KR20170016756A - New method for preparation of chiral chromanol derivatives - Google Patents

New method for preparation of chiral chromanol derivatives Download PDF

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KR20170016756A
KR20170016756A KR1020150110248A KR20150110248A KR20170016756A KR 20170016756 A KR20170016756 A KR 20170016756A KR 1020150110248 A KR1020150110248 A KR 1020150110248A KR 20150110248 A KR20150110248 A KR 20150110248A KR 20170016756 A KR20170016756 A KR 20170016756A
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compound represented
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KR101769204B1 (en
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김은선
고동현
권재홍
김영주
이성아
최광도
허승평
이지윤
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씨제이헬스케어 주식회사
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Priority to JP2018505683A priority patent/JP6676146B2/en
Priority to PCT/KR2016/008580 priority patent/WO2017023124A1/en
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    • 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
    • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
    • B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
    • B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
    • B01J23/46—Ruthenium, rhodium, osmium or iridium
    • 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
    • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
    • B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
    • B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
    • B01J23/46—Ruthenium, rhodium, osmium or iridium
    • B01J23/462—Ruthenium
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
    • C07F15/0046—Ruthenium compounds

Abstract

The present invention relates to a novel production method for a chromanol derivative. According to the production method for the optically active chromanol derivative, the produced chromanol shows high optical purity, and does not require additional purification processes, unlike previously known optical activity reduction reactions. Additionally, since the production method does not involve harsh reaction conditions as well as hazardous reagents, the production method is suitable for the mass-production while ensuring high production yields.

Description

크로마놀 유도체의 신규한 제조방법{New method for preparation of chiral chromanol derivatives}TECHNICAL FIELD The present invention relates to a novel method for preparing chiral chromanol derivatives,

본 발명은 광학 활성을 가지는 크로마놀 유도체의 신규한 제조방법에 관한 것이다.The present invention relates to a novel process for producing optically active chromanol derivatives.

키랄 크로마놀(chromanol) 유도체 화합물은 의약 및 화학 분야에서 다양한 활성을 가지는 물질로써, 현재 개발 중인 의약품 등에서도 키랄 크로마놀 구조 화합물이 많이 존재한다. 그런데, 동일한 분자식을 가진 크로마놀 유도체 화합물이라도 3차원 입체구조에 따라 약효가 매우 다르게 나타나는 경우가 많다. 그러므로 키랄 크로마놀 유도체 화합물을 입체선택적으로 합성하는 것은 의약합성 및 유기합성에서 대단히 중요하다. 그러나, 키랄 크로마놀 유도체 화합물의 중요성에도 불구하고, 키랄 크로마놀 유도체 화합물을 손쉽게 합성하는 방법은 많이 보고되고 있지 않다. Chiral chromanol derivative compounds have various activities in the fields of medicine and chemistry, and many chiral chromanol structural compounds exist in pharmaceuticals currently under development. However, even in the case of chromanol derivative compounds having the same molecular formula, there are many cases in which the effect is very different depending on the three-dimensional structure. Therefore, stereoselectively synthesizing chiral chromanol derivative compounds is of great importance in pharmaceutical synthesis and organic synthesis. However, despite the importance of chiral cholanol derivative compounds, a method for easily synthesizing chiral cholanol derivative compounds has not been reported.

국제공보 WO 2007/072146에는 5,7-디플루오로크로만-4-온을 출발물질로 사용하여 5,7-디플루오로크로만-4-올을 제조하는 방법이 기재되어 있다. 그러나 상기 특허에 기재된 제조방법은 1차 결정화 공정에서 86%ee 값의 낮은 광학 입체 선택성을 가지며 광학 입체 선택성을 증가 시키기 위해 정제공정이 반드시 필요하다고 명기되어 있다. 이러한 이유로 상기 특허에 기재되어 있는 방법은 제조 단가가 높으며 추가된 정제 공정에도 불구하고 58%의 매우 낮은 수득률을 가진다. 또한 1차 고체화 분리에 실리카겔 상에서의 컬럼 크로마토그래피를 사용함으로 인하여 대량생산의 공정에는 적합하지 않은 문제점이 있다.International Publication WO 2007/072146 describes a process for preparing 5,7-difluorochroman-4-ol using 5,7-difluorochroman-4-one as a starting material. However, the production process described in the patent has a low optical stereoselectivity of 86% ee in the primary crystallization process and it is stated that a purification process is necessarily required to increase optical stereoselectivity. For this reason, the process described in the patent has a high production cost and a very low yield of 58% despite the additional purification process. In addition, there is a problem that column chromatography on silica gel is used for the primary solidification separation, which is not suitable for the mass production process.

이에 따라, 의약 및 화학분야에서 매우 중요한 약물 특이 분자단으로 알려진 광학활성을 갖는 크로마놀 유도체를 고순도의 광학품질 및 고수율로 산업적으로 대량생산할 수 있는 신규한 제조방법이 필요한 실정이다.Accordingly, there is a need for a novel production method capable of industrially mass-producing chromanol derivatives having optical activity, which is known as drug-specific molecular stages very important in the fields of medicine and chemistry, with high purity optical quality and high yield.

국제공개특허 제2007/072146호International Publication No. 2007/072146

본 발명은 높은 광학순도를 나타내어 별도의 정제 공정이 필요하지 않으며, 생산공정에 위험한 시약을 사용하지 않고, 생산 수율이 우수한 크로마놀 유도체의 제조방법을 제공한다.The present invention provides a method for producing a chromanol derivative which exhibits high optical purity and does not require a separate purification step, and which does not use dangerous reagents in the production process and is excellent in production yield.

본 발명은, According to the present invention,

하기 화학식 Ⅱ로 표시되는 화합물을 하기 화학식 Ⅲ 또는 화학식 Ⅳ로 표시되는 촉매 하에 키랄 환원 반응시켜 하기 화학식 Ⅰ로 표시되는 화합물을 제조하는 단계를 포함하는 화학식 Ⅰ로 표시되는 화합물의 제조방법을 제공한다. Which comprises the step of subjecting a compound represented by the formula (II) to a chiral reduction reaction under a catalyst represented by the following formula (III) or (IV) to prepare a compound represented by the formula (I).

[화학식 Ⅰ](I)

Figure pat00001
Figure pat00001

[화학식 Ⅱ] [Formula II]

Figure pat00002
Figure pat00002

[화학식 Ⅲ][Formula (III)

Figure pat00003
Figure pat00003

[화학식 Ⅳ][Formula IV]

Figure pat00004
Figure pat00004

상기 화학식 Ⅰ에서 *는 Chiral center를 나타낸다. * In the above formula (I) represents a chiral center.

본 발명의 상기 제조 방법은 종래 알려진 광학 활성 환원반응 기술과 달리, 제조되는 크로마놀이 높은 광학순도를 나타내어 별도의 정제 공정을 필요로 하지 않으며, 혹독한 반응 조건을 포함하지 않고 위험한 시약을 사용하지 않기 때문에 대량생산에 유리하고 제조수율 또한 우수한 장점을 가진다. Unlike the known optically active reduction reaction technique, the above-described production method of the present invention does not require a separate purification step because the produced chromanol exhibits a high optical purity, does not include a harsh reaction condition, and does not use dangerous reagents It is advantageous in mass production and has an excellent production yield.

상기 화학식 Ⅰ로 표시되는 화합물을 제조하는 단계는 상기 화학식 Ⅲ 또는 Ⅳ의 촉매를 이용한 키랄 환원 반응(Chiral reduction)으로서, 상기 화학식 Ⅱ로 표시되는 화합물과 수소 공여체를 상기 화학식 Ⅲ 또는 화학식 Ⅳ로 표시되는 촉매하에 반응시켜 선택적으로 광학 활성을 가지는 상기 화학식 Ⅰ로 표시되는 화합물을 제조한다. The step of preparing the compound represented by the formula (I) is a chiral reduction reaction using the catalyst of the formula (III) or (IV), wherein the compound represented by the formula (II) and the hydrogen donor are represented by the formula (III) To produce a compound represented by the above formula (I) having selective optical activity.

이 때 상기 화학식 Ⅱ으로 표시되는 화합물과 화학식 Ⅲ 또는 화학식 Ⅳ로 표시되는 촉매의 반응 몰비는 1:0.0001 내지 1:0.1일 수 있으며, 바람직하게, 0.005 내지 0.001 일 수 있다. In this case, the reaction molar ratio of the compound represented by the formula (II) to the catalyst represented by the formula (III) or (IV) may be 1: 0.0001 to 1: 0.1, preferably 0.005 to 0.001.

본 발명에 있어서, 상기 화학식 Ⅰ로 표시되는 화합물을 제조하는 단계의 반응용매는 업계에서 널리 사용되는 무극성 유기용매가 사용될 수 있다. 예컨대, 이에 제한되지 않으나, 디클로로메탄, 클로로폼, 1,2-디클로로에탄 같은 할로겐화된 탄화수소; 디에틸에테르, 디이소프로필에테르, 테트라히드로푸란 및 디옥산 같은 에테르; 벤젠, 톨루엔 및 니트로벤젠 같은 방향족 탄화수소; 디메틸 설폭시드 같은 설폭시드; 디메틸포름아미드 같은 포름산아미드; 메탄올, 에탄올, 2-프로판올 및 부탄올 같은 알코올; 또는 이들의 혼합 용매일 수 있다. 바람직하게, 테트라하이드로푸란일 수 있다. In the present invention, the non-polar organic solvent widely used in the industry may be used as the reaction solvent in the step of preparing the compound represented by Formula (I). Halogenated hydrocarbons such as, but not limited to, dichloromethane, chloroform, 1,2-dichloroethane; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; Aromatic hydrocarbons such as benzene, toluene and nitrobenzene; Sulfoxide such as dimethyl sulfoxide; Formic amides such as dimethylformamide; Alcohols such as methanol, ethanol, 2-propanol and butanol; Or a mixture thereof. Preferably, it may be tetrahydrofuran.

본 발명의 수소공여체는 포름산, 포름산의 금속염, 포름산의 암모늄염, 및 포름산과 아민의 혼합물 중에서 선택될 수 있다. 바람직하게 상기 수소 공여체는 포름산과 아민의 혼합물일 수 있으며, 보다 바람직하게 트리에틸아민(TEA) 및 포름산, 또는 디이소프로필에틸아민(DIPEA) 및 포름산 일 수 있다.The hydrogen donor of the present invention can be selected from formic acid, a metal salt of formic acid, an ammonium salt of formic acid, and a mixture of formic acid and amine. Preferably, the hydrogen donor may be a mixture of formic acid and amine, more preferably triethylamine (TEA) and formic acid, or diisopropylethylamine (DIPEA) and formic acid.

상기 화학식 Ⅰ로 표시되는 화합물을 제조하는 단계에서 화학식 Ⅱ로 표시되는 화합물의 화학식 Ⅲ 또는 화학식 Ⅳ로 표시되는 촉매 하에 키랄 환원 반응 은 25℃ 내지 80℃에서, 바람직하게 30 내지 50℃에서 이루어질 수 있다. 이보다 온도가 낮으면 반응시간이 지나치게 길어지고, 온도가 높으면 광학순도(chiral purity)가 지나치게 낮아지므로 상업적 생산에 부적합하다. In the step of producing the compound represented by Formula (I), the chiral reduction reaction may be carried out at 25 ° C to 80 ° C, preferably 30 to 50 ° C, under the catalyst represented by Formula (III) or (IV) of the compound represented by Formula . The lower the temperature, the longer the reaction time becomes, and the higher the temperature, the lower the optical purity (chiral purity), which is not suitable for commercial production.

상기 화학식 Ⅰ로 표시되는 화합물을 제조하는 단계는 결정화 용매로 결정화를 수행하는 단계를 더 포함할 수 있다. 상기 결정화 용매는 화합물의 결정화를 위한 것으로, 헥산, 헵탄과 같은 C6~ 7 의 지방족 탄화수소; 디에틸에테르, 디이소프로필에테르 같은 에테르; 또는 이들의 혼합 용매등이 사용될 수 있다. 바람직하게는 헥산, 헵탄과 같은 C6~7 의 지방족 탄화수소를 사용할 수 있다. The step of preparing the compound represented by Formula (I) may further include a step of performing crystallization with a crystallization solvent. The crystallization solvent is for crystallization of the compound, and includes C 6 to C 7 aliphatic hydrocarbons such as hexane and heptane; Ethers such as diethyl ether, diisopropyl ether; Or a mixed solvent thereof may be used. C 6 to C 7 aliphatic hydrocarbons such as hexane and heptane can be preferably used.

본 발명은, According to the present invention,

하기 화학식 Ⅱ로 표시되는 화합물과 수소 공여체를 하기 화학식 Ⅲ 또는 화학식 Ⅳ로 표시되는 촉매 하에 반응시켜 하기 화학식 Ⅰ로 표시되는 화합물을 제조하는 단계를 포함하는 화학식 Ⅰ로 표시되는 화합물의 제조방법을 제공한다. Which comprises reacting a compound represented by the formula (II) with a hydrogen donor under a catalyst represented by the following formula (III) or (IV) to prepare a compound represented by the formula (I) .

[화학식 Ⅰ](I)

Figure pat00005
Figure pat00005

[화학식 Ⅱ] [Formula II]

Figure pat00006
Figure pat00006

[화학식 Ⅲ][Formula (III)

Figure pat00007
Figure pat00007

[화학식 Ⅳ][Formula IV]

Figure pat00008
Figure pat00008

상기 화학식 Ⅰ에서 *는 Chiral center를 나타낸다. * In the above formula (I) represents a chiral center.

본 발명의 일 실시양태에 따르면, 본 발명은 Ⅱ로 표시되는 화합물을 화학식 Ⅲ으로 표시되는 촉매 하에 키랄 환원 반응시켜 하기 화학식 Ⅰ-1로 표시되는 화합물을 제조하는 단계를 포함하는 화학식 Ⅰ-1로 표시되는 화합물의 제조방법을 제공한다. According to one embodiment of the present invention, the present invention provides a process for producing a compound represented by the general formula (I-1), comprising the step of subjecting a compound represented by the formula (II) to a chiral reduction reaction under the catalyst represented by the formula A method for producing a compound to be displayed is provided.

[화학식 Ⅰ-1] (R)-5,7-디플루오로크로만-4-올[Formula I-1] (R) -5,7-difluorochroman-4-ol

Figure pat00009
Figure pat00009

본 발명의 다른 실시양태에 따르면, 본 발명은 Ⅱ로 표시되는 화합물을 화학식 Ⅳ로 표시되는 촉매 하에 키랄 환원 반응시켜 하기 화학식 Ⅰ-2로 표시되는 화합물을 제조하는 단계를 포함하는 화학식 Ⅰ-2로 표시되는 화합물의 제조방법을 제공한다. According to another embodiment of the present invention, the present invention provides a process for producing a compound represented by the general formula (I-2), comprising the step of subjecting a compound represented by the formula (II) to a chiral reduction reaction under the presence of a catalyst represented by the formula A method for producing a compound to be displayed is provided.

[화학식 Ⅰ-2] (S)-5,7-디플루오로크로만-4-올[Formula I-2] Synthesis of (S) -5,7-difluorochroman-4-ol

Figure pat00010
Figure pat00010

상기와 같이, 본 발명에 따른 제조방법에 따라 화학식 Ⅱ의 화합물을 화학식 Ⅲ 또는 화학식 Ⅳ의 촉매 존재 하에 수소 공여체와 키랄 환원반응을 시키면 화학식 Ⅰ-1 또는 화학식 Ⅰ-2의 높은 광학활성을 가지는 크로마놀 화합물을 제조할 수 있다. As described above, when the compound of the formula (II) is subjected to a chiral reduction reaction with a hydrogen donor in the presence of a catalyst of the formula (III) or (IV), a chroma having a high optical activity represented by the formula (I-1) Nol compounds can be prepared.

예를 들면, 본 발명에 따른 화학식 Ⅰ로 표시되는 화합물의 제조 방법은 하기 반응식 I로 표시될 수 있다. For example, the process for preparing a compound of formula (I) according to the present invention can be represented by the following scheme (I).

[반응식 Ⅰ][Reaction Scheme I]

Figure pat00011
Figure pat00011

상기 반응식 Ⅰ과 같이, 화학식 Ⅲ 또는 화학식 Ⅳ로 표시되는 루테늄 촉매 하에 무극성 유기 용매 하의 화학식 Ⅱ의 화합물을 수소 공여체와 반응시켜 화학식 Ⅰ의 화합물을 제조할 수 있다. The compound of formula (I) can be prepared by reacting a compound of formula (II) with a hydrogen donor under a non-polar organic solvent under a ruthenium catalyst represented by formula (III) or (IV)

본 발명의 일실시양태에 따르면, 하기 반응식 Ⅰ-1과 같이 화학식 Ⅲ 으로 표시되는 루테늄 촉매 하에 화학식 Ⅱ의 화합물을 수소공여체와 반응시켜 화학식 Ⅰ-1의 화합물을 제조할 수 있다. According to one embodiment of the present invention, a compound of formula (I-1) can be prepared by reacting a compound of formula (II) with a hydrogen donor under a ruthenium catalyst represented by formula (III) as shown in Scheme I-1 below.

[반응식 Ⅰ-1][Reaction Scheme I-1]

Figure pat00012
Figure pat00012

본 발명의 또다른 실시양태에 따르면, 하기 반응식 Ⅰ-2과 같이, 화학식 Ⅳ로 표시되는 촉매 하에 화학식 Ⅱ의 화합물을 수소공여체와 반응시켜 화학식 Ⅰ-2의 화합물을 제조할 수 있다. According to another embodiment of the present invention, a compound of formula (I-2) can be prepared by reacting a compound of formula (II) with a hydrogen donor under the catalyst of formula (IV), as shown in Scheme I-2 below.

[반응식 Ⅰ-2][Reaction Scheme I-2]

Figure pat00013
Figure pat00013

본 발명에 따른 광학 활성을 갖는 크로마놀 유도체의 제조 방법은 종래 알려진 광학 활성 환원반응 기술과 달리, 제조되는 크로마놀이 높은 광학순도를 나타내어 별도의 정제 공정을 필요로 하지 않으며, 혹독한 반응 조건을 포함하지 않고 위험한 시약을 사용하지 않기 때문에 대량생산에 유리하고 제조수율 또한 우수한 장점을 가진다. The method of producing optically active chromanol derivatives according to the present invention, unlike the known optically active reduction reaction techniques, exhibits a high optical purity of chromanol which does not require a separate purification step and does not involve severe reaction conditions It does not use dangerous reagents, so it is advantageous for mass production and has an excellent manufacturing yield.

또한, 상기 제조방법에 의하여 제조되는 최종 생성물은 광학 활성을 갖는 크로마놀 구조를 가지는 다른 화합물을 제조하는데 사용할 수 있으며, 특히 항균제, 항궤양제, 항염증 치료제로 사용 가능한 화합물의 제조를 위한 중간체로 사용할 수 있다.In addition, the final product prepared by the above production method can be used for producing other compounds having an optically active chromanol structure, and in particular, as an intermediate for the production of a compound usable as an antimicrobial agent, an anti-ulcer agent, Can be used.

이하, 하기 실시예 및 실험예를 통하여 본 발명을 보다 상세히 설명하고자 한다. 그러나, 하기 실시예 및 실험예는 본 발명을 예시하기 위한 것으로 이들 실시예 및 실험예에 의하여 본 발명의 범위가 한정되는 것은 아니다. Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, the following examples and experimental examples are provided for illustrating the present invention, and the scope of the present invention is not limited by these examples and experimental examples.

이하에서 언급된 시약 및 용매는 특별한 언급이 없는 한 Sigma Aldrich로부터 구입한 것이며, 1H-NMR는 Bruker NMR 270MHz 로 측정하였으며, 광학 활성은 Rudolph research analytical autoV 로 측정하였다. The reagents and solvents mentioned below were purchased from Sigma Aldrich unless otherwise noted. 1 H-NMR was measured by Bruker NMR at 270 MHz and the optical activity was determined by Rudolph research analytical autoV.

실시예Example 1: (R)-5,7- 1: (R) -5,7- 디플루오로크로만Difluorochroman -4-올의 제조4-ol

반응기에 트리에틸아민 30 g을 투입하고 -10 ℃로 냉각하였다. 여기에 포름산 27 g을 10 ℃ 이하에서 천천히 투입하였다. 루테늄 촉매 RuCl(p-cymene)[(R,R)-Ts-DPEN] 56 mg을 투입하였다. 5,7-디플루오로크로만-4-온 33 g을 테트라히드로푸란 87 g에 용해하여 반응기에 10 ℃ 이하에서 투입하였다. 40 ℃로 승온하고, 반응하였다. 반응이 종결된 후 실온으로 냉각하고, 에틸아세테이트 293 g와 정제수 163 g을 투입하여 교반 후 유기층 분리하였다. 40 ℃ 이하에서 감압 농축하고, 헵탄 222 g을 투입하여 25 ℃로 교반 후 생성된 고체를 여과하였다. 40 ℃에서 진공 건조하여 (R)-5,7-디플루오로크로만-4-올(30 g, 91%, 100%ee)을 수득하였다.30 g of triethylamine was added to the reactor and cooled to -10 캜. 27 g of formic acid was slowly added thereto at 10 DEG C or lower. 56 mg of ruthenium catalyst RuCl (p-cymene) [(R, R) -Ts-DPEN] was added. 33 g of 5,7-difluorochroman-4-one was dissolved in 87 g of tetrahydrofuran and added to the reactor at 10 ° C or lower. The temperature was raised to 40 占 폚 and reacted. After the reaction was completed, the reaction mixture was cooled to room temperature, and 293 g of ethyl acetate and 163 g of purified water were added thereto. After stirring, the organic layer was separated. The mixture was concentrated under reduced pressure at 40 DEG C or lower, 222 g of heptane was added thereto, stirred at 25 DEG C, and the resulting solid was filtered. (R) -5,7-difluorochroman-4-ol (30 g, 91%, 100% ee) was obtained by vacuum drying at 40 占 폚.

1 H-NMR (270MHz, CDCl 3 ): δ: 6.47-6.36 (m, 2H), 5.05-4.97 (m, 1H), 4.36-4.20 (m, 2H), 2.16-1.92 (m, 3H) ppm 1 H-NMR (270MHz, CDCl 3): δ: 6.47-6.36 (m, 2H), 5.05-4.97 (m, 1H), 4.36-4.20 (m, 2H), 2.16-1.92 (m, 3H) ppm

광학 회전: [α]Optical rotation: [?] DD 24 24 = +143.6° (c=1.00, 메탄올)= + 143.6 [deg.] (C = 1.00, methanol)

실시예Example 2: (S)-5,7- 2: (S) -5,7- 디플루오로크로만Difluorochroman -4-올의 제조4-ol

반응기에 트리에틸아민 30 g을 투입하고 -10℃로 냉각하였다. 여기에 포름산 27 g을 10 ℃ 이하에서 천천히 투입하였다. 루테늄 촉매 RuCl(p-cymene)[(S,S)-Ts-DPEN] 56 mg을 투입하였다. 5,7-디플루오로크로만-4-온 33 g을 테트라히드로푸란 87 g에 용해하여 반응기에 10 ℃ 이하에서 투입하였다. 40 ℃로 승온하고, 반응하였다. 반응이 종결된 후 25 ℃로 냉각하고, 에틸아세테이트 293 g와 정제수163 g을 투입하여 교반 후 유기층 분리하였다. 40 ℃ 이하에서 감압 농축하고, 헵탄222 g을 투입하여 25 ℃로 교반 후 생성된 고체를 여과하였다. 40 ℃에서 진공 건조하여 (S)-5,7-디플루오로크로만-4-올(28 g, 85%, 100%ee)을 수득하였다.30 g of triethylamine was added to the reactor and cooled to -10 캜. 27 g of formic acid was slowly added thereto at 10 DEG C or lower. 56 mg of ruthenium catalyst RuCl (p-cymene) [(S, S) -Ts-DPEN] was added thereto. 33 g of 5,7-difluorochroman-4-one was dissolved in 87 g of tetrahydrofuran and added to the reactor at 10 ° C or lower. The temperature was raised to 40 占 폚 and reacted. After the reaction was completed, the reaction mixture was cooled to 25 ° C, 293 g of ethyl acetate and 163 g of purified water were added thereto. The mixture was concentrated under reduced pressure at 40 DEG C or lower, 222 g of heptane was added thereto, stirred at 25 DEG C, and the resulting solid was filtered. (S) -5,7-difluorochroman-4-ol (28 g, 85%, 100% ee) was obtained by vacuum drying at 40 ° C.

1 H-NMR: 스펙트럼 데이터는 (R)-크로마놀(실시예 1)의 데이터와 동일하였다. ≪ 1 & gt; H-NMR: The spectral data were the same as the data of (R) -chromanol (Example 1).

광학 회전: [α]Optical rotation: [?] DD 24 24 = -143.6° (c=1.00, 메탄올)= -143.6 [deg.] (C = 1.00, methanol)

Claims (9)

하기 화학식 Ⅱ로 표시되는 화합물을 하기 화학식 Ⅲ 또는 화학식 Ⅳ로 표시되는 촉매 하에 키랄 환원 반응시켜 하기 화학식 Ⅰ로 표시되는 화합물을 제조하는 단계를 포함하는 화학식 Ⅰ로 표시되는 화합물의 제조방법:
[화학식 Ⅰ]
Figure pat00014

[화학식 Ⅱ]
Figure pat00015

[화학식 Ⅲ]
Figure pat00016

[화학식 Ⅳ]
Figure pat00017

상기에서 *는 카이랄 중심임.
A process for producing a compound represented by the formula (I), comprising the step of subjecting a compound represented by the following formula (II) to a chiral reduction reaction under a catalyst represented by the following formula (III) or (IV)
(I)
Figure pat00014

[Formula II]
Figure pat00015

[Formula (III)
Figure pat00016

[Formula IV]
Figure pat00017

Wherein * is a chiral center.
제1항에 있어서, 상기 화학식 Ⅱ로 표시되는 화합물을 화학식 Ⅲ으로 표시되는 촉매 하에 키랄 환원 반응시켜 하기 화학식 Ⅰ-1로 표시되는 화합물을 제조하는 단계를 포함하는 화학식 Ⅰ로 표시되는 화합물의 제조방법:
[화학식 Ⅰ-1]
Figure pat00018
.
The process according to claim 1, wherein the compound represented by the formula (II) is subjected to a chiral reduction reaction under the catalyst represented by the formula (III) to prepare a compound represented by the formula (I-1) :
[Formula (I-1)
Figure pat00018
.
제1항에 있어서, 화학식 Ⅱ로 표시되는 화합물을 화학식 Ⅳ로 표시되는 촉매 하에 키랄 환원 반응시켜 하기 화학식 Ⅰ-2로 표시되는 화합물을 제조하는 단계를 포함하는 화학식 Ⅰ로 표시되는 화합물의 제조방법:
[화학식 Ⅰ-2]
Figure pat00019
.
A process for producing a compound represented by the formula (I) according to claim 1, which comprises the step of subjecting a compound represented by the formula (II) to a chiral reduction reaction under a catalyst represented by the formula (IV)
[Formula I-2]
Figure pat00019
.
제1항 내지 제3항 중 어느 한 항에 있어서, 상기 화학식 Ⅱ로 표시되는 화합물과 촉매의 반응 몰비는 1:0.0001 내지 1:0.1인 화학식 Ⅰ로 표시되는 화합물의 제조방법.
The process according to any one of claims 1 to 3, wherein the molar ratio of the compound represented by the formula (II) to the catalyst is 1: 0.0001 to 1: 0.1.
제1항 내지 제3항 중 어느 한 항에 있어서, C6~ 7 의 지방족 탄화수소; 에테르; 또는 이들의 혼합 용매로 결정화 시키는 단계를 더 포함하는 화학식 Ⅰ로 표시되는 화합물의 제조방법.
4. The curable resin composition according to any one of claims 1 to 3, wherein the aliphatic hydrocarbon having 6 to 7 carbon atoms; ether; Or a mixed solvent thereof. ≪ RTI ID = 0.0 > (I) < / RTI >
제1항 내지 제3항 중 어느 한 항에 있어서, 상기 키랄 환원 반응에 사용되는 수소 공여체는 포름산, 포름산의 금속염, 포름산의 암모늄염, 및 포름산과 아민의 혼합물 중에서 선택되는 어느 하나인 화학식 Ⅰ로 표시되는 화합물의 제조방법.
The method according to any one of claims 1 to 3, wherein the hydrogen donor used in the chiral reduction reaction is any one selected from the group consisting of formic acid, a metal salt of formic acid, an ammonium salt of formic acid, and a mixture of formic acid and amine. ≪ / RTI >
제6항에 있어서, 상기 수소 공여체는 포름산 및 트리에틸아민인 화학식 Ⅰ로 표시되는 화합물의 제조방법.
7. The method of claim 6, wherein the hydrogen donor is formic acid and triethylamine.
제1항 내지 제3항 중 어느 한 항에 있어서, 화학식 Ⅱ로 표시되는 화합물의 화학식 Ⅲ 또는 화학식 Ⅳ로 표시되는 촉매 하에 키랄 환원 반응은 25 내지 80 ℃에서 수행되는 화학식 Ⅰ로 표시되는 화합물의 제조방법.
The process according to any one of claims 1 to 3, wherein the chiral reduction reaction of the compound represented by the formula (II) under the catalyst represented by the formula (III) or (IV) is carried out at 25 to 80 ° C, Way.
제1항 내지 제3항 중 어느 한 항에 있어서, 화학식 Ⅱ로 표시되는 화합물의 화학식 Ⅲ 또는 화학식 Ⅳ로 표시되는 촉매 하에 키랄 환원 반응은 무극성 유기 용매 하에 수행되는 화학식 Ⅰ로 표시되는 화합물의 제조방법.
The process according to any one of claims 1 to 3, wherein the chiral reduction reaction of the compound represented by the general formula (II) under the catalyst represented by the general formula (III) or (IV) is carried out in a nonpolar organic solvent .
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