴설폰으로 치환하여 다음 반응에 사용하게 된다.The metal salts or esters of (S) -2-halopropionic acid used in the present invention are fermented to produce large amounts of (R) -lactic acid and its metal salts or esters, and then the thionyl chloride (SOCl 2 ) It is prepared by substituting a hydroxy group with chlorine, and a metal salt or ester of (S) -2-alkyl (aryl) sulfonoxypropionic acid is also fermented to produce (S) -lactic acid and its metal salt or ester in large quantities, and then The hydroxy group is reacted with methanesulfonyl chloride (mesyl chloride), ethanesulfonyl chloride, paratoluenesulfonyl chloride, benzenesulfonyl chloride or paranitrobenzenesulfonyl chloride to be substituted with alkylsulfone or arylsulphone for use in the next reaction. .

본 발명에서 반응온도는 -30℃ 내지 100℃의 범위이며, 바람직하게는 -10℃ 내지 30℃이다.In the present invention, the reaction temperature is in the range of -30 ° C to 100 ° C, preferably -10 ° C to 30 ° C.

본 발명에서 사용된 용매는 테트라하이드로푸란, 에테르, 이소프로필에테르 등의 유기용매를 포함한다.The solvent used in the present invention includes organic solvents such as tetrahydrofuran, ether and isopropyl ether.

반응이 완결되면 반응용액에 산을 가하고 유기용매로 추출하거나 또는 알칼리를 가하여 수층으로 추출한 후 산으로 다시 재결정화되며, 사용량은 2당량 내지 10당량 사용하여 수행한다. 추출하는 용매로는 에틸아세테이트, 에테르, 벤젠, 톨루엔, 니트로벤젠, 메틸렌클로라이드, 클로로포름 등이 적당하며 추출한 용액은 농축시킨 후 유기용매를 가하여 결정화시킨다. 결정화할 때 사용하는 용매로는 에틸아세테이트, 에테르, 벤젠, 톨루엔, 1,4-디옥산, 테트라하이드로푸란 등의 유기용매를 포함한다.When the reaction is completed, an acid is added to the reaction solution and extracted with an organic solvent or an alkali is added to the aqueous layer and then recrystallized with an acid. The amount is used in an amount of 2 to 10 equivalents. Ethyl acetate, ether, benzene, toluene, nitrobenzene, methylene chloride, chloroform and the like are suitable as extraction solvents, and the extracted solution is concentrated and crystallized by adding an organic solvent. Solvents used for crystallization include organic solvents such as ethyl acetate, ether, benzene, toluene, 1,4-dioxane and tetrahydrofuran.

이하 실시예를 들어 본 발명을 구체적으로 설명하나 본 발명이 이에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.

실시예 1Example 1

(S)-에틸 2-메탄설포닐옥시프로피온 에스테르의 제조Preparation of (S) -ethyl 2-methanesulfonyloxypropion ester

120g의 (S)-에틸락테이트와 120g의 메탄설포닐클로라이드를 천천히 적가하였다. 약 1시간 30분 경과 후, 용액을 20℃로 하고, 순수에 부어 층분리를시켰다. 유기층을 마그네슘설페이트로 건조시킨 다음, 감압증류하여 160g의 (S)-에틸 2-메틸설포닐옥시프로피온 에스테르를 제조하였다. 비선광도는 [α]25 D=-44°였다.120 g of (S) -ethyllactate and 120 g of methanesulfonylchloride were slowly added dropwise. After about 1 hour and 30 minutes, the solution was brought to 20 ° C and poured into pure water to separate layers. The organic layer was dried over magnesium sulfate and then distilled under reduced pressure to prepare 160 g of (S) -ethyl 2-methylsulfonyloxypropion ester. Specific light intensity was [α] 25 D = -44 °.

NMR 스펙트럼: δ=1.28(t,j=2.2), 1.57(d,j=2.3), 3.12, 4.23(q,j=2.2), 5.12 (q,j=2.3)NMR spectrum: δ = 1.28 (t, j = 2.2), 1.57 (d, j = 2.3), 3.12, 4.23 (q, j = 2.2), 5.12 (q, j = 2.3)

실시예 2Example 2

(S)-2-(6'-메톡시-2'-나프틸)프로피온산의 제조 (화합물(1))Preparation of (S) -2- (6'-methoxy-2'-naphthyl) propionic acid (Compound (1))

마그네슘 2.64g, 에테르 250g을 넣고 질소분위기로 유지하였다. 2-브롬모-6-메톡시나프탈렌 25g을 적가하고, 적가완료 후 1시간동안 30℃로 반응시켰다. 반응 후 반응액의 온도를 0℃이하로 냉각하고 염화아연 0.25g을 반응액에 투입하였다. 실시예 1에서 얻어진 (S)-에틸 2-메탄설포닐옥시프로피온 에스테르 17g을 분할투입하였다. 투입완료 후 다시 30℃에서 1시간 동안 반응시키고 반응완료 후 물 100g을투입한 다음 1N 염산을 투입하였다. 유기층을 물 100g으로 세정하고 감압하에서 용매를 제거하였다. 농축액에 물 100g과 1N 염산을 가하여 2시간 동안 환류시키고, 에테르로 추출한 후, 감압증류로 용매를 제거하여 상기 화합물 20g을 얻었다.2.64 g of magnesium and 250 g of ether were added thereto and kept in a nitrogen atmosphere. 25 g of 2-bromo-6-methoxynaphthalene was added dropwise and reacted at 30 ° C. for 1 hour after completion of the dropwise addition. After the reaction, the temperature of the reaction solution was cooled to 0 ° C. or lower, and 0.25 g of zinc chloride was added to the reaction solution. 17 g of (S) -ethyl 2-methanesulfonyloxypropion ester obtained in Example 1 was separately injected. After completion of the reaction, the reaction was again performed at 30 ° C. for 1 hour, and after completion of the reaction, 100 g of water was added thereto, followed by addition of 1N hydrochloric acid. The organic layer was washed with 100 g of water and the solvent was removed under reduced pressure. 100 g of water and 1N hydrochloric acid were added to the concentrate, and the mixture was refluxed for 2 hours, extracted with ether, and the solvent was removed by distillation under reduced pressure to obtain 20 g of the compound.

수율 85%, 순도 99.2%, 비선광도[α]25 D=+66°, 녹는점 157℃Yield 85%, Purity 99.2%, Specific Radiance [α] 25 D = + 66 °, Melting Point 157 ℃

실시예 3Example 3

(S)-2-클로로프로피온산 나트륨 염의 제조Preparation of (S) -2-chloropropionate sodium salt

120g의 (R)-젖산과 120g의 트리에틸아민을 500ml의 톨루엔에 용해시키고, 온도를 10-15℃로 유지하면서 120g의 염화티오닐(SOCl2)을 천천히 적가하였다. 약 1시간 30분 경과 후, 용액을 20℃로 한 다음, 순수에 부어 1시간 교반하였다. 층분리를 시킨 후, 유기층을 40% 수산화나트륨 용액으로 처리하여 130g의 (R)-2-클로로프로피온산 나트륨염을 제조하였다.120 g of (R) -lactic acid and 120 g of triethylamine were dissolved in 500 ml of toluene and 120 g of thionyl chloride (SOCl 2 ) was slowly added dropwise while maintaining the temperature at 10-15 ° C. After about 1 hour and 30 minutes, the solution was brought to 20 ° C, poured into pure water, and stirred for 1 hour. After layer separation, the organic layer was treated with 40% sodium hydroxide solution to prepare 130 g of (R) -2-chloropropionate sodium salt.

실시예 4Example 4

(S)-2-(6'-메톡시-2'-나프틸) 프로피온산의 제조 (화합물(1))Preparation of (S) -2- (6'-methoxy-2'-naphthyl) propionic acid (Compound (1))

마그네슘 2.64g, 에테르 250g을 넣고 질소분위기로 유지하였다. 2-브롬모-6-메톡시나프탈렌 25g을 적가하고, 적가완료 후 1시간 동안 30도로 반응시켰다. 반응 후 반응액의 온도를 0℃ 이하로 냉각하고 염화아연 0.25g을 반응액에 투입하였다. 실시예 3에서 얻어진 (R)-2-클로로프로피온산나트륨 염 12g을 분할투입하고 투입완료 후 다시 30도에서 1시간 동안 반응시켰다. 반응완료 후 물 100g을 투입한 다음, 1N 염산을 투입하였다. 유기층을 물 100g으로 세정하고 감압하에서 용매를 제거하여 상기 화합물 19g을 얻었다.2.64 g of magnesium and 250 g of ether were added thereto and kept in a nitrogen atmosphere. 25 g of 2-bromo-6-methoxynaphthalene was added dropwise and reacted at 30 ° C. for 1 hour after completion of the dropwise addition. After the reaction, the temperature of the reaction solution was cooled to 0 ° C or lower, and 0.25 g of zinc chloride was added to the reaction solution. 12 g of (R) -2-chloropropionate salt obtained in Example 3 was added in portions and reacted for 1 hour at 30 ° C. after completion of the addition. After completion of the reaction, 100g of water was added, followed by 1N hydrochloric acid. The organic layer was washed with 100 g of water, and the solvent was removed under reduced pressure to obtain 19 g of the compound.

수율 80%, 순도 99.4%, 비선광도 [α]25 D=+66°, 녹는점 157℃Yield 80%, purity 99.4%, specific light intensity [α] 25 D = + 66 °, melting point 157 ° C

본 발명에 따른 공정은 종래의 공정에 비해 반응단계가 간단하고 저가일 뿐만 아니라 광학순도 및 수율이 월등히 우수하다는 장점이 있다.The process according to the present invention has advantages in that the reaction step is simple and inexpensive as well as the optical purity and yield are superior to the conventional process.

Claims (3)

하기 화학식(1)의 화합물과 하기 화학식(2)의 화합물을 그린야드반응시키는 것을 특징으로 하는 광학적으로 순수한 하기 화학식(3)의 (S)-2-(6'-메톡시-2'-나프틸) 프로피온산 및 그 유도체의 제조방법:Optically pure (S) -2- (6'-methoxy-2'-naph) of the formula (3), characterized by green yard reaction of the compound of formula (1) with the compound of formula (2) Tyl) propionic acid and derivatives thereof: 상기 식에서 X는 브롬, 요오드, 염소 등의 할로겐이거나 -OSO2R'(여기서 R'는메틸, 에틸, 파라톨루엔, 벤젠, 파라니트로벤젠이다)이고; L은 메틸, 에틸이거나 나트륨, 칼륨이다.In which X is halogen, such as bromine, iodine, chlorine or -OSO 2 R 'wherein R' is methyl, ethyl, paratoluene, benzene, paranitrobenzene; L is methyl, ethyl or sodium, potassium. 제 1항에 있어서, 상기 화학식(1)의 화합물은 (S)-젖산 또는 그 유도체에 염화 티오닐을 사용하여 그것의 히드록시기를 염소로 치환시켜 제조하거나, (R)-젖산 또는 그 유도체에 메탄설포닐 클로라이드, 에탄설포닐 클로라이드, 파라톨루엔설포닐 클로라이드, 벤젠설포닐 클로라이드 또는 파라니트로벤젠설포닐 클로라이드와 반응시켜 알킬설폰 또는 아릴설폰으로 치환하여 제조하는 것을 특징으로 하는 방법.The compound of formula (1) is prepared by substituting a hydroxy group for chlorine using thionyl chloride in (S) -lactic acid or a derivative thereof, or methane in (R) -lactic acid or a derivative thereof. A method characterized in that it is prepared by reacting with sulfonyl chloride, ethanesulfonyl chloride, paratoluenesulfonyl chloride, benzenesulfonyl chloride or paranitrobenzenesulfonyl chloride and replacing with alkylsulfone or arylsulfone. 제 1항에 있어서, 반응온도가 -30℃ 내지 100℃의 범위인 것을 특징으로 하는 방법.The method of claim 1 wherein the reaction temperature is in the range of -30 ° C to 100 ° C.
KR1020000072231A 2000-12-01 2000-12-01 Process for optically active (S)-2-(6'-methoxy-2'-naphthyl) propionic acid and derivatives thereof KR20020042888A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5995239A (en) * 1982-11-22 1984-06-01 Mitsubishi Petrochem Co Ltd Preparation of alpha-(6-methoxy-2-naphthyl)propionic acid
US4723033A (en) * 1982-11-24 1988-02-02 Syntex Pharmaceuticals International Ltd. Manufacture of optically active α-arylalkanoic acids and precursors thereof
KR920003778A (en) * 1990-07-12 1992-02-29 아오이 죠이치 Orthogonal Multiple Signal Processing Unit

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5995239A (en) * 1982-11-22 1984-06-01 Mitsubishi Petrochem Co Ltd Preparation of alpha-(6-methoxy-2-naphthyl)propionic acid
US4723033A (en) * 1982-11-24 1988-02-02 Syntex Pharmaceuticals International Ltd. Manufacture of optically active α-arylalkanoic acids and precursors thereof
KR920003778A (en) * 1990-07-12 1992-02-29 아오이 죠이치 Orthogonal Multiple Signal Processing Unit

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