KR100458983B1 - Processes for preparing an optically active serine derivative - Google Patents

Processes for preparing an optically active serine derivative Download PDF

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KR100458983B1
KR100458983B1 KR1020040014957A KR20040014957A KR100458983B1 KR 100458983 B1 KR100458983 B1 KR 100458983B1 KR 1020040014957 A KR1020040014957 A KR 1020040014957A KR 20040014957 A KR20040014957 A KR 20040014957A KR 100458983 B1 KR100458983 B1 KR 100458983B1
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serine
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유호성
홍유화
장도영
권순정
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주식회사 에스텍파마
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    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • E04G7/00—Connections between parts of the scaffold
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Abstract

PURPOSE: Provided are a method for preparing an optically active L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine or its salt known as droxidopa having an activity to the central nervous system and the circulation system, in a high yield and high purity, and an intermediate compound of the preparation method. CONSTITUTION: The method comprises the steps of decomposing a compound represented by the formula 2 with an acid in a polar organic solvent, to obtain a compound represented by the formula 1b; and obtaining an L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine or its salt represented by the formula 1a by the hydroxylation of the compound of the formula 1b, wherein R1 and R2 are independently a benzyl group, a p-nitrobenzyl group, a p-fluorobenzyl group, a p-trifluorobenzyl group, a C1-C4 alkoxy C1-C4 alkyl group or a C1-C4 alkyl group; and M is Cu2+, Ni2+ or Zn2+. Preferably the polar organic solvent is selected from the group consisting of a C1-C7 alcohol, tetrahydrofuran, acetonitrile, dimethyl formaldehyde and their mixture; and the acid is HCl, HBr, sulfuric acid, nitric acid, acetic acid or trifluoromethylacetic acid.

Description

광학적으로 활성인 세린 유도체의 제조방법{Processes for preparing an optically active serine derivative}Process for preparing an optically active serine derivative

본 발명은 광학적으로 활성인 세린 유도체의 제조방법에 관한 것으로, 더욱 상세하게는 드록시도파(droxidopa)로 알려진 광학적으로 활성인 세린 유도체 또는 그의 염의 제조방법 및 그의 제조 중간체에 관한 것이다.The present invention relates to a method for preparing an optically active serine derivative, and more particularly, to a method for preparing an optically active serine derivative or salt thereof known as droxidopa, and an intermediate for producing the same.

드록시도파(droxidopa) 또는 그의 염은 순환계 및 중추신경계에 활성을 가지며, 파킨슨병, 우울증, 말초기립성 저혈압 등의 치료제로서 유용한 약물이다. 드록시도파는 광학적으로 활성인 세린 유도체로서, 그 화학명은 L-쓰레오-(2S,3R)-3-(3,4-디히드록시페닐)세린[L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine]이고, 하기 화학식 1a의 구조를 갖는다.Droxidopa or a salt thereof is active in the circulatory system and central nervous system, and is a drug useful as a therapeutic agent for Parkinson's disease, depression, peripheral orthostatic hypotension and the like. Droxydopa is an optically active serine derivative whose chemical name is L-threo- (2S, 3R) -3- (3,4-dihydroxyphenyl) serine [L-threo- (2S, 3R)- 3- (3,4-dihydroxyphenyl) serine] and has the structure of Formula 1a.

미국특허 제3,920,728은 4가지의 이성체 형태(isomeric form)로부터 드록시도파를 포함한 각각의 이성체를 분리하는 방법을 개시하고 있다. 그러나, 4가지의 이성체 형태(isomeric form)로부터 분리를 수행함으로써, 최대 수율이 25%을 초과할 수 없다는 문제점이 있다.U.S. Patent No. 3,920,728 discloses a method for separating each isomer, including doxydopa, from four isomeric forms. However, by carrying out the separation from the four isomeric forms, there is a problem that the maximum yield cannot exceed 25%.

또한, 미국특허 제5,739,387호(일본 특개평 제9-031038호, 제9-301961호, 제8-231518호)는 DOPA로부터 얻어진 N-아세틸 DOPA 유도체로부터 드록시도파를 제조하는 방법을 개시한 바 있다. 그러나, 이 방법은 고가의 시약인 DOPA를 사용함으로써, 고비용의 제조경비가 소요되는 단점이 있다.In addition, U. S. Patent No. 5,739, 387 (Japanese Patent Laid-Open Nos. 9-031038, 9-301961, and 8-231518) discloses a process for preparing doxydopa from N-acetyl DOPA derivatives obtained from DOPA. have. However, this method has a disadvantage in that expensive manufacturing costs are required by using DOPA, which is an expensive reagent.

일본 특개평 제9-249626호는 키랄 디올(chiral diol) 유도체를 합성한 후, 아지도(azido)기를 도입하고 환원시켜, 드록시도파를 제조하는 방법을 개시한 바 있으며, 일본 특개소 제61-275254호 및 일본 특개평 제5-239025호는 벤즈알데히드(Benzaldehyde) 유도체를 출발물질로 사용하여 쓰레오-N-프탈로일-3-(3,4-디히드록시페닐)세린을 제조한 후, 드록시도파를 제조하는 방법을 개시한 바 있다. 그러나, 상업적 규모의 대량생산 및 수율의 측면에서 새로운 제조방법의 개발이 당업계에 요구된다.Japanese Patent Laid-Open No. 9-249626 discloses a method for preparing a hydroxydopa by synthesizing a chiral diol derivative and then introducing and reducing an azido group. -275254 and Japanese Patent Laid-Open No. 5-239025 prepare beo-N-phthaloyl-3- (3,4-dihydroxyphenyl) serine using benzaldehyde derivatives as starting materials. It has been disclosed a method for preparing hydroxydopa. However, there is a need in the art for the development of new manufacturing methods in terms of commercial scale mass production and yield.

한편, J. Am. Chem. Soc. 107, 4252-4259, 1985 는 알데히드 및 케톤을 글라이신과 축합하여 디아스테레오(diastereo-) 및 에난티오(enantio-) 선택성 β-히드록시-α-아미노산의 제조방법을 개시한 바 있다. 즉, 하기 구조식을 갖는 글라이신과 금속의 키랄 착물(chiral complex)을, 알데히드 및 케톤 등과 반응시켜 D-쓰레오-(2R,3S)-β-페닐세린 유도체를 제조하는 방법을 개시한 바 있다.Meanwhile, J. Am. Chem. Soc. 107, 4252-4259, 1985 discloses a process for the preparation of diastereo- and enantio-selective β-hydroxy-α-amino acids by condensing aldehydes and ketones with glycine. That is, a method of preparing a D-threo- (2R, 3S) -β-phenylserine derivative by reacting a chiral complex of glycine with a metal having the following structural formula with an aldehyde, a ketone, or the like has been disclosed.

또한, J. Chem. Soc. Perkin Trans. 1, 3143-3154, 1993 은 상기 키랄 착물을 이용하여 측쇄에 불소(fluorine) 원자를 갖는 β-히드록시-α-아미노산의 제조방법을 개시한 바 있다.In addition, J. Chem. Soc. Perkin Trans. 1, 3143-3154, 1993 discloses a method for producing β-hydroxy-α-amino acids having fluorine atoms in the side chain using the chiral complex.

그러나, 상기 선행기술들(즉, J. Am. Chem. Soc. 107, 4252-4259, 1985 또는 J. Chem. Soc. Perkin Trans. 1, 3143-3154, 1993)을 이용하여 광학적으로 활성인 세린 유도체를 제조하고자 할 경우, D-쓰레오-(2R,3S)-3-(3,4-디히드록시페닐)세린이 주로 얻어지게 되며, 드록시도파인 L-쓰레오-(2S,3R)-3-(3,4-디히드록시페닐)세린은 순수하게 얻기가 매우 곤란하다. 더욱이, 상기 선행기술에 따라 드록시도파를 제조할 경우, 트리에틸아민-메탄올 혼합용매에서의 반응시간이 3일 이상 소요되고, 쓰레오-(2S,3R) 형태 및 에리쓰로-(2S,3S) 형태의 1:1 ∼ 2:1 혼합물이 생성되며, (2R,3S) 및 (2R,3R)의 혼합물도 5 ∼ 20% 생성됨으로써, 순수한 목적화합물인 L-쓰레오-(2S,3R)-3-(3,4-디히드록시페닐)세린 즉, 드록시도파 제조를 위한 상업적 적용은 매우 어렵다는 문제점이 있다.However, serine that is optically active using the prior art (ie, J. Am. Chem. Soc. 107, 4252-4259, 1985 or J. Chem. Soc. Perkin Trans. 1, 3143-3154, 1993) When the derivative is to be prepared, D-threo- (2R, 3S) -3- (3,4-dihydroxyphenyl) serine is mainly obtained, and hydroxydopine L-threo- (2S, 3R ) -3- (3,4-dihydroxyphenyl) serine is very difficult to obtain pure. Furthermore, when preparing hydroxydopa according to the above prior art, the reaction time in the triethylamine-methanol mixed solvent takes three days or more, and is in the form of threo- (2S, 3R) and erythro- (2S, 3S) forms a 1: 1 to 2: 1 mixture, and a mixture of (2R, 3S) and (2R, 3R) is also produced by 5-20%, thereby yielding the pure target compound L-Threo- (2S, 3R ) -3- (3,4-dihydroxyphenyl) serine, that is, the commercial application for the preparation of hydroxydopa has a problem that is very difficult.

또한, 상기 선행기술들에 따라 드록시도파를 제조하는 경우, 페닐 고리에 존재하는 2개의 히드록시기로 인하여 반응(즉, 알돌 축합반응) 자체가 진행되지 않는다는 문제점이 있다.In addition, when preparing the hydroxydopa according to the prior arts, there is a problem that the reaction (that is, aldol condensation) itself does not proceed due to the two hydroxyl groups present in the phenyl ring.

본 발명은 높은 광학적 순도를 갖는 드록시도파를 높은 수율로 제조할 수 있는 새로운 제조방법 및 그의 제조 중간체를 제공한다. 즉, 본 발명은 L-쓰레오-(2S,3R)-β-히드록시-α-아미노산의 입체화학을 갖는 드록시도파를 높은 순도와 높은 수율로 제조하는 입체선택적 제조 방법 및 그의 제조 중간체로서 유용한 키랄 금속 착물을 제공한다.The present invention provides a novel manufacturing method and intermediates for its preparation which can produce doxydopa having high optical purity in high yield. That is, the present invention provides a stereoselective preparation method for producing hydroxydopa having a stereochemistry of L-Threo- (2S, 3R) -β-hydroxy-α-amino acid with high purity and high yield, and a preparation intermediate thereof. Provide useful chiral metal complexes.

따라서, 본 발명은 드록시도파의 제조방법을 제공하는 것을 목적으로 한다.Accordingly, an object of the present invention is to provide a method for producing doxydopa.

또한, 본 발명의 목적은 드록시도파의 제조 중간체로서 유용한 중간체를 제공하는 것을 포함한다.It is also an object of the present invention to provide intermediates useful as intermediates for the preparation of doxydopa.

본 발명의 일 태양에 따라, 화학식 2의 화합물을 극성 유기용매 중에서 산으로 분해하여 화학식 1b의 화합물을 얻는 단계; 및 상기 화학식 1b의 화합물의 히드록실화(hydroxylation) 반응을 수행하는 단계를 포함하는, 드록시도파(즉, L-쓰레오-(2S,3R)-3-(3,4-디히드록시페닐)세린) 또는 그의 염의 제조방법이 제공된다:According to an aspect of the present invention, the compound of formula 2 is decomposed to an acid in a polar organic solvent to obtain a compound of formula 1b; And performing a hydroxylation reaction of the compound of Formula 1b, that is, hydroxydopa (ie, L-threo- (2S, 3R) -3- (3,4-dihydroxyphenyl). Serine) or a salt thereof is provided:

식 중, R1및 R2는, 각각 독립적으로, 벤질, p-니트로벤질, p-플루오로벤질, p-트리플루오로벤질, C1∼C4알콕시 C1∼C4알킬, 또는 C1∼C4알킬이며; M은 Cu2+, Ni2+, 또는 Zn2+이다.Wherein, R 1 and R 2 are, each independently, benzyl, p- nitrobenzyl, in a p- fluorobenzyl, p- trifluoromethyl, benzyl, C 1 ~C 4 alkoxy C 1 ~C 4 alkyl, or C 1 ˜C 4 alkyl; M is Cu 2+ , Ni 2+ , or Zn 2+ .

본 발명의 제조방법에 있어서, R1및 R2가 모두 벤질인 경우, 히드록실화 반응을 쉽게 진행할 수 있으므로, 바람직하다.In the manufacturing method of this invention, when both R <1> and R <2> are benzyl, since hydroxylation reaction can advance easily, it is preferable.

본 발명의 제조방법에 있어서, 상기 극성 유기용매로는 C1∼C7의 알콜, 테트라히드로퓨란, 아세토니트릴, 디메틸포름아미드, 및 이들의 혼합용매로 이루어진 군으로부터 선택될 수 있으며, 바람직하게는 메탄올을 사용할 수 있다. 또한, 화학식 1b의 화합물을 제조하는 데 사용되는 상기 산으로는 무기산 및 유기산을 모두 사용할 수 있으며, 예를 들면, 염산, 브롬산, 황산, 질산, 초산, 또는 트리플루오로메틸아세트산 등을 사용할 수 있고, 바람직하게는 염산을 사용할 수 있다.In the preparation method of the present invention, the polar organic solvent may be selected from the group consisting of C 1 to C 7 alcohols, tetrahydrofuran, acetonitrile, dimethylformamide, and mixed solvents thereof, preferably Methanol can be used. In addition, as the acid used to prepare the compound of Formula 1b, both inorganic and organic acids may be used. For example, hydrochloric acid, bromic acid, sulfuric acid, nitric acid, acetic acid, or trifluoromethylacetic acid may be used. And preferably hydrochloric acid can be used.

상기 산의 사용량은 사용하는 산의 종류에 따라 상이하나, 화학식 2의 화합물 1당량에 대하여, 약 20 당량 이상, 바람직하게는 약 30 당량을 사용할 수 있다. 상기 화학식 2의 화합물의 분해반응은 -10 ∼ 100 ℃, 바람직하게는 약 50℃에서 수행할 수 있으며, 약 10분 ∼ 5 시간, 바람직하게는 약 1 시간 동안 수행할 수 있다.The amount of the acid used varies depending on the type of acid used, but may be used in an amount of about 20 equivalents or more, preferably about 30 equivalents, based on 1 equivalent of the compound of Formula 2. Decomposition of the compound of Formula 2 may be carried out at -10 to 100 ℃, preferably about 50 ℃, may be performed for about 10 minutes to 5 hours, preferably about 1 hour.

분해 반응후 남게되는 중간체 즉, D-2-[N-(N'-벤질프롤릴)아미노]벤조페논은 90% 이상 회수가 가능하며, 라세미화가 일어나지 않고 다음 반응에 계속적으로 사용이 가능하므로, 경제적으로 매우 유리하다.The intermediates remaining after the decomposition reaction, namely D-2- [N- (N'-benzylprolyl) amino] benzophenone, can be recovered more than 90% and can be used continuously in the next reaction without racemization. , Economically very advantageous.

상기 히드록실화 반응은 통상의 히드록실화 반응을 사용할 수 있으며, 바람직하게는 Pd/C, Pt 등의 금속 및 산(예를 들어, HCl, HBr 등) 존재하에서 수소를 가함으로써 수행될 수 있다. 또한, 용매는 상기한 바와 같은 극성 유기용매(예를 들어, 에탄올)를 사용하여 -10 ∼ 100℃, 바람직하게는 약 20℃에서 반응을 수행할 수 있다.The hydroxylation reaction may use a conventional hydroxylation reaction, preferably by adding hydrogen in the presence of metals such as Pd / C, Pt and acids (eg, HCl, HBr, etc.). . In addition, the solvent may be carried out at -10 to 100 ℃, preferably about 20 ℃ using a polar organic solvent (for example, ethanol) as described above.

본 발명의 제조방법에서, 상기 화학식 2의 화합물은 화학식 3의 화합물과 화학식 4의 화합물을, 염기 존재하에서, 반응시켜 제조할 수 있다.In the preparation method of the present invention, the compound of Formula 2 may be prepared by reacting the compound of Formula 3 with the compound of Formula 4 in the presence of a base.

식 중, R1, R2, 및 M은 상기에서 정의한 바와 같다.In the formula, R 1 , R 2 , and M are as defined above.

상기 염기로는 수산화나트륨, 수산화칼륨 및 수산화리튬 등의 알칼리금속 수산화물; 수산화마그네슘, 수산화칼슘 및 수산화바륨 등의 알칼리토금속 수산화물; 소듐 메톡사이드, 소듐 에톡사이드 및 포타시움 t-부톡사이드 등의 알칼리금속 알콕사이드; NHR3R4(R3및 R4는 같거나 상이할 수 있으며, 각각 C1∼C7의 알킬이다); NH2R5(R5는 C1∼C9의 알킬이다); 테트라부틸암모니움 히드록사이드 및 벤질트리메틸암모니움 히드록사이드 등의 4급 아민 수산화물; NaH; 및 NaNH2로 이루어진 군으로부터 선택될 수 있다. 이 중, 입체선택성을 최대한 증대시키기 위해서, 알칼리금속 알콕사이드(예를 들어, 소듐 메톡사이드), NaH, 또는 NaNH2를 바람직하게 사용할 수 있다. 상기 염기의 사용량은 사용하는 염기의 종류에 따라 상이하나, 화학식 3의 화합물 1당량에 대하여, 약 3 당량 이상, 바람직하게는 약 7 당량을 사용할 수 있다.Examples of the base include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide and barium hydroxide; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide; NHR 3 R 4 (R 3 and R 4 may be the same or different and are each C 1 to C 7 alkyl); NH 2 R 5 (R 5 is C 1 -C 9 alkyl); Quaternary amine hydroxides such as tetrabutylammonium hydroxide and benzyltrimethylammonium hydroxide; NaH; And NaNH 2 . Among these, alkali metal alkoxides (for example, sodium methoxide), NaH, or NaNH 2 can be preferably used to increase stereoselectivity as much as possible. The amount of the base used varies depending on the type of the base to be used, but about 3 equivalents or more, preferably about 7 equivalents, based on 1 equivalent of the compound of Formula 3, may be used.

화학식 3의 화합물과 화학식 4의 화합물과의 반응은 비대칭 알돌 축합 반응으로서, 극성 유기용매(예를 들어, 상기한 극성 유기용매; 바람직하게는 메탄올) 중에서 약 1시간 동안 반응시켜 수행할 수 있다. 화학식 3의 화합물 1당량에 대한 화학식 4의 화합물의 사용량은 약 1 당량이 바람직하다. 그러나, 화학식 4의 화합물이 상대적으로 저렴한 것을 감안하여, 화학식 3의 화합물에 대하여 과량으로 사용하는 것이 바람직하다.The reaction of the compound of Formula 3 with the compound of Formula 4 is an asymmetric aldol condensation reaction, which may be carried out by reacting in a polar organic solvent (for example, the polar organic solvent described above; preferably methanol) for about 1 hour. The amount of the compound of Formula 4 to 1 equivalent of the compound of Formula 3 is preferably about 1 equivalent. However, considering that the compound of formula 4 is relatively inexpensive, it is preferably used in excess of the compound of formula 3.

상기 화학식 3의 화합물은 D-프롤린과 벤질클로라이드를 반응시켜 D-N-벤질프롤린을 제조하는 단계; 상기 D-N-벤질프롤린과 2-아미노벤조페논을 반응시켜 D-2-[N-(N'-벤질프롤릴)아미노]벤조페논을 제조하는 단계; 및 상기 D-2-[N-(N'-벤질프롤릴)아미노]벤조페논, M(즉, Cu2+, Ni2+, 또는 Zn2+)을 포함하는 염 또는 그의 수화물, 및 글라이신을 반응시키는 단계를 포함하는 방법으로 제조될 수 있다. 상기 화학식 3의 화합물의 제조방법을 반응식으로 요약하면 반응식 1과 같다.The compound of Formula 3 is prepared by reacting D-proline and benzyl chloride to prepare DN-benzylproline; Reacting DN-benzylproline with 2-aminobenzophenone to produce D-2- [N- (N'-benzylprolyl) amino] benzophenone; And a salt or a hydrate thereof including D-2- [N- (N'-benzylprolyl) amino] benzophenone, M (ie Cu 2+ , Ni 2+ , or Zn 2+ ), and glycine It may be prepared by a method including the step of reacting. The method of preparing the compound of Chemical Formula 3 is summarized in Scheme 1, as in Scheme 1.

D-프롤린과 벤질클로라이드를 반응시켜 D-N-벤질프롤린을 제조하는 단계는 수산화칼륨 등의 염기 존재하에서, 이소프로필알콜 등의 알콜 중에서 수행할 수 있다. 상기 반응은 약 40℃ 중에서 약 6 시간 동안 수행할 수 있다.The step of preparing D-N-benzylproline by reacting D-proline with benzyl chloride may be carried out in an alcohol such as isopropyl alcohol in the presence of a base such as potassium hydroxide. The reaction can be carried out in about 40 ° C. for about 6 hours.

상기 D-N-벤질프롤린과 2-아미노벤조페논을 반응시켜 D-2-[N-(N'-벤질프롤릴)아미노]벤조페논을 제조하는 단계는 티오닐 클로라이드(SOCl2) 존재하에서 디클로메탄 등의 통상의 유기용매를 사용하여 수행할 수 있다. 즉, D-N-벤질프롤린의 디클로로메탄 용액을 약 -20 ∼ -30 ℃로 유지하면서 티오닐 클로라이드(SOCl2)를 서서히 적가한 다음, 2-아미노벤조페논을 서서히 가함으로써 반응을 수행할 수 있다.The reaction of DN-benzylproline with 2-aminobenzophenone to produce D-2- [N- (N'-benzylprolyl) amino] benzophenone is performed by dichloromethane in the presence of thionyl chloride (SOCl 2 ). It may be carried out using a conventional organic solvent such as. That is, the reaction may be carried out by slowly adding dropwise thionyl chloride (SOCl 2 ) while maintaining a dichloromethane solution of DN-benzylproline at about −20 to −30 ° C., and then slowly adding 2-aminobenzophenone.

또한, 상기 D-2-[N-(N'-벤질프롤릴)아미노]벤조페논, M(즉, Cu2+, Ni2+, 또는 Zn2+)을 포함하는 염 또는 그의 수화물, 및 글라이신을 반응시키는 단계는 수산화칼륨 등의 염기 존재하서 메탄올 등의 알콜을 용매로 사용하여 약 40∼50 ℃ 중에서 수행할 수 있다. 상기 Cu2+, Ni2+, 또는 Zn2+을 포함하는 염으로는 질산염 형태(예를 들어, Ni(NO3)2등), 할로겐염 형태(예를 들어, NiCl2, NiBr2등), 아세테이트 형태(예를 들어, Ni(OAc)2등), 또는 황산염 형태(예를 들어, NiSO4등)일 수 있다. 또한, 상기 Cu2+, Ni2+, 또는 Zn2+을 포함하는 염의 수화물로는 다양한 형태의 수화물을 사용할 수 있으며, 바람직하게는 Ni(NO3)2·6H2O 를 사용할 수 있다.Further, the salt comprising the above D-2- [N- (N'-benzylprolyl) amino] benzophenone, M (ie Cu 2+ , Ni 2+ , or Zn 2+ ) or a hydrate thereof, and glycine The reaction may be performed at about 40 to 50 ° C. using an alcohol such as methanol as a solvent in the presence of a base such as potassium hydroxide. Salts comprising Cu 2+ , Ni 2+ , or Zn 2+ include nitrate forms (eg, Ni (NO 3 ) 2, etc.), halogen salt forms (eg, NiCl 2 , NiBr 2, etc.) , Acetate form (eg Ni (OAc) 2, etc.), or sulfate form (eg NiSO 4, etc.). In addition, various types of hydrates may be used as the hydrate of the salt containing Cu 2+ , Ni 2+ , or Zn 2+ , and preferably Ni (NO 3 ) 2 .6H 2 O may be used.

본 발명의 제조방법을, 화학식 3의 화합물을 출발물질로 하여, 전체적인 반응식으로 나타내면 하기 반응식 1로 요약할 수 있다.The preparation method of the present invention can be summarized by the following Reaction Scheme 1 by using the compound of Formula 3 as a starting material.

본 발명의 다른 태양에 따라, 드록시도파의 제조용 중간체로서 유용한 화학식 2의 화합물 및/또는 화학식 3의 화합물을 제공한다.According to another aspect of the present invention, there is provided a compound of formula (2) and / or a compound of formula (3) which is useful as an intermediate for the preparation of doxydopa.

<화학식 2><Formula 2>

<화학식 3><Formula 3>

식 중, R1, R2, 및 M은 상기에서 정의한 바와 같다.In the formula, R 1 , R 2 , and M are as defined above.

이하, 본 발명을 실시예를 통하여 더욱 상세히 설명한다. 그러나, 이들 실시예는 본 발명을 예시하기 위한 것으로 본 발명이 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are only for illustrating the present invention and the present invention is not limited by the examples.

실시예 1. D-N-벤질프롤린(D-N-benzylproline)의 제조Example 1 Preparation of D-N-benzylproline

D-프롤린(115g, 1mol), 수산화칼륨(168.3g, 3mol), 및 이소프로필알콜(1L)의 현탁액을 40℃에서 교반하였다. 현탁액이 투명해진 후, 벤질클로라이드(137.3g,1.1mol)를 서서히 첨가하여 40℃에서 6시간 동안 교반하였다. 반응액을 0 ∼ 5 ℃로 냉각 후, 진한 염산(145mL)으로 pH를 5 ∼ 6으로 조절하였다. 이 반응액을 클로로포름(3L)으로 희석하여 18시간 교반한 후, 생성된 염화칼륨을 여과하여 제거하였다. 여액을 농축하여 아세톤으로 재결정하여 표제화합물 161.8g(수율 79%)을 제조하였다.A suspension of D-proline (115 g, 1 mol), potassium hydroxide (168.3 g, 3 mol), and isopropyl alcohol (1 L) was stirred at 40 ° C. After the suspension became clear, benzyl chloride (137.3 g, 1.1 mol) was added slowly and stirred at 40 ° C. for 6 hours. After cooling the reaction liquid to 0-5 degreeC, pH was adjusted to 5-6 with concentrated hydrochloric acid (145 mL). The reaction solution was diluted with chloroform (3 L), stirred for 18 hours, and the resulting potassium chloride was filtered off. The filtrate was concentrated and recrystallized with acetone to give 161.8 g (79% yield) of the title compound.

1H-NMR(CDCl3,ppm) : δ 7.2∼7.4(m, 5H), 4.0∼4.4(dd, 2H), 3.8(dd,1H), 3.6∼3.7(m,1H), 2.8(dd,1H), 1.8∼2.4(m,4H) 1 H-NMR (CDCl 3, ppm): δ 7.2 to 7.4 (m, 5H), 4.0 to 4.4 (dd, 2H), 3.8 (dd, 1H), 3.6 to 3.7 (m, 1H), 2.8 (dd, 1H) ), 1.8 to 2.4 (m, 4H)

[α]D 25= + 28.4 (c = 1, EtOH)[α] D 25 = + 28.4 (c = 1, EtOH)

녹는점 = 174 ∼ 175 ℃Melting Point = 174-175 ℃

실시예 2. D-2-[N-(N'-벤질프롤릴)아미노]벤조페논(D-2-[N-(N'-benzylprolyl) amino]benzophenone)의 제조Example 2. Preparation of D-2- [N- (N'-benzylprolyl) amino] benzophenone (D-2- [N- (N'-benzylprolyl) amino] benzophenone)

디클로로메탄(500mL) 중의 D-N-벤질프롤린(100g, 487mmol) 용액을 -20 ∼ -30 ℃로 유지하면서 티오닐 클로라이드(SOCl2)(35.5mL, 487mmol)를 서서히 적가 하였다. 이 반응액이 투명해질 때까지 -10 ℃를 유지하면서 교반한 후, 2-아미노벤조페논(86.5g, 438mmol)이 디클로로메탄(250mL)에 용해된 용액을 -30 ℃로 유지하면서 서서히 적가하였다. 아실 클로라이드가 반응상에서 소모된 것이 확인된 다음, 0℃로 냉각하여 탄산나트륨 수용액를 첨가하였다. 이 반응액을 디클로로메탄으로 추출하여 증류수 및 포화소금물로 세척한 후, 무수 황산마그네슘으로 건조하여 농축하였다. 잔류물을 에탄올로 재결정 및 여과하여 표제화합물 126g(수율 74%)를 제조 하였다.Thionyl chloride (SOCl 2 ) (35.5 mL, 487 mmol) was slowly added dropwise while maintaining a solution of DN-benzylproline (100 g, 487 mmol) in dichloromethane (500 mL) at −20 to −30 ° C. The reaction solution was stirred while maintaining at -10 ° C until it became clear, and then a solution in which 2-aminobenzophenone (86.5 g, 438 mmol) was dissolved in dichloromethane (250 mL) was slowly added dropwise while maintaining at -30 ° C. After acyl chloride was found to have been consumed in the reaction phase, it was cooled to 0 ° C. and an aqueous sodium carbonate solution was added. The reaction solution was extracted with dichloromethane, washed with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized with ethanol and filtered to give 126 g (74% yield) of the title compound.

1H-NMR(CDCl3,ppm) : δ 7.0∼8.62(m, 14H), 3.6∼4.0(d, 2H), 3.4(dd,1H), 3.1∼1.8(m,6H) 1 H-NMR (CDCl 3 , ppm): δ 7.0 to 8.62 (m, 14H), 3.6 to 4.0 (d, 2H), 3.4 (dd, 1H), 3.1 to 1.8 (m, 6H)

[α]D 25= + 133.1 (c = 0.5, MeOH)[α] D 25 = + 133.1 (c = 0.5, MeOH)

녹는점 = 100 ∼ 100.5 ℃Melting Point = 100 ~ 100.5 ℃

실시예 3. 글라이신-Ni-D-2-[N-(N'-벤질프롤릴)아미노]벤조페논(glycine-Ni-D-2-[N-(N'-benzylprolyl)amino]benzophenone)의 제조Example 3. Glycine-Ni-D-2- [N- (N'-benzylprolyl) amino] benzophenone (glycine-Ni-D-2- [N- (N'-benzylprolyl) amino] benzophenone) Produce

D-2-[N-(N'-벤질프롤릴)아미노]벤조페논(60g, 156mmol), Ni(NO3)2·6H2O(91g, 312mmol), 글라이신(58.5g, 780mmol)을 메탄올(600mL)에 녹였다. 온도를 40∼50 ℃로 가온하여 반응혼합물이 녹색으로 변한 다음, 수산화칼륨(61.3g, 1.1mol)을 메탄올(250mL)에 녹인 용액을 적가하였다. 온도를 45∼55 ℃로 유지하면서 한시간 동안 교반한 후, 온도를 10℃로 내리고 아세트산(55mL)를 천천히 적가하였다. 물을 가하여 반응혼합물의 부피를 2.5L까지 맞추고, 6시간 교반하였다. 생성된 고체를 여과하고 물로 세척하여 표제화합물 58g(수율 75%)을 제조하였다.D-2- [N- (N'-benzylprolyl) amino] benzophenone (60 g, 156 mmol), Ni (NO 3 ) 2 .6H 2 O (91 g, 312 mmol), glycine (58.5 g, 780 mmol) (600 mL). The reaction mixture turned green by warming the temperature to 40-50 ° C., and then a solution of potassium hydroxide (61.3 g, 1.1 mol) in methanol (250 mL) was added dropwise. After stirring for one hour while maintaining the temperature at 45-55 ° C., the temperature was lowered to 10 ° C. and acetic acid (55 mL) was slowly added dropwise. Water was added to adjust the volume of the reaction mixture to 2.5 L and stirred for 6 hours. The resulting solid was filtered and washed with water to give 58 g (75% yield) of the title compound.

1H-NMR(CDCl3,ppm) : δ 8.2∼6.6(m, 14H), 4.4(d, 1H), 3.68(s, 2H),3.5(d,1H), 3.9∼1.8(m,7H) 1 H-NMR (CDCl 3 , ppm): δ 8.2 to 6.6 (m, 14H), 4.4 (d, 1H), 3.68 (s, 2H), 3.5 (d, 1H), 3.9 to 1.8 (m, 7H)

[α]D 25= - 2005 (c = 0.5, MeOH)[α] D 25 =-2005 (c = 0.5, MeOH)

실시예 4. 1-히드록시-1-(3,4-디벤질옥시페닐)글라이신-Ni-D-2-[N-(N'-벤질프롤릴)아미노]벤조페논(1-hydroxy-1-(3,4-dibenzyloxyphenyl)glycine-Ni-D-2-[N-(N'-benzylprolyl)amino]benzophenone)의 제조Example 4. 1-hydroxy-1- (3,4-dibenzyloxyphenyl) glycine-Ni-D-2- [N- (N'-benzylprolyl) amino] benzophenone (1-hydroxy-1 Preparation of-(3,4-dibenzyloxyphenyl) glycine-Ni-D-2- [N- (N'-benzylprolyl) amino] benzophenone)

[방법 1] 건조된 플라스크에 질소 풍선을 달고, 3,4-디벤질옥시벤즈알데히드(18.4g, 58mmol), 소듐 메톡사이드(20mL 28% in MeOH, 90mmol), 글라이신-Ni-D-2-[N-(N'-벤질프롤릴)아미노]벤조페논(20g, 40mmol), 및 메탄올(50mL)을 넣고 교반하였다. 1시간 동안 교반하여 반응이 완결된 것을 확인한 후, 여과하여 녹지 않은 3,4-디벤질옥시벤즈알데히드를 제거하였다. 여액을 20% 아세트산(40mL)에 천천히 적가한 후, 생성되는 고체를 여과하였다. 얻어진 고체를 물로 세척한 후, 건조하여 적색의 표제화합물 26.8g (수율 82%)을 제조하였다.[Method 1] The dried flask was equipped with a nitrogen balloon, 3,4-dibenzyloxybenzaldehyde (18.4 g, 58 mmol), sodium methoxide (20 mL 28% in MeOH, 90 mmol), glycine-Ni-D-2- [ N- (N'-benzylprolyl) amino] benzophenone (20 g, 40 mmol) and methanol (50 mL) were added and stirred. After stirring for 1 hour to confirm that the reaction was completed, the insoluble 3,4-dibenzyloxybenzaldehyde was removed by filtration. The filtrate was slowly added dropwise to 20% acetic acid (40 mL), and then the resulting solid was filtered off. The obtained solid was washed with water and dried to give 26.8 g (yield 82%) of the title compound in red.

1H-NMR(CDCl3,ppm) : δ 8.6∼6.0(m, 27H), 5.2∼3.5(d, 8H), 4.6∼1.4(m, 7H) 1 H-NMR (CDCl 3 , ppm): δ 8.6 to 6.0 (m, 27H), 5.2 to 3.5 (d, 8H), 4.6 to 1.4 (m, 7H)

[α]D 25= + 563.2 (c = 0.5, CHCl3)[α] D 25 = + 563.2 (c = 0.5, CHCl 3 )

[방법 2] 리튬 (0.18g, 25mmol)를 메탄올 (10mL)에 용해시키고, 질소 기류하실온에서 글라이신-Ni-D-2-[N-(N'-벤질프롤릴)아미노]벤조페논 (5g, 10mmole)을 가하였다. 10분간 교반한 후, 3,4-디벤질옥시벤즈알데히드 (6.4g, 20mmol)를 가하고 50℃에서 30분간 교반하였다. 반응혼합물을 여과하여 녹지않은 3,4-디벤질옥시벤즈알데히드를 제거하였다. 여액을 20% 아세트산(10mL)에 천천히 적가한 후, 생성되는 고체를 여과하였다. 얻어진 고체를 물로 세척한 후, 건조하여 적색의 표제화합물 6.53g(80%)를 얻었다.[Method 2] Lithium (0.18 g, 25 mmol) was dissolved in methanol (10 mL), and glycine-Ni-D-2- [N- (N'-benzylprolyl) amino] benzophenone (5 g) at nitrogen stream current temperature. , 10mmole) was added. After stirring for 10 minutes, 3,4-dibenzyloxybenzaldehyde (6.4 g, 20 mmol) was added and stirred at 50 ° C for 30 minutes. The reaction mixture was filtered to remove insoluble 3,4-dibenzyloxybenzaldehyde. The filtrate was slowly added dropwise to 20% acetic acid (10 mL), and then the resulting solid was filtered off. The obtained solid was washed with water and dried to give the red title compound. 6.53 g (80%) were obtained.

1H-NMR(CDCl3, ppm) : δ 8.6∼6.0(m, 27H), 5.2∼3.5(d, 8H), 4.6∼1.4(m, 7H) 1 H-NMR (CDCl 3 , ppm): δ 8.6 to 6.0 (m, 27H), 5.2 to 3.5 (d, 8H), 4.6 to 1.4 (m, 7H)

[α]D 25= + 563.2 (c = 0.5, CHCl3)[α] D 25 = + 563.2 (c = 0.5, CHCl 3 )

실시예 5. L-쓰레오-(2S,3R)-3-(3,4-디벤질옥시페닐)세린(L-threo-(2S,3R)-3-(3,4-dibenzyloxyphenyl)serine)의 제조Example 5. L-threo- (2S, 3R) -3- (3,4-dibenzyloxyphenyl) serine (L-threo- (2S, 3R) -3- (3,4-dibenzyloxyphenyl) serine) Manufacture

1-히드록시-1-(3,4-디벤질옥시페닐)글라이신-Ni-D-2-[N-(N'-벤질프롤릴)아미노]벤조페논(5g, 6mmol)를 메탄올(75mL) 및 5N-염산(37.5mL)의 혼합용매에 현탁시키고, 50℃로 가온하였다. 한시간 교반한 후, 반응이 완결된 것을 확인하였다. 반응혼합물 중의 메탄올을 농축하고, 암모니아수로 pH를 6.6으로 하였다. 생성된 고체를 여과하고 물로 세척하였다. 고체를 완전히 건조한 후, 아세톤에 현탁시키고 여과하였다. 얻어진 고체를 건조하여 표제화합물 2.2g (수율 93%)을 제조하였다.1-hydroxy-1- (3,4-dibenzyloxyphenyl) glycine-Ni-D-2- [N- (N'-benzylprolyl) amino] benzophenone (5 g, 6 mmol) in methanol (75 mL) And 5 N-hydrochloric acid (37.5 mL) were suspended in a mixed solvent and warmed to 50 ° C. After stirring for an hour, it was confirmed that the reaction was completed. Methanol in the reaction mixture was concentrated and the pH was adjusted to 6.6 with ammonia water. The resulting solid was filtered off and washed with water. The solid was completely dried, then suspended in acetone and filtered. The obtained solid was dried to give 2.2 g (yield 93%) of the title compound.

녹는점 = 119.5 ∼ 120.4 ℃Melting Point = 119.5 ~ 120.4 ℃

1H-NMR(DMSO-d6,ppm) : δ 7.25 - 6.8(m, 13H), 5.1(s, 4H), 5.0(d, 1H), 3.25(d, 1H) 1 H-NMR (DMSO-d 6 , ppm): δ 7.25-6.8 (m, 13H), 5.1 (s, 4H), 5.0 (d, 1H), 3.25 (d, 1H)

실시예 6. L-쓰레오-(2S,3R)-3-(3,4-디히드록시페닐)세린(L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine)의 제조Example 6. L-threo- (2S, 3R) -3- (3,4-dihydroxyphenyl) serine (L-threo- (2S, 3R) -3- (3,4-dihydroxyphenyl) serine) Manufacture

L-쓰레오-3-(3,4-디벤질옥시페닐)세린 (7g, 18mmol)를 에탄올(400mL)에 현탁시키고, 진한 염산(100mL) 및 10% Pd/C(600mg)를 가한 후, 1-2 기압하에서 교반하였다. 반응혼합물을 여과하여 Pd/C를 제거하고, 여액을 농축하였다. 얻어진 반응혼합물을 에탄올에 녹이고, 디에틸아민과 에탄올의 혼합용액으로 pH를 5로 조절하였다. 반응혼합물을 0℃에서 24 시간 동안 방치하고, 생성된 고체를 여과한 다음, 에탄올과 에테르로 세척하여 표제화합물 3.16g (수율 85%)을 제조하였다.L-Threo-3- (3,4-dibenzyloxyphenyl) serine (7 g, 18 mmol) was suspended in ethanol (400 mL) and concentrated hydrochloric acid (100 mL) and 10% Pd / C (600 mg) were added. Stirred under 1-2 atm. The reaction mixture was filtered to remove Pd / C and the filtrate was concentrated. The obtained reaction mixture was dissolved in ethanol, and the pH was adjusted to 5 with a mixed solution of diethylamine and ethanol. The reaction mixture was left at 0 ° C. for 24 hours, and the resulting solid was filtered and washed with ethanol and ether to give 3.16 g (yield 85%) of the title compound.

1H-NMR(D2O/NaOH,ppm) : δ 6.5(dd, 2H), 6.4(d, 1H), 4.7(d, 1H) 1 H-NMR (D 2 O / NaOH, ppm): δ 6.5 (dd, 2H), 6.4 (d, 1H), 4.7 (d, 1H)

[α]D 25= -39 (c = 1, 1N HCl)[α] D 25 = -39 (c = 1, 1N HCl)

녹는점 = 232 ∼ 243 ℃Melting Point = 232∼243 ℃

본 발명의 제조방법은 저가의 반응시약을 사용하여 고순도 및 고수율로 L-쓰레오-(2S,3R)-33-(3,4-디히드록시페닐)세린 또는 그의 염을 제조할 수 있으며, 화학식 2 및/또는 3의 화합물은 드록시도파의 제조 중간체로서 유용하게 사용될 수 있다.The production method of the present invention can prepare L-Threo- (2S, 3R) -33- (3,4-dihydroxyphenyl) serine or a salt thereof in high purity and high yield using a low-cost reaction reagent. Compounds of formulas (2) and / or (3) may be usefully used as intermediates for the preparation of drodopa.

Claims (10)

화학식 2의 화합물을 극성 유기용매 중에서 산으로 분해하여 화학식 1b의 화합물을 얻는 단계; 및Decomposing the compound of Formula 2 with an acid in a polar organic solvent to obtain a compound of Formula 1b; And 상기 화학식 1b의 화합물의 히드록실화(hydroxylation) 반응을 수행하는 단계를 포함하는 L-쓰레오-(2S,3R)-3-(3,4-디히드록시페닐)세린 또는 그의 염의 제조방법:A method for preparing L-threo- (2S, 3R) -3- (3,4-dihydroxyphenyl) serine or a salt thereof, comprising the step of performing a hydroxylation reaction of the compound of Formula 1b: <화학식 1b><Formula 1b> <화학식 2><Formula 2> 식 중, R1및 R2는, 각각 독립적으로, 벤질, p-니트로벤질, p-플루오로벤질, p-트리플루오로벤질, C1∼C4알콕시 C1∼C4알킬, 또는 C1∼C4알킬이며;Wherein, R 1 and R 2 are, each independently, benzyl, p- nitrobenzyl, in a p- fluorobenzyl, p- trifluoromethyl, benzyl, C 1 ~C 4 alkoxy C 1 ~C 4 alkyl, or C 1 ˜C 4 alkyl; M은 Cu2+, Ni2+, 또는 Zn2+이다.M is Cu 2+ , Ni 2+ , or Zn 2+ . 제1항에 있어서, R1및 R2가 모두 벤질인 것을 특징으로 하는 제조방법.The process according to claim 1, wherein both R 1 and R 2 are benzyl. 제1항에 있어서, 상기 극성 유기용매가 C1∼C7의 알콜, 테트라히드로퓨란, 아세토니트릴, 디메틸포름아미드, 및 이들의 혼합용매로 이루어진 군으로부터 선택된 것임을 특징으로 하는 제조방법.The method of claim 1, wherein the polar organic solvent is selected from the group consisting of C 1 to C 7 alcohols, tetrahydrofuran, acetonitrile, dimethylformamide, and mixed solvents thereof. 제1항에 있어서, 상기 산이 염산, 브롬산, 황산, 질산, 초산, 또는 트리플루오로메틸아세트산인 것을 특징으로 하는 제조방법.The process according to claim 1, wherein the acid is hydrochloric acid, bromic acid, sulfuric acid, nitric acid, acetic acid, or trifluoromethylacetic acid. 제4항에 있어서, 상기 히드록실화 반응이 금속 및 산 존재하에서 수소를 가함으로써 수행되는 것을 특징으로 하는 제조방법.5. A process according to claim 4, wherein the hydroxylation reaction is carried out by adding hydrogen in the presence of a metal and an acid. 제1항 내지 제5항 중 어느 한 항에 있어서, 상기 화학식 2의 화합물이 화학식 3의 화합물과 화학식 4의 화합물을, 염기 존재하에서, 반응시켜 얻어진 것임을특징으로 하는 제조방법:The process according to any one of claims 1 to 5, wherein the compound of formula 2 is obtained by reacting a compound of formula 3 with a compound of formula 4 in the presence of a base: <화학식 3><Formula 3> <화학식 4><Formula 4> 식 중, R1, R2, 및 M은 제1항에서 정의한 바와 같다.Wherein R 1 , R 2 , and M are as defined in claim 1. 제6항에 있어서, 상기 염기가 알칼리금속 수산화물; 알칼리토금속 수산화물; 알칼리금속 알콕사이드; NHR3R4(R3및 R4는 같거나 상이할 수 있으며, 각각 C1∼C7의 알킬이다); NH2R5(R5는 C1∼C9의 알킬이다); 4급 아민 수산화물; NaH; 및 NaNH2로 이루어진 군으로부터 선택되는 것을 특징으로 하는 제조방법.The method of claim 6, wherein the base is an alkali metal hydroxide; Alkaline earth metal hydroxides; Alkali metal alkoxides; NHR 3 R 4 (R 3 and R 4 may be the same or different and are each C 1 to C 7 alkyl); NH 2 R 5 (R 5 is C 1 -C 9 alkyl); Quaternary amine hydroxides; NaH; And NaNH 2 . 제6항에 있어서, 상기 화학식 3의 화합물은According to claim 6, wherein the compound of Formula 3 is D-프롤린과 벤질클로라이드를 반응시켜 D-N-벤질프롤린을 제조하는 단계;Reacting D-proline with benzyl chloride to prepare D-N-benzylproline; 상기 D-N-벤질프롤린과 2-아미노벤조페논을 반응시켜 D-2-[N-(N'-벤질프롤릴)아미노]벤조페논을 제조하는 단계; 및Reacting the D-N-benzylproline with 2-aminobenzophenone to produce D-2- [N- (N'-benzylprolyl) amino] benzophenone; And 상기 D-2-[N-(N'-벤질프롤릴)아미노]벤조페논, M(Cu2+, Ni2+, 또는 Zn2+)을 포함하는 염 또는 그의 수화물, 및 글라이신을 반응시키는 단계Reacting the salt containing D-2- [N- (N'-benzylprolyl) amino] benzophenone, M (Cu 2+ , Ni 2+ , or Zn 2+ ) or a hydrate thereof, and glycine; 를 포함하는 방법으로 제조된 것임을 특징으로 하는 제조방법.Manufacturing method characterized in that it is manufactured by a method comprising a. 하기 화학식 2의 화합물:A compound of formula <화학식 2><Formula 2> 식 중, R1, R2, 및 M은 제1항에서 정의한 바와 같다.Wherein R 1 , R 2 , and M are as defined in claim 1. 삭제delete
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