KR101404614B1 - Method for preparation of chiral α-chloro-α-fluoro-β-keto phosphonate derivatives - Google Patents

Method for preparation of chiral α-chloro-α-fluoro-β-keto phosphonate derivatives Download PDF

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KR101404614B1
KR101404614B1 KR1020120114640A KR20120114640A KR101404614B1 KR 101404614 B1 KR101404614 B1 KR 101404614B1 KR 1020120114640 A KR1020120114640 A KR 1020120114640A KR 20120114640 A KR20120114640 A KR 20120114640A KR 101404614 B1 KR101404614 B1 KR 101404614B1
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chloro
chiral
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KR20140048551A (en
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김대영
우샛별
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순천향대학교 산학협력단
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    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • 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
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1845—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing phosphorus
    • 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
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0261—Complexes comprising ligands with non-tetrahedral chirality
    • 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
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/824—Palladium

Abstract

키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체의 제조방법이 개시되어 있다. 본 발명은, 키랄 팔라듐 촉매 존재하에서, 알파-클로로-베타-케토 포스포네이트(α-chloro-β-keto phosphonate)유도체를 엔-플루오로벤젠술폰이미드(N-fluorobenzenesulfonimide)와 반응시키는 것을 특징으로 한다.A process for the preparation of chiral alpha-chloro-alpha-fluoro-beta-ketophosphonate derivatives is disclosed. The present invention is characterized by reacting an α-chloro-β-keto phosphonate derivative with N-fluorobenzenesulfonimide in the presence of a chiral palladium catalyst .

Description

키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체의 제조방법{Method for preparation of chiral α-chloro-α-fluoro-β-keto phosphonate derivatives}[0001] The present invention relates to a chiral alpha-chloro-alpha-fluoro-beta-keto phosphonate derivatives,

본 발명은 키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체의 제조방법에 관한 것으로, 특히 키랄 팔라듐 촉매를 이용하여 광학 순도가 높은 광학 활성물질을 효율적으로 제조할 수 있는 키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체의 제조방법에 관한 것이다.The present invention relates to a process for preparing chiral alpha-chloro-alpha-fluoro-beta-ketophosphonate derivatives, and more particularly, to a process for producing optically active chiral alpha -chloro-alpha-fluoro- -Chloro-alpha-fluoro-beta-ketophosphonate derivatives.

자연에 존재하는 많은 생리 활성분자들은 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 합성방법에 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, and active research on efficient synthesis of chiral compounds is underway.

키랄 화합물을 얻는 방법으로 가장 효율적이고 경제적인 방법은 비대칭 촉매를 이용한 방법으로 다양한 키랄 중간체를 제조하는 촉매 비대칭 반응의 개발은 의학 화학분야에서 매우 중요하다. The most efficient and economical method for obtaining the chiral compound is the development of a catalyst asymmetric reaction for preparing various chiral intermediates by the method using the asymmetric catalyst is very important in the field of medical chemistry.

비대칭 반응에 사용되고 있는 대부분의 촉매들은 공기 중이나 수분에 불안정하여 무수반응조건 등 까다로운 반응조건이 필요하여 산업적 활용에 큰 단점으로 지적되고 있다. 따라서 공기나 수분에 안정하고 저렴한 촉매를 이용한 비대칭 반응의 개발은 매우 필요하고 중요하다.Most of the catalysts used in the asymmetric reaction are unstable in the air or water and require severe reaction conditions such as anhydrous reaction conditions, which is pointed out as a serious disadvantage in industrial utilization. Therefore, it is very necessary and important to develop an asymmetric reaction using a stable and cheap catalyst for air or moisture.

키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체들은 생리활성과 관련하여 매우 중요하게 인식되어 이들의 비대칭 합성은 매우 중요하다. Chiral alpha-chloro-alpha-fluoro-beta-ketophosphonate derivatives are very important in relation to physiological activity and their asymmetric synthesis is very important.

본 발명의 목적은 상기의 문제점을 해결하기 위한 것으로, 키랄 팔라듐 촉매를 이용하여 광학 순도가 높은 키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체의 제조방법을 제공하는 데 있다.It is an object of the present invention to provide a process for preparing a chiral alpha-chloro-alpha-fluoro-beta-ketophosphonate derivative having high optical purity using a chiral palladium catalyst.

본 발명의 다른 목적은 적은 양의 키랄 팔라듐 촉매를 이용하여 키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체의 제조방법을 제공하는 데 있다.Another object of the present invention is to provide a process for preparing chiral alpha-chloro-alpha-fluoro-beta-ketophosphonate derivatives using a small amount of chiral palladium catalyst.

상기 목적을 달성하기 위해 본 발명에 따른 키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체의 제조방법은, 키랄 팔라듐 촉매 존재하에서 알파-클로로-베타-케토 포스포네이트(α-chloro-β-keto phosphonate)유도체를 엔-플루오로벤젠술폰이미드(N-fluorobenzenesulfonimide)와 반응시키는 것을 특징으로 한다.In order to accomplish the above object, the present invention provides a process for preparing a chiral alpha-chloro-alpha-fluoro-beta-ketophosphonate derivative according to the present invention, comprising reacting alpha-chloro-beta-ketophosphonate chloro-β-keto phosphonate derivative is reacted with N-fluorobenzenesulfonimide.

상술한 바와 같이, 본 발명에서 공기나 수분에 안정하고 취급이 용이한 키랄 팔라듐 촉매를 이용하여 키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체를 효율적으로 제조할 수 있다는 효과가 얻어진다.As described above, in the present invention, it is possible to efficiently produce a chiral alpha-chloro-alpha-fluoro-beta-ketophosphonate derivative using a chiral palladium catalyst which is stable to air and moisture and easy to handle .

또한, 본 발명에 의하면, 적은 촉매량으로 광학순도와 수율이 높은 키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체를 제조할 수 있다는 장점이 있다.Also, according to the present invention, there is an advantage that a chiral alpha-chloro-alpha-fluoro-beta-ketophosphonate derivative having high optical purity and high yield can be produced with a small amount of catalyst.

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 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체의 제조방법의 특징에 대해 설명한다. First, the process for producing the chiral alpha-chloro-alpha-fluoro-beta-ketophosphonate derivative according to the present invention will be described.

본 발명의 일 실시 예에 따른 키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체의 제조방법은 키랄 팔라듐 촉매 존재 하에서 알파-클로로-베타-케토 포스포네이트 유도체를 엔-플루오로벤젠술폰이미드와 반응시켜 키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체를 제조할 수 있다. 상기 제조방법은 키랄 촉매를 이용하여 광학 순도가 높은 광학활성물질을 효율적으로 제조하기 위한 것이다.
The process for preparing chiral alpha-chloro-alpha-fluoro-beta-ketophosphonate derivatives according to an embodiment of the present invention comprises reacting alpha-chloro-beta-ketophosphonate derivatives with en- Benzene sulfonimide to produce chiral alpha-chloro-alpha-fluoro-beta-ketophosphonate 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 팔라듐 촉매는 하기 화학식 1의 화합물이다.The chiral palladium catalyst used in the above production process is a compound of the following formula (1).

Figure 112012083853598-pat00001
Figure 112012083853598-pat00001

상기 화학식 1에서 키랄 촉매의 함량은 반응 물질들의 전체 몰수를 기준으로, 0.1몰% 이다. 0.1몰%를 사용하면 광학 순도와 수율이 높은 키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체를 효율적으로 제조할 수 있다.
The content of the chiral catalyst in the above formula (1) is 0.1 mol% based on the total moles of the reactants. When 0.1 mol% is used, chiral alpha-chloro-alpha-fluoro-beta-ketophosphonate derivatives having high optical purity and high yield can be efficiently produced.

상기 알파-클로로-베타-케토 포스포네이트(α-chloro-β-keto phosphonate) 유도체는 하기 화학식 2의 구조를 갖는 화합물일 수 있다.The alpha-chloro-beta-keto phosphonate derivative may be a compound having a structure of the following formula (2).

Figure 112012083853598-pat00002
Figure 112012083853598-pat00002

상기 화학식 2에서 Ar은 C6-C14의 아릴기 또는 C4-C10의 방향족 헤테로 고리 화합물이다. 상기 아릴기는 C1-C10의 알콕시기, 알킬기, C1-C10알킬 아민기가 치환된 아릴기 또는 할로겐으로 치환될 수 있다. 상기 방향족 헤테로 고리 화합물은 퓨릴 (furyl), 싸이에닐 (thienyl) 또는 피리딜 (pyridyl)일 수 있다.
In the above formula (2), Ar is a C 6 -C 14 aryl group or a C 4 -C 10 aromatic heterocyclic compound. The aryl group may be substituted with a C 1 -C 10 alkoxy group, an alkyl group, an aryl group substituted with a C 1 -C 10 alkylamine group, or a halogen. The aromatic heterocyclic compound may be furyl, thienyl or pyridyl.

상기 엔-플루오로벤젠술폰이미드 (N-fluorobenzenesulfonimide)는 하기의 화학식 3의 구조를 갖는 화합물일 수 있다.The N-fluorobenzenesulfonimide may be a compound having a structure represented by the following formula (3).

Figure 112012083853598-pat00003
Figure 112012083853598-pat00003

상기 키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트(α-chloro-α-fluoro-β-keto phosphonate) 유도체는 화학식 4를 갖는 화합물일 수 있다.The chiral alpha-chloro-alpha-fluoro-beta-keto phosphonate derivative may be a compound having the formula (4).

Figure 112012083853598-pat00004
Figure 112012083853598-pat00004

상기 화학식 4에서 Ar은 C6-C14의 아릴기 또는 C4-C10의 방향족 헤테로 고리 화합물이다. 상기 아릴기는 C1-C10의 알콕시기, 알킬기, C1-C10알킬 아민기가 치환된 아릴기 또는 할로겐으로 치환될 수 있다. 상기 방향족 헤테로 고리 화합물은 퓨릴 (furyl), 싸이에닐 (thienyl) 또는 피리딜 (pyridyl)일 수 있다.
In the above formula (4), Ar is a C 6 -C 14 aryl group or a C 4 -C 10 aromatic heterocyclic compound. The aryl group may be substituted with a C 1 -C 10 alkoxy group, an alkyl group, an aryl group substituted with a C 1 -C 10 alkylamine group, or a halogen. The aromatic heterocyclic compound may be furyl, thienyl or pyridyl.

또한, 본 발명의 일 실시 예에서 알파-클로로-베타-케토 포스포네이트 유도체를 키랄 팔라듐 촉매 존재 하에서 엔-플루오로벤젠술폰이미드와 반응시켜 키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체를 제조할 수 있다. 구제적인 반응식은 하기 반응식 1과 같다.Also, in one embodiment of the present invention, an alpha-chloro-beta-ketophosphonate derivative is reacted with en-fluorobenzenesulfonimide in the presence of a chiral palladium catalyst to form chiral alpha-chloro-alpha-fluoro- Phosphonate derivatives can be prepared. The remedial equation is shown in the following reaction formula 1.

[ 반응식 1 ] [Reaction Scheme 1]

Figure 112012083853598-pat00005
Figure 112012083853598-pat00005

상기 반응식 1에서 Ar 은 위에서 정의한 바와 같다.
In the above Reaction Scheme 1, Ar is as defined above.

이하, 하기 실시 예 등에 의하여 본 발명을 더욱 상세하게 설명하고자 한다. 다만, 하기 실시 예 등은 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들만으로 한정되는 것은 아니다.
Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

입체 선택적인 키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체의 합성을 위해 하기 반응식 2, 3과 같이 키랄 팔라듐 촉매를 이용한 비대칭 반응을 수행한 결과 높은 수율과 입체선택성을 나타내었다.For the synthesis of the stereoselective chiral alpha-chloro-alpha-fluoro-beta-ketophosphonate derivatives, asymmetric reactions using chiral palladium catalysts as shown in the following Schemes 2 and 3 showed high yield and stereoselectivity .

하기 반응식 2와 같이 화학식 1의 촉매를 사용하여 키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체를 합성한 결과, 높은 수율과 입체선택성을 나타내었다.The chiral alpha-chloro-alpha-fluoro-beta-ketophosphonate derivatives were synthesized using the catalyst of Formula 1 as shown in Reaction Scheme 2, and showed high yield and stereoselectivity.

[반응식 2] [Reaction Scheme 2]

Figure 112012083853598-pat00006

Figure 112012083853598-pat00006

촉매catalyst 시간(d)Time (d) 수율(%)a Yield (%) a 거울상입체선택(%)b Mirror image stereoscopic selection (%) b 1One 화학식 1Formula 1 1One 9090 9191

a 정제한 수율 a purified yield

b 거울상입체이성질체 비율은 키랄 HPLC를 이용하여 결정함.
 b The enantiomeric ratio was determined using chiral HPLC.

하기 반응식 3 과 같이, 0.1 몰%의 촉매량을 사용하여 키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체를 합성하였고 그 결과를 표 2에 나타내었다.A chiral alpha-chloro-alpha-fluoro-beta-ketophosphonate derivative was synthesized using a catalyst amount of 0.1 mol% as shown in Reaction Scheme 3 below.

[반응식 3] [Reaction Scheme 3]

Figure 112012083853598-pat00007

Figure 112012083853598-pat00007

2, Ar2, Ar 시간(d)Time (d) 수율(%)a Yield (%) a 거울상입체선택(%)b Mirror image stereoscopic selection (%) b 1One 2a, Ph 2a , Ph 1One 4a, 90 4a , 90 9191 22 2b, 4-MeC6H4 2b , 4-MeC 6 H 4 1One 4b, 95 4b , 95 9595 33 2c, 4-MeOC6H4 2c, 4-MeOC 6 H 4 1One 4c, 97 4c , 97 9191 44 2d, 4-FC6H4 2d, 4-FC 6 H 4 1One 4d, 93 4d , 93 9393 55 2e, 4-ClC6H4 2e, 4-ClC 6 H 4 1One 4e, 90 4e , 90 9191 66 2f, 4-BrC6H4 2f, 4-BrC 6 H 4 1One 4f, 96 4f , 96 9191 77 2g, 4-NO2C6H4 2 g , 4-NO 2 C 6 H 4 1One 4g, 95 4 g , 95 8383 88 2h, 2-thienyl 2h , 2-thienyl 1One 4h, 90 4h , 90 8585 99 2i, 2-naphthyl 2i , 2-naphthyl 1One 4i, 92 4i , 92 9595

a 정제한 수율 a purified yield

b 거울상입체이성질체 비율은 키랄 HPLC를 이용하여 결정함.
 b The enantiomeric ratio was determined using chiral HPLC.

(S)-Diethyl 1-chloro-1-fluoro-2-oxo-2-phenylethylphosphonate (4a)( S ) -Diethyl 1-chloro-1-fluoro-2-oxo-2-phenylethylphosphonate ( 4a )

Figure 112012083853598-pat00008
Figure 112012083853598-pat00008

플라스크에 다이에틸 1-클로로-2-옥소-2-페닐에틸포스포네이트(Diethyl 1-chloro-2-oxo-2-phenylethylphosphonate), 3 mmol, 메탄올 12 mL, 상기 촉매 0.003 mmol을 넣고 상온에서 교반한다. 엔-플루오로벤젠설폰이미드(N-fluorobenzenesulfonimide) 3.3 mmol을 넣고 상온에서 24시간 교반한다. 반응 진행이 완료되면 반응 혼합물을 농축 후, 컬럼크로마토크래피로 분리 정제하여 화학식 4a를 90% 수율, 91% ee (enantiomeric excess)의 거울상 입체선택성으로 얻는다.3 mmol of diethyl 1-chloro-2-oxo-2-phenylethylphosphonate, 12 mL of methanol and 0.003 mmol of the above catalyst were added to a flask and stirred at room temperature do. 3.3 mmol of N-fluorobenzenesulfonimide was added and the mixture was stirred at room temperature for 24 hours. Upon completion of the reaction, the reaction mixture is concentrated and then separated and purified by column chromatography to obtain an enantiomeric excess of enantiomeric excess of 91% ee (90% yield).

[α]20 D = +10.2 (c = 0.70, CHCl3); 1H NMR (CDCl3) δ 8.16 (d, 2H, J = 8.6 Hz), 7.64 (dd, 1H, J = 8.2, 7.6 Hz), 7.50 (dd, 2H, J = 8.4, 8.0 Hz), 4.48 - 4.27 (m, 4H), 1.41 (t, 3H, J = 7.0 Hz), 1.38 (t, 3H, J = 7.0 Hz); 13C NMR (CDCl3) δ 188.7 (dd, J = 25.3, 6.9 Hz), 134.5, 130.6, 128.6, 103.3 (dd, J = 273.3, 185.9 Hz), 66.2 (d, J = 6.8 Hz), 65.8 (d, J = 6.8 Hz), 25.3, 16.3; HPLC (n-hexane : i-PrOH = 5 : 1, 254 nm, 1.0 mL/min) Chiralpak IC column, tR = 20.3 min (major), 15.3 min (minor), 91% ee.
 [α] 20 D = +10.2 ( c = 0.70, CHCl 3); 1 H NMR (CDCl 3) δ 8.16 (d, 2H, J = 8.6 Hz), 7.64 (dd, 1H, J = 8.2, 7.6 Hz), 7.50 (dd, 2H, J = 8.4, 8.0 Hz), 4.48 - 4.27 (m, 4H), 1.41 (t, 3H, J = 7.0 Hz), 1.38 (t, 3H, J = 7.0 Hz); 13 C NMR (CDCl 3) δ 188.7 (dd, J = 25.3, 6.9 Hz), 134.5, 130.6, 128.6, 103.3 (dd, J = 273.3, 185.9 Hz), 66.2 (d, J = 6.8 Hz), 65.8 ( d, J = 6.8 Hz), 25.3, 16.3; HPLC (n-hexane: i -PrOH = 5: 1, 254 nm, 1.0 mL / min) Chiralpak IC column, t R = 20.3 min (major), 15.3 min (minor), 91% ee.

Claims (6)

하기 [화학식 1]의 구조를 갖는 키랄 팔라듐 촉매 존재 하에서, 하기 [화학식 2]의 구조를 갖는 알파-클로로-베타-케토 포스포네이트 유도체를 하기 [화학식 3]의 구조를 갖는 엔-플루오로벤젠술폰이미드와 반응시키는 것을 특징으로 하는 키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체의 제조방법.
[화학식 1]
Figure 112014001779531-pat00013

[화학식 2]
Figure 112014001779531-pat00009

[화학식 3]
Figure 112014001779531-pat00014

상기 [화학식 2]에서 Ar은 C6-C14의 아릴기 또는 C4-C10의 방향족 헤테로 고리 화합물이다. 상기 아릴기는 C1-C10의 알콕시기, 알킬기, C1-C10알킬 아민기가 치환된 아릴기 또는 할로겐으로 치환될 수 있고, 상기 방향족 헤테로고리 화합물은 퓨릴 (furyl), 싸이에닐 (thienyl) 또는 피리딜 (pyridyl)일 수 있다.A process for producing alpha-chloro-beta-ketophosphonate derivatives having a structure represented by the following formula (2) in the presence of a chiral palladium catalyst having a structure represented by the following formula (1) Alpha-fluoro-beta-ketophosphonate derivative according to claim 1, wherein the chiral alpha-chloro-alpha-fluoro-beta-ketophosphonate derivative is reacted with a sulfonimide.
[Chemical Formula 1]
Figure 112014001779531-pat00013

(2)
Figure 112014001779531-pat00009

(3)
Figure 112014001779531-pat00014

In the above formula (2), Ar is a C 6 -C 14 aryl group or a C 4 -C 10 aromatic heterocyclic compound. The aryl group may be substituted with a C 1 -C 10 alkoxy group, an alkyl group, an aryl group substituted with a C 1 -C 10 alkylamine group, or a halogen, and the aromatic heterocyclic compound may be substituted with furyl, thienyl, ) Or pyridyl. 삭제delete 삭제delete 삭제delete 제 1항에 있어서,
상기 키랄 팔라듐 촉매의 함량은, 반응 물질들의 전체 몰수를 기준으로, 0.1 몰%인 것을 특징으로 하는 키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체의 제조방법. The method according to claim 1,
Wherein the content of said chiral palladium catalyst is 0.1 mole% based on the total moles of reactants. ≪ RTI ID = 0.0 > 11. < / RTI > 제 1항에 있어서,
알파-클로로-베타-케토 포스포네이트 유도체와 키랄 팔라듐 촉매 존재 하에서 하기 [반응식 1]과 같이 엔-플루오로벤젠술폰이미드와 반응시켜 키랄 알파-클로로-알파-플루오로-베타-케토 포스포네이트 유도체의 제조방법.
[반응식 1]
Figure 112014001779531-pat00012

상기 [반응식 1]에서 Ar은 C6-C14의 아릴기 또는 C4-C10의 방향족 헤테로 고리 화합물이다. 상기 아릴기는 C1-C10의 알콕시기, 알킬기, C1-C10알킬 아민기가 치환된 아릴기 또는 할로겐으로 치환될 수 있고, 상기 방향족 헤테로고리 화합물은 퓨릴 (furyl), 싸이에닐 (thienyl) 또는 피리딜 (pyridyl)일 수 있다.
The method according to claim 1,
Is reacted with en-fluorobenzenesulfonimide in the presence of an alpha-chloro-beta-ketophosphonate derivative and a chiral palladium catalyst as shown in Reaction Scheme 1 to produce chiral alpha-chloro-alpha-fluoro-beta-ketophosphate / RTI >
[Reaction Scheme 1]
Figure 112014001779531-pat00012

In the above Reaction Scheme 1, Ar is a C 6 -C 14 aryl group or a C 4 -C 10 aromatic heterocyclic compound. The aryl group may be substituted with a C 1 -C 10 alkoxy group, an alkyl group, an aryl group substituted with a C 1 -C 10 alkylamine group, or a halogen, and the aromatic heterocyclic compound may be substituted with furyl, thienyl, ) Or pyridyl.
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Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Angew. Chem. Int. Ed., 2008, vol.47, pp.5796-5798 *
Bull. Korean Chem. Soc., 2007, vol.28, No.12, pp.2191-2192 *
Org. Lett., 2003, vol.5, no.10, pp.1709-1712 *

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