KR20120128097A - Precursor of f-labeled pet radiopharmaceuticlas and preparation method thereof - Google Patents

Precursor of f-labeled pet radiopharmaceuticlas and preparation method thereof Download PDF

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KR20120128097A
KR20120128097A KR1020120050050A KR20120050050A KR20120128097A KR 20120128097 A KR20120128097 A KR 20120128097A KR 1020120050050 A KR1020120050050 A KR 1020120050050A KR 20120050050 A KR20120050050 A KR 20120050050A KR 20120128097 A KR20120128097 A KR 20120128097A
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지대윤
이병세
박찬수
이민형
차효진
조우진
강희원
김경훈
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서강대학교산학협력단
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    • C07D233/12—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
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Abstract

PURPOSE: A precursor comprising is provided to simplify existing complex production steps for manufacturing radiopharmaceuticals to one single step, to reduce production cost because a large amount of phase change catalyst is not necessary, to facilitate separation of compounds after a reaction and to have quick reaction rate. CONSTITUTION: A precursor comprises an organic salt leaving group represented by chemical formula 1. In chemical formula 1, R1 is a C1-1000 hydrocarbon group which is 18F-labeled radioactive tracer except a part of -X-CH2-18F. Carbon of the backbone of the C1-100 hydrocarbon group can be substituted or unsubstituted by oxygen, nitrogen, sulfur, phosphorous or combinations thereof, halogen of the backbone can be substituted or unsubstituted by halogen, X is oxygen, sulfur or -C(O)-, and the leaving group is a substituted or unsubstituted C2-50 tetravalent ammonium salt. [Reference numerals] (AA) Leaving group

Description

１８Ｆ-표지 ＰＥＴ 방사성의약품의 전구체 및 그 제조방법{PRECURSOR OF １８F-LABELED PET RADIOPHARMACEUTICLAS AND PREPARATION METHOD THEREOF}Precursor of 1F-labeled PET radiopharmaceuticals and preparation method therefor {PRECURSOR OF 1F-LABELED PET RADIOPHARMACEUTICLAS AND PREPARATION METHOD THEREOF}

본 발명은 양전자방출 단층촬영술(PET) 방사성의약품의 전구체, 그 제조방법과 응용에 관한 것으로, 더욱 상세하게는 4가 유기염의 이탈기를 갖는 전구체, 그 제조방법 및 이를 이용하여 단일 단계로 18F를 도입함으로써 짧은 제조시간 내에 원하는 18F-표지 PET 방사성의약품을 높은 방사화학적 수율로 제조하는 방법에 관한 것이다.The present invention is a 18 F in a single step by positron emission tomography (PET) relates to a precursor, a method of manufacturing and application of the radiopharmaceutical, and more particularly 4 precursor having an organic salt of departure, a method of manufacturing and using this The present invention relates to a method for producing a desired 18 F-labeled PET radiopharmaceutical with high radiochemical yield within a short manufacturing time.

인체를 실시간 영상화하는 핵의학 분자영상 기법인 양전자방출 단층촬영술(Positron Emission Tomography, PET)은 질병 초기에 일어나는 인체 내 생화학적, 생리학적 변화를 검출할 수 있는 효과적인 인체영상 기법으로 의료영상 시장에서 가장 가파른 성장세를 보이고 있다. 새로운 질병에 대한 초기 PET 의약품 연구에서 양전자방출 방사성 동위원소인 11C이 사용되고 있는데, 비교적 표지가 용이하고 유기물의 기본 골격인 탄소이라는 장점을 보유하기 때문이다. 하지만 11C는 반감기가 20분으로 짧기 때문에 상업적으로 사용하기엔 적합하지 않다는 단점이 있다. Positron emission tomography (PET), a nuclear medicine molecular imaging technique for real-time imaging of the human body, is an effective human imaging technique that can detect biochemical and physiological changes in the human body that occur early in the disease. The market is showing steep growth. In the initial PET drug research on new diseases, 11 C, a positron emitting radioisotope, is used because it is relatively easy to label and has the advantage of being the basic skeleton of organic matter. 11 C, however, has a short half-life of 20 minutes, making it unsuitable for commercial use.

한편, 다른 방사성 동위원소인 18F은 싸이클로트론으로부터 쉽게 대량 생산 가능하다는 점 등의 여러 우수한 특성들이 있고, 특히 110분의 비교적 긴 반감기로 인해 최근 상업적으로 이용 가능한 핵종으로 주목 받고 있다. 이러한 18F의 유용성 때문에, 기존에 개발된 11C 표지 화합물을 18F-표지 화합물로 대체하거나, 새롭게 개발된 질병-표적 화합물에 18F을 도입하는 방안으로 [18F]플루오로프로필 작용기를 도입하는 방법이 일반화되어 있다. 하지만 [18F]플루오로프로필 작용기가 도입된 방사성의약품은 표적 물질에 대한 결합력이 감소되는 경향을 나타내고, 친유성의 증가로 일부 조직에서 높은 섭취가 이루어지고, 비특이적 결합의 증가로 선택성이 감소되어 영상이 나빠지는 문제점이 있다. [18F]플루오로프로필 작용기 대신 [11C]메틸기와 구조적으로 유사한 [18F]플루오로메틸기를 도입하면 이러한 문제점을 해결할 수 있다. On the other hand, 18 F, another radioisotope, has several excellent properties, such as being easily mass-produced from cyclotron, and has recently attracted attention as a commercially available nuclide due to its relatively long half-life of 110 minutes. Since usefulness of 18 F, the 11 C-labeled compounds developed to replace existing or newly developed disease with 18 F- labeled compounds - introducing profile functional as a way to introduce 18 F in the target compound as a [18 F] fluoro How to do is generalized. However, radiopharmaceuticals incorporating [ 18 F] fluoropropyl functional groups have a tendency to decrease the binding force to the target material, increase in lipophilic intake in some tissues, increased selectivity due to increased non-specific binding There is a problem that the image is bad. This problem can be solved by introducing a [ 18 F] fluoromethyl group structurally similar to the [ 11 C] methyl group instead of the [ 18 F] fluoropropyl functional group.

[18F]플루오로메틸기를 도입하는 기존의 방법은 [18F]플루오로메틸화 시약을 사용하는 것이다. 이러한 시약은 일반적으로 이탈기를 두 개 이상 갖는 메탄 화합물에 18F을 표지함으로 얻어낼 수 있다. 이를 전구체와 친핵성 치환반응시키면 원하는 [18F]플루오로메틸기가 도입된 방사성의약품을 제조할 수 있다. 하지만 상기 방법은 18F 표지에 두 단계의 합성 과정이 필요하며 따라서 과정이 복잡하고 제조시간이 길어지는 단점이 있다. 제조 과정이 복잡하면 상업화에 필수적 요소인 자동화 합성 시스템 구현이 어렵게 된다. An existing method for introducing [ 18 F] fluoromethyl groups is to use [ 18 F] fluoromethylation reagents. Such reagents can generally be obtained by labeling 18 F with methane compounds having two or more leaving groups. The nucleophilic substitution reaction with the precursor may produce a radiopharmaceutical into which a desired [ 18 F] fluoromethyl group is introduced. However, this method requires a two-step synthesis process for the 18 F label, and thus has a disadvantage in that the process is complicated and the manufacturing time is long. Complex manufacturing processes make it difficult to implement automated synthesis systems that are essential to commercialization.

본 발명의 목적은 18F-표지 PET 방사성의약품 제조를 위한 4가 유기염 전구체를 제공하는 것이다. It is an object of the present invention to provide tetravalent organic salt precursors for the preparation of 18 F-labeled PET radiopharmaceuticals.

본 발명의 다른 목적은 18F-표지 PET 방사성의약품 제조를 위한 4가 유기염 전구체의 제조방법을 제공하는 것이다. Another object of the present invention is to provide a method for preparing a tetravalent organic salt precursor for preparing an 18 F-labeled PET radiopharmaceutical.

본 발명의 또 다른 목적은 4가 유기염 전구체를 이용하는 친핵성 플루오르화 반응을 제공하는 것이다. Another object of the present invention is to provide a nucleophilic fluorination reaction using a tetravalent organic salt precursor.

본 발명의 또 다른 목적은 4가 유기염 전구체의 친핵성 플루오르화 반응을 통해 제조한 18F-표지 PET 방사성의약품을 제공하는 것이다.It is still another object of the present invention to provide an 18 F-labeled PET radiopharmaceutical prepared by nucleophilic fluorination of a tetravalent organic salt precursor.

상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 4가 유기염 이탈기를 포함하는 전구체를 제공한다. In order to achieve the above object, the present invention provides a precursor comprising a tetravalent organic salt leaving group represented by the following formula (1).

Figure pat00001
Figure pat00001

상기 화학식 1에서,In Formula 1,

R1은 18F이 표지된 방사성추적자에서 -X-CH2-18F 부분을 제외한 부분으로, C1-C1000의 탄화수소기이고, 상기 C1-C1000의 탄화수소기는 주쇄의 탄소가 산소, 질소, 황, 인 또는 이들의 조합으로 치환 또는 비치환될 수 있고, 주쇄의 수소가 할로겐으로 치환 또는 비치환될 수 있고, R 1 is -X-CH 2 at the 18 F radiotracer the cover - as a portion other than the portions 18 F, C 1 -C 1000 and a hydrocarbon group, the group is a C 1 carbon of the main chain hydrocarbon -C oxygen 1000, May be substituted or unsubstituted with nitrogen, sulfur, phosphorus or a combination thereof, hydrogen in the main chain may be substituted or unsubstituted with halogen,

X는 산소, 황, 또는 -C(O)-이고,X is oxygen, sulfur, or -C (O)-,

이탈기는 치환된 또는 비치환된 C2-C50의 4가 암모늄염이다.
The leaving group is a substituted or unsubstituted tetravalent ammonium salt of C 2 -C 50 .

바람직하게는, 화학식 1에서,Preferably, in Formula 1,

R1은 C1-C200의 탄화수소기이고, 상기 C1-C200의 탄화수소기는 주쇄의 탄소가 산소, 질소, 황, 인 또는 이들의 조합으로 치환 또는 비치환될 수 있고, 주쇄의 수소가 할로겐으로 치환 또는 비치환될 수 있고, R 1 is a C 1 -C 200 hydrocarbon group, the C 1 -C 200 hydrocarbon group may be unsubstituted or substituted with oxygen, nitrogen, sulfur, phosphorus or a combination of carbon in the main chain, hydrogen of the main chain May be substituted or unsubstituted with halogen,

X는 산소, 황, 또는 -C(O)-이고,X is oxygen, sulfur, or -C (O)-,

이탈기는

Figure pat00002
이고, 상기 이탈기에서, Breakaway
Figure pat00002
And in the leaving group,

A, B, C, D 및 E는 서로 독립적으로 질소, 산소, 황 또는 탄소로서, A, B, C, D and E are independently of each other nitrogen, oxygen, sulfur or carbon,

(i) 각 탄소의 수소는 R2 또는 R3로 치환 또는 비치환될 수 있고, (i) hydrogen of each carbon may be substituted or unsubstituted with R 2 or R 3 ,

(ii) 각 질소의 경우, R2 또는 R3로 치환 또는 비치환될 수 있고, (ii) for each nitrogen, R 2 or May be substituted or unsubstituted with R 3 ,

R2와 R3는 서로 독립적으로 C1-C20의 탄화수소기로서, 주쇄의 탄소가 산소, 질소, 황 또는 이들의 조합으로 치환 또는 비치환될 수 있고, 주쇄의 수소가 할로겐으로 치환 또는 비치환될 수 있고, R 2 and R 3 are independently of each other a C 1 -C 20 hydrocarbon group in which carbon in the main chain may be substituted or unsubstituted with oxygen, nitrogen, sulfur, or a combination thereof, and hydrogen in the main chain may be substituted or unsubstituted. Can be exchanged,

Y는 할로겐 음이온, 설포네이트 음이온, BF4 -, PF6 -, SbF6 -, N(SO2CF3)2 - 및 N(CN)2 -로 이루어지는 군으로부터 선택되고,Y is a halogen anion, a sulfonate anion, BF 4 - is selected from the group consisting of, -, PF 6 -, SbF 6 -, N (SO 2 CF 3) 2 - and N (CN) 2

n은 0 또는 1이다.
n is 0 or 1;

바람직하게는, 화학식 1에서, Preferably, in Formula 1,

R1은 C1-C100의 탄화수소기이고, 상기 C1-C100의 탄화수소기는 주쇄의 탄소가 산소, 질소, 황, 인 또는 이들의 조합으로 치환 또는 비치환될 수 있고, 주쇄의 수소가 할로겐으로 치환 또는 비치환될 수 있고, R 1 is a C 1 -C 100 hydrocarbon group, the C 1 -C 100 hydrocarbon group may be unsubstituted or substituted with oxygen, nitrogen, sulfur, phosphorus or a combination of carbon of the main chain, hydrogen of the main chain May be substituted or unsubstituted with halogen,

X는 산소, 황, 또는 -C(O)-이고,X is oxygen, sulfur, or -C (O)-,

이탈기는Breakaway

(i)

Figure pat00003
또는
Figure pat00004
중에서 선택되는 4가 양이온; 및 (ii) Y인 음이온으로 구성되는 염이고, (i)
Figure pat00003
or
Figure pat00004
Tetravalent cation selected from; And (ii) a salt consisting of Y anion,

4가 양이온의 고리 내 하나의 질소가 R3으로 치환되며 각 탄소는 서로 독립적으로 R2로 치환 또는 비치환될 수 있고,One nitrogen in the ring of the tetravalent cation is substituted with R 3 and each carbon can be independently substituted or unsubstituted with R 2 ,

R2 및 R3는 C1-C20의 탄화수소기로서 주쇄의 탄소가 산소, 질소, 황 또는 이들의 조합으로 치환 또는 비치환될 수 있고, 주쇄의 수소가 할로겐으로 치환 또는 비치환될 수 있고,R 2 and R 3 are C 1 -C 20 hydrocarbon groups, carbon of the main chain may be substituted or unsubstituted with oxygen, nitrogen, sulfur or a combination thereof, hydrogen of the main chain may be substituted or unsubstituted with halogen, ,

Y는 서로 독립적으로 트리플루오로메탄설포네이트(CF3SO3 -), 파라톨루엔설포네이트, 메탄설포네이트 및 파라니트로벤젠설포네이트로 이루어지는 군으로부터 선택된다.
Y is independently selected from the group consisting of trifluoromethanesulfonate (CF 3 SO 3 − ), paratoluenesulfonate, methanesulfonate and paranitrobenzenesulfonate.

바람직하게는, 화학식 1에서, Preferably, in Formula 1,

R1은

Figure pat00005
,
Figure pat00006
,
Figure pat00007
,
Figure pat00008
,
Figure pat00009
,
Figure pat00010
,
Figure pat00011
,
Figure pat00012
,
Figure pat00013
,
Figure pat00014
,
Figure pat00015
및
Figure pat00016
로 이루어지는 군으로부터 선택되고,R 1 is
Figure pat00005
,
Figure pat00006
,
Figure pat00007
,
Figure pat00008
,
Figure pat00009
,
Figure pat00010
,
Figure pat00011
,
Figure pat00012
,
Figure pat00013
,
Figure pat00014
,
Figure pat00015
And
Figure pat00016
Is selected from the group consisting of

X는 산소, 황, 또는 -C(O)-이고,X is oxygen, sulfur, or -C (O)-,

이탈기는Breakaway

(i)

Figure pat00017
또는
Figure pat00018
중에서 선택되는 4가 양이온; 및 (ii) Y인 음이온으로 구성되는 염이고, (i)
Figure pat00017
or
Figure pat00018
Tetravalent cation selected from; And (ii) a salt consisting of Y anion,

4가 양이온의 고리 내 하나의 질소가 R3으로 치환되며 각 탄소는 서로 독립적으로 R2로 치환 또는 비치환될 수 있고, R2 및 R3는 서로 독립적으로 C1 -4 직쇄 또는 분지쇄 알킬기, 예컨대, 메틸, 에틸, n-프로필, iso-프로필, n-부틸, iso-부틸, t-부틸 등, 페닐,

Figure pat00019
,
Figure pat00020
, 및
Figure pat00021
로 이루어지는 군으로부터 선택되고, 4 is a nitrogen in a ring of the cation substituted with R 3 each carbon may be unsubstituted or substituted by R 2 independently from each other, R 2 and R 3 are independently C 1 -4 straight or branched chain alkyl groups each For example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl and the like, phenyl,
Figure pat00019
,
Figure pat00020
, And
Figure pat00021
Is selected from the group consisting of

Y는 서로 독립적으로 트리플루오로메탄설포네이트(CF3SO3 -), 파라톨루엔설포네이트, 메탄설포네이트 및 파라니트로벤젠설포네이트로 이루어지는 군으로부터 선택된다.
Y is independently selected from the group consisting of trifluoromethanesulfonate (CF 3 SO 3 − ), paratoluenesulfonate, methanesulfonate and paranitrobenzenesulfonate.

바람직하게는, 화학식 1로 표시되는 전구체는, Preferably, the precursor represented by the formula (1),

4-tert-부틸-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트; 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate;

4-메톡시카보닐-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트; 4-methoxycarbonyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate;

4-[3,5-디(트리플루오르메틸)페닐]-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트; 4- [3,5-di (trifluoromethyl) phenyl] -3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate;

4-(4-메톡시페닐)-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트; 4- (4-methoxyphenyl) -3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate;

3-메틸-4-페닐-1-(2-페닐에테인-2-온-1-일)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;3-methyl-4-phenyl-1- (2-phenylethane-2-one-1-yl) -1,2,3-triazolium trifluoromethanesulfonate;

4-tert-부틸-3-메틸-1-[(페닐싸이오)메틸]-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;4-tert-butyl-3-methyl-1-[(phenylthio) methyl] -1,2,3-triazolium trifluoromethanesulfonate;

3-메틸-1-((2-나프톡시)메틸)-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;3-methyl-1-((2-naphthoxy) methyl) -4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;

3-메틸-1-[3-(2-나프톡시)-n-프로필]옥시메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;3-methyl-1- [3- (2-naphthoxy) -n -propyl] oxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;

1-[1-메틸설포닐옥시-3-(2-나프틸)-2-옥시프로필]옥시메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;1- [1-methylsulfonyloxy-3- (2-naphthyl) -2-oxypropyl] oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;

3-메틸-(2-나프틸)메틸옥시메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트; 3-methyl- (2-naphthyl) methyloxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;

3-메틸-1-((2-나프톡시)메틸)-4-페닐이미다졸륨 트리플루오로메탄설포네이트;3-methyl-1-((2-naphthoxy) methyl) -4-phenylimidazolium trifluoromethanesulfonate;

(S)-1-(4-(2-BOC-아미노-2-(t-부톡시카보닐)에틸)페닐옥시메틸)-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;(S) -1- (4- (2-BOC-amino-2- (t-butoxycarbonyl) ethyl) phenyloxymethyl) -4-phenyl-1,2,3-triazolium trifluoromethanesulfo Nate;

1-(4-바이페닐)옥시메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;1- (4-biphenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;

1-(4-브로모-2-메틸페닐)옥시메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;1- (4-bromo-2-methylphenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;

1-(3,4-디메톡시페닐)옥시메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;1- (3,4-dimethoxyphenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;

3-메틸-1-(4-니트로페닐)옥시메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;3-methyl-1- (4-nitrophenyl) oxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;

1-(4-아세틸아미노페닐)옥시메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;1- (4-acetylaminophenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;

1-(3-O-에스트로닐)메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트; 및1- (3- O -estronyl) methyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate; And

3-아세토나프틸-1-메틸이미다졸륨으로 이루어지는 군으로부터 선택될 수 있다.
It may be selected from the group consisting of 3-acetonaphthyl-1-methylimidazolium.

또한, 본 발명은 화학식 1로 표시되는 4가 유기염 이탈기를 포함하는 전구체의 제조방법은 화학식 1의 하위 개념에 따라 여러 가지 제법으로 제공될 수 있고, 구체적으로는 하기 제법 1 내지 4로 제공될 수 있다.
In addition, the present invention is a method for producing a precursor containing a tetravalent organic salt leaving group represented by the formula (1) may be provided by various methods according to the sub-concept of the formula (1), specifically to be provided by the following methods 1 to 4 Can be.

제법 1:Method 1:

구체적으로 하기 반응식 1로 표시되는 바와 같이,Specifically, as represented by Scheme 1 below,

화학식 2으로 표시되는 화합물로부터 화학식 3의 아지도 화합물을 합성하는 단계 (단계 1);Synthesizing an azido compound of formula 3 from the compound represented by formula 2 (step 1);

단계 1에서 얻은 화학식 3의 아지도 화합물과 화학식 4로 표시되는 알킨 화합물간의 [3+2]고리화첨가반응을 통해 화학식 5의 화합물을 합성하는 단계 (단계 2);Synthesizing the compound of formula 5 through a [3 + 2] cycloaddition reaction between the azido compound of formula 3 obtained in step 1 and the alkyne compound represented by formula 4 (step 2);

단계 2에서 얻은 화학식 5의 화합물을 화학식 6으로 표시되는 알킬화 시약을 이용하여 화학식 1-a의 유기염을 합성하는 단계 (단계 3)를 포함하는 화학식 1-a의 화합물 제조방법을 제공한다.
It provides a compound of Formula 1-a comprising the step (step 3) of synthesizing the organic salt of Formula 1-a using the compound of Formula 5 obtained in step 2 using the alkylation reagent represented by Formula 6.

[반응식 1][Reaction Scheme 1]

Figure pat00022
Figure pat00022

상기 반응식 1에서, R1, R2, R3 및 Y는 상기 정의한 바와 같고, Z는 염소, 브롬, 요오드, R4SO3 - 이다. 여기서 R4는 C1-C20 탄화수소기로서 주쇄의 탄소가 산소, 질소, 황 또는 이들의 조합으로 치환 또는 비치환될 수 있고, 주쇄의 수소가 할로겐으로 치환 또는 비치환될 수 있다.
In Scheme 1, R 1 , R 2 , R 3 and Y are as defined above and Z is chlorine, bromine, iodine, R 4 SO 3 − . Wherein R 4 is a C 1 -C 20 hydrocarbon group where carbon in the main chain may be substituted or unsubstituted with oxygen, nitrogen, sulfur or a combination thereof, and hydrogen in the main chain may be substituted or unsubstituted with halogen.

본 발명의 4가 유기염 이탈기를 포함하는 전구체의 제조방법에 있어서, 상기 반응식 1의 단계 1은 화학식 2로 표시되는 화합물로부터 화학식 3의 아지도 화합물을 합성하는 단계이고, 여기서 사용되는 시약과 반응용매는 통상적으로 적용되는 유기화학반응을 이용할 수 있다. 상기 반응식 1의 단계 2는 단계 1에서 얻은 화학식 3의 아지도 화합물과 화학식 4로 표시되는 알킨 화합물간의 구리(I)-촉매하의 알킨/아자이드 [3+2]고리화첨가반응 (Copper(I)-catalyzed Alkyne/Azide [3+2]Cycloaddition, CuAAC)을 통해 온화한 조건에서 화학식 5의 화합물을 합성하는 단계이고, 여기서 화학식 2와 3의 화합물은 상업적으로 구매가 가능하거나 통상적인 방법으로 합성이 가능한 화합물이고, 사용되는 반응용매는 아지도 화합물과 알킨 화합물간의 구리(I)-촉매하의 알킨/아자이드 [3+2]고리화첨가반응에서 통상적으로 사용되는 용매를 사용할 수 있다. 상기 반응식 1의 단계 3은 단계 2에서 얻은 화학식 5의 1,2,3-트리아졸 화합물을 화학식 6으로 표시되는 알킬화 시약을 이용하여 화학식 1-a의 유기염을 합성하는 단계이고, 여기서 화학식 6으로 표시되는 화합물은 상업적으로 구매가 가능하거나 통상적인 방법으로 합성이 가능한 화합물이고, 사용되는 반응용매는 유기염 제조 반응에서 통상적으로 사용되는 용매를 사용할 수 있다.
In the method for preparing a precursor including a tetravalent organic salt leaving group of the present invention, Step 1 of Scheme 1 is a step of synthesizing the azido compound of Formula 3 from the compound represented by Formula 2, and reacts with the reagent used herein The solvent may use an organic chemical reaction that is commonly applied. Step 2 of Scheme 1 is a copper (I) -catalyzed alkyne / azide [3 + 2] cycloaddition reaction between the azido compound of Formula 3 obtained in Step 1 and the alkyne compound represented by Formula 4 (Copper (I ) -catalyzed Alkyne / Azide [3 + 2] Cycloaddition (CuAAC) to synthesize compounds of formula 5 under mild conditions, wherein the compounds of formulas 2 and 3 are commercially available or can be synthesized by conventional methods. It is a possible compound, and the reaction solvent used may be a solvent conventionally used in the alkyne / azide [3 + 2] cycloaddition reaction under the copper (I) -catalyst between the azido compound and the alkyne compound. Step 3 of Scheme 1 is a step of synthesizing an organic salt of Formula 1-a using an alkylating reagent represented by Formula 1 to 1,2,3-triazole compound of Formula 5 obtained in Step 2, wherein Formula 6 The compound represented by is a compound which is commercially available or can be synthesized by a conventional method, the reaction solvent used may be a solvent commonly used in organic salt production reaction.

제법 2: Recipe 2 :

구체적으로 하기 반응식 2로 표시되는 바와 같이,Specifically, as represented by Scheme 2 below,

화학식 7로 표시되는 화합물과 화학식 8로 표시되는 화합물간의 친핵성 치환반응을 통해 화학식 5의 화합물을 합성하는 단계 (단계 1); 및Synthesizing the compound of Formula 5 through a nucleophilic substitution reaction between the compound represented by Formula 7 and the compound represented by Formula 8 (step 1); And

단계 1에서 얻은 화학식 5의 화합물을 화학식 6으로 표시되는 알킬화 시약을 이용하여 화학식 1-b의 유기염을 합성하는 단계 (단계 2)를 포함하는 화학식 1-b의 화합물의 제조방법을 제공한다.
Provided is a method for preparing a compound of Formula 1-b, comprising the step (step 2) of synthesizing an organic salt of Formula 1-b using an alkylation reagent represented by Formula 6 with the compound of Formula 5 obtained in Step 1.

[반응식 2]Scheme 2

Figure pat00023
Figure pat00023

상기 반응식 2에서, R1, R2, R3, A, B, C, D, E, X, Y 및 n은 상기 정의한 바와 같고, Z는 상기 제법 1에서 정의한 바와 같다.
In Scheme 2, R 1 , R 2 , R 3 , A, B, C, D, E, X, Y and n are as defined above, Z is as defined in Preparation Method 1 above.

본 발명의 4가 유기염 이탈기를 포함하는 화학식 1의 전구체 화합물의 제조방법에 있어서, 상기 반응식 2의 단계 1은 화학식 7로 표시되는 화합물과 화학식 8로 표시되는 화합물간의 친핵성 치환반응을 통해 화학식 5의 화합물을 합성하는 단계이고, 여기서 화학식 7과 8로 표시되는 화합물은 상업적으로 구매가 가능하거나 통상적인 방법으로 합성이 가능한 화합물이고, 사용되는 반응용매는 친핵성 치환반응에서 통상적으로 사용되는 용매를 사용할 수 있다. 상기 반응식 2의 단계 2는 단계 1에서 얻은 화학식 5의 화합물을 화학식 6으로 표시되는 알킬화 시약을 이용하여 화학식 1-b의 유기염을 합성하는 단계이고, 여기서 화학식 6으로 표시되는 화합물은 상업적으로 구매가 가능하거나 통상적인 방법으로 합성이 가능한 화합물이고, 사용되는 반응용매는 유기염 제조 반응에서 통상적으로 사용되는 용매를 사용할 수 있다.
In the method for preparing a precursor compound of Formula 1 comprising a tetravalent organic salt leaving group of the present invention, Step 1 of Scheme 2 is carried out through a nucleophilic substitution reaction between the compound represented by Formula 7 and the compound represented by Formula 8 Synthesis of the compound of Formula 5, wherein the compounds represented by Formulas 7 and 8 are commercially available or can be synthesized by conventional methods, the reaction solvent used is a solvent commonly used in nucleophilic substitution reaction Can be used. Step 2 of Scheme 2 is a step of synthesizing an organic salt of Formula 1-b using an alkylation reagent represented by Formula 6 to the compound of Formula 5 obtained in Step 1, wherein the compound represented by Formula 6 is commercially purchased Is a compound which can be synthesized by a conventional method or available, and the reaction solvent used may be a solvent commonly used in organic salt preparation reaction.

제법 3:Recipe 3:

구체적으로 하기 반응식 3으로 표시되는 바와 같이,Specifically, as represented by Scheme 3 below,

화학식 7로 표시되는 화합물과 화학식 9로 표시되는 화합물간의 친핵성 치환반응을 통해 화학식 1-b의 화합물을 합성하는 단계 (단계 1)를 포함하는 화학식 1-b의 화합물의 제조방법을 제공한다.
It provides a method for preparing a compound of Formula 1-b comprising the step (step 1) of synthesizing the compound of Formula 1-b through a nucleophilic substitution reaction between the compound represented by Formula 7 and the compound represented by Formula 9.

[반응식 3]Scheme 3

Figure pat00024
Figure pat00024

상기 반응식 3에서, R1, R2, R3, A, B, C, D, E, X, Y 및 n은 상기 정의한 바와 같고, Z는 상기 제법 1에서 정의한 바와 같다.
In Scheme 3, R 1 , R 2 , R 3 , A, B, C, D, E, X, Y and n are as defined above, and Z is as defined in Preparation Method 1 above.

본 발명의 4가 유기염 이탈기를 포함하는 화학식 1의 전구체 화합물의 제조방법에 있어서, 상기 반응식 3의 단계 1은 화학식 7로 표시되는 화합물과 화학식 9로 표시되는 화합물간의 친핵성 치환반응을 통해 화학식 1의 화합물을 합성하는 단계이고, 여기서 화학식 7로 표시되는 화합물은 상업적으로 구매가 가능하거나 통상적인 방법으로 합성이 가능한 화합물이고, 화학식 9로 표시되는 화합물은 상기 제법 2의 화학식 8로 표시되는 화합물을 화학식 6으로 표시되는 알킬화 시약과 반응시켜 합성할 수 있다. 단계 1에서 사용되는 반응용매는 유기염 제조 반응에서 통상적으로 사용되는 용매를 사용할 수 있다.
In the method for preparing a precursor compound of Formula 1 comprising a tetravalent organic salt leaving group of the present invention, Step 1 of Scheme 3 is carried out through a nucleophilic substitution reaction between the compound represented by Formula 7 and the compound represented by Formula 9 Comprising the step of synthesizing the compound of Formula 1, wherein the compound represented by the formula (7) is commercially available or can be synthesized by a conventional method, the compound represented by the formula (9) is a compound represented by the formula (8) Can be synthesized by reacting with an alkylation reagent represented by the formula (6). The reaction solvent used in step 1 may be a solvent commonly used in organic salt preparation reaction.

제법 4: Recipe 4 :

구체적으로 하기 반응식 4로 표시되는 바와 같이,Specifically, as represented by Scheme 4 below,

화학식 10으로 표시되는 화합물과 화학식 11로 표시되는 화합물간의 친핵성 치환반응을 통해 화학식 1-b의 화합물을 합성하는 단계 (단계 1)를 포함하는 화학식 1-b의 화합물 제조방법을 제공한다.
It provides a method for preparing a compound of Formula 1-b comprising the step (step 1) of synthesizing the compound of Formula 1-b through a nucleophilic substitution reaction between the compound represented by Formula 10 and the compound represented by Formula 11.

[반응식 4]Scheme 4

Figure pat00025
Figure pat00025

상기 반응식 4에서, R1, R2, R3, A, B, C, D, E, X, Y 및 n은 상기 정의한 바와 같다.
In Scheme 4, R 1 , R 2 , R 3 , A, B, C, D, E, X, Y and n are as defined above.

본 발명의 4가 유기염 이탈기를 포함하는 화학식 1의 전구체 화합물의 제조방법에 있어서, 상기 반응식 4의 단계 1은 화학식 10으로 표시되는 화합물과 화학식 11로 표시되는 화합물간의 친핵성 치환반응을 통해 화학식 1-b의 유기염을 합성하는 단계이고, 여기서 화학식 10과 11로 표시되는 화합물은 상업적으로 구매가 가능하거나 통상적인 방법으로 합성이 가능한 화합물이고, 사용되는 반응용매는 유기염 제조 반응에서 통상적으로 사용되는 용매를 사용할 수 있다.
In the method for preparing a precursor compound of Formula 1 comprising a tetravalent organic salt leaving group of the present invention, Step 1 of Scheme 4 is carried out through a nucleophilic substitution reaction between the compound represented by Formula 10 and the compound represented by Formula 11 In the step of synthesizing the organic salt of 1-b, wherein the compounds represented by formulas (10) and (11) are commercially available or can be synthesized in a conventional manner, the reaction solvent used is usually in the organic salt production reaction The solvent used can be used.

또한, 본 발명은 하기 반응식 5와 같이 상기 화학식 1로 표시되는 4가 유기염 이탈기를 포함하는 화합물과 화학식 MF로 표시되는 플루오르염을 반응시키는 것을 특징으로 하는 18F-표지 화합물의 제조방법(친핵성 플루오르화 반응)과 화학식 12로 표시되는 18F-표지 화합물을 제공한다.
In addition, the present invention is a method for producing a 18 F-labeled compound characterized in that the compound containing a tetravalent organic salt leaving group represented by the formula (1) and the fluorine salt represented by the formula MF as shown in Scheme 5 Nuclear fluorination reaction) and an 18 F-labeled compound represented by Formula 12.

[반응식 5]Scheme 5

Figure pat00026

Figure pat00026

상기 반응식 5에서, R1, X 및 이탈기는 상기 화학식 1에서 정의한 바와 같고, M은 Li, Na, K, Rb 및 Cs로 이루어지는 군으로부터 선택되는 금속 양이온; 4가 암모늄 양이온이고; 또는 4가 포스포늄 양이온이고, F는 18F이다.
In Scheme 5, R 1 , X and leaving groups are as defined in Formula 1, M is a metal cation selected from the group consisting of Li, Na, K, Rb and Cs; Tetravalent ammonium cation; Or a tetravalent phosphonium cation, F is 18 F.

본 발명에 따른 화학식 1의 4가 유기염 이탈기를 포함하는 화합물은 도 1에 나타낸 바와 같이 다양한 금속염 또는 유기염 형태의 플루오라이드 음이온과의 친핵성 플루오르화 반응에서 전구체로 사용될 수 있다. 도 1에서 중간체 화합물은 4가 유기염 전구체가 금속염 또는 유기염 형태의 플루오라이드 음이온과 상호작용하여 음이온 교환이 일어나 생성되며, 이는 분자 내 친핵성 플루오르화 반응을 통해 빠르게 생성물인 화학식 12의 F-표지 화합물로 전환된다. 여기서 친핵성 플루오르화 반응(F가 18F임)은 통상적으로 사용되는 반응조건에서 수행될 수 있다.
Compounds containing tetravalent organic salt leaving groups of Formula 1 according to the present invention can be used as precursors in nucleophilic fluorination reactions with fluoride anions in the form of various metal salts or organic salts, as shown in FIG. In Figure 1, the intermediate compound is formed by the reaction of a tetravalent organic salt precursor with a fluoride anion in the form of a metal salt or an organic salt, resulting in anion exchange, which is a product of the formula F- Converted to a labeled compound. The nucleophilic fluorination reaction (F is 18 F) can be carried out under reaction conditions that are commonly used.

나아가, 본 발명은 상기 반응식 5의 생성물인 18F-표지 화합물을 제공한다. Furthermore, the present invention provides 18 F-labeled compound which is the product of Scheme 5.

본 발명의 전구체는 18F-플루오로메틸기를 간단한 한 단계 정으로 방사성 의약품에 도입할 수 있다. 또한, 4가 유기염을 활성화된 이탈기를 전구체에 도입하여 한 단계 공정으로 18F-플루오로메틸기를 제조함으로써 기존의 다단계의 복잡한 합성을 단순화시키는 효과가 있다. 또한 전구체의 이탈기에 포함된 4가 유기염이 상전이 촉매 역할을 하기 때문에 일반적인 친핵성 [18F]플루오르화 반응에 요구되는 추가적인 과량의 상전이 촉매가 필요 없어 생산 비용을 절감할 수 있고, 반응 후 화합물 분리가 용이한 장점이 있다. 이러한 전구체 내의 4가 유기염에 의한 상전이 촉매 작용은 분자내 친핵성 플루오르화 반응을 유도하여 일반적인 분자간 친핵성 플루오르화 반응에 비해 반응속도가 훨씬 빠른 장점이 있다. 이러한 특징은 자동화 합성 시스템에 의한 [18F]방사성의약품 대량생산에 적합하다.Precursors of the present invention can introduce 18 F-fluoromethyl groups into radiopharmaceuticals in a simple one step tablet. In addition, by introducing a tetravalent organic salt to the precursor leaving the activated leaving group to produce 18 F-fluoromethyl group in one step, there is an effect of simplifying the existing multi-step complex synthesis. In addition, since the tetravalent organic salt contained in the leaving group of the precursor acts as a phase transfer catalyst, an additional excess phase transfer catalyst required for a general nucleophilic [ 18 F] fluorination reaction is not required, thereby reducing production costs. There is an advantage of easy separation. The phase transfer catalysis by tetravalent organic salts in such precursors induces intramolecular nucleophilic fluorination reaction and has a much faster reaction rate than general intermolecular nucleophilic fluorination reaction. This feature is well suited for mass production of [ 18 F] radiopharmaceuticals by automated synthesis systems.

도 1은 본 발명의 4가 유기염 이탈기를 갖는 전구체를 이용하여 단일 단계로 18F-표지화합물을 제조하는 반응식이다.1 is a scheme for preparing an 18 F-labeled compound in a single step using a precursor having a tetravalent organic salt leaving group of the present invention.

이하, 본 발명을 제조예와 실시예에 의해 더욱 상세하게 설명한다. 단, 하기의 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 이에 한정되는 것은 아니다.
Hereinafter, the present invention will be described in more detail with reference to Production Examples and Examples. However, the following examples are merely to illustrate the present invention, but the content of the present invention is not limited thereto.

제조예 1: 2-(아지도메톡시)나프탈렌(3a)의 제조 Preparation Example 1 Preparation of 2- (azidomethoxy) naphthalene ( 3a )

Figure pat00027
Figure pat00027

단계 1:Step 1:

2-나프톨 (7a, 1.15 g, 8.0 mmol)을 헥사메틸포스포라마이드 (hexamethylphosphoramide, HMPA, 40 mL)에 녹인 후, 소듐하이드라이드 (NaH, 352 mg, 8.8 mmol)을 첨가한 뒤 30분 동안 상온에서 교반하고 클로로메틸-메틸 설파이드 (0.737 mL, 8.8. mmol)을 첨가한 다음 실온에서 16시간 동안 교반시켰다. 물을 가하여 반응을 종결시킨 다음, 에틸 아세테이트로 유기화합물을 추출하였다. 추출된 에틸 아세테이트 용액을 무수 황산 나트륨으로 처리한 뒤 컬럼 크로마토그래피 (20% 에틸아세테이트/n-헥산)를 수행하여 설파이드 중간체(13, 410 mg, 25%)를 얻었다. Dissolve 2-naphthol ( 7a , 1.15 g, 8.0 mmol) in hexamethylphosphoramide (hexamethylphosphoramide, HMPA, 40 mL), add sodium hydride (NaH, 352 mg, 8.8 mmol), and wait for 30 minutes at room temperature. Stir at and add chloromethyl-methyl sulfide (0.737 mL, 8.8 mmol) and then stir at rt for 16 h. Water was added to terminate the reaction, and then the organic compound was extracted with ethyl acetate. The extracted ethyl acetate solution was treated with anhydrous sodium sulfate and then subjected to column chromatography (20% ethyl acetate / n -hexane) to obtain a sulfide intermediate ( 13 , 410 mg, 25%).

1H NMR (500 MHz, CDCl3) δ 2.26 (s, 3H), 5.22 (s, 2H), 7.20-7.16 (m, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.73 (m, 3H).
 1 H NMR (500 MHz, CDCl 3 ) δ 2.26 (s, 3H), 5.22 (s, 2H), 7.20-7.16 (m, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.73 (m, 3H).

단계 2:Step 2:

단계 1에서 얻어진 설파이드 화합물 (13, 410 mg, 2.0 mmol)을 디클로로메탄에 녹인 뒤 설퍼릴클로라이드 (1.0 M SO2Cl2/CH2Cl2 용액, 2.4 mL, 2.4 mmol)를 천천히 가해준 뒤 30분 동안 교반시킨 다음 용매와 반응 잔여물을 감압하여 제거하였다. 남은 유기물을 디메틸포름아미드(DMF) 용매에 다시 녹인 후 소듐 아자이드(NaN3, 650 mg, 10 mmol)을 넣고 12시간 동안 교반시켰다. 물을 가하여 반응을 종결시키고, 에틸 아세테이트로 유기화합물을 추출하였다. 추출된 에틸 아세테이트 용액을 무수 황산 나트륨으로 처리한 뒤 컬럼 크로마토그래피 (10% 에틸아세테이트/n-헥산)를 수행하여 목적화합물인 2-(아지도메톡시)나프탈렌 (3a, 279 mg, 70%)를 얻었다.The sulfide compound ( 13 , 410 mg, 2.0 mmol) obtained in step 1 was dissolved in dichloromethane and then sulfuryl chloride (1.0 M SO 2 Cl 2 / CH 2 Cl 2). 2.4 mL, 2.4 mmol) was slowly added to the solution, stirred for 30 minutes, and then the solvent and the reaction residue were removed under reduced pressure. The remaining organics were dissolved in dimethylformamide (DMF) solvent and then sodium azide (NaN 3 , 650 mg, 10 mmol) was added thereto and stirred for 12 hours. Water was added to terminate the reaction, and the organic compound was extracted with ethyl acetate. The extracted ethyl acetate solution was treated with anhydrous sodium sulfate, and then subjected to column chromatography (10% ethyl acetate / n -hexane) to give a target compound, 2- (azidomethoxy) naphthalene ( 3a , 279 mg, 70%). Got.

1H NMR (500 MHz, CDCl3) δ 5.27 (s, 2H), 7.21 (dd, J = 9.0 Hz, J = 2.5 Hz, 2H), 7.30 (d, J = 2.5 Hz, 1H), 7.40-7.37 (m, 1H), 7.48-7.45 (m, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 9.0 Hz, 2H).
 1 H NMR (500 MHz, CDCl 3 ) δ 5.27 (s, 2H), 7.21 (dd, J = 9.0 Hz, J = 2.5 Hz, 2H), 7.30 (d, J = 2.5 Hz, 1H), 7.40-7.37 (m, 1H), 7.48-7.45 (m, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 9.0 Hz, 2H).

제조예 2: 2-아지도아세토페논 (3b)의 제조 Preparation Example 2 Preparation of 2 -azidoacetophenone ( 3b )

Figure pat00028

Figure pat00028

2-브로모아세토페논 (10a, 1.97 g, 10.0 mmol)을 아세토니트릴 (40 mL)에 녹인 후 소듐 아자이드 (NaN3, 650 mg, 11.0 mmol)을 넣고 12시간 동안 교반시켰다. 물을 가하여 반응을 종결시키고, 디클로로메탄으로 유기화합물을 추출하였다. 추출된 디클로로메탄 용액을 무수 황산 나트륨으로 처리한 뒤 컬럼 크로마토그래피 (10% 에틸아세테이트/n-헥산)를 수행하여 목적화합물인 2-아지도아세토페논 (3b, 2.11 g, 100%)를 얻었다.2-bromoacetophenone ( 10a , 1.97 g, 10.0 mmol) was dissolved in acetonitrile (40 mL), and sodium azide (NaN 3 , 650 mg, 11.0 mmol) was added thereto, followed by stirring for 12 hours. Water was added to terminate the reaction, and the organic compound was extracted with dichloromethane. The extracted dichloromethane solution was treated with anhydrous sodium sulfate and subjected to column chromatography (10% ethyl acetate / n -hexane) to obtain 2- azidoacetophenone ( 3b , 2.11 g, 100%) as a target compound.

1H NMR (500 MHz, CDCl3) δ 4.56 (s, 2H), 7.49 (t, J = 6.2 Hz, 2H), 7.62 (t, J = 6.0 Hz, 1H), 7.90 (d, J = 7.6 Hz, 2H).
 1 H NMR (500 MHz, CDCl 3 ) δ 4.56 (s, 2H), 7.49 (t, J = 6.2 Hz, 2H), 7.62 (t, J = 6.0 Hz, 1H), 7.90 (d, J = 7.6 Hz , 2H).

제조예 3: 아지도메틸 페닐 설파이드 (3c)의 제조 Preparation Example 3 Preparation of Azidomethyl Phenyl Sulfide ( 3c )

Figure pat00029

Figure pat00029

브로모메틸 페닐 설파이드 (10b, 1.58 g, 10.0 mmol)을 디메틸포름아마이드 (40 mL)에 녹인 후 소듐 아자이드 (NaN3, 1.3 g, 20.0 mmol)을 넣고 12시간 동안 교반시켰다. 물을 가하여 반응을 종결시키고, 에틸아세테이트로 유기화합물을 추출하였다. 추출된 에틸아세테이트 용액을 무수 황산 나트륨으로 처리한 뒤 컬럼 크로마토그래피 (1% 에틸아세테이트/n-헥산)를 수행하여 목적화합물인 아지도메틸 페닐 설파이드 (3c, 1.62g, 98%)를 얻었다.Bromomethyl phenyl sulfide ( 10b , 1.58 g, 10.0 mmol) was dissolved in dimethylformamide (40 mL), and sodium azide (NaN 3 , 1.3 g, 20.0 mmol) was added thereto, followed by stirring for 12 hours. Water was added to terminate the reaction, and the organic compound was extracted with ethyl acetate. The extracted ethyl acetate solution was treated with anhydrous sodium sulfate and subjected to column chromatography (1% ethyl acetate / n -hexane) to obtain azidomethyl phenyl sulfide ( 3c , 1.62g, 98%) as a target compound.

1H NMR (500 MHz, CDCl3) δ 4.54 (s, 2H), 7.37-7.25 (m, 3H), 7.45 (d, J = 8.0 Hz, 2H).
 1 H NMR (500 MHz, CDCl 3 ) δ 4.54 (s, 2H), 7.37-7.25 (m, 3H), 7.45 (d, J = 8.0 Hz, 2H).

실시예Example 1: 4- 1: 4- terttert -부틸-3--Butyl-3- 메틸methyl -1-((2--1-((2- 나프톡시Naphthoxy )) 메틸methyl )-1,2,3-) -1,2,3- 트리아졸륨Triazolium 트리플루오로메탄설포네이트Trifluoromethanesulfonate (1a)의 제조 Preparation of (1a)

Figure pat00030

Figure pat00030

단계 1:Step 1:

상기 제조예 1의 단계 2에서 얻은 화합물 2-(아지도메톡시)나프탈렌 (3a, 390 mg, 2.0 mmol)과 3,3-다이메틸-1-부틴 (4a, 246 mg, 3.0 mmol)을 아세토니트릴 (8 mL)에 녹인 후 요오드화 구리 (77 mg, 0.4 mmol)와 트리에틸아민 (0.056 mL, 0.4 mmol)을 가하고 상온에서 2시간 동안 교반한 다음 감압하여 농축한 후 컬럼 크로마토그래피 (1% 메탄올/디클로로메탄)를 수행하여 목적화합물 4-tert-부틸-1-((2-나프톡시)메틸) -1,2,3-트리아졸 (5a, 477 mg, 85%)을 얻었다.Compound 2- (azidomethoxy) naphthalene ( 3a , 390 mg, 2.0 mmol) and 3,3-dimethyl-1-butyne ( 4a , 246 mg, 3.0 mmol) obtained in step 2 of Preparation Example 1 were treated with aceto. After dissolving in nitrile (8 mL), copper iodide (77 mg, 0.4 mmol) and triethylamine (0.056 mL, 0.4 mmol) were added, stirred at room temperature for 2 hours, concentrated under reduced pressure, and then column chromatography (1% methanol). / Dichloromethane) was carried out to give the title compound 4-tert-butyl-1-((2-naphthoxy) methyl) -1,2,3-triazole ( 5a , 477 mg, 85%).

1H NMR (500 MHz, CDCl3) δ 1.35 (s, 9H), 6.30 (s, 2H), 7.19 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H), 7.40-7.38 (m, 1H), 7.46-7.44 (m, 2H), 7.51 (s, 1H), 7.76 (t, J = 8.0 Hz, 3H); 1 H NMR (500 MHz, CDCl 3 ) δ 1.35 (s, 9H), 6.30 (s, 2H), 7.19 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H), 7.40-7.38 (m, 1H) , 7.46-7.44 (m, 2H), 7.51 (s, 1H), 7.76 (t, J = 8.0 Hz, 3H);

13C NMR (125 MHz, CDCl3) δ 158.8, 154.3, 134.3, 130.14, 130.05, 127.8, 127.5, 126.9, 124.9, 118.7, 118.6, 109.9, 76.2, 31.0, 30.4.
13 C NMR (125 MHz, CDCl 3 ) δ 158.8, 154.3, 134.3, 130.14, 130.05, 127.8, 127.5, 126.9, 124.9, 118.7, 118.6, 109.9, 76.2, 31.0, 30.4.

단계 2:Step 2:

단계 1에서 얻은 4-tert-부틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸 (5a, 477 mg, 1.69 mmol)을 아세토니트릴 (7.0 mL)에 녹이고 메틸 트리플루오로메탄설포네이트 (6a, MeOTf, 0.278 mL, 2.5 mmol)를 가한 뒤, 0℃에서 30분간 교반시킨 뒤, 용매를 감압하에 제거하여 목적화합물 4-tert-부틸-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1a, 580 mg, 77%)를 얻었다.4-tert-butyl-1-((2-naphthoxy) methyl) -1,2,3-triazole ( 5a , 477 mg, 1.69 mmol) obtained in step 1 was dissolved in acetonitrile (7.0 mL) and methyl tri Fluoromethanesulfonate ( 6a , MeOTf, 0.278 mL, 2.5 mmol) was added, stirred at 0 ° C. for 30 minutes, and the solvent was removed under reduced pressure to afford the desired compound 4-tert-butyl-3-methyl-1- ( (2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a , 580 mg, 77%) was obtained.

1H NMR (500 MHz, CDCl3) δ 1.46 (s, 9H), 4.35 (s, 3H), 6.60 (s, 2H), 7.22 (dd, J = 9.0, 2.5 Hz, 1H), 7.42-7.39 (m, 1H), 7.49-7.45 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 8.5 Hz, 2H), 8.60 (s, 1H); 1 H NMR (500 MHz, CDCl 3 ) δ 1.46 (s, 9H), 4.35 (s, 3H), 6.60 (s, 2H), 7.22 (dd, J = 9.0, 2.5 Hz, 1H), 7.42-7.39 ( m, 1H), 7.49-7.45 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 8.5 Hz, 2H), 8.60 (s, 1H);

13C NMR (125 MHz, CDCl3) d 153.1, 152.3, 134.1, 130.6, 130.4, 128.4, 127.8, 127.6, 127.2, 125.4, 120.8 (q, J = 319 Hz), 118.0, 110.2, 79.2, 40.9, 31.6, 28.4.
 13 C NMR (125 MHz, CDCl 3 ) d 153.1, 152.3, 134.1, 130.6, 130.4, 128.4, 127.8, 127.6, 127.2, 125.4, 120.8 (q, J = 319 Hz), 118.0, 110.2, 79.2, 40.9, 31.6 , 28.4.

실시예Example 2: 4- 2: 4- 메톡시카보닐Methoxycarbonyl -3--3- 메틸methyl -1-((2--1-((2- 나프톡시Naphthoxy )) 메틸methyl )-1,2,3-) -1,2,3- 트리아졸륨Triazolium 트리플루오로메탄설포네이트 (1b)의 제조 Preparation of Trifluoromethanesulfonate (1b)

Figure pat00031
Figure pat00031

단계 1:Step 1:

실시예 1의 단계 1에서 사용한 3,3-다이메틸-1-부틴 (4a) 대신에 메틸프로피오레이트 (4b, 252 mg, 3.0 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 4-메톡시카보닐-1-((2-나프톡시)메틸)-1,2,3-트리아졸 (5b, 346 mg, 61%)을 얻었다. Proceed in the same manner except using methylpropiorate ( 4b , 252 mg, 3.0 mmol) instead of 3,3-dimethyl-1-butyne ( 4a ) used in step 1 of Example 1 Methoxycarbonyl-1-((2-naphthoxy) methyl) -1,2,3-triazole ( 5b , 346 mg, 61%) was obtained.

1H NMR (500 MHz, CDCl3) δ 3.94 (s, 3H), 6.41 (s, 2H), 7.17 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H), 7.36 (d, J = 2.5 Hz, 1 H), 7.42-7.39 (m, 1H), 7.49-7.45 (m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.79-7.77 (m, 2H), 8.34 (s, 1H); 1 H NMR (500 MHz, CDCl 3 ) δ 3.94 (s, 3H), 6.41 (s, 2H), 7.17 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H), 7.36 (d, J = 2.5 Hz , 1 H), 7.42-7.39 (m, 1H), 7.49-7.45 (m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.79-7.77 (m, 2H), 8.34 (s, 1H) ;

13C NMR (125 MHz, CDCl3) δ 161.0, 153.6, 141.0, 134.1, 130.5, 130.3, 127.9, 127.6, 127.4, 127.1, 125.2, 118.3, 110.2, 76.7, 52.5.
13 C NMR (125 MHz, CDCl 3 ) δ 161.0, 153.6, 141.0, 134.1, 130.5, 130.3, 127.9, 127.6, 127.4, 127.1, 125.2, 118.3, 110.2, 76.7, 52.5.

단계 2:Step 2:

실시예 1의 단계 2에서 사용한 4-tert-부틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸 (5a) 대신에 4-메톡시카보닐-1-((2-나프톡시)메틸)-1,2,3-트리아졸 (5b, 346 mg, 1.22 mmol)을 사용하는 것을 제외하고는 동일한 방법으로 진행하여 4-메톡시카보닐-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1b, 513 mg, 94%)을 얻었다. Instead of 4-tert-butyl-1-((2-naphthoxy) methyl) -1,2,3-triazole ( 5a ) used in step 2 of Example 1, 4-methoxycarbonyl-1-(( Proceed in the same manner except using 2-naphthoxy) methyl) -1,2,3-triazole ( 5b , 346 mg, 1.22 mmol) 4-methoxycarbonyl-3-methyl-1- ((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1b , 513 mg, 94%) was obtained.

1H NMR (500 MHz, CDCl3) δ 3.96 (s, 3H), 4.35 (s, 3H), 6.70 (s, 2H), 7.22 (dd, J = 9.0 Hz, 2.5 Hz, 1H), 7.41 (td, J = 7.8, 1.2 Hz, 1H), 7.47 (td, J = 7.3, 1.3 Hz, 1H), 7.51 (d, J = 2.5 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 9.0 Hz, 2H), 9.26 (s, 1H); 1 H NMR (500 MHz, CDCl 3 ) δ 3.96 (s, 3H), 4.35 (s, 3H), 6.70 (s, 2H), 7.22 (dd, J = 9.0 Hz, 2.5 Hz, 1H), 7.41 (td , J = 7.8, 1.2 Hz, 1H), 7.47 (td, J = 7.3, 1.3 Hz, 1H), 7.51 (d, J = 2.5 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 9.0 Hz, 2H), 9.26 (s, 1H);

13C NMR (125 MHz, CDCl3) δ 155.4, 152.9, 134.1, 133.8, 133.3, 130.8, 130.7, 127.8, 127.7, 127.3, 125.6, 120.7 (t, J = 318 Hz), 118.0, 110.9, 80.3, 54.3, 41.5.
 13 C NMR (125 MHz, CDCl 3 ) δ 155.4, 152.9, 134.1, 133.8, 133.3, 130.8, 130.7, 127.8, 127.7, 127.3, 125.6, 120.7 (t, J = 318 Hz), 118.0, 110.9, 80.3, 54.3 , 41.5.

실시예Example 3: 4-[3,5-디( 3: 4- [3,5-di ( 트리플루오르메틸Trifluoromethyl )) 페닐Phenyl ]-3-] -3- 메틸methyl -1-((2--1-((2- 나프톡시Naphthoxy )) 메틸methyl )-1,2,3-) -1,2,3- 트리아졸륨Triazolium 트리플루오로메탄설포네이트Trifluoromethanesulfonate (1c)의 제조 Preparation of (1c)

Figure pat00032
Figure pat00032

단계 1:Step 1:

실시예 1의 단계 1에서 사용한 3,3-다이메틸-1-부틴 (4a) 대신에 1-에틴일-3,5-비스(트리플루오르메틸)벤젠 (4c, 530㎕, 3.0 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 4-[3,5-디(트리플루오르메틸)페닐]-1-((2-나프톡시)메틸)-1,2,3-트리아졸 (5c, 700 mg, 80%)을 얻었다. 1-ethynyl-3,5-bis (trifluoromethyl) benzene ( 4c , 530 μl, 3.0 mmol) was used in place of the 3,3-dimethyl-1-butyne ( 4a ) used in Step 1 of Example 1 In the same manner, except that 4- [3,5-di (trifluoromethyl) phenyl] -1-((2-naphthoxy) methyl) -1,2,3-triazole ( 5c , 700 mg, 80%).

1H NMR (500 MHz, CDCl3) δ 6.45 (s, 2H), 7.20 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H), 7.41-7.38 (m, 1H), 7.43 (d, J = 2.5 Hz, 1 H), 7.49-7.45 (m, 1H), 7.80-7.75 (m, 3H), 7.83 (s, 1H), 8.19 (s, 1H); 1 H NMR (500 MHz, CDCl 3 ) δ 6.45 (s, 2H), 7.20 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H), 7.41-7.38 (m, 1H), 7.43 (d, J = 2.5 Hz, 1 H), 7.49-7.45 (m, 1 H), 7.80-7.75 (m, 3 H), 7.83 (s, 1 H), 8.19 (s, 1 H);

13C NMR (125 MHz, CDCl3) δ 134.2, 132.6, 132.4, 132.3, 130.4, 130.2, 127.9, 127.4, 127.1, 125.9, 125.2, 124.4, 122.2, 122.1, 120.7, 118.4, 109.9, 76.5.
13 C NMR (125 MHz, CDCl 3 ) δ 134.2, 132.6, 132.4, 132.3, 130.4, 130.2, 127.9, 127.4, 127.1, 125.9, 125.2, 124.4, 122.2, 122.1, 120.7, 118.4, 109.9, 76.5.

단계 2:Step 2:

실시예 1의 단계 2에서 사용한 4-tert-부틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸 (5a) 대신에 4-[3,5-디(트리플루오르메틸)페닐]-1-((2-나프톡시)메틸)-1,2,3-트리아졸 (5c, 700 mg, 1.60 mmol)을 사용하는 것을 제외하고는 동일한 방법으로 진행하여 4-[3,5-디(트리플루오르메틸)페닐]-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1c, 860 mg, 89%)을 얻었다. 4- [3,5-di (trifluor) instead of 4-tert-butyl-1-((2-naphthoxy) methyl) -1,2,3-triazole ( 5a ) used in step 2 of Example 1 Proceed in the same manner, except that methyl) phenyl] -1-((2-naphthoxy) methyl) -1,2,3-triazole ( 5c , 700 mg, 1.60 mmol) is used. , 5-di (trifluoromethyl) phenyl] -3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1c , 860 mg, 89%) was obtained.

1H NMR (500 MHz, MeOD) δ 4.36 (s, 3H), 6.81 (s, 2H), 7.35 (dd J = 9.0 Hz, 2.5 Hz, 1H), 7.43 (td, J = 7.0 Hz, 1.0 Hz, 1H), 7.50 (td, J = 7.0 Hz, 1.0 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.85 (t, J = 7.0 Hz, 2H), 7.73 (d, J = 9.0 Hz, 1H), 8.33 (s, 1H), 8.36 (s, 2H); 1 H NMR (500 MHz, MeOD) δ 4.36 (s, 3H), 6.81 (s, 2H), 7.35 (dd J = 9.0 Hz, 2.5 Hz, 1H), 7.43 (td, J = 7.0 Hz, 1.0 Hz, 1H), 7.50 (td, J = 7.0 Hz, 1.0 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.85 (t, J = 7.0 Hz, 2H), 7.73 (d, J = 9.0 Hz , 1H), 8.33 (s, 1 H), 8.36 (s, 2 H);

13C NMR (125 MHz, MeOD) δ 153.2, 141.2, 134.2, 132.7 (q, J = 34 Hz), 130.6, 130.4 (d, J = 3 Hz), 130.2, 127.4, 127.1, 126.7, 125.4 (q, J = 4 Hz), 125.0, 124.9, 123.9, 121.8, 120.4 (q, J = 317 Hz), 117.8, 110.7, 79.8, 38.4.
 13 C NMR (125 MHz, MeOD) δ 153.2, 141.2, 134.2, 132.7 (q, J = 34 Hz), 130.6, 130.4 (d, J = 3 Hz), 130.2, 127.4, 127.1, 126.7, 125.4 (q, J = 4 Hz), 125.0, 124.9, 123.9, 121.8, 120.4 (q, J = 317 Hz), 117.8, 110.7, 79.8, 38.4.

실시예Example 4: 4-(4- 4: 4- (4- 메톡시페닐Methoxyphenyl )-3-) -3- 메틸methyl -1-((2--1-((2- 나프톡시Naphthoxy )) 메틸methyl )-1,2,3-) -1,2,3- 트리아졸륨Triazolium 트리플루오로메탄설포네이트 (1d)의 제조 Preparation of Trifluoromethanesulfonate (1d)

Figure pat00033

Figure pat00033

단계 1:Step 1:

실시예 1의 단계 1에서 사용한 3,3-다이메틸-1-부틴 (4a) 대신에 4-에틴일아니솔 (4d, 252 mg, 3.0 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 4-(4-메톡시페닐)-1-((2-나프톡시)메틸)-1,2,3-트리아졸 (5d, 391 mg, 59%)을 얻었다. Proceed in the same manner except using 4-ethynylanisole ( 4d , 252 mg, 3.0 mmol) instead of 3,3-dimethyl-1-butyne ( 4a ) used in step 1 of Example 1 4- (4-methoxyphenyl) -1-((2-naphthoxy) methyl) -1,2,3-triazole ( 5d , 391 mg, 59%) was obtained.

1H NMR (500 MHz, CDCl3) δ 3.83 (s, 3H), 6.39 (s, 2H), 7.00-6.93 (m, 2H), 7.20 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1 H), 7.40-7.37 (m, 1H), 7.47-7.44 (m, 2H), 7.78-7.72 (m, 5H), 7.93 (s, 1H); 1 H NMR (500 MHz, CDCl 3 ) δ 3.83 (s, 3H), 6.39 (s, 2H), 7.00-6.93 (m, 2H), 7.20 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H) , 7.27 (d, J = 9.0 Hz, 1H), 7.40-7.37 (m, 1H), 7.47-7.44 (m, 2H), 7.78-7.72 (m, 5H), 7.93 (s, 1H);

13C NMR (125 MHz, CDCl3) δ 134.3, 133.9, 130.3, 130.2, 129.9, 127.8, 127.5, 127.4, 127.3, 127.0, 125.0, 123.0, 118.7, 118.6, 114.5, 110.1, 76.5, 55.5.
13 C NMR (125 MHz, CDCl 3 ) δ 134.3, 133.9, 130.3, 130.2, 129.9, 127.8, 127.5, 127.4, 127.3, 127.0, 125.0, 123.0, 118.7, 118.6, 114.5, 110.1, 76.5, 55.5.

단계 2:Step 2:

실시예 1의 단계 2에서 사용한 4-tert-부틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸 (5a) 대신에 4-(4-메톡시페닐)-1-((2-나프톡시)메틸) -1,2,3-트리아졸 (5d, 391 mg, 1.18 mmol)을 사용하는 것을 제외하고는 동일한 방법으로 진행하여 4-(4-메톡시페닐)-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1d, 521 mg, 89%)을 얻었다. 4- (4-methoxyphenyl) -1 instead of 4-tert-butyl-1-((2-naphthoxy) methyl) -1,2,3-triazole ( 5a ) used in step 2 of Example 1 Proceed in the same manner except using ((2-naphthoxy) methyl) -1,2,3-triazole ( 5d , 391 mg, 1.18 mmol) 4- (4-methoxyphenyl)- 3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1d , 521 mg, 89%) was obtained.

1H NMR (500 MHz, CDCl3) δ 3.82 (s, 3H), 4.25 (s, 3H), 6.65 (s, 2H), 7.03-7.00 (m, 2H), 7.25 (dd, J = 9.0, 2.5 Hz, 1H), 7.42 (td, J = 7.5, 1.0 Hz, 1H), 7.53-7.47 (m, 4H), 7.79 (d, J = 8.5 Hz, 1H), 7.83 (t, J = 9.0 Hz, 2H), 8.76 (s, 1H); 1 H NMR (500 MHz, CDCl 3 ) δ 3.82 (s, 3H), 4.25 (s, 3H), 6.65 (s, 2H), 7.03-7.00 (m, 2H), 7.25 (dd, J = 9.0, 2.5 Hz, 1H), 7.42 (td, J = 7.5, 1.0 Hz, 1H), 7.53-7.47 (m, 4H), 7.79 (d, J = 8.5 Hz, 1H), 7.83 (t, J = 9.0 Hz, 2H ), 8.76 (s, 1 H);

13C NMR (125 MHz, CDCl3) δ 162.7, 153.1, 144.1, 134.2, 131.3, 130.8, 130.6, 128.5, 127.8, 127.7, 118.0, 115.5, 113.5, 110.5, 79.6, 55.7, 38.9.
13 C NMR (125 MHz, CDCl 3 ) δ 162.7, 153.1, 144.1, 134.2, 131.3, 130.8, 130.6, 128.5, 127.8, 127.7, 118.0, 115.5, 113.5, 110.5, 79.6, 55.7, 38.9.

실시예Example 5: 3- 5: 3- 메틸methyl -4--4- 페닐Phenyl -1-(2--1- (2- 페닐에테인Phenylethane -2-온-1-일)-1,2,3--2-one-1-yl) -1,2,3- 트리아졸륨Triazolium 트리플루오로메탄설포네이트Trifluoromethanesulfonate (1e)의 제조 Preparation of (1e)

Figure pat00034

Figure pat00034

단계 1:Step 1:

2-아지도아세토페논 (3b, 322 mg, 2.0 mmol)과 페닐아세틸렌 (4e, 225 mg, 2.2 mmol)을 아세토니트릴 (8 mL)에 녹인 후 요오드화 구리 (77 mg, 0.4 mmol)와 트리에틸아민 (0.056 mL, 0.4 mmol)을 가하고 상온에서 2시간 동안 교반한 다음 감압하여 농축한 후 컬럼 크로마토그래피 (1% 메탄올/디클로로메탄)를 수행하여 목적화합물 4-페닐-1-(2-페닐에테인-2-온-1-일)-1,2,3-트리아졸 (5e, 520 mg, 83%)을 얻었다.2-Azidoacetophenone ( 3b , 322 mg, 2.0 mmol) and phenylacetylene ( 4e , 225 mg, 2.2 mmol) were dissolved in acetonitrile (8 mL), followed by copper iodide (77 mg, 0.4 mmol) and triethylamine (0.056 mL, 0.4 mmol) was added thereto, stirred at room temperature for 2 hours, concentrated under reduced pressure, and subjected to column chromatography (1% methanol / dichloromethane) to give the title compound 4-phenyl-1- (2-phenylethane- 2-on-1-yl) -1,2,3-triazole ( 5e , 520 mg, 83%) was obtained.

1H NMR (500 MHz, CDCl3) δ 5.90 (s, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 2H), 7.55 (t, J = 7.8Hz, 2H), 7.68 (t, J = 7.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.95 (s, 1H), 8.03 (t, J = 8.4 Hz, 2H).
1 H NMR (500 MHz, CDCl 3 ) δ 5.90 (s, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 2H), 7.55 (t, J = 7.8 Hz , 2H), 7.68 (t, J = 7.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.95 (s, 1H), 8.03 (t, J = 8.4 Hz, 2H).

단계 2:Step 2:

단계 1에서 얻은 4-페닐-1-(2-페닐에테인-2-온-1-일)-1,2,3-트리아졸 (5e, 520 mg, 1.67 mmol)을 아세토니트릴 (7.0 mL)에 녹이고 메틸 트리플루오로메탄설포네이트 (6a, MeOTf, 0.278 mL, 2.5 mmol)를 가한 뒤, 0℃에서 30분간 교반시킨 뒤, 용매를 감압하여 목적화합물 3-메틸-4-페닐-1-(2-페닐에테인-2-온-1-일)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1e, 694 mg, 87%)를 얻었다.4-phenyl-1- (2-phenylethane-2-one-1-yl) -1,2,3-triazole ( 5e , 520 mg, 1.67 mmol) obtained in step 1 was added to acetonitrile (7.0 mL). After dissolving, methyl trifluoromethanesulfonate ( 6a , MeOTf, 0.278 mL, 2.5 mmol) was added thereto, stirred at 0 ° C. for 30 minutes, and the solvent was distilled off under reduced pressure to yield the title compound 3-methyl-4-phenyl-1- (2 -Phenylethane-2-one-1-yl) -1,2,3-triazolium trifluoromethanesulfonate ( 1e , 694 mg, 87%) was obtained.

1H NMR (500 MHz, CDCl3) δ 4.31 (s, 3H), 6.43 (s, 2H), 7.55-7.72 (m, 8H), 8.04 (d, J = 6.0 Hz, 2H), 8.76 (s, 1H).
 1 H NMR (500 MHz, CDCl 3 ) δ 4.31 (s, 3H), 6.43 (s, 2H), 7.55-7.72 (m, 8H), 8.04 (d, J = 6.0 Hz, 2H), 8.76 (s, 1H).

실시예Example 6: 4- 6: 4- terttert -부틸-3--Butyl-3- 메틸methyl -1-[(-One-[( 페닐싸이오Phenylthio )) 메틸methyl ]-1,2,3-] -1,2,3- 트리아졸륨Triazolium 트리플루오로메탄설포네이트Trifluoromethanesulfonate (1f)의 제조 (1f) Preparation

Figure pat00035

Figure pat00035

단계 1:Step 1:

상기 제조예 3에서 얻은 화합물 아지도메틸 페닐 설파이드 (3c, 330 mg, 2.0 mmol)과 3,3-다이메틸-1-부틴 (4a, 246 mg, 3.0 mmol)을 아세토니트릴 (8 mL)에 녹인 후 요오드화 구리 (77 mg, 0.4 mmol)와 트리에틸아민 (0.056 mL, 0.4 mmol)을 가하고 상온에서 2시간 동안 교반시킨 다음 감압하여 농축한 후 컬럼 크로마토그래피 (1% 메탄올/디클로로메탄)를 수행하여 목적화합물 4-tert-부틸-1-[(페닐싸이오)메틸]-1,2,3-트라이아졸 (5f, 411 mg, 83%)을 얻었다.Compound azidomethyl phenyl sulfide ( 3c , 330 mg, 2.0 mmol) and 3,3-dimethyl-1-butyne ( 4a , 246 mg, 3.0 mmol) obtained in Preparation Example 3 were dissolved in acetonitrile (8 mL). Then copper iodide (77 mg, 0.4 mmol) and triethylamine (0.056 mL, 0.4 mmol) were added thereto, stirred at room temperature for 2 hours, concentrated under reduced pressure, and then subjected to column chromatography (1% methanol / dichloromethane). Target compound 4-tert-butyl-1-[(phenylthio) methyl] -1,2,3-triazole ( 5f , 411 mg, 83%) was obtained.

1H NMR (500 MHz, CDCl3) δ 1.23 (s, 9H), 5.90 (s, 2H), 7.45-7.34 (m, 5H), 7.76 (s, 1H).
1 H NMR (500 MHz, CDCl 3 ) δ 1.23 (s, 9H), 5.90 (s, 2H), 7.45-7.34 (m, 5H), 7.76 (s, 1H).

단계 2:Step 2:

단계 1에서 얻은 4-tert-부틸-1-[(페닐싸이오)메틸]-1,2,3-트라이아졸 (5f, 411 mg, 1.66 mmol)을 아세토니트릴 (7.0 mL)에 녹이고 메틸 트리플루오로메탄설포네이트 (6a, MeOTf, 0.278 mL, 2.5 mmol)를 가한 뒤, 0℃에서 30분간 교반시킨 뒤, 용매를 감압하여 목적화합물 4-tert-부틸-3-메틸-1-[(페닐싸이오)메틸]-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1f, 615 mg, 90%)를 얻었다.4-tert-butyl-1-[(phenylthio) methyl] -1,2,3-triazole ( 5f , 411 mg, 1.66 mmol) obtained in step 1 was dissolved in acetonitrile (7.0 mL) and methyl trifluor After adding romethanesulfonate ( 6a , MeOTf, 0.278 mL, 2.5 mmol), stirring at 0 ° C. for 30 minutes, and then decompressing the solvent to give the desired compound 4-tert-butyl-3-methyl-1-[(phenylthio). 5) methyl] -1,2,3-triazolium trifluoromethanesulfonate ( 1f , 615 mg, 90%) was obtained.

1H NMR (500 MHz, CDCl3) δ 1.46 (s, 9H), 4.28 (s, 3H), 5.93 (s, 2H), 7.43-7.38 (m, 5H), 8.17 (s, 1H).
 1 H NMR (500 MHz, CDCl 3 ) δ 1.46 (s, 9H), 4.28 (s, 3H), 5.93 (s, 2H), 7.43-7.38 (m, 5H), 8.17 (s, 1H).

실시예Example 7: 3- 7: 3- 메틸methyl -1-((2--1-((2- 나프톡시Naphthoxy )) 메틸methyl )-4-)-4- 페닐Phenyl -1,2,3--1,2,3- 트리아졸륨Triazolium 트리플루오로메탄설포네이트Trifluoromethanesulfonate (1g)의 제조 (1g) Preparation

Figure pat00036

Figure pat00036

단계 1:Step 1:

2-나프톨 (7a, 720 mg, 5.0 mmol)과 포타슘카보네이트 (2.07 g, 15 mmol)을 아세토니트릴 (20 mL)에 녹인 후, 1-(클로로메틸)-4-페닐-1,2,3-트리아졸 (8a, 1.45 g, 7.5 mmol)을 첨가한 뒤 80도 가열조건에서 5시간 동안 교반시켰다. 물을 가하여 반응을 종결시킨 다음, 에틸아세테이트로 유기화합물을 추출하였다. 추출된 에틸아세테이트 용액을 무수 황산 나트륨으로 처리한 뒤 컬럼 크로마토그래피 (30% 에틸아세테이트/n-헥산)를 수행하여 4-페닐-1-((2-나프톡시)메틸)-1,2,3-트리아졸 (5g, 1.13 g, 75%)를 얻었다. 2-naphthol ( 7a , 720 mg, 5.0 mmol) and potassium carbonate (2.07 g, 15 mmol) were dissolved in acetonitrile (20 mL), and then 1- (chloromethyl) -4-phenyl-1,2,3- Triazole ( 8a , 1.45 g, 7.5 mmol) was added and stirred at 80 ° C. for 5 hours. Water was added to terminate the reaction, and then the organic compound was extracted with ethyl acetate. The extracted ethyl acetate solution was treated with anhydrous sodium sulfate, and then subjected to column chromatography (30% ethyl acetate / n -hexane) to 4-phenyl-1-((2-naphthoxy) methyl) -1,2,3 -Triazole ( 5 g , 1.13 g, 75%) was obtained.

1H NMR (500 MHz, CDCl3) δ 6.40 (s, 2H), 7.20 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H), 7.26 (d, J = 9.5 Hz, 1H), 7.47-7.31 (m, 6H), 7.79-7.76 (m, 3H), 7.83-7.81 (m, 2H), 8.01 (s, 1H); 1 H NMR (500 MHz, CDCl 3 ) δ 6.40 (s, 2H), 7.20 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H), 7.26 (d, J = 9.5 Hz, 1H), 7.47-7.31 (m, 6H), 7.79-7.76 (m, 3H), 7.83-7.81 (m, 2H), 8.01 (s, 1H);

13C NMR (125 MHz, CDCl3) δ 134.2, 133.9, 130.3, 130.2, 129.9, 129.0, 128.6, 127.8, 127.5, 127.0, 126.03, 125.94, 125.0, 119.6, 118.5, 110.1, 76.5.
 13 C NMR (125 MHz, CDCl 3 ) δ 134.2, 133.9, 130.3, 130.2, 129.9, 129.0, 128.6, 127.8, 127.5, 127.0, 126.03, 125.94, 125.0, 119.6, 118.5, 110.1, 76.5.

단계 2:Step 2:

단계 1에서 얻은 4-페닐-1-((2-나프톡시)메틸)-1,2,3-트리아졸 (5g, 1.13 g, 3.75 mmol)을 아세토니트릴 (15.0 mL)에 녹이고 메틸 트리플루오로메탄설포네이트 (6a, MeOTf, 0.618 mL, 5.63 mmol)를 가한 뒤, 0℃에서 30분간 교반시킨 다음, 용매를 감압하에 제거하여 목적화합물 4-페닐-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1g, 1.68 g, 96%)를 얻었다.4-phenyl-1-((2-naphthoxy) methyl) -1,2,3-triazole ( 5 g , 1.13 g, 3.75 mmol) obtained in step 1 was dissolved in acetonitrile (15.0 mL) and methyl trifluoro Methanesulfonate ( 6a , MeOTf, 0.618 mL, 5.63 mmol) was added, stirred at 0 ° C. for 30 minutes, and the solvent was removed under reduced pressure to afford the desired compound 4-phenyl-3-methyl-1-((2-naph). Methoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1 g , 1.68 g, 96%) was obtained.

1H NMR (500 MHz, CDCl3) d 3.81 (s, 3H), 6.35 (s, 2H), 7.22 (dd, J = 9. 0 Hz, 2. 0 Hz, 1H), 7.40-7.35 (m, 3H), 7.54-7.43 (m, 6H), 7.75 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.85 (t, J = 8.5 Hz, 1H), 9.63 (s, 1H); 1 H NMR (500 MHz, CDCl 3 ) d 3.81 (s, 3H), 6.35 (s, 2H), 7.22 (dd, J = 9. 0 Hz, 2. 0 Hz, 1H), 7.40-7.35 (m, 3H), 7.54-7.43 (m, 6H), 7.75 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.85 (t, J = 8.5 Hz, 1H), 9.63 ( s, 1 H);

13C NMR (125 MHz, CDCl3) d 152.8, 138.3, 136.6, 134.3, 131.1, 130.6, 130.4, 129.64, 129.60, 127.7, 127.2, 125.3, 124.5, 120.9 (d, J = 319 Hz), 118.4, 118.1, 110.3, 76.0, 35.1.
 13 C NMR (125 MHz, CDCl 3 ) d 152.8, 138.3, 136.6, 134.3, 131.1, 130.6, 130.4, 129.64, 129.60, 127.7, 127.2, 125.3, 124.5, 120.9 (d, J = 319 Hz), 118.4, 118.1 , 110.3, 76.0, 35.1.

실시예Example 8: 3- 8: 3- 메틸methyl -1-[3-(2--1- [3- (2- 나프톡시Naphthoxy )-) - nn -프로필]-profile] 옥시메틸Oxymethyl -4--4- 페닐Phenyl -1,2,3--1,2,3- 트리아졸륨Triazolium 트리플루오로메탄설포네이트Trifluoromethanesulfonate (1h)의 제조  (1h) Preparation

Figure pat00037

Figure pat00037

단계 1:Step 1:

3-(2-나프톡시)프로판올 (7b, 1.01 g, 5.0 mmol)과 포타슘-tert-부톡사이드 (1.69 g, 15 mmol)을 테트라하이드로퓨란 (20 mL)에 녹인 후, 1-(클로로메틸)-4-페닐-1,2,3-트리아졸 (8a, 1.16 g, 6.0 mmol)을 첨가한 뒤 상온에서 3시간 동안 교반시켰다. 물을 가하여 반응을 종결시킨 다음, 디클로로메탄으로 유기화합물을 추출하였다. 추출된 디클로로메탄 용액을 무수 황산 나트륨으로 처리한 뒤 컬럼 크로마토그래피 (30% 에틸아세테이트/n-헥산)를 수행하여 1-[3-(2-나프톡시)-n-프로필]옥시메틸-4-페닐-1,2,3-트리아졸 (5h, 1.25 g, 70%)를 얻었다. 3- (2-naphthoxy) propanol ( 7b , 1.01 g, 5.0 mmol) and potassium tert -butoxide (1.69 g, 15 mmol) were dissolved in tetrahydrofuran (20 mL), followed by 1- (chloromethyl) 4-phenyl-1,2,3-triazole ( 8a , 1.16 g, 6.0 mmol) was added and stirred at room temperature for 3 hours. Water was added to terminate the reaction, and then the organic compound was extracted with dichloromethane. The extracted dichloromethane solution was treated with anhydrous sodium sulfate and then subjected to column chromatography (30% ethyl acetate / n -hexane) to give 1- [3- (2-naphthoxy) -n -propyl] oxymethyl-4- Phenyl-1,2,3-triazole ( 5h , 1.25 g, 70%) was obtained.

1H NMR (500 MHz, CDCl3) δ 2.10 (q, J = 6.0 Hz, 2H), 3.79 (t, J = 6.3 Hz, 2H), 4.12 (t, J = 6.3 Hz, 2H), 5.74 (s, 2H), 7.05 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H), 7.09 (d, J = 2.5 Hz, 1H), 7.38-7.31 (m, 4H), 7.44-7.41 (m, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.76-7.73 (m, 3H), 7.87 (s, 1H); 1 H NMR (500 MHz, CDCl 3 ) δ 2.10 (q, J = 6.0 Hz, 2H), 3.79 (t, J = 6.3 Hz, 2H), 4.12 (t, J = 6.3 Hz, 2H), 5.74 (s , 2H), 7.05 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H), 7.09 (d, J = 2.5 Hz, 1H), 7.38-7.31 (m, 4H), 7.44-7.41 (m, 1H) , 7.65 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.76-7.73 (m, 3H), 7.87 (s, 1H);

13C NMR (125 MHz, CDCl3) δ 156.9, 148.9, 134.7, 130.4, 129.6, 129.2, 129.0, 128.5, 127.8, 126.9, 126.5, 126.0, 123.8, 119.3, 118.9, 106.8, 79.3, 66.5, 64.2, 29.3.
 13 C NMR (125 MHz, CDCl 3 ) δ 156.9, 148.9, 134.7, 130.4, 129.6, 129.2, 129.0, 128.5, 127.8, 126.9, 126.5, 126.0, 123.8, 119.3, 118.9, 106.8, 79.3, 66.5, 64.2, 29.3 .

단계 2:Step 2:

단계 1에서 얻은 1-[3-(2-나프톡시)-n-프로필]옥시메틸-4-페닐-1,2,3-트리아졸 (5h, 1.25 mg, 3.5 mmol)을 아세토니트릴 (14.0 mL)에 녹이고 메틸 트리플루오로메탄설포네이트 (6a, MeOTf, 0.57 mL, 5.25 mmol)를 가한 뒤, 0℃에서 30분간 교반시킨 뒤, 용매를 감압하에 제거하고 목적화합물 3-메틸-1-[3-(2-나프톡시)-n-프로필]옥시메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1h, 1.4 g, 76%)를 얻었다.1- [3- (2-naphthoxy) -n -propyl] oxymethyl-4-phenyl-1,2,3-triazole ( 5h , 1.25 mg, 3.5 mmol) obtained in step 1 was purified by acetonitrile (14.0 mL ), Methyl trifluoromethanesulfonate ( 6a , MeOTf, 0.57 mL, 5.25 mmol) was added, stirred at 0 ° C. for 30 minutes, the solvent was removed under reduced pressure, and the desired compound 3-methyl-1- [3 -(2-naphthoxy) -n -propyl] oxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1h , 1.4 g, 76%) was obtained.

1H NMR (500 MHz, CDCl3) d 2.11 (q, J = 5.8 Hz, 2H), 4.01-3.99 (m, 5H), 4.08 (t, J = 5.5 Hz, 2H), 5.95 (s, 2H), 7.01 (dd, J = 9.0, 2.5 Hz, 1H), 7.07 (d, J = 2.5 Hz, 1H), 7.44-7.26 (m, 7H), 7.51-7.48 (m, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 8.68 (s, 1H),; 1 H NMR (500 MHz, CDCl 3 ) d 2.11 (q, J = 5.8 Hz, 2H), 4.01-3.99 (m, 5H), 4.08 (t, J = 5.5 Hz, 2H), 5.95 (s, 2H) , 7.01 (dd, J = 9.0, 2.5 Hz, 1H), 7.07 (d, J = 2.5 Hz, 1H), 7.44-7.26 (m, 7H), 7.51-7.48 (m, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 8.68 (s, 1H);

13C NMR (125 MHz, CDCl3) d 156.7, 143.8, 134.7, 132.0, 129.71, 129.66, 129.5, 129.1, 128.3, 127.8, 126.9, 126.8, 12.0, 121.7, 120.8 (d, J = 318 Hz), 118.6, 106.8, 83.6, 68.2, 63.7, 38.7, 29.1
 13 C NMR (125 MHz, CDCl 3 ) d 156.7, 143.8, 134.7, 132.0, 129.71, 129.66, 129.5, 129.1, 128.3, 127.8, 126.9, 126.8, 12.0, 121.7, 120.8 (d, J = 318 Hz), 118.6 , 106.8, 83.6, 68.2, 63.7, 38.7, 29.1

실시예Example 9: 1-[1- 9: 1- [1- 메틸설포닐옥시Methylsulfonyloxy -3-(2--3- (2- 나프틸Naphthyl )-2-)-2- 옥시프로필Oxypropyl ]] 옥시메틸Oxymethyl -3--3- 메틸methyl -4--4- 페닐Phenyl -1,2,3--1,2,3- 트리아졸륨Triazolium 트리플루오로메탄설포네이트Trifluoromethanesulfonate (1i)의 제조  Preparation of (1i)

Figure pat00038

Figure pat00038

실시예 8에서 사용한 3-(2-나프톡시)프로판올 (7b) 대신에 2-하이드록시-3-(2-나프탈렌일옥시)프로필 메탄설포네이트 (7c, 889 mg, 3.0 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 1-[1-메틸설포닐옥시-3-(2-나프틸)-2-옥시프로필]옥시메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1i, 1.39 g, 75%)를 얻었다. Use of 2-hydroxy-3- (2-naphthalenyloxy) propyl methanesulfonate ( 7c , 889 mg, 3.0 mmol) instead of the 3- (2-naphthoxy) propanol ( 7b ) used in Example 8 Proceed in the same manner except 1- [1-methylsulfonyloxy-3- (2-naphthyl) -2-oxypropyl] oxymethyl-3-methyl-4-phenyl-1,2,3-tria Zolium trifluoromethanesulfonate ( 1i , 1.39 g, 75%) was obtained.

1H NMR (500 MHz, CDCl3) δ 2.99 (s, 3H), 4.15 (s, 3H), 4.31-4.22 (m, 2H), 4.43 (d, J = 5.5 Hz, 2H), 4.69-4.67 (m, 1H), 6.22 (q, J = 9.3 Hz, 2H), 7.07 (dd, J = 8.8, 2.8 Hz, 1H), 7.13 (d, J = 2.5 Hz, 1H), 7.43 (td, J = 7.5 Hz, 1.0 Hz, 1H), 7.52-7.48 (m, 4H), 7.57-7.54 (m, 1H), 7.69 (d, J = 9.0 Hz, 2H), 7.23 (t, J = 8.0 Hz, 2H), 8.91 (s, 1H); 1 H NMR (500 MHz, CDCl 3 ) δ 2.99 (s, 3H), 4.15 (s, 3H), 4.31-4.22 (m, 2H), 4.43 (d, J = 5.5 Hz, 2H), 4.69-4.67 ( m, 1H), 6.22 (q, J = 9.3 Hz, 2H), 7.07 (dd, J = 8.8, 2.8 Hz, 1H), 7.13 (d, J = 2.5 Hz, 1H), 7.43 (td, J = 7.5 Hz, 1.0 Hz, 1H), 7.52-7.48 (m, 4H), 7.57-7.54 (m, 1H), 7.69 (d, J = 9.0 Hz, 2H), 7.23 (t, J = 8.0 Hz, 2H), 8.91 (s, 1 H);

13C NMR (125 MHz, CDCl3) δ 155.9, 143.9, 134.5, 132.1, 129.9, 129.8, 129.6, 129.5, 128.8, 127.8, 127.2, 126.9, 124.4, 122.0, 120.9 (d, J = 319 Hz), 118.3, 107.5, 82.8, 78.5, 69.7, 67.2, 38.8, 37.4.
13 C NMR (125 MHz, CDCl 3 ) δ 155.9, 143.9, 134.5, 132.1, 129.9, 129.8, 129.6, 129.5, 128.8, 127.8, 127.2, 126.9, 124.4, 122.0, 120.9 (d, J = 319 Hz), 118.3 , 107.5, 82.8, 78.5, 69.7, 67.2, 38.8, 37.4.

실시예Example 10: 3- 10: 3- 메틸methyl -(2--(2- 나프틸Naphthyl )) 메틸옥시메틸Methyloxymethyl -4--4- 페닐Phenyl -1,2,3--1,2,3- 트리아졸륨Triazolium 트리플루오로메탄설포네이트Trifluoromethanesulfonate (1j)의 제조  Preparation of (1j)

Figure pat00039

Figure pat00039

실시예 8에서 사용한 3-(2-나프톡시)프로판올 (7b) 대신에 나프탈렌메탄올 (7d, 475 mg, 3.0 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 3-메틸-(2-나프틸)메틸옥시메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1j, 1.09 g, 76%)을 얻었다. Proceed in the same manner except using naphthalenemethanol ( 7d , 475 mg, 3.0 mmol) instead of 3- (2-naphthoxy) propanol ( 7b ) used in Example 8 and proceeding with 3-methyl- (2-naph Tyl) methyloxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1j , 1.09 g, 76%) was obtained.

1H NMR (500 MHz, CDCl3) δ 3.96 (s, 3H), 4.88 (s, 2H), 5.94 (s, 2H), 7.24 (d, J = 7.5 Hz, 2H), 7.45-7.32 (m, 6H), 7.68 (d, J = 8.5 Hz, 1H), 7.76-7.71 (m, 3H), 8.48 (s, 1H); 1 H NMR (500 MHz, CDCl 3 ) δ 3.96 (s, 3H), 4.88 (s, 2H), 5.94 (s, 2H), 7.24 (d, J = 7.5 Hz, 2H), 7.45-7.32 (m, 6H), 7.68 (d, J = 8.5 Hz, 1H), 7.76-7.71 (m, 3H), 8.48 (s, 1H);

13C NMR (125 MHz, CDCl3) δ 143.39, 143.38, 133.1, 132.9, 131.8, 129.5, 129.3, 128.3, 128.2, 128.1, 127.69, 127.67, 126.61, 126.55, 125.9, 124.6, 121.59, 121.58, 120.8 (q, J = 319 Hz), 82.7, 73.9, 38.5.
 13 C NMR (125 MHz, CDCl 3 ) δ 143.39, 143.38, 133.1, 132.9, 131.8, 129.5, 129.3, 128.3, 128.2, 128.1, 127.69, 127.67, 126.61, 126.55, 125.9, 124.6, 121.59, 121.58, 120.8 (q , J = 319 Hz), 82.7, 73.9, 38.5.

실시예Example 11: (S)-1-(4-(2- 11: (S) -1- (4- (2- BOCBOC -아미노-2-(t--Amino-2- (t- 부톡시카보닐Butoxycarbonyl )에틸))ethyl) 페닐옥시메틸Phenyloxymethyl )-4-페닐-1,2,3-) -4-phenyl-1,2,3- 트리아졸륨Triazolium 트리플루오로메탄설포네이트Trifluoromethanesulfonate (1k)의 제조 (1k) Preparation

Figure pat00040
Figure pat00040

단계 1: Step 1:

N-BOC-L-타이로신 tert-부틸 에스터 (7e, 0.79 g, 2.35 mmol)를 아세톤 (23 mL) 에 용해시킨 후 세슘카보네이트 (2.00g, 5.87 mmol), 1-(클로로메틸)-4-페닐-1,2,3-트리아졸 (8a, 0.46 g, 2.59 mmol)를 차례로 가하고 50℃에서 6시간 동안 교반하였다. 이 반응물을 감압증류 하고 에틸 아세테이트로 희석한 뒤 여과한다. 그 여액을 1.0 노르말 염산 수용액, 물, 포화 염화나트륨 수용액 순으로 세척한다. 세척한 유기층을 무수 황산 나트륨으로 건조하고 농축 후 컬럼 크로마토그래피 (SiO2 , 20% 에틸아세테이트/헥산)를 시행하여 흰색 고체 화합물 (S)-1-(4-(2-BOC-아미노-2-(t-부톡시카보닐)에틸)페닐오시메틸)-4-페닐-1,2,3-트리아졸 (5k, 1.07 g, 2.16 mmol, 92%)을 얻었다.
N-BOC-L-tyrosine tert-butyl ester ( 7e, 0.79 g, 2.35 mmol) was dissolved in acetone (23 mL), followed by cesium carbonate (2.00 g, 5.87 mmol), 1- (chloromethyl) -4-phenyl -1,2,3-triazole ( 8a , 0.46 g, 2.59 mmol) was added sequentially and stirred at 50 ° C. for 6 hours. The reaction was distilled under reduced pressure, diluted with ethyl acetate and filtered. The filtrate is washed with 1.0 normal aqueous hydrochloric acid solution, water and saturated aqueous sodium chloride solution in that order. The washed organic layer was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (SiO 2 , 20% ethyl acetate / hexane) to give a white solid compound (S) -1- (4- (2-BOC-amino-2- (t-butoxycarbonyl) ethyl) phenyloxymethyl) -4-phenyl-1,2,3-triazole ( 5k , 1.07 g, 2.16 mmol, 92%) was obtained.

1H NMR (400 MHz, CDCl3) δ 1.38 (s, 18H), 2.99 (s, 2H), 4.39 (d, J = 6.4 Hz, 1H), 5.03 (d, J = 8 Hz, 1H), 6.23 (s, 3H), 7.09 (d, J = 8 Hz, 2H), 7.33 (d, J = 6.4 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.82 (d, J = 7.6 Hz, 2H), 7.97 (s, 1H),
1 H NMR (400 MHz, CDCl 3 ) δ 1.38 (s, 18H), 2.99 (s, 2H), 4.39 (d, J = 6.4 Hz, 1H), 5.03 (d, J = 8 Hz, 1H), 6.23 (s, 3H), 7.09 (d, J = 8 Hz, 2H), 7.33 (d, J = 6.4 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.82 (d, J = 7.6 Hz , 2H), 7.97 (s, 1H),

단계 2:Step 2:

상기 단계 1에서 얻은 (S)-1-(4-(2-BOC-아미노-2-(t-부톡시카보닐)에틸)페닐오시메틸)-4-페닐-1,2,3-트리아졸 (5k, 0.47 g, 0.96 mmol)를 아세토니트릴 (2.5mL)에 녹인 후 메틸 트리플루오르메탄설포네이트 (6a, 53 ㎕, 0.48 mmol) 을 가하고 90분 동안 상온에서 교반한다. 이 반응물을 농축한 후 컬럼 크로마토그래피 (SiO2, 5% 메탄올/디클로로메탄)를 시행하여 목적화합물 (S)-1-(4-(2-BOC-아미노-2-(t-부톡시카보닐)에틸)페닐옥시메틸)-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1k, 0.22 g, 0.34 mmol, 70%) 얻었다. (S) -1- (4- (2-BOC-amino-2- (t-butoxycarbonyl) ethyl) phenyloxymethyl) -4-phenyl-1,2,3-triazole obtained in step 1 above. ( 5k , 0.47 g, 0.96 mmol) is dissolved in acetonitrile (2.5 mL), and methyl trifluoromethanesulfonate ( 6a , 53 μl, 0.48 mmol) is added and stirred at room temperature for 90 minutes. The reaction mixture was concentrated and subjected to column chromatography (SiO 2, 5% methanol / dichloromethane) to give the target compound (S) -1- (4- (2-BOC-amino-2- (t-butoxycarbonyl). ) Ethyl) phenyloxymethyl) -3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1k , 0.22 g, 0.34 mmol, 70%) was obtained.

1H NMR (400 MHz, CDCl3) δ 1.40 (s, 18H), 3.04-2.98 (m, 2H), 4.30 (s, 3H) 4.37 (d, J = 6.0 Hz, 1H), 5.00 (d ,J = 8.0 Hz, 1H), 6.54 (s,2H), 7.03 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H), 7.61-7.54 (m, 5H), 8.70 (s,1H).
 1 H NMR (400 MHz, CDCl 3 ) δ 1.40 (s, 18H), 3.04-2.98 (m, 2H), 4.30 (s, 3H) 4.37 (d, J = 6.0 Hz, 1H), 5.00 (d, J = 8.0 Hz, 1H), 6.54 (s, 2H), 7.03 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H), 7.61-7.54 (m, 5H), 8.70 (s , 1H).

실시예Example 12: 3- 12: 3- 메틸methyl -1-((2--1-((2- 나프톡시Naphthoxy )) 메틸methyl )-4-)-4- 페닐이미다졸륨Phenylimidazolium 트리플루오로메탄설포네이트Trifluoromethanesulfonate (1l)의 제조 (1l) Preparation

Figure pat00041

Figure pat00041

단계 1:Step 1:

2-나프톨 (7a, 720 mg, 5.0 mmol)과 포타슘카보네이트 (2.07 g, 15 mmol)을 아세토니트릴 (20 mL)에 녹인 후, 1-(클로로메틸)-4-페닐-이미다졸 (8b, 1.44 g, 7.5 mmol)을 첨가한 뒤 80℃ 가열조건에서 5시간 동안 교반시켰다. 물을 가하여 반응을 종결시킨 다음, 에틸아세테이트로 유기화합물을 추출하였다. 추출된 에틸아세테이트 용액을 무수 황산 나트륨으로 처리한 뒤 컬럼 크로마토그래피 (20% 에틸아세테이트/n-헥산)를 수행하여 4-페닐-1-((2-나프톡시)메틸)이미다졸 (5l, 931 mg, 62%)를 얻었다. 2-naphthol ( 7a , 720 mg, 5.0 mmol) and potassium carbonate (2.07 g, 15 mmol) were dissolved in acetonitrile (20 mL) and then 1- (chloromethyl) -4-phenyl-imidazole ( 8b, 1.44 g, 7.5 mmol) was added, followed by stirring for 5 hours at 80 ° C. heating conditions. Water was added to terminate the reaction, and then the organic compound was extracted with ethyl acetate. The extracted ethyl acetate solution was treated with anhydrous sodium sulfate and subjected to column chromatography (20% ethyl acetate / n -hexane) to 4-phenyl-1-((2-naphthoxy) methyl) imidazole ( 5l , 931 mg, 62%).

1H NMR (500 MHz, CDCl3) δ 5.94 (s, 2H), 7.13 (dd, J = 9.2 Hz, J = 2.4 Hz, 1H), 7.28-7.24 (m, 2H), 7.43-7.36 (m, 4H), 7.48 (td, J = 7.4 Hz, J = 1.2 Hz, 1H), 7.71 (d, J = 1.2 HZ, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.81-7.77 (m, 4H).
 1 H NMR (500 MHz, CDCl 3 ) δ 5.94 (s, 2H), 7.13 (dd, J = 9.2 Hz, J = 2.4 Hz, 1H), 7.28-7.24 (m, 2H), 7.43-7.36 (m, 4H), 7.48 (td, J = 7.4 Hz, J = 1.2 Hz, 1H), 7.71 (d, J = 1.2 HZ, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.81-7.77 (m, 4H).

단계 2:Step 2:

단계 1에서 얻은 4-페닐-1-((2-나프톡시)메틸)이미다졸 (5l, 931 mg, 3.10 mmol)을 아세토니트릴 (15.0 mL)에 녹이고 메틸 트리플루오로메탄설포네이트 (6a, MeOTf, 0.51 mL, 4.65 mmol)를 가한 뒤, 0℃에서 30분간 교반시킨 뒤, 용매를 감압하에 제거하여 목적화합물 4-페닐-3-메틸-1-((2-나프톡시)메틸)이미다졸륨 트리플루오로메탄설포네이트 (1l, 734 mg, 51%)를 얻었다.4-phenyl-1-((2-naphthoxy) methyl) imidazole ( 5l , 931 mg, 3.10 mmol) obtained in step 1 was dissolved in acetonitrile (15.0 mL) and methyl trifluoromethanesulfonate ( 6a , MeOTf , 0.51 mL, 4.65 mmol) was added, followed by stirring at 0 ° C. for 30 minutes, and then the solvent was removed under reduced pressure to yield the desired compound 4-phenyl-3-methyl-1-((2-naphthoxy) methyl) imidazolium Trifluoromethanesulfonate ( 1L , 734 mg, 51%) was obtained.

1H NMR (500 MHz, CDCl3) d 3.78 (s, 3H), 6.33 (s, 2H), 7.21 (dd, J = 8.8, 2.3 Hz, 1H),7.38-7.34 (m, 3H), 7.52-7.41 (m, 6H), 7.73 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 9.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 9.57 (s, 1H); 1 H NMR (500 MHz, CDCl 3 ) d 3.78 (s, 3H), 6.33 (s, 2H), 7.21 (dd, J = 8.8, 2.3 Hz, 1H), 7.78-7.34 (m, 3H), 7.52- 7.41 (m, 6H), 7.73 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 9.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 9.57 (s, 1H);

13C NMR (125 MHz, CDCl3) d 152.9, 138.1, 136.5, 134.3, 131.0, 130.6, 130.3, 129.6, 129.5, 127.72, 127.69, 127.1, 125.2, 124.5, 120.9 (q, J = 319 Hz), 118.5, 118.2, 110.3, 76.0, 35.1.
 13 C NMR (125 MHz, CDCl 3 ) d 152.9, 138.1, 136.5, 134.3, 131.0, 130.6, 130.3, 129.6, 129.5, 127.72, 127.69, 127.1, 125.2, 124.5, 120.9 (q, J = 319 Hz), 118.5 , 118.2, 110.3, 76.0, 35.1.

실시예Example 13: 3- 13: 3- 메틸methyl -1-((2--1-((2- 나프톡시Naphthoxy )) 메틸methyl )-4-)-4- 페닐Phenyl -1,2,3--1,2,3- 트리아졸륨Triazolium 트리플루오로메탄설포네이트Trifluoromethanesulfonate (1g)의 제조 (1g) Preparation

Figure pat00042

Figure pat00042

2-나프톨 (7a, 288 mg, 2.0 mmol)과 포타슘카보네이트 (829 mg, 6.0 mmol)을 아세토니트릴 (8 mL)에 녹인 후, 1-(클로로메틸)-4-페닐-3-메틸-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (9a, 858 mg, 2.4 mmol)을 첨가한 뒤 80℃ 가열조건에서 5시간 동안 교반시켰다. 물을 가하여 반응을 종결시킨 다음, 디클로로메탄으로 유기화합물을 추출하였다. 추출된 디클로로메탄 용액을 무수 황산 나트륨으로 처리한 뒤 컬럼 크로마토그래피 (5% 메탄올/디클로로메탄)를 수행하여 상기 실시예 7과 동일한 목적화합물 4-페닐-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1g, 577 mg, 62%)를 얻었다.2-naphthol ( 7a , 288 mg, 2.0 mmol) and potassium carbonate (829 mg, 6.0 mmol) were dissolved in acetonitrile (8 mL), and then 1- (chloromethyl) -4-phenyl-3-methyl-1, 2,3-triazolium trifluoromethanesulfonate ( 9a , 858 mg, 2.4 mmol) was added, followed by stirring at 80 ° C. for 5 hours. Water was added to terminate the reaction, and then the organic compound was extracted with dichloromethane. The extracted dichloromethane solution was treated with anhydrous sodium sulfate, and then subjected to column chromatography (5% methanol / dichloromethane) to give the same target compound 4-phenyl-3-methyl-1-((2-naph) as in Example 7. Oxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1g , 577 mg, 62%) was obtained.

1H NMR (500 MHz, CDCl3) d 3.81 (s, 3H), 6.35 (s, 2H), 7.22 (dd, J = 9. 0 Hz, 2. 0 Hz, 1H), 7.40-7.35 (m, 3H), 7.54-7.43 (m, 6H), 7.75 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.85 (t, J = 8.5 Hz, 1H), 9.63 (s, 1H); 1 H NMR (500 MHz, CDCl 3 ) d 3.81 (s, 3H), 6.35 (s, 2H), 7.22 (dd, J = 9. 0 Hz, 2. 0 Hz, 1H), 7.40-7.35 (m, 3H), 7.54-7.43 (m, 6H), 7.75 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.85 (t, J = 8.5 Hz, 1H), 9.63 ( s, 1 H);

13C NMR (125 MHz, CDCl3) d 152.8, 138.3, 136.6, 134.3, 131.1, 130.6, 130.4, 129.64, 129.60, 127.7, 127.2, 125.3, 124.5, 120.9 (d, J = 319), 118.4, 118.1, 110.3, 76.0, 35.1.
 13 C NMR (125 MHz, CDCl 3 ) d 152.8, 138.3, 136.6, 134.3, 131.1, 130.6, 130.4, 129.64, 129.60, 127.7, 127.2, 125.3, 124.5, 120.9 (d, J = 319), 118.4, 118.1, 110.3, 76.0, 35.1.

실시예Example 14: 1-(4- 14: 1- (4- 바이페닐Biphenyl )) 옥시메틸Oxymethyl -3--3- 메틸methyl -4--4- 페닐Phenyl -1,2,3--1,2,3- 트리아졸륨Triazolium 트리플루오로메탄설포네이트Trifluoromethanesulfonate (1m)의 제조 (1 m)

Figure pat00043

Figure pat00043

실시예 12에서 사용한 2-나프톨 (7a) 대신에 4-페닐페놀 (7f, 510 mg, 3.0 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 1-(4-바이페닐)옥시메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1m, 1.28 g, 87%)을 얻었다. Proceed in the same manner except using 4-phenylphenol ( 7f , 510 mg, 3.0 mmol) instead of 2-naphthol ( 7a ) used in Example 12 and proceeding with 1- (4-biphenyl) oxymethyl-3 -Methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1m , 1.28 g, 87%) was obtained.

1H NMR (500 MHz, CDCl3) δ 4.26 (s, 3H), 6.56 (s, 2H), 7.19 (q, J = 5.0 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 7.32 (td, J = 7.5, 1.3 Hz, 1H), 7.41 (t, J = 7.8 Hz, 2H), 7.61-7.50 (m, 9H), 7.80 (t, J = 8.5 Hz, 2H), 8.79 (s, 1H); 1 H NMR (500 MHz, CDCl 3 ) δ 4.26 (s, 3H), 6.56 (s, 2H), 7.19 (q, J = 5.0 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 7.32 (td, J = 7.5, 1.3 Hz, 1H), 7.41 (t, J = 7.8 Hz, 2H), 7.61-7.50 (m, 9H), 7.80 (t, J = 8.5 Hz, 2H), 8.79 (s, 1H);

13C NMR (125 MHz, CDCl3) δ 154.8, 144.0, 140.0, 137.4, 132.3, 129.9, 129.7, 129.0, 128.9, 128.8, 127., 121.7, 120.8 (q, J = 319 Hz), 116.6, 79.7, 39.1.
 13 C NMR (125 MHz, CDCl 3 ) δ 154.8, 144.0, 140.0, 137.4, 132.3, 129.9, 129.7, 129.0, 128.9, 128.8, 127., 121.7, 120.8 (q, J = 319 Hz), 116.6, 79.7, 39.1.

실시예Example 15: 1-(4- 15: 1- (4- 브로모Bromo -2--2- 메틸페닐Methylphenyl )) 옥시메틸Oxymethyl -3--3- 메틸methyl -4--4- 페닐Phenyl -1,2,3--1,2,3- 트리아졸륨Triazolium 트리플루오로메탄설포네이트Trifluoromethanesulfonate (1n)의 제조 Preparation of (1n)

Figure pat00044

Figure pat00044

실시예 12에서 사용한 2-나프톨 (7a) 대신에 4-브로모-2-메틸페놀 (7g, 561 mg, 3.0 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 1-(4-바이페닐)옥시메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1n, 1.14 g, 75%)을 얻었다. Proceed in the same manner except using 4-bromo-2-methylphenol ( 7g , 561 mg, 3.0 mmol) instead of 2-naphthol ( 7a ) used in Example 12 and proceeding with 1- (4-biphenyl ) Oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1n , 1.14 g, 75%) was obtained.

1H NMR (500 MHz, CDCl3) δ 2.20 (s, 3H), 4.28 (s, 3H), 7.04 (d, J = 9.5 Hz, 2H), 7.31-7.27 (m, 2H), 7.61-7.53 (m, 5H), 8.83 (s, 1H); 1 H NMR (500 MHz, CDCl 3 ) δ 2.20 (s, 3H), 4.28 (s, 3H), 7.04 (d, J = 9.5 Hz, 2H), 7.31-7.27 (m, 2H), 7.61-7.53 ( m, 5H), 8.83 (s, 1 H);

13C NMR (125 MHz, CDCl3) δ 152.8, 144.0, 134.5, 132.3, 130.5, 130.4, 129.9, 129.7, 128.9, 121.7, 120.7 (q, J = 319 Hz), 116.6, 115.3, 79.6, 39.1, 16.1.
 13 C NMR (125 MHz, CDCl 3 ) δ 152.8, 144.0, 134.5, 132.3, 130.5, 130.4, 129.9, 129.7, 128.9, 121.7, 120.7 (q, J = 319 Hz), 116.6, 115.3, 79.6, 39.1, 16.1 .

실시예Example 16: 1-(3,4- 16: 1- (3,4- 디메톡시페닐Dimethoxyphenyl )) 옥시메틸Oxymethyl -3--3- 메틸methyl -4--4- 페닐Phenyl -1,2,3--1,2,3- 트리아졸륨Triazolium 트리플루오로메탄설포네이트 (1o)의 제조 Preparation of Trifluoromethanesulfonate (1o)

Figure pat00045

Figure pat00045

실시예 12에서 사용한 2-나프톨 (7a) 대신에 3,4-디메톡시페놀 (7h, 462 mg, 3.0 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 1-(3,4-디메톡시페닐)옥시메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1o, 927 mg, 65%)을 얻었다. Proceed in the same manner except using 3,4-dimethoxyphenol ( 7h , 462 mg, 3.0 mmol) instead of 2-naphthol ( 7a ) used in Example 12 and proceeding with 1- (3,4-dimethoxy Phenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1o , 927 mg, 65%) was obtained.

1H NMR (500 MHz, CDCl3) δ 3.79 (s, 3H), 3.82 (s, 3H), 4.24 (s, 3H), 6.43 (s, 2H), 6.62 (dd, J = 8.5, 2.8 Hz, 1H), 6.68 (s, 1H), 6.76 (d, J = 8.5 Hz, 1H), 7.58-7.48 (m, 5H), 8.72 (s, 1H); 1 H NMR (500 MHz, CDCl 3 ) δ 3.79 (s, 3H), 3.82 (s, 3H), 4.24 (s, 3H), 6.43 (s, 2H), 6.62 (dd, J = 8.5, 2.8 Hz, 1H), 6.68 (s, 1H), 6.76 (d, J = 8.5 Hz, 1H), 7.58-7.48 (m, 5H), 8.72 (s, 1H);

13C NMR (125 MHz, CDCl3) δ 105.2, 149.4, 146.0, 143.8, 132.2, 129.8, 129.5, 128.6, 121.7, 120.7 (q, J = 319 Hz), 111.7, 106.8, 102.4, 80.6, 56.3, 56.2, 39.0.
 13 C NMR (125 MHz, CDCl 3 ) δ 105.2, 149.4, 146.0, 143.8, 132.2, 129.8, 129.5, 128.6, 121.7, 120.7 (q, J = 319 Hz), 111.7, 106.8, 102.4, 80.6, 56.3, 56.2 , 39.0.

실시예Example 17: 3- 17: 3- 메틸methyl -1-(4--1- (4- 니트로페닐Nitrophenyl )) 옥시메틸Oxymethyl -4--4- 페닐Phenyl -1,2,3--1,2,3- 트리아졸륨Triazolium 트리플루오로메탄설포네이트Trifluoromethanesulfonate (1p)의 제조 (1p)

Figure pat00046

Figure pat00046

실시예 12에서 사용한 2-나프톨 (7a) 대신에 4-니트로페놀 (7i, 417 mg, 3.0 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 3-메틸-1-(4-니트로페닐)옥시메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1p, 898 mg, 65%)을 얻었다. Proceed in the same manner except 4-nitrophenol ( 7i , 417 mg, 3.0 mmol) instead of 2-naphthol ( 7a ) used in Example 12, proceeding in the same manner as 3-methyl-1- (4-nitrophenyl) Oxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1p , 898 mg, 65%) was obtained.

1H NMR (500 MHz, CDCl3) δ 4.36 (s, 3H), 6.79 (s, 2H), 7.41 (d, J = 9.5 Hz, 2H), 7.72-7.64 (m, 5H), 8.30 (d, J = 9.5 Hz, 2H); 1 H NMR (500 MHz, CDCl 3 ) δ 4.36 (s, 3H), 6.79 (s, 2H), 7.41 (d, J = 9.5 Hz, 2H), 7.72-7.64 (m, 5H), 8.30 (d, J = 9.5 Hz, 2H);

13C NMR (125 MHz, CDCl3) δ 160.1, 144.2, 143.8, 131.8, 129.4, 129.2, 125.7, 122.1, 120.4 (d, J = 317 Hz, only two peaks of quartet of CF3-C were shown), 116.3, 78.5, 38.3.
 13 C NMR (125 MHz, CDCl 3 ) δ 160.1, 144.2, 143.8, 131.8, 129.4, 129.2, 125.7, 122.1, 120.4 (d, J = 317 Hz, only two peaks of quartet of CF 3 -C were shown), 116.3, 78.5, 38.3.

실시예Example 18: 1-(4- 18: 1- (4- 아세틸아미노페닐Acetylaminophenyl )) 옥시메틸Oxymethyl -3--3- 메틸methyl -4--4- 페닐Phenyl -1,2,3--1,2,3- 트리아졸륨Triazolium 트리플루오로메탄설포네이트Trifluoromethanesulfonate (1q)의 제조 Preparation of (1q)

Figure pat00047

Figure pat00047

실시예 12에서 사용한 2-나프톨 (7a) 대신에 3-아세트아미노페놀 (7j, 453 mg, 3.0 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 1-(4-아세틸아미노페닐)옥시메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1q, 1.08 g, 76%)을 얻었다. Proceed in the same manner except using 3-acetaminophenol ( 7j , 453 mg, 3.0 mmol) instead of 2-naphthol ( 7a ) used in Example 12 and proceeding with 1- (4-acetylaminophenyl) oxymethyl 3-Methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1q , 1.08 g, 76%) was obtained.

1H NMR (500 MHz, CDCl3) δ 2.09 (s, 3H), 6.41 (s, 2H) 4.26 (s, 3H), 6.72 (dd, J = 8.3, 2.3 Hz, 1H), 7.20-7.15 (m, 2H), 7.63-7.49 (m, 5H), 7.66 (d, J = 8.0 Hz, 1H), 8.70 (s, 1H), 8.93 (s, 1H); 1 H NMR (500 MHz, CDCl 3 ) δ 2.09 (s, 3H), 6.41 (s, 2H) 4.26 (s, 3H), 6.72 (dd, J = 8.3, 2.3 Hz, 1H), 7.20-7.15 (m , 2H), 7.63-7.49 (m, 5H), 7.66 (d, J = 8.0 Hz, 1H), 8.70 (s, 1H), 8.93 (s, 1H);

13C NMR (125 MHz, CDCl3) δ 170.0, 155.4, 144.1, 140.9, 132.5, 130.8, 130.0, 129.7, 128.3, 121.7, 120.7 (q, J = 318 Hz), 116.0, 112.5, 106.6, 80.1, 39.2, 24.5.
 13 C NMR (125 MHz, CDCl 3 ) δ 170.0, 155.4, 144.1, 140.9, 132.5, 130.8, 130.0, 129.7, 128.3, 121.7, 120.7 (q, J = 318 Hz), 116.0, 112.5, 106.6, 80.1, 39.2 , 24.5.

실시예Example 19: 1-(3- 19: 1- (3- OO -- 에스트로닐Estroneil )) 메틸methyl -3--3- 메틸methyl -4--4- 페닐Phenyl -1,2,3--1,2,3- 트리아졸륨Triazolium 트리플루오로메탄설포네이트Trifluoromethanesulfonate (1r)의 제조 Preparation of (1r)

Figure pat00048

Figure pat00048

실시예 12에서 사용한 2-나프톨 (7a) 대신에 에스트론 (7k, 811 mg, 3.0 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 1-(3-O-에스트로닐)메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1r, 1.26 g, 71%)을 얻었다. Proceed in the same manner except using estrone ( 7k , 811 mg, 3.0 mmol) instead of 2-naphthol ( 7a ) used in Example 12 and proceeding with 1- (3- O -estronyl) methyl-3- Methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1r , 1.26 g, 71%) was obtained.

1H NMR (500 MHz, CDCl3) δ 0.89 (s, 3H), 1.64-1.39 (m, 6H), 1.95-1.93 (m, 1H), 2.16-1.98 (m, 4H), 2.24-2.20 (m, 1H), 2.37-2.35 (m, 1H), 2.49 (dd, J = 19.0, 8.5 Hz, 2H), 2.92-2.90 (m, 2H), 4.27 (s, 3H), 6.50 (s, 2H), 6.88-6.87 (m, 2H), 7.24 (d, J = 9.5 Hz, 1H), 7.62-7.55 (m, 5H), 8.70 (s, 1H); 1 H NMR (500 MHz, CDCl 3 ) δ 0.89 (s, 3H), 1.64-1.39 (m, 6H), 1.95-1.93 (m, 1H), 2.16-1.98 (m, 4H), 2.24-2.20 (m , 1H), 2.37-2.35 (m, 1H), 2.49 (dd, J = 19.0, 8.5 Hz, 2H), 2.92-2.90 (m, 2H), 4.27 (s, 3H), 6.50 (s, 2H), 6.88-6.87 (m, 2H), 7.24 (d, J = 9.5 Hz, 1H), 7.62-7.55 (m, 5H), 8.70 (s, 1H);

13C NMR (125 MHz, CDCl3) δ 220.7, 153.5, 144.0, 139.3, 136.1, 132.3, 129.9, 129.7, 128.7, 127.2, 121.8, 120.8 (q, J = 319 Hz), 116.3, 113.5, 80.0, 50.6, 48.1, 44.2, 39.0, 38.3, 36.0, 31.7, 29.6, 26.5, 26.0, 21.7, 14.0.
 13 C NMR (125 MHz, CDCl 3 ) δ 220.7, 153.5, 144.0, 139.3, 136.1, 132.3, 129.9, 129.7, 128.7, 127.2, 121.8, 120.8 (q, J = 319 Hz), 116.3, 113.5, 80.0, 50.6 , 48.1, 44.2, 39.0, 38.3, 36.0, 31.7, 29.6, 26.5, 26.0, 21.7, 14.0.

실시예Example 20: 3- 20: 3- 아세트나프틸Acetnaphthyl -1--One- 메틸이미다졸륨Methylimidazolium (1s)의 제조 Manufacture of 1s

Figure pat00049

Figure pat00049

2-브로모-2-아세토나프톤 (10a, 2.49 g, 10 mmol)을 아세토니트릴 (50 mL)에 녹인 후, 메틸이미다졸 (11a, 0.836 mL, 10.5 mmol)을 첨가한 뒤 80도 가열조건에서 12시간 동안 교반시켰다. 반응이 종결되면 반응 용매를 감압하여 제거한 후에 컬럼 크로마토그래피 (10% 메탄올/다이클로로메탄)를 수행하여 목적화합물 3-아세트나프틸-1-메틸이미다졸륨 (1s, 3.08 g, 93%)를 얻었다.2-bromo-2-acetonaphtone ( 10a , 2.49 g, 10 mmol) was dissolved in acetonitrile (50 mL), followed by addition of methylimidazole ( 11a , 0.836 mL, 10.5 mmol) and heating at 80 degrees. Stirred under conditions for 12 hours. After the reaction was completed, the reaction solvent was removed under reduced pressure, and then column chromatography (10% methanol / dichloromethane) was carried out to obtain the desired compound 3-acetnaphthyl-1-methylimidazolium ( 1s , 3.08 g, 93%). Got it.

1H NMR (500 MHz, CDCl3) δ 4.02 (s, 3H), 6.15 (s, 2H), 7.68 (m, 4H), 7.99 (m, 4H), 8.74 (s, 1H), 9.01 (s, 1H); 1 H NMR (500 MHz, CDCl 3 ) δ 4.02 (s, 3H), 6.15 (s, 2H), 7.68 (m, 4H), 7.99 (m, 4H), 8.74 (s, 1H), 9.01 (s, 1H);

13C NMR (125 MHz, CDCl3) δ 191.3, 139.5, 137.7, 134.0, 132.5, 130.9, 130.5, 130.0, 129.4, 129.0,128.7, 125.4, 124.6, 124.3, 56.3, 36.8.
 13 C NMR (125 MHz, CDCl 3 ) δ 191.3, 139.5, 137.7, 134.0, 132.5, 130.9, 130.5, 130.0, 129.4, 129.0, 128.7, 125.4, 124.6, 124.3, 56.3, 36.8.

실시예Example 21:  21: 친핵성Nucleophilicity 플루오르화 반응 Fluorination reaction

Figure pat00050

Figure pat00050

상기 실시예 1에서 얻은 4-tert-부틸-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1a, 0.5 mmol)와 테트라부틸암모늄 플루오라이드 (TBAF, 0.75 mmol)을 반응용기에 넣은 다음 아세토니트릴 (2.0 mL)을 가하여 녹인 뒤 80℃ 가열 조건에서 1시간 동안 교반시켰다. 물을 가하여 반응을 종결시킨 다음, 디클로로메탄으로 유기화합물을 추출하였다. 추출된 디클로로메탄 용액을 무수 황산 나트륨으로 처리한 뒤 컬럼 크로마토그래피 (2% 에틸아세테이트/헥산)를 수행하여 목적화합물인 2-플루오로메톡시나프탈렌의 (12a, 78 mg, 89%)를 얻었다.4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a , 0.5 mmol) and tetra obtained in Example 1 above Butyl ammonium fluoride (TBAF, 0.75 mmol) was added to the reaction vessel, acetonitrile (2.0 mL) was added thereto, dissolved, and the mixture was stirred at 80 ° C. for 1 hour. Water was added to terminate the reaction, and then the organic compound was extracted with dichloromethane. The extracted dichloromethane solution was treated with anhydrous sodium sulfate and column chromatography (2% ethyl acetate / hexane) was carried out to obtain ( 12a , 78 mg, 89%) of the target compound 2-fluoromethoxynaphthalene.

1H NMR (500 MHz, CDCl3) δ 5.85 (d, J = 55.0 Hz, 2H), 7.29 (dd, J = 9.0, 2.5 Hz, 1H), 7.44 (t, J = 7.3 Hz, 1H), 7.52-7.49 (m, 2H), 7.81 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 9.0 Hz, 2H); 1 H NMR (500 MHz, CDCl 3 ) δ 5.85 (d, J = 55.0 Hz, 2H), 7.29 (dd, J = 9.0, 2.5 Hz, 1H), 7.44 (t, J = 7.3 Hz, 1H), 7.52 -7.49 (m, 2H), 7.81 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 9.0 Hz, 2H);

13C NMR (125 MHz, CDCl3) δ 154.9, 134.5, 130.5, 130.1, 128.0, 127.6, 126.9, 125.1, 118.8, 111.4, 101.1 (d, J = 218 Hz).
 13 C NMR (125 MHz, CDCl 3 ) δ 154.9, 134.5, 130.5, 130.1, 128.0, 127.6, 126.9, 125.1, 118.8, 111.4, 101.1 (d, J = 218 Hz).

실시예Example 22: 다양한 유기용매 조건하에서 플루오르화 반응 22: Fluorination Reaction Under Various Organic Solvent Conditions

상기 실시예 1에서 얻은 4-tert-부틸-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1a, 0.5 mmol)와 테트라부틸암모늄 플루오라이드 (TBAF, 196 mg, 0.75 mmol)을 사용하고 아세토니트릴 용매 대신에 tert-부탄올, 테트라하이드로퓨란, 디메틸포름아마이드와 같은 다양한 유기용매 (2.0 mL)를 사용하여 상기 실시예 20과 동일한 방법으로 플루오르화 반응을 진행시켰다. 각각의 반응에 대해 반응시간을 확인하였으며 플루오르화 반응에 대한 생성물인 2-플루오로메톡시나프탈렌의 생성량을 측정하였다. 측정된 결과는 하기 표 1에 나타내었다. 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a , 0.5 mmol) and tetra obtained in Example 1 above The same as Example 20 above using butylammonium fluoride (TBAF, 196 mg, 0.75 mmol) and various organic solvents (2.0 mL) such as tert-butanol, tetrahydrofuran, dimethylformamide instead of acetonitrile solvent The fluorination reaction was advanced by the method. The reaction time was confirmed for each reaction and the amount of 2-fluoromethoxynaphthalene which was a product for the fluorination reaction was measured. The measured results are shown in Table 1 below.

Figure pat00051
Figure pat00051

용매menstruum 시간 (분)Time (min) 수율 (%)Yield (%) MeCNMeCN 6060 8989 t-BuOHt-BuOH 6060 8181 THFTHF 4040 8585 DMFDMF 2020 7979

실시예Example 22: 다양한  22: various 플루오로화Fluorination 시약을 사용한 반응 Reaction with reagent

상기 실시예 1에서 얻은 4-tert-부틸-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1a, 0.5 mmol)을 사용하고 플루오로화 시약으로 테트라부틸암모늄 플루오라이드 대신에 세슘플루오라이드를 사용하여 상기 실시예 21과 동일한 방법으로 플루오르화 반응을 진행시켰다. 각각의 반응에 대해 반응시간을 확인하였으며 플루오르화 반응에 대한 생성물인 2-플루오로메톡시나프탈렌의 생성량을 측정하였다. 측정된 결과는 하기 표 2에 나타내었다. 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a , 0.5 mmol) obtained in Example 1 was used. The fluorination reaction was carried out in the same manner as in Example 21 using cesium fluoride instead of tetrabutylammonium fluoride as the fluorination reagent. The reaction time was confirmed for each reaction and the amount of 2-fluoromethoxynaphthalene which was a product for the fluorination reaction was measured. The measured results are shown in Table 2 below.

Figure pat00052
Figure pat00052

MF (당량)MF (equivalent) 시간time 수율 (%)Yield (%) CsF (3.0)CsF (3.0) 24 시간24 hours 3838 TBAF (1.5)TBAF (1.5) 60 분60 minutes 8989

실시예Example 24: 2-(3- 24: 2- (3- 플루오르메톡시Fluoromethoxy -- nn -- 프로폭시Propoxy )나프탈렌 (12b)의 제조Preparation of Naphthalene (12b)

Figure pat00053

Figure pat00053

실시예 21에서 사용한 4-tert-부틸-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1a) 대신에 3-메틸-1-[3-(2-나프톡시)-n-프로필]옥시메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1h, 262 mg, 0.5 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 2-(3-플루오르메톡시-n-프로폭시)나프탈렌 (12b, 90 mg, 77%)을 얻었다. 3-methyl- instead of 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a ) used in Example 21 Using 1- [3- (2-naphthoxy) -n -propyl] oxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1h , 262 mg, 0.5 mmol) The procedure was followed in the same manner except to obtain 2- (3-fluoromethoxy- n -propoxy) naphthalene ( 12b , 90 mg, 77%).

1H NMR (500 MHz, CDCl3) δ 2.19 (q, J = 6.1 Hz, 2H), 3.98 (td, J = 6.3, 2.0 Hz, 2H), 4.21 (t, J = 6.0 Hz, 2H), 5.30 (d, J = 56.0 Hz, 2H), 7.16-7.14 (m, 2H), 7.34 (td, J = 7.5, 1.2 Hz, 1H), 7.45 (td, J = 7.5, 2.0 Hz, 1H), 7.78-7.72 (m, 3H); 1 H NMR (500 MHz, CDCl 3 ) δ 2.19 (q, J = 6.1 Hz, 2H), 3.98 (td, J = 6.3, 2.0 Hz, 2H), 4.21 (t, J = 6.0 Hz, 2H), 5.30 (d, J = 56.0 Hz, 2H), 7.16-7.14 (m, 2H), 7.34 (td, J = 7.5, 1.2 Hz, 1H), 7.45 (td, J = 7.5, 2.0 Hz, 1H), 7.78- 7.72 (m, 3 H);

13C NMR (125 MHz, CDCl3) δ 154.9, 134.5, 130.5, 130.1, 128.0, 127.6, 126.9, 125.1, 118.8, 111.4, 101.1 (d, J = 218 Hz).
 13 C NMR (125 MHz, CDCl 3 ) δ 154.9, 134.5, 130.5, 130.1, 128.0, 127.6, 126.9, 125.1, 118.8, 111.4, 101.1 (d, J = 218 Hz).

실시예Example 25: 2-(2- 25: 2- (2- 플루오르메톡시Fluoromethoxy -3--3- 메탄설포닐옥시Methanesulfonyloxy -- nn -- 프로폭시Propoxy )나프탈렌 (12c)의 제조Preparation of Naphthalene (12c)

Figure pat00054

Figure pat00054

실시예 21에서 사용한 4-tert-부틸-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1a) 대신에 1-[1-메틸설포닐옥시-3-(2-나프틸)-2-옥시프로필]옥시메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1i, 310 mg, 0.5 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 2-(2-플루오르메톡시-3-메탄설포닐옥시-n-프로폭시)나프탈렌 (12c, 110 mg, 67%)을 얻었다.
1- [1 instead of 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a ) used in Example 21 -Methylsulfonyloxy-3- (2-naphthyl) -2-oxypropyl] oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1i , 310 mg , (0.5 mmol) was used in the same manner to obtain 2- (2-fluoromethoxy-3-methanesulfonyloxy- n -propoxy) naphthalene ( 12c , 110 mg, 67%).

1H NMR (500 MHz, CDCl3) δ 3.06 (s, 3H), 4.37-4.23 (m, 3H), 4.58-4.49 (m, 2H), 5.46 (ddd, J = 55.8, 17.5, 3.0 Hz, 2H), 7.16-7.14 (m, 2H), 7.37 (td, J = 8.0, 1.0 Hz, 1H), 7.47 (td, J = 8.3, 1.3 Hz, 1H), 7.76 (q, J = 9.00 Hz, 3H); 1 H NMR (500 MHz, CDCl 3 ) δ 3.06 (s, 3H), 4.37-4.23 (m, 3H), 4.58-4.49 (m, 2H), 5.46 (ddd, J = 55.8, 17.5, 3.0 Hz, 2H ), 7.16-7.14 (m, 2H), 7.37 (td, J = 8.0, 1.0 Hz, 1H), 7.47 (td, J = 8.3, 1.3 Hz, 1H), 7.76 (q, J = 9.00 Hz, 3H) ;

13C NMR (125 MHz, CDCl3) δ 156.1, 134.6, 130.0, 129.5, 127.9, 127.1, 126.9, 124.4, 118.7, 107.2, 103.8 (d, J = 216 Hz), 69.1, 67.0, 37.8.
 13 C NMR (125 MHz, CDCl 3 ) δ 156.1, 134.6, 130.0, 129.5, 127.9, 127.1, 126.9, 124.4, 118.7, 107.2, 103.8 (d, J = 216 Hz), 69.1, 67.0, 37.8.

실시예Example 26: (2- 26: (2- 플루오르메톡시Fluoromethoxy )-2-메틸나프탈렌 (12d)의 제조) -2-methylnaphthalene (12d) Preparation

Figure pat00055
Figure pat00055

실시예 21에서 사용한 4-tert-부틸-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1a) 대신에 3-메틸-(2-나프틸)메틸옥시메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1j, 240 mg, 0.5 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 (2-플루오르메톡시)-2-메틸나프탈렌 (12d, 75 mg, 79%)을 얻었다. 3-methyl- instead of 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a ) used in Example 21 Proceed in the same manner except using (2-naphthyl) methyloxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1j , 240 mg, 0.5 mmol) ( 2-fluoromethoxy) -2-methylnaphthalene ( 12d , 75 mg, 79%) was obtained.

1H NMR (500 MHz, CDCl3) δ 4.95 (s, 2H), 5.40 (d, J = 56.4 Hz, 2H), 7.75 Hz, 2H), 7.51-7.47 (m, 3H), 7.87-7.83 (m, 4H); 1 H NMR (500 MHz, CDCl 3 ) δ 4.95 (s, 2H), 5.40 (d, J = 56.4 Hz, 2H), 7.75 Hz, 2H), 7.51-7.47 (m, 3H), 7.87-7.83 (m , 4H);

13C NMR (125 MHz, CDCl3) δ 134.0, 133.4, 133.3, 128.6, 128.1, 127.9, 127.2, 126.5, 126.4, 125.9, 102.9 (d, J = 213 Hz), 72.0.
 13 C NMR (125 MHz, CDCl 3 ) δ 134.0, 133.4, 133.3, 128.6, 128.1, 127.9, 127.2, 126.5, 126.4, 125.9, 102.9 (d, J = 213 Hz), 72.0.

실시예Example 27: O- 27: O- 플루오로메틸Fluoromethyl -N--N- BOCBOC -L-티로신-L-tyrosine terttert -부틸 에스터 (12e)의 제조Preparation of -Butyl Ester 12e

Figure pat00056

Figure pat00056

실시예 21에서 사용한 4-tert-부틸-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1a) 대신에 (S)-1-(4-(2-BOC-아미노-2-(t-부톡시카보닐)에틸)페닐옥시 메틸)-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1k, 0.22g, 0.36 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 O-플루오로메틸-N-BOC-L-티로신-tert-부틸 에스터 (12e, 75 mg, 60%)를 얻었다.(S)-instead of 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a ) used in Example 21 1- (4- (2-BOC-amino-2- (t-butoxycarbonyl) ethyl) phenyloxy methyl) -3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfo Proceed in the same manner except using Nate ( 1k , 0.22g, 0.36 mmol) to give O-fluoromethyl-N-BOC-L-tyrosine-tert-butyl ester ( 12e , 75 mg, 60%). Got it.

1H NMR (400 MHz, CDCl3) δ 1.42 (d, J = 4.0 Hz, 18H), 3.01-3.04 (m, 2H), 4.42 (d, J = 6.8 Hz, 1H), 4.98 (d, J = 6.8 Hz, 1H), 5.62 (s, 1H), 5.76 (s, 1H), 7.00 (d, J= 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H).
1 H NMR (400 MHz, CDCl 3 ) δ 1.42 (d, J = 4.0 Hz, 18H), 3.01-3.04 (m, 2H), 4.42 (d, J = 6.8 Hz, 1H), 4.98 (d, J = 6.8 Hz, 1H), 5.62 (s, 1H), 5.76 (s, 1H), 7.00 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H).

실시예Example 28: 4- 28: 4- 플루오르메톡시바이페닐Fluoromethoxybiphenyl (12e)의 제조 Preparation of 12e

Figure pat00057

Figure pat00057

실시예 21에서 사용한 4-tert-부틸-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1a) 대신에 1-(4-바이페닐)옥시메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1m, 246 mg, 0.5 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 4-플루오르메톡시바이페닐 (12f, 74 mg, 73%)을 얻었다. 1- (4 instead of 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a ) used in Example 21 -Biphenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1m , 246 mg, 0.5 mmol) 4- Fluoromethoxybiphenyl ( 12f , 74 mg, 73%) was obtained.

1H NMR (500 MHz, CDCl3) δ 5.78 (d, J = 55.0 Hz, 2H), 7.21 (d, J = 9.0 Hz, 2H), 7.39 (td, J = 7.5, 1.0 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H), 7.61 (d, J = 8.5 Hz, 4H); 1 H NMR (500 MHz, CDCl 3 ) δ 5.78 (d, J = 55.0 Hz, 2H), 7.21 (d, J = 9.0 Hz, 2H), 7.39 (td, J = 7.5, 1.0 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H), 7.61 (d, J = 8.5 Hz, 4H);

13C NMR (125 MHz, CDCl3) δ 156.59, 156.57, 140.7, 136.9, 129.1, 128.7, 127.4, 127.2, 117.23, 117.22, 101.0 (d, J = 218 Hz).
 13 C NMR (125 MHz, CDCl 3 ) δ 156.59, 156.57, 140.7, 136.9, 129.1, 128.7, 127.4, 127.2, 117.23, 117.22, 101.0 (d, J = 218 Hz).

실시예Example 29: 5- 29: 5- 브로모Bromo -2--2- 플루오르메톡시톨루엔Fluoromethoxytoluene (12g)의 제조 (12g) Preparation

Figure pat00058

Figure pat00058

실시예 21에서 사용한 4-tert-부틸-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1a) 대신에 1-(4-브로모-2-메틸페닐)옥시메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1n, 254 mg, 0.5 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 5-브로모-2-플루오르메톡시톨루엔 (12g, 91 mg, 83%)을 얻었다. 1- (4 instead of 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a ) used in Example 21 -Bromo-2-methylphenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1n , 254 mg, 0.5 mmol) same Proceed to the method 5-bromo-2-fluoromethoxytoluene ( 12g , 91 mg, 83%) was obtained.

1H NMR (500 MHz, CDCl3) δ 2.24 (s, 3H), 5.70 (d, J = 54.5 Hz, 2H), 6.95 (d, J = 8.5 Hz, 1H) 7.31 (m, 2H); 1 H NMR (500 MHz, CDCl 3 ) δ 2.24 (s, 3H), 5.70 (d, J = 54.5 Hz, 2H), 6.95 (d, J = 8.5 Hz, 1H) 7.31 (m, 2H);

13C NMR (125 MHz, CDCl3) δ 154.4, 133.9, 130.5, 130.0, 116.6, 116.0, 101.0 (d, J = 218 Hz), 16.2.
 13 C NMR (125 MHz, CDCl 3 ) δ 154.4, 133.9, 130.5, 130.0, 116.6, 116.0, 101.0 (d, J = 218 Hz), 16.2.

실시예Example 30: 4- 30: 4- 플루오르메톡시Fluoromethoxy -1,2--1,2- 디메톡시벤젠Dimethoxybenzene (12h)의 제조 Preparation of 12h

Figure pat00059
Figure pat00059

실시예 21에서 사용한 4-tert-부틸-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1a) 대신에 1-(3,4-디메톡시페닐)옥시메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1o, 238 mg, 0.5 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 4-플루오르메톡시-1,2-디메톡시벤젠 (12h, 70 mg, 75%)을 얻었다. 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate (1a1- (3,4-dimethoxyphenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate (1o, 238 mg, 0.5 mmol) was used in the same manner to yield 4-fluoromethoxy-1,2-dimethoxybenzene (12h, 70 mg, 75%).

1H NMR (500 MHz, CDCl3) δ 3.84 (s, 3H), 3.85 (s, 3H), 5.64 (d, J = 55.0 Hz, 2H), 6.65-6.61 (m, 2H), 6.78 (d, J = 8.5 Hz, 1H); 1 H NMR (500 MHz, CDCl 3 ) δ 3.84 (s, 3H), 3.85 (s, 3H), 5.64 (d, J = 55.0 Hz, 2H), 6.65-6.61 (m, 2H), 6.78 (d, J = 8.5 Hz, 1H);

13C NMR (125 MHz, CDCl3) δ 151.3, 149.8, 145.5, 111.6, 107.6, 102.6, 101.8 (d, J = 217 Hz), 56.4, 56.0.
 13 C NMR (125 MHz, CDCl 3 ) δ 151.3, 149.8, 145.5, 111.6, 107.6, 102.6, 101.8 (d, J = 217 Hz), 56.4, 56.0.

실시예Example 31: 4- 31: 4- 플루오르메톡시Fluoromethoxy -1-니트로벤젠 (12i)의 제조Preparation of -1-nitrobenzene (12i)

Figure pat00060

Figure pat00060

실시예 21에서 사용한 4-tert-부틸-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1a) 대신에 3-메틸-1-(4-니트로페닐)옥시메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1p, 230 mg, 0.5 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 4-플루오르메톡시-1-니트로벤젠 (12i, 62 mg, 72%)을 얻었다. 3-methyl- instead of 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a ) used in Example 21 Proceed in the same manner except using 1- (4-nitrophenyl) oxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1p , 230 mg, 0.5 mmol) 4-Fluoromethoxy-1-nitrobenzene ( 12i , 62 mg, 72%) was obtained.

1H NMR (500 MHz, CDCl3) δ 5.79 (d, J = 53.0 Hz, 2H), 7.18-7.17 (m, 2H), 8.26-8.24 (m, 2H); 1 H NMR (500 MHz, CDCl 3 ) δ 5.79 (d, J = 53.0 Hz, 2H), 7.18-7.17 (m, 2H), 8.26-8.24 (m, 2H);

13C NMR (125 MHz, CDCl3) δ 161.3, 143.7, 126.1, 116.6, 99.8 (d, J = 221 Hz).
 13 C NMR (125 MHz, CDCl 3 ) δ 161.3, 143.7, 126.1, 116.6, 99.8 (d, J = 221 Hz).

실시예Example 32:  32: NN -(3-- (3- 플루오르메톡시페닐Fluoromethoxyphenyl )) 아세트아마이드Acetamide (12j)의 제조 Preparation of 12j

Figure pat00061

Figure pat00061

실시예 21에서 사용한 4-tert-부틸-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1a) 대신에 1-(4-아세틸아미노페닐)옥시메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1q, 236 mg, 0.5 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 N-(3-플루오르메톡시페닐)아세트아마이드 (12j, 70 mg, 76%)을 얻었다. 1- (4 instead of 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a ) used in Example 21 -Acetylaminophenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1q , 236 mg, 0.5 mmol) proceeds in the same manner To give N- (3-fluoromethoxyphenyl) acetamide ( 12j , 70 mg, 76%).

1H NMR (500 MHz, CDCl3) δ 2.20 (s, 3H), 5.72 (d, J = 54.5 Hz, 2H), 6.85 (d, J = 7.0 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.29-7.26 (m, 1H), 7.41 (s, 1H), 7.46 (bs, 1H); 1 H NMR (500 MHz, CDCl 3 ) δ 2.20 (s, 3H), 5.72 (d, J = 54.5 Hz, 2H), 6.85 (d, J = 7.0 Hz, 1H), 7.20 (d, J = 7.5 Hz , 1H), 7.29-7.26 (m, 1H), 7.41 (s, 1H), 7.46 (bs, 1 H);

13C NMR (125 MHz, CDCl3) δ 168.7, 157.4, 139.5, 130.2, 115.0, 112.5, 108.7, 100.9 (d, J = 218 Hz), 24.9.
 13 C NMR (125 MHz, CDCl 3 ) δ 168.7, 157.4, 139.5, 130.2, 115.0, 112.5, 108.7, 100.9 (d, J = 218 Hz), 24.9.

실시예Example 33: 3 33: 3 -O--O- 플루오르메틸에스트론Fluoromethyl Estrone (12j)의 제조 Preparation of 12j

Figure pat00062

Figure pat00062

실시예 21에서 사용한 4-tert-부틸-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1a) 대신에 1-(3-O-에스트로닐)메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1r, 296 mg, 0.5 mmol)를 사용하는 것을 제외하고는 동일한 방법으로 진행하여 3-O-플루오르메틸에스트론 (12k, 125 mg, 83%)을 얻었다.1- (3 instead of 4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate ( 1a ) used in Example 21 In the same manner except using O -estronyl) methyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1r , 296 mg, 0.5 mmol) Proceeded to 3 -O- fluoromethyl estrone ( 12k , 125 mg, 83%).

1H NMR (500 MHz, CDCl3) δ 0.89 (s, 3H), 1.66-1.39 (m, 7H), 2.16-1.93 (m, 5H), 2.25-2.20 (m, 1H), 2.40-2.36 (m, 1H), 2.48 (dd, J = 19.0, 8.5 Hz, 1H), 2.89 (t, J = 4.3 Hz, 2H), 5.66 (d, J = 55.0 Hz, 2H), 6.81 (d, J = 2.5 Hz, 1H), 6.86 (dd, J = 8.5, 2.5 Hz, 1H), 7.22 (d, J = 8.5 Hz, 4H); 1 H NMR (500 MHz, CDCl 3 ) δ 0.89 (s, 3H), 1.66-1.39 (m, 7H), 2.16-1.93 (m, 5H), 2.25-2.20 (m, 1H), 2.40-2.36 (m , 1H), 2.48 (dd, J = 19.0, 8.5 Hz, 1H), 2.89 (t, J = 4.3 Hz, 2H), 5.66 (d, J = 55.0 Hz, 2H), 6.81 (d, J = 2.5 Hz , 1H), 6.86 (dd, J = 8.5, 2.5 Hz, 1H), 7.22 (d, J = 8.5 Hz, 4H);

13C NMR (125 MHz, CDCl3) δ 220.9, 155.1, 138.4, 135.2, 126.8, 117.0, 114.3, 101.1 (d, J = 217 Hz), 50.6, 48.2, 44.2, 38.4, 36.1, 31.8, 29.8, 26.7, 21.8, 14.1.
 13 C NMR (125 MHz, CDCl 3 ) δ 220.9, 155.1, 138.4, 135.2, 126.8, 117.0, 114.3, 101.1 (d, J = 217 Hz), 50.6, 48.2, 44.2, 38.4, 36.1, 31.8, 29.8, 26.7, 21.8, 14.1.

실시예Example 34: 3 34: 3 -O--O- [[ 1818 F]-F]- 플루오르메틸에스트론Fluoromethyl Estrone ([ ([ 1818 F]12k)의 제조F] 12k) production

Figure pat00063

Figure pat00063

크로마픽스 (Chromafix®)에 증류수 (2.0 mL)와 0.2 M 소듐 메탄설포네이트 수용액 (2.0 mL)을 차례대로 흘려주고 다시 증류수 (2.0 mL)를 이용하여 세척하였다. 싸이클로트론에서 생산된 [18F]플루오라이드 [18O]H2O 용액(1-10 mCi)을 서서히 흘려준 뒤 증류수(2.0 mL)를 이용하여 세척하였다. [18F]플루오라이드가 잡힌 카트리지에 메탄올(2.0 mL)을 흘려주어 수분을 제거하고 0.1 M 테트라부틸암모늄 메탄설포네이트 용액 (0.5 mL)을 흘려주어 [18F]플루오라이드 이온을 용출해 내었다. 100 oC로 가열하며 질소를 불어주어 용매를 제거한 뒤 1-(3-O-에스트로닐)메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트 (1r, 5 mg)을 아세토니트릴 혹은 t-아밀알코올에 녹여 넣어준 다음 포타슘카보네이트 (3 mg)을 넣고 120도 가열조건에서 20분간 교반시켰다. Radio-TLC를 이용하여 각 반응의 수율을 측정하였고, 이를 하기 표3에 나타내었다.
Distilled water (2.0 mL) and 0.2 M aqueous sodium methanesulfonate solution (2.0 mL) were sequentially added to Chromafix® and washed again with distilled water (2.0 mL). [ 18 F] fluoride [ 18 O] H 2 O solution (1-10 mCi) produced in cyclotron was slowly flown and washed with distilled water (2.0 mL). Methanol (2.0 mL) was poured into the cartridge containing [ 18 F] fluoride to remove water, and 0.1 M tetrabutylammonium methanesulfonate solution (0.5 mL) was poured out to elute the [ 18 F] fluoride ion. The solvent was removed by heating to 100 o C and blowing nitrogen to remove 1- (3- O -estronyl) methyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate ( 1r , 5 mg) was dissolved in acetonitrile or t-amyl alcohol, and then potassium carbonate (3 mg) was added thereto, followed by stirring for 20 minutes at 120 ° C heating conditions. Radio-TLC was used to measure the yield of each reaction, which is shown in Table 3 below.

아세토니트릴Acetonitrile t-아밀알코올t-amyl alcohol Radio-TLC (%)Radio-TLC (%) 100100 8282

Claims (11)

하기 화학식 1로 표시되는 4가 유기염 이탈기를 포함하는 전구체.
[화학식 1]
Figure pat00064

상기 화학식 1에서,
R1은 18F이 표지된 방사성추적자에서 -X-CH2-18F 부분을 제외한 부분으로, C1-C1000의 탄화수소기이고, 상기 C1-C1000의 탄화수소기는 주쇄의 탄소가 산소, 질소, 황, 인 또는 이들의 조합으로 치환 또는 비치환될 수 있고, 주쇄의 수소가 할로겐으로 치환 또는 비치환될 수 있고,
X는 산소, 황, 또는 -C(O)-이고,
이탈기는 치환된 또는 비치환된 C2-C50의 4가 암모늄염이다.
A precursor comprising a tetravalent organic salt leaving group represented by the following formula (1).
[Formula 1]
Figure pat00064

In Chemical Formula 1,
R 1 is -X-CH 2 at the 18 F radiotracer the cover - as a portion other than the portions 18 F, C 1 -C 1000 and a hydrocarbon group, the group is a C 1 carbon of the main chain hydrocarbon -C oxygen 1000, May be substituted or unsubstituted with nitrogen, sulfur, phosphorus or a combination thereof, hydrogen in the main chain may be substituted or unsubstituted with halogen,
X is oxygen, sulfur, or -C (O)-,
The leaving group is a substituted or unsubstituted tetravalent ammonium salt of C 2 -C 50 .
제1항에 있어서,
상기 화학식 1에서,
R1은 C1-C200의 탄화수소기이고, 상기 C1-C200의 탄화수소기는 주쇄의 탄소가 산소, 질소, 황, 인 또는 이들의 조합으로 치환 또는 비치환될 수 있고, 주쇄의 수소가 할로겐으로 치환 또는 비치환될 수 있고,
X는 산소, 황, 또는 -C(O)-이고,
이탈기는
Figure pat00065
이고, 상기 이탈기에서,
A, B, C, D 및 E는 서로 독립적으로 질소, 산소, 황 또는 탄소로서,
(i) 각 탄소의 수소는 R2 또는 R3로 치환 또는 비치환될 수 있고,
(ii) 각 질소의 경우, R2 또는 R3로 치환 또는 비치환될 수 있고,
R2와 R3는 서로 독립적으로 C1-C20의 탄화수소기로서, 주쇄의 탄소가 산소, 질소, 황 또는 이들의 조합으로 치환 또는 비치환될 수 있고, 주쇄의 수소가 할로겐으로 치환 또는 비치환될 수 있고,
Y는 할로겐 음이온, 설포네이트 음이온, BF4 -, PF6 -, SbF6 -, N(SO2CF3)2 - 및 N(CN)2 -로 이루어지는 군으로부터 선택되고,
n은 0 또는 1인 것을 특징으로 하는 4가 유기염 이탈기를 포함하는 전구체.
The method of claim 1,
In Chemical Formula 1,
R 1 is a C 1 -C 200 hydrocarbon group, the C 1 -C 200 hydrocarbon group may be unsubstituted or substituted with oxygen, nitrogen, sulfur, phosphorus or a combination of carbon in the main chain, hydrogen of the main chain May be substituted or unsubstituted with halogen,
X is oxygen, sulfur, or -C (O)-,
Breakaway
Figure pat00065
And in the leaving group,
A, B, C, D and E are independently of each other nitrogen, oxygen, sulfur or carbon,
(i) hydrogen of each carbon may be substituted or unsubstituted with R 2 or R 3 ,
(ii) for each nitrogen, R 2 or May be substituted or unsubstituted with R 3 ,
R 2 and R 3 are independently of each other a C 1 -C 20 hydrocarbon group in which carbon in the main chain may be substituted or unsubstituted with oxygen, nitrogen, sulfur, or a combination thereof, and hydrogen in the main chain may be substituted or unsubstituted. Can be exchanged,
Y is a halogen anion, a sulfonate anion, BF 4 - is selected from the group consisting of, -, PF 6 -, SbF 6 -, N (SO 2 CF 3) 2 - and N (CN) 2
n is a precursor comprising a tetravalent organic salt leaving group, characterized in that 0 or 1.
제1항에 있어서,
상기 화학식 1에서,
R1은 C1-C100의 탄화수소기이고, 상기 C1-C100의 탄화수소기는 주쇄의 탄소가 산소, 질소, 황, 인 또는 이들의 조합으로 치환 또는 비치환될 수 있고, 주쇄의 수소가 할로겐으로 치환 또는 비치환될 수 있고,
X는 산소, 황, 또는 -C(O)-이고,
이탈기는
(i)
Figure pat00066
또는
Figure pat00067
중에서 선택되는 4가 양이온; 및
(ii) Y인 음이온으로 구성되는 염이고,
상기 4가 양이온의 고리 내 하나의 질소가 R3으로 치환되며 각 탄소는 서로 독립적으로 R2로 치환 또는 비치환될 수 있고,
R2 및 R3는 C1-C20의 탄화수소기로서 주쇄의 탄소가 산소, 질소, 황 또는 이들의 조합으로 치환 또는 비치환될 수 있고, 주쇄의 수소가 할로겐으로 치환 또는 비치환될 수 있고,
Y는 서로 독립적으로 트리플루오로메탄설포네이트(CF3SO3 -), 파라톨루엔설포네이트, 메탄설포네이트 및 파라니트로벤젠설포네이트로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 4가 유기염 이탈기를 포함하는 전구체.
The method of claim 1,
In Chemical Formula 1,
R 1 is a C 1 -C 100 hydrocarbon group, the C 1 -C 100 hydrocarbon group may be unsubstituted or substituted with oxygen, nitrogen, sulfur, phosphorus or a combination of carbon of the main chain, hydrogen of the main chain May be substituted or unsubstituted with halogen,
X is oxygen, sulfur, or -C (O)-,
Breakaway
(i)
Figure pat00066
or
Figure pat00067
Tetravalent cation selected from; And
(ii) a salt consisting of an anion that is Y,
One nitrogen in the tetravalent cation ring is substituted with R 3 and each carbon may be independently substituted or unsubstituted with R 2 ,
R 2 and R 3 are C 1 -C 20 hydrocarbon groups, carbon of the main chain may be substituted or unsubstituted with oxygen, nitrogen, sulfur or a combination thereof, hydrogen of the main chain may be substituted or unsubstituted with halogen, ,
Y is a carbonate sulfonium trifluoromethane independently of each other (CF 3 SO 3 -), p-toluene sulfonate, methane sulfonate, and para-nitrobenzene The sulfonate 4, characterized in that selected from the group consisting of containing an organic salt release Precursor.
제1항에 있어서,
상기 화학식 1에서,
R1은
Figure pat00068
,
Figure pat00069
,
Figure pat00070
,
Figure pat00071
,
Figure pat00072
,
Figure pat00073
,
Figure pat00074
,
Figure pat00075
,
Figure pat00076
,
Figure pat00077
,
Figure pat00078
및
Figure pat00079
로 이루어지는 군으로부터 선택되고,
X는 산소, 황, 또는 -C(O)-이고,
이탈기는
(i)
Figure pat00080
또는
Figure pat00081
중에서 선택되는 4가 양이온; 및
(ii) Y인 음이온으로 구성되는 염이고,
상기 4가 양이온의 고리 내 하나의 질소가 R3으로 치환되며 각 탄소는 서로 독립적으로 R2로 치환 또는 비치환될 수 있고, R2 및 R3는 서로 독립적으로 C1 -4 직쇄 또는 분지쇄 알킬기, 페닐,
Figure pat00082
,
Figure pat00083
, 및
Figure pat00084
로 이루어지는 군으로부터 선택되고, ,
Y는 서로 독립적으로 트리플루오로메탄설포네이트(CF3SO3 -), 파라톨루엔설포네이트, 메탄설포네이트 및 파라니트로벤젠설포네이트로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 4가 유기염 이탈기를 포함하는 전구체.
The method of claim 1,
In Chemical Formula 1,
R 1 is
Figure pat00068
,
Figure pat00069
,
Figure pat00070
,
Figure pat00071
,
Figure pat00072
,
Figure pat00073
,
Figure pat00074
,
Figure pat00075
,
Figure pat00076
,
Figure pat00077
,
Figure pat00078
And
Figure pat00079
Is selected from the group consisting of
X is oxygen, sulfur, or -C (O)-,
Breakaway
(i)
Figure pat00080
or
Figure pat00081
Tetravalent cation selected from; And
(ii) a salt consisting of an anion that is Y,
The tetravalent and nitrogen within a ring of the cation substituted with R 3 may be unsubstituted or substituted on each carbon is independently R 2 together, R 2 and R 3 are independently C 1 -4 straight or branched chain with each other Alkyl groups, phenyl,
Figure pat00082
,
Figure pat00083
, And
Figure pat00084
Selected from the group consisting of
Y is a carbonate sulfonium trifluoromethane independently of each other (CF 3 SO 3 -), p-toluene sulfonate, methane sulfonate, and para-nitrobenzene The sulfonate 4, characterized in that selected from the group consisting of containing an organic salt release Precursor.
제1항에 있어서,
화학식 1로 표시되는 전구체가,
4-tert-부틸-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;
4-메톡시카보닐-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;
4-[3,5-디(트리플루오르메틸)페닐]-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;
4-(4-메톡시페닐)-3-메틸-1-((2-나프톡시)메틸)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;
3-메틸-4-페닐-1-(2-페닐에테인-2-온-1-일)-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;
4-tert-부틸-3-메틸-1-[(페닐싸이오)메틸]-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;
3-메틸-1-((2-나프톡시)메틸)-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;
3-메틸-1-[3-(2-나프톡시)-n-프로필]옥시메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;
1-[1-메틸설포닐옥시-3-(2-나프틸)-2-옥시프로필]옥시메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;
3-메틸-(2-나프틸)메틸옥시메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;
3-메틸-1-((2-나프톡시)메틸)-4-페닐이미다졸륨 트리플루오로메탄설포네이트;
(S)-1-(4-(2-BOC-아미노-2-(t-부톡시카보닐)에틸)페닐옥시메틸)-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;
1-(4-바이페닐)옥시메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;
1-(4-브로모-2-메틸페닐)옥시메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;
1-(3,4-디메톡시페닐)옥시메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;
3-메틸-1-(4-니트로페닐)옥시메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;
1-(4-아세틸아미노페닐)옥시메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트;
1-(3-O-에스트로닐)메틸-3-메틸-4-페닐-1,2,3-트리아졸륨 트리플루오로메탄설포네이트; 및
3-아세토나프틸-1-메틸이미다졸륨으로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 4가 유기염 이탈기를 포함하는 전구체.
The method of claim 1,
A precursor represented by the formula (1),
4-tert-butyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate;
4-methoxycarbonyl-3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate;
4- [3,5-di (trifluoromethyl) phenyl] -3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate;
4- (4-methoxyphenyl) -3-methyl-1-((2-naphthoxy) methyl) -1,2,3-triazolium trifluoromethanesulfonate;
3-methyl-4-phenyl-1- (2-phenylethane-2-one-1-yl) -1,2,3-triazolium trifluoromethanesulfonate;
4-tert-butyl-3-methyl-1-[(phenylthio) methyl] -1,2,3-triazolium trifluoromethanesulfonate;
3-methyl-1-((2-naphthoxy) methyl) -4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;
3-methyl-1- [3- (2-naphthoxy) -n -propyl] oxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;
1- [1-methylsulfonyloxy-3- (2-naphthyl) -2-oxypropyl] oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;
3-methyl- (2-naphthyl) methyloxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;
3-methyl-1-((2-naphthoxy) methyl) -4-phenylimidazolium trifluoromethanesulfonate;
(S) -1- (4- (2-BOC-amino-2- (t-butoxycarbonyl) ethyl) phenyloxymethyl) -4-phenyl-1,2,3-triazolium trifluoromethanesulfo Nate;
1- (4-biphenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;
1- (4-bromo-2-methylphenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;
1- (3,4-dimethoxyphenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;
3-methyl-1- (4-nitrophenyl) oxymethyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;
1- (4-acetylaminophenyl) oxymethyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate;
1- (3- O -estronyl) methyl-3-methyl-4-phenyl-1,2,3-triazolium trifluoromethanesulfonate; And
A precursor comprising a tetravalent organic salt leaving group, characterized in that it is selected from the group consisting of 3-acetonaphthyl-1-methylimidazolium.
하기 반응식 1로 표시되는 바와 같이,
화학식 2로 표시되는 화합물로부터 화학식 3의 아지도 화합물을 합성하는 단계 (단계 1);
단계 1에서 얻은 화학식 3의 아지도 화합물과 화학식 4로 표시되는 알킨 화합물간의 [3+2]고리화첨가반응을 통해 화학식 5의 화합물을 합성하는 단계 (단계 2);
단계 2에서 얻은 화학식 5의 화합물을 화학식 6으로 표시되는 알킬화 시약을 이용하여 화학식 1-a의 유기염을 합성하는 단계 (단계 3)를 포함하는 화학식 1-a의 화합물 제조방법.
[반응식 1]
Figure pat00085

상기 반응식 1에서, R1, R2, R3 및 Y는 제2항에서 정의한 바와 같고, Z는 R4SO3 - 이다. 여기서 R4는 C1-C20 탄화수소기로서 주쇄의 탄소가 산소, 질소, 황 또는 이들의 조합으로 치환 또는 비치환될 수 있고, 주쇄의 수소가 할로겐으로 치환 또는 비치환될 수 있다.
As represented by Scheme 1 below,
Synthesizing an azido compound of formula 3 from the compound represented by formula 2 (step 1);
Synthesizing the compound of formula 5 through a [3 + 2] cycloaddition reaction between the azido compound of formula 3 obtained in step 1 and the alkyne compound represented by formula 4 (step 2);
Method of preparing a compound of formula 1-a comprising the step (step 3) of synthesizing the organic salt of formula 1-a using the alkylation reagent represented by formula 6 to the compound of formula 5 obtained in step 2.
[Reaction Scheme 1]
Figure pat00085

In Scheme 1, R 1 , R 2 , R 3 and Y are as defined in claim 2, and Z is R 4 SO 3 − . Wherein R 4 is a C 1 -C 20 hydrocarbon group where carbon in the main chain may be substituted or unsubstituted with oxygen, nitrogen, sulfur or a combination thereof, and hydrogen in the main chain may be substituted or unsubstituted with halogen.
하기 반응식 2로 표시되는 바와 같이,
화학식 7로 표시되는 화합물과 화학식 8로 표시되는 화합물간의 친핵성 치환반응을 통해 화학식 5의 화합물을 합성하는 단계 (단계 1); 및
단계 1에서 얻은 화학식 5의 화합물을 화학식 6으로 표시되는 알킬화 시약을 이용하여 화학식 1-b의 유기염을 합성하는 단계 (단계 2)를 포함하는 화학식 1-b의 화합물의 제조방법.

[반응식 2]
Figure pat00086

상기 반응식 2에서, R1, R2, R3, A, B, C, D, E, X, Y 및 n은 제2항에서 정의한 바와 같고, Z는 제6항에서 정의한 바와 같다.
As represented by Scheme 2 below,
Synthesizing the compound of Formula 5 through a nucleophilic substitution reaction between the compound represented by Formula 7 and the compound represented by Formula 8 (step 1); And
Method for preparing a compound of formula 1-b comprising the step (step 2) of synthesizing the organic salt of formula 1-b by using the alkylation reagent represented by formula 6 to the compound of formula 5 obtained in step 1.

[Reaction Scheme 2]
Figure pat00086

In Scheme 2, R 1 , R 2 , R 3 , A, B, C, D, E, X, Y and n are as defined in claim 2, Z is as defined in claim 6.
하기 반응식 3으로 표시되는 바와 같이,
화학식 7로 표시되는 화합물과 화학식 9로 표시되는 화합물간의 친핵성 치환반응을 통해 화학식 1-b의 화합물을 합성하는 단계 (단계 1)를 포함하는 화학식 1-b의 화합물의 제조방법.

[반응식 3]
Figure pat00087

상기 반응식 3에서, R1, R2, R3, A, B, C, D, E, X, Y 및 n은 제2항에서 정의한 바와 같고, Z는 제6항에서 정의한 바와 같다.
As represented by Scheme 3 below,
A method for preparing a compound of Formula 1-b, comprising the step (step 1) of synthesizing a compound of Formula 1-b through a nucleophilic substitution reaction between a compound represented by Formula 7 and a compound represented by Formula 9.

[Reaction Scheme 3]
Figure pat00087

In Scheme 3, R 1 , R 2 , R 3 , A, B, C, D, E, X, Y and n are as defined in claim 2, Z is as defined in claim 6.
하기 반응식 4로 표시되는 바와 같이,
화학식 10으로 표시되는 화합물과 화학식 11로 표시되는 화합물간의 친핵성 치환반응을 통해 화학식 1-b의 화합물을 합성하는 단계 (단계 1)를 포함하는 화학식 1-b의 화합물 제조방법.

[반응식 4]
Figure pat00088

상기 반응식 4에서, R1, R2, R3, A, B, C, D, E, X, Y 및 n은 제2항에서 정의한 바와 같다.
As represented by Scheme 4 below,
A method for preparing a compound of Formula 1-b comprising the step of synthesizing the compound of Formula 1-b through a nucleophilic substitution reaction between the compound represented by Formula 10 and the compound represented by Formula 11.

[Reaction Scheme 4]
Figure pat00088

In Scheme 4, R 1 , R 2 , R 3 , A, B, C, D, E, X, Y and n are as defined in claim 2.
하기 반응식 5과 같이,
제1항의 화학식 1로 표시되는 4가 유기염 이탈기를 포함하는 화합물과 화학식 MF로 표시되는 플루오르염을 반응시키는 것을 특징으로 하는 18F-표지 화합물의 제조방법.
[반응식 5]
Figure pat00089

상기 반응식 5에서, R1, X 및 이탈기는 제1항에서 정의한 바와 같고,
M은 Li, Na, K, Rb 및 Cs로 이루어지는 군으로부터 선택되는 금속 양이온; 4가 암모늄 양이온; 또는 4가 포스포늄 양이온이고,
F는 18F이다.
As shown in Scheme 5,
A method for producing an 18 F-labeled compound comprising reacting a compound comprising a tetravalent organic salt leaving group represented by Formula 1 with a fluorine salt represented by Formula MF.
Scheme 5
Figure pat00089

In Scheme 5, R 1 , X and leaving groups are as defined in claim 1,
M is a metal cation selected from the group consisting of Li, Na, K, Rb and Cs; Tetravalent ammonium cation; Or a tetravalent phosphonium cation,
F is 18 F.
제1항의 화학식 1로 표시되는 4가 유기염 이탈기를 포함하는 전구체로부터 합성되는 18F-표지 화합물. 18 F-labeled compound synthesized from a precursor comprising a tetravalent organic salt leaving group represented by the formula (1).
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