KR20150009840A - Method for preparation of chiral chromane derivatives - Google Patents

Method for preparation of chiral chromane derivatives Download PDF

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KR20150009840A
KR20150009840A KR20130084276A KR20130084276A KR20150009840A KR 20150009840 A KR20150009840 A KR 20150009840A KR 20130084276 A KR20130084276 A KR 20130084276A KR 20130084276 A KR20130084276 A KR 20130084276A KR 20150009840 A KR20150009840 A KR 20150009840A
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KR101498803B1 (en
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김대영
이현아
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순천향대학교 산학협력단
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    • C07—ORGANIC CHEMISTRY
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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
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    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds

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Abstract

Disclosed is a method for producing chiral chromane derivatives. 1-hydroxy naphthalene is reacted with (E)-alkyl 2-oxo- 4-arylbut-3-enoate derivatives in the presence of a chiral organic catalyst having an optical isomer structure. In Chemical Formula 3 or Reaction Formula 1, an aryl group is an aryl compound of C6-C10 or a heterocyclic compound; the aryl group can be substituted by an alkyl group of C1-C3, an alkoxy group of C1-C3, or halogen; and a hetero cycle may be furyl or thienyl; and R is alkyl group of C1-C3.

Description

키랄 크로만 유도체의 제조방법{Method for preparation of chiral chromane derivatives}TECHNICAL FIELD The present invention relates to a method for preparing chiral chroman derivatives,

본 발명은 키랄 크로만 유도체의 제조방법에 관한 것으로, 보다 구체적으로는 키랄 유기 촉매를 이용하여 광학 순도가 높은 광학활성물질을 효율적으로 제조할 수 있고, 반응시간이나 촉매량을 크게 절감할 수 있도록 한 키랄 크로만 유도체의 제조방법에 관한 것이다.The present invention relates to a process for producing chiral chroman derivatives, and more particularly, to a process for producing an optically active substance having a high optical purity using a chiral organic catalyst, Chiral chroman derivatives.

자연에 존재하는 많은 생리활성분자들은 광학활성을 나타내는 한 가지 이성질체로만 구성된 경우가 많다. 대부분의 생리활성 분자의 경우 한 가지 입체 이성질체만 약리효과를 나타낸다고 알려져 있고, 다른 입체 이성질체는 부작용을 유발할 수 있는 위험성을 지니는 것으로 알려져 있어 키랄 화합물의 효율적인 제조방법에 대한 활발한 연구가 진행되고 있다. Many of the physiologically active molecules present in nature are often composed of only one isomer that exhibits optical activity. In the case of most physiologically active molecules, only one stereoisomer is known to exhibit a pharmacological effect, and other stereoisomers are known to have a risk of causing adverse effects. Therefore, active researches on efficient production methods of chiral compounds are underway.

키랄 크로만 유도체는 항암 효능을 가진 생리 활성 화합물이기 때문에, 본 발명에서 제공하는 키랄 크로만 유도체의 제조방법은 의학화학분야의 유용한 중간체 제조방법으로 사용되어 의학화학분야를 발전시키는 효과가 기대된다.Since the chiral chroman derivative is a physiologically active compound having an anticancer effect, the method for preparing the chiral chroman derivative provided in the present invention is expected to be used as a useful intermediate preparation method in the field of medical chemistry, thereby developing the field of medical chemistry.

키랄 크로만 유도체 제조방법은 알려져 있으나 반응시간이 길고, 촉매량을 많이 사용하여 비효율적이라는 단점이 있다. A method for preparing chiral chroman derivatives is known, but has a disadvantage in that the reaction time is long and the catalytic amount is large, which is inefficient.

키랄 크로만 유도체는 항암 효능을 가진 생리 활성 화합물로 알려져 있고, 이런 다양한 키랄 중간체들을 제조하는 비대칭 반응의 개발은 의학화학분야에서 매우 유용하게 사용될 수 있다. 그리고 본 발명에서의 제조방법과 같은 비대칭 촉매를 이용한 반응은 키랄 중간체을 얻는 가장 효율적이고 경제적인 방법이다. 그러나 이러한 촉매 비대칭 반응의 다른 제조방법들은 대 다수가 공기 중이나 수분에 불안정한 촉매를 사용한 방법이여서, 무수 반응 같은 까다로운 반응조건이 필요하다. 이는 산업적 활용에 큰 단점으로 지적되고 있다. 촉매를 이용한 키랄 크로만 유도체를 제조하는 방법은 알려져 있지만, 그 제조 방법은 반응 시간이 매우 길고, 많은 촉매량을 사용했다는 단점이 있다. Chiral chroman derivatives are known as physiologically active compounds having anticancer efficacy, and the development of an asymmetric reaction to produce these various chiral intermediates can be very useful in the field of medical chemistry. And the reaction using an asymmetric catalyst such as the production method of the present invention is the most efficient and economical method for obtaining a chiral intermediate. However, other methods of preparing such catalyst asymmetric reactions are those using catalysts which are unstable in air or water, and therefore, require severe reaction conditions such as anhydrous reactions. This is pointed out as a major drawback to industrial applications. Although a method for producing a chiral chroman derivative using a catalyst is known, the production method has a disadvantage in that the reaction time is very long and a large amount of catalyst is used.

본 발명의 목적은 키랄 유기 촉매를 이용하여 광학 순도가 높은 키랄 크로만 유도체의 효율적인 제조방법을 제공하는 데 있다.An object of the present invention is to provide a method for efficiently producing a chiral chroman derivative having high optical purity using a chiral organic catalyst.

본 발명의 다른 목적은 반응 시간을 월등히 감소할 수 있고 촉매량도 크게 줄일 수 있도록 하는 키랄 크로만 유도체의 제조방법을 제공하는 데 있다.Another object of the present invention is to provide a process for preparing chiral chroman derivatives which can significantly reduce the reaction time and greatly reduce the amount of the catalyst.

본 발명의 또 다른 목적은 공기나 수분에 안정하고 취급이 용이한 촉매를 이용한 비대칭 반응으로서, 효율적으로 반응시킬 수 있는 키랄 크로만 유도체의 제조방법을 제공하는 데 있다.Another object of the present invention is to provide a process for producing chiral chroman derivatives which can be efficiently reacted as an asymmetric reaction using a catalyst which is stable to air or moisture and easy to handle.

상기 목적을 달성하기 위하여, 본 발명에 따른 키랄 크로만 유도체의 제조방법은, 광학 이성질체의 구조를 갖는 키랄 유기촉매 존재 하에서, 1-하이드록시나프탈렌과 (E)-알킬 2-옥소-4-아릴부텐오에이트 유도체[(E)-alkyl 2-oxo- 4-arylbut-3-enoate derivatives]를 반응시키는 것을 특징으로 한다.In order to achieve the above object, the present invention provides a process for preparing chiral chroman derivatives, which comprises reacting 1-hydroxy naphthalene with (E) -alkyl 2-oxo-4-aryl (E) -alkyl 2-oxo-4-arylbut-3-enoate derivatives of the present invention.

본 발명의 제조 방법에 의하면, 반응 시간(2시간)은 기존의 방법에서의 반응 시간(36시간)보다 매우 짧다. 그리고 촉매량이 1 mol%인 적은 양으로도 광학순도가 높은 키랄 크로만 유도체를 얻을 수 있다. 따라서, 본 발명에 의하면, 반응 시간도 월등히 절약되고, 촉매량을 적게 사용하여도 광학순도가 높은 키랄 크로만 유도체를 합성할 수 있는 것이다.According to the production method of the present invention, the reaction time (2 hours) is much shorter than the reaction time (36 hours) in the conventional method. Chiral chroman derivatives having high optical purity can also be obtained in a small amount of 1 mol% of the catalyst. Therefore, according to the present invention, the reaction time is also greatly reduced, and chiral chroman derivatives having high optical purity can be synthesized even when the catalytic amount is small.

본 발명에서는 공기나 수분에 안정하고 취급이 용이한 키랄 유기 촉매를 이용하여 기존의 키랄 크로만 유도체의 제조방법보다 짧은 반응시간과 적은 량의 촉매를 사용하여 효율적으로 제조를 할 수 있다. 따라서, 본 발명의 제조방법은 기존의 키랄 크로만 유도체 제조 방법보다 효율적이기 때문에, 산업적으로 매우 경제적인 효과가 기대된다. In the present invention, it is possible to efficiently produce chiral organic catalysts which are stable to air or moisture and easy to handle, using a shorter reaction time and a smaller amount of catalyst than conventional methods for producing chiral chroman derivatives. Therefore, the manufacturing method of the present invention is more efficient than the conventional method of producing chiral chroman derivatives, and therefore, it is expected to have a very economical effect in industry.

본 발명의 상기 및 그 밖의 목적과 새로운 특징은 본 명세서에 의해서 더욱 명확하게 될 것이다. These and other objects and novel features of the present invention will become more apparent from the following description.

먼저 본 발명에 따른 키랄 크로만 유도체의 제조방법 특징에 대해 설명한다. 본 발명의 일 실시 예에 따른 키랄 크로만 유도체의 제조방법은 키랄 유기 촉매 존재하에서, 1-하이드록시나프탈렌와 (E)-알킬 2-옥소-4-아릴부텐오에이트 유도체[(E)-alkyl 2-oxo-4-arylbut-3-enoate derivatives]를 반응시키는 것을 특징으로 한다. 상기 제조방법은 키랄 촉매를 이용하여 광학 순도가 높은 광학활성물질을 효율적으로 제조하기 위한 것이다.
First, the production method of the chiral chroman derivative according to the present invention will be described. The process for preparing a chiral chroman derivative according to an embodiment of the present invention comprises reacting 1 -hydroxynaphthalene with (E) -alkyl 2-oxo-4-arylbutenioate derivative [(E) -alkyl 2 -oxo-4-arylbut-3-enoate derivatives]. The above production method is for efficiently producing an optically active substance having high optical purity using a chiral catalyst.

위 제조방법에서 사용되는 키랄 유기 촉매는 하기 [화학식 1] 또는 그 광학 이성질체의 구조를 갖는 화합물이다.The chiral organic catalyst used in the above production method is a compound having a structure of the following Chemical Formula 1 or its optical isomer.

[화학식 1][Chemical Formula 1]

Figure pat00001

Figure pat00001

상기 1-하이드록시나프탈렌은 하기 [화학식 2]의 구조를 갖는다.The 1-hydroxy naphthalene has a structure represented by the following formula (2).

[화학식 2](2)

Figure pat00002

Figure pat00002

상기 (E)-알킬 2-옥소-4-아릴부텐오에이트 유도체는 하기 [화학식 3]의 구조를 갖는다.The (E) -alkyl 2-oxo-4-arylbutenioate derivative has a structure represented by the following formula (3).

[화학식 3](3)

Figure pat00003
Figure pat00003

상기 [화학식 3]에서 아릴기(Ar)는 C6-C10의 아릴 화합물이거나 헤테로고리 화합물이고, 상기 아릴기는 C1-C3의 알킬기, C1-C3의 알콕시기 또는 할로겐이 치환될 수 있으며, 상기 헤테로고리는 퓨릴(furyl)이거나 싸이에닐(thienyl)일 수 있다. 상기 [화학식 3]에서 R은 C1-C3의 알킬기이다.
In the above formula (3), the aryl group (Ar) is a C 6 -C 10 aryl compound or a heterocyclic compound, and the aryl group is substituted with a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group or a halogen And the heterocycle may be furyl or thienyl. In the above formula (3), R is a C 1 -C 3 alkyl group.

발명을 실시하기 위한 구체적인 제조방법은 아래 [반응식 1] 과 같다. A specific production method for carrying out the invention is as shown in the following Reaction Scheme 1.

[반응식 1][Reaction Scheme 1]

Figure pat00004
Figure pat00004

상기 [반응식 1]에서 아릴기(Ar)는 C6-C10의 아릴 화합물이거나 헤테로고리 화합물이고, 상기 아릴기는 C1-C3의 알킬기, C1-C3의 알콕시기 또는 할로겐이 치환될 수 있으며, 상기 헤테로고리는 퓨릴(furyl)이거나 싸이에닐(thienyl)일 수 있다. 상기 [반응식 1]에서 R은 C1-C3의 알킬기이다.
The [Reaction 1] the aryl group (Ar) is an aryl compound or a heterocyclic compound of C 6 -C 10, and the aryl group be a halogen or an alkoxy group of C 1 -C 3 alkyl, C 1 -C 3 substituted in And the heterocycle may be furyl or thienyl. In the above Reaction Scheme 1, R is a C 1 -C 3 alkyl group.

상기 키랄 크로만(chromane) 유도체는 [화학식 4]를 갖는 화합물일 수 있다.The chiral chromane derivative may be a compound having the formula (4).

[화학식 4][Chemical Formula 4]

Figure pat00005
Figure pat00005

상기 [화학식 4]에서 아릴기(Ar)는 C6-C10의 아릴 화합물이거나 헤테로고리 화합물이고, 상기 아릴기에는 C1-C3의 알킬기, C1-C3의 알콕시기 또는 할로겐이 치환될 수 있으며, 상기 헤테로고리는 퓨릴(furyl)이거나 싸이에닐(thienyl)일 수 있다. 상기 [화학식 4]에서 R은 C1-C3의 알킬기이다.
In the formula 4, the aryl group (Ar) is a C 6 -C 10 aryl compound or a heterocyclic compound, and the aryl group may be substituted with a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group or a halogen , And the heterocycle may be furyl or thienyl. In the above-mentioned [Chemical Formula 4] R is an alkyl group of C 1 -C 3.

플라스크에 1-하이드록시나프탈렌(화학식 2)을 0.3 mmol, 톨루엔을 3 mL, 상기 키랄 유기촉매(화학식 1)을 0.003 mmol, (E)-에틸 2-옥소-4-페닐부텐오에이트(화학식 3)를 0.36 mmol를 넣고 상온에서 2 ∼ 3 시간 교반한다. 반응 진행이 완료되면 반응 혼합물을 농축 후, 컬럼 크로마토크래피로 분리 정제하여 [화학식 4]의 구조를 갖는 키랄 크로만 유도체를 높은 거울상 입체선택성으로 얻는다.
0.3 mmol of 1 -hydroxynaphthalene (Formula 2), 3 mL of toluene, 0.003 mmol of the chiral organic catalyst (Formula 1), (E) -ethyl 2-oxo-4-phenylbutenioate ), And the mixture is stirred at room temperature for 2 to 3 hours. After completion of the reaction, the reaction mixture is concentrated and then separated and purified by column chromatography to obtain chiral chroman derivatives having the structure of Formula 4 as high enantioselectivity.

상기 제조방법은 적은 양의 키랄 촉매를 사용하였고 반응 시간도 매우 짧은데에 불구하고 광학 순도가 높은 광학활성물질을 효율적으로 제조할 수 있다는 것에 큰 장점이 있다.
The above process has a great advantage in that an optically active substance having a high optical purity can be efficiently produced despite using a small amount of chiral catalyst and a very short reaction time.

본 발명의 일 실시 예에는, 하기 [반응식 2]과 같이, 1 몰%의 촉매량을 사용하여 키랄 크로만 유도체를 합성하였으며 그 결과를 표 1에 나타내었다.In one embodiment of the present invention, a chiral chroman derivative was synthesized using a catalyst amount of 1 mol% as shown in Reaction Scheme 2 below, and the results are shown in Table 1.

[반응식 2] [Reaction Scheme 2]

Figure pat00006

Figure pat00006

Ar, RAr, R 시간(h)Time (h) 수율(%)a Yield (%) a 부분입체이성체비율b The diastereomer ratio b 거울상 이성질체
초과량 (%)c Enantiomer
Excess (%) c 1One 3a, Ph, Me 3a , Ph, Me 22 4a, 90 4a , 90 10:110: 1 9898 22 3b, 4-FC6H4, Me 3b, 4-FC 6 H 4 , Me 22 4b, 90 4b , 90 10:110: 1 9292 33 3c, 2-FC6H4, Me 3c, 2-FC 6 H 4 , Me 33 4c, 88 4c , 88 10:110: 1 9898 44 3d, 4-ClC6H4, Me 3d, 4-ClC 6 H 4 , Me 22 4d, 95 4d , 95 10:110: 1 9292 55 3e, 4-BrC6H4, Me 3e, 4-BrC 6 H 4 , Me 22 4e, 90 4e , 90 10:110: 1 9090 66 3f, 5-F, 2-BrC6H3, Me 3f, 5-F, 2-BrC 6 H 3 , Me 22 4f, 92 4f , 92 10:110: 1 9292 77 3g, 4-MeC6H4, Me 3 g , 4-MeC 6 H 4 , Me 33 4g, 93 4 g , 93 10:110: 1 9494 88 3h, 4-MeOC6H4, Me 3h, 4-MeOC 6 H 4 , Me 22 4h, 91 4h , 91 10:110: 1 9090 99 3i, 2-naphthyl, Me 3i , 2-naphthyl, Me 22 4i, 90 4i , 90 10:110: 1 9898 1010 3j, 2-thienyl, Me 3j, 2-thienyl, Me 33 4j, 90 4j, 90 10:110: 1 9797 1111 3k, 2-furyl, Me 3k, 2-furyl, Me 22 4k, 90 4k, 90 10:110: 1 9292

a 정제한 수율 a purified yield

b 부분입체이성질체 (diastereomer) 비율은 1H-NMR을 이용하여 결정하였다. The diastereomeric ratio of b was determined using 1 H-NMR.

c 거울상이성질체 초과량(enantiomeric excess)은 키랄 HPLC를 이용하여 결정함
 The c enantiomeric excess was determined using chiral HPLC.

[실시예 1][Example 1]

(2S,4R)-methyl2-hydroxy-4-phenyl-3,4-dihydro-2H-benzo[h]chromene-2-carboxylate (4a) (2S, 4R) -methyl2-hydroxy -4-phenyl-3,4-dihydro-2H-benzo [h] chromene-2-carboxylate (4a)

Figure pat00007
Figure pat00007

상기 키랄 크로만 유도체의 제조방법으로, 화학식 4a를 90% 수율, 98% ee (enantiomeric excess)의 거울상 입체선택성으로 얻는다.According to the process for the preparation of the chiral chroman derivative, the compound of formula ( 4a ) is obtained in 90% yield with enantioselectivity of 98% ee (enantiomeric excess).

1H NMR (400 MHz, CDCl3) δ 8.16-8.20(m, 1 H), 7.70-7.79(m, 1 H), 7.44-7.48(m, 2 H), 7.25-7.39(m, 6 H), 6.86(d, J = 8.4 Hz, 1 H), 4.46-4.52(m, 2 H), 3.95(s, 3 H), 2.53-2.62(m, 1 H), 2.41(dd, J = 5.7 Hz, 13.2 Hz, 1 H); 13C NMR (100MHz, CDCl3): δ 170.2, 146.2, 143.8, 133.2, 130.9, 128.9, 128.8, 127.4, 127.0, 126.7, 126.1, 125.5, 124.8, 121.5, 120.9, 119.1, 94.4, 53.4, 37.8, 36.7; HPLC-major diastereomer: ee was determined by HPLC analysis (Chiralcel AD-H, i-PrOH/ Hexane = 20/80, 1.0 mL/min, 236 nm.) Retention time: tmajor = 9.07 min, tminor = 11.59 min, ee = 98%.
 1 H NMR (400 MHz, CDCl 3 )? 8.16-8.20 (m, 1H), 7.70-7.79 (m, 1H), 7.44-7.48 (m, 2H), 7.25-7.39 , 6.86 (d, J = 8.4 Hz, 1 H), 4.46-4.52 (m, 2 H), 3.95 (s, 3 H), 2.53-2.62 (m, 1 H), 2.41 (dd, J = 5.7 Hz , 13.2 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ 170.2, 146.2, 143.8, 133.2, 130.9, 128.9, 128.8, 127.4, 127.0, 126.7, 126.1, 125.5, 124.8, 121.5, 120.9, 119.1, 94.4, ; HPLC-major diastereomer: ee was determined by HPLC analysis (Chiralcel AD-H, i- PrOH / Hexane = 20/80, 1.0 mL / min, 236 nm.) Retention time: t major = 9.07 min, t minor = 11.59 min , ee = 98%.

[실시예 2][Example 2]

(2R,4S)-methyl4-(4-fluorophenyl)-2-hydroxy-3,4-dihydro-2H-benzo[h]chromene-2-carboxylate (4b)(2R, 4S) -methyl4- (4 -fluorophenyl) -2-hydroxy-3,4-dihydro-2H-benzo [h] chromene-2-carboxylate (4b)

Figure pat00008
Figure pat00008

상기 키랄 크로만 유도체의 제조방법으로, 화학식 4b를 90% 수율, 92% ee (enantiomeric excess)의 거울상 입체선택성으로 얻는다.As a method for preparing the chiral chroman derivative, Formula 4b is obtained in 90% yield with enantioselectivity of 92% ee (enantiomeric excess).

1H NMR (400 MHz, CDCl3) δ 8.15-8.20(m, 1 H), 7.72-7.76(m, 1 H), 7.45-7.50(m, 2 H), 7.32(d, J = 8.7 Hz, 1 H), 7.21-7.26(m, 2 H), 7.01-7.07(m, 2 H), 6.84(d, J = 8.7 Hz, 1 H), 4.45-4.51(m, 2 H), 3.96(s, 3 H), 2.48-2.57(m, 1 H), 2.36-2.42(dd, J = 6.0 Hz, 13.5 Hz, 1 H); 13C NMR (100MHz, CDCl3) δ 170.2, 146.2, 139.2, 139.2, 133.4, 130.4, 130.3, 127.4, 126.4, 126.2, 125.6, 124.8, 121.5, 121.0, 118.9, 115.8, 115.5, 94.3, 53.6, 37.2, 37.0; HPLC-major diastereomer (Chiralcel AD-H, i-PrOH/ Hexane = 20/80, 1.0 mL/min, 235 nm): Retention time: t(major) = 10.27 min, t(minor) = 14.25 min, ee = 92%.
1 H NMR (400 MHz, CDCl 3 )? 8.15-8.20 (m, 1H), 7.72-7.76 (m, 1H), 7.45-7.50 1 H), 7.21-7.26 (m, 2 H), 7.01-7.07 (m, 2 H), 6.84 (d, J = 8.7 Hz, , 3 H), 2.48-2.57 (m, 1H), 2.36-2.42 (dd, J = 6.0 Hz, 13.5 Hz, 1H); 13 C NMR (100MHz, CDCl 3 ) δ 170.2, 146.2, 139.2, 139.2, 133.4, 130.4, 130.3, 127.4, 126.4, 126.2, 125.6, 124.8, 121.5, 121.0, 118.9, 115.8, 115.5, 94.3, 53.6, 37.2, 37.0; (Major) = 10.27 min, t (minor) = 14.25 min, ee = 20 min, HPLC-major diastereomer (Chiralcel AD-H, i- PrOH / Hexane = 20/80, 1.0 mL / min, 92%.

[실시예 3][Example 3]

(2R,4R)-methyl4-(2-fluorophenyl)-2-hydroxy-3,4-dihydro-2H-benzo[h]chromene-2-carboxylate (4c) (2R, 4R) -methyl4- (2 -fluorophenyl) -2-hydroxy-3,4-dihydro-2H-benzo [h] chromene-2-carboxylate (4c)

Figure pat00009
Figure pat00009

상기 키랄 크로만 유도체의 제조방법으로, 화학식 4c를 88% 수율, 98% ee (enantiomeric excess)의 거울상 입체선택성으로 얻는다.As a method for preparing the chiral chroman derivative, the compound of formula ( 4c ) is obtained with an enantioselectivity of 98% ee (enantiomeric excess) in 88% yield.

1H NMR (400 MHz, CDCl3): δ 8.16-8.19(m, 1 H), 7.73-7.76(m, 1 H), 7.44-7.50(m, 2 H), 7.33-7.36(d, J = 8.7 Hz, 1 H),7.27-7.30(m, 1 H), 7.18-7.23(m, 1 H), 7.08-7.14(m, 1 H),6.88(d, J = 8.4 Hz, 1 H), 4.85(dd, J = 5.7 Hz, 12.6 Hz, 1 H), 4.45(d, J = 2.1 Hz, 1 H), 3.96(s, 3 H), 2.59-2.68(m, 1 H), 2.41(dd, J = 6.0 Hz, 13.2 Hz, 1 H); 13C NMR (100MHz, CDCl3): δ 170.2, 146.3, 133.4, 128.7, 128.6, 127.4, 126.1, 126.0, 125.6, 124.9, 124.5, 124.5, 121.5, 121.0, 118.1, 115.9, 115.6, 94.3, 53.6, 34.9; HPLC-major diastereomer(Chiralcel AD-H, i-PrOH/ Hexane = 20/80, 1.0 mL/min, 238 nm): Retention time: t(major) = 9.34 min, t(minor) = 12.60 min, ee = 98%.
 1 H NMR (400 MHz, CDCl 3): δ 8.16-8.19 (m, 1 H), 7.73-7.76 (m, 1 H), 7.44-7.50 (m, 2 H), 7.33-7.36 (d, J = (M, 1H), 7.08-7.14 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 7.18-7.23 (D, J = 5.7 Hz, 12.6 Hz, 1H), 4.45 (d, J = 2.1 Hz, 1H), 3.96 (s, 3H), 2.59-2.68 , ≪ / RTI > J = 6.0 Hz, 13.2 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ 170.2, 146.3, 133.4, 128.7, 128.6, 127.4, 126.1, 126.0, 125.6, 124.9, 124.5, 124.5, 121.5, 121.0, 118.1, 115.9, 115.6, 94.3, ; HPLC-major diastereomer (Chiralcel AD-H, i- PrOH / Hexane = 20/80, 1.0 mL / min, 238 nm): Retention time: t (major) = 9.34 min, t (minor) = 12.60 min, ee = 98%.

[실시예 4][Example 4]

(2R,4R)-methyl2-hydroxy-4-(thiophen-2-yl)-3,4-dihydro-2H-benzo[h]chromene-2-carboxy late (4j) (2R, 4R) -methyl2-hydroxy -4- (thiophen-2-yl) -3,4-dihydro-2H-benzo [h] chromene-2-carboxy late (4j)

Figure pat00010
Figure pat00010

상기 키랄 크로만 유도체의 제조방법으로, 화학식 4j를 90% 수율, 97% ee (enantiomeric excess)의 거울상 입체선택성으로 얻는다.As a method for preparing the above chiral chroman derivative, the compound of formula ( 4j ) is obtained in an enantioselectivity of 97% ee (enantiomeric excess) in 90% yield.

1H NMR (400 MHz, CDCl3): δ 8.14-8.19(m, 1 H), 7.72-7.76(m, 1 H), 7.45-7.48(m, 2 H), 7.35-7.38(d, J = 8.4 Hz, 1 H), 7.26(m, 1 H), 7.01-7.08(m, 3 H), 4.82-4.89(q, J = 6.0 Hz, 1 H), 4.46(d, J = 1.8 Hz, 1 H), 3.97(s, 3 H), 2.61-2.70(m, 1 H), 2.49-2.55(dd, J = 6.0 Hz, 13.5 Hz, 1 H); 1 3C NMR (100MHz, CDCl3): δ 170.1, 146.4, 145.8, 133.5, 127.3, 126.7, 126.4, 126.2, 126.0, 125.6, 124.7, 124.5, 121.6, 120.9, 118.8, 94.3, 53.6, 37.3, 33.2; HPLC-major diastereomer (Chiralcel OD-H, i-PrOH/ Hexane = 5/95, 1.0 mL/min, 239 nm): Retention time: t(major) = 18.21 min, t(minor) = 22.56 min, ee = 97%.
 1 H NMR (400 MHz, CDCl 3): δ 8.14-8.19 (m, 1 H), 7.72-7.76 (m, 1 H), 7.45-7.48 (m, 2 H), 7.35-7.38 (d, J = J = 6.0 Hz, 1 H), 4.46 (d, J = 1.8 Hz, 1 H), 7.26 (m, 1H), 7.01-7.08 H), 3.97 (s, 3H), 2.61-2.70 (m, 1H), 2.49-2.55 (dd, J = 6.0 Hz, 13.5 Hz, 1H); 1 3 C NMR (100 MHz, CDCl 3 ): δ 170.1, 146.4, 145.8, 133.5, 127.3, 126.7, 126.4, 126.2, 126.0, 125.6, 124.7, 124.5, 121.6, 120.9, 118.8, 94.3, 53.6, 37.3, 33.2; (Major) = 18.21 min, t (minor) = 22.56 min, ee = 0.75 min, HPLC-major diastereomer (Chiralcel OD-H, i- PrOH / Hexane = 5/95, 1.0 mL / min, 239 nm) 97%.

[실시예 5][Example 5]

(2R,4R)-methyl4-(furan-2-yl)-2-hydroxy-3,4-dihydro-2H-benzo[h]chromene-2-carboxylate(4k)(2R, 4R) -methyl4- (furan -2-yl) -2-hydroxy-3,4-dihydro-2H-benzo [h] chromene-2-carboxylate (4k)

Figure pat00011
Figure pat00011

상기 키랄 크로만 유도체의 제조방법으로, 화학식 4k를 90% 수율, 92% ee (enantiomeric excess)의 거울상 입체선택성으로 얻는다.As a method for preparing the above chiral chroman derivative, the compound of formula ( 4k ) is obtained in 90% yield with enantioselectivity of 92% ee (enantiomeric excess).

1H NMR (400 MHz, CDCl3) δ 8.13-8.16(m, 1 H), 7.73-7.76(m, 1 H), 7.44-7.47(m, 2 H), 7.36-7.39(m, 2 H), 6.99-7.02(d, J = 5.4 Hz, 1 H), 6.39-6.40(dd, J = 1.8 Hz, 3.0Hz, 1 H), 6.32-6.33(d, J = 3.0 Hz, 1 H), 4.61-4.67(dd, J = 5.4 Hz, 12.9 Hz, 1 H), 4.45-4.46(d, J = 2.1 Hz, 1 H), 3.96(s, 3 H), 2.72-2.82(m, 1 H), 2.37-2.43(dd, J = 5.4 Hz, 13.2 Hz, 1 H); 13C NMR (100MHz, CDCl3) δ 170.2, 155.0, 145.8, 142.1, 133.5, 127.4, 126.1, 125.5, 125.4, 124.8, 121.5, 121.0, 116.7, 110.2, 107.7, 94.3, 53.6, 33.1, 31.4; HPLC-major diastereomer (Chiralcel OD-H, i-PrOH/ Hexane = 10/90, 1.0 mL/min, 238 nm): Retention time: t(major) = 11.15 min, t(minor) = 12.63 min, ee = 92%. 1 H NMR (400 MHz, CDCl 3 )? 8.13-8.16 (m, 1H), 7.73-7.76 (m, 1H), 7.44-7.47 (m, 2H), 7.36-7.39 , 6.99-7.02 (d, J = 5.4 Hz, 1H), 6.39-6.40 (dd, J = 1.8 Hz, 3.0 Hz, 1H), 6.32-6.33 (D, J = 5.4 Hz, 12.9 Hz, 1H), 4.45-4.46 (d, J = 2.1 Hz, 1H), 3.96 (s, 3H), 2.72-2.82 2.37-2.43 (dd, J = 5.4 Hz, 13.2 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 )? 170.2, 155.0, 145.8, 142.1, 133.5, 127.4, 126.1, 125.5, 125.4, 124.8, 121.5, 121.0, 116.7, 110.2, 107.7, 94.3, 53.6, 33.1, 31.4; (Major) = 11.15 min, t (minor) = 12.63 min, ee = 1 / min, 92%.

Claims (3)

하기 [화학식 1]의 광학 이성질체의 구조를 갖는 키랄 유기촉매 존재 하에서, 하기 [화학식 2]의 구조를 갖는 1-하이드록시나프탈렌과 하기 [화학식 3]의 구조를 갖는 (E)-알킬 2-옥소-4-아릴부텐오에이트 유도체[(E)-alkyl 2-oxo- 4-arylbut-3-enoate derivatives]를 하기 [반응식 1]과 같이 반응시키는 것을 특징으로 하는 키랄 크로만 유도체의 제조방법.
[화학식 1]
Figure pat00012

[화학식 2]
Figure pat00013

[화학식 3]
Figure pat00014

[반응식 1]
Figure pat00015

상기 [화학식 3] 또는 [반응식 1]에서 아릴기(Ar)는 C6-C10의 아릴 화합물이거나 헤테로고리 화합물이고, 상기 아릴기에는 C1-C3의 알킬기, C1-C3의 알콕시기 또는 할로겐이 치환될 수 있으며, 상기 헤테로고리는 퓨릴(furyl)이거나 싸이에닐(thienyl)일 수 있다. R은 C1-C3의 알킬기이다.A process for producing an optically active 1-hydroxy naphthalene represented by the following formula (2) and an optically active (E) -alkyl 2-oxo 4-arylbut-3-enoate derivatives of the present invention are reacted as shown in Reaction Scheme 1 below.
[Chemical Formula 1]
Figure pat00012

(2)
Figure pat00013

(3)
Figure pat00014

[Reaction Scheme 1]
Figure pat00015

The aryl group (Ar) in the above Chemical Formula 3 or Reaction Scheme 1 is an aryl compound of C 6 -C 10 or a heterocyclic compound, and the aryl group may be substituted by a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy Group or halogen may be substituted, and the heterocycle may be furyl or thienyl. R is an alkyl group of C 1 -C 3. 제 1항에 있어서,
상기 반응에서, 용매는 톨루엔인 것을 특징으로 하는 키랄 크로만 유도체의 제조방법.The method according to claim 1,
In the above reaction, the solvent is toluene. 제 1항에 있어서,
상기 반응에서, 키랄유기촉매의 함량은 [화학식 2]의 구조를 갖는 1-하이드록시나프탈렌의 1몰%인 것을 특징으로 하는 키랄 크로만 유도체의 제조방법.The method according to claim 1,
In the above reaction, the content of the chiral organic catalyst is 1 mol% of the 1-hydroxy naphthalene having the structure of the formula (2).
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Publication number Priority date Publication date Assignee Title
CN105693681A (en) * 2015-12-23 2016-06-22 上海大学 Trifluoromethyl chromene derivative and synthetic method thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105693681A (en) * 2015-12-23 2016-06-22 上海大学 Trifluoromethyl chromene derivative and synthetic method thereof

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