CN112939829A - 芳基三氟甲基硫醚的合成方法 - Google Patents
芳基三氟甲基硫醚的合成方法 Download PDFInfo
- Publication number
- CN112939829A CN112939829A CN202110238774.8A CN202110238774A CN112939829A CN 112939829 A CN112939829 A CN 112939829A CN 202110238774 A CN202110238774 A CN 202110238774A CN 112939829 A CN112939829 A CN 112939829A
- Authority
- CN
- China
- Prior art keywords
- aryl
- copper salt
- bromo
- salt catalyst
- nmr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B45/00—Formation or introduction of functional groups containing sulfur
- C07B45/06—Formation or introduction of functional groups containing sulfur of mercapto or sulfide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/28—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/38—One sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/46—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/70—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明提供一种芳基三氟甲基硫基醚化合物的合成方法,将芳基卤化物、三氟甲烷硫醇银、铜盐催化剂、含氮有机配体与有机溶剂混合,在20~120℃搅拌反应1~60h;反应完毕后,得到芳基三氟甲基硫醚化合物。本发明具有原料廉价易得、反应条件温和、底物普适性好、收率高、适用于工业化应用等优点。
Description
技术领域
本发明属化学合成方法领域,特别涉及一种制备芳基包含芳杂基三氟甲基硫醚化合物的方法。
背景技术
含氟有机化合物在医药、农药以及材料领域的广泛应用极大促进了向有机分子中引入氟原子和各种含氟官能团。众所周知,三氟甲硫基(-SCF3)具有强吸电子性和高亲脂性,而亲脂性的增强有利于提高有机分子的渗透作用和吸收率,因此,三氟甲硫醚化合物在医药、农药、材料领域都有着重大的应用前景。
目前,具有重要生物活性的含三氟甲硫基的分子主要包括抗球虫药物妥曲珠利(Toltrazuril)、食欲减退药物替氟雷(Tiflorex)、抗高血压药氯沙坦(Losartananalogue)等。制备这类化合物的传统方法主要是间接三氟甲硫基化方法,包含氟卤交换的氟化法以及对硫原子的三氟甲基化方法。但是,前者的条件苛刻,产生大量的废酸酸水会造成严重的环境问题,已不能适应可持续发展的战略方针;而后者则需要预先制备苯硫酚前体,这类前体往往伴随着恶臭,既不利于原子经济性,也无法满足工业化生产。
随着过渡金属催化的偶联反应的发展,新型三氟甲硫基化试剂逐渐被发现,直接的三氟甲硫基化方法也随之完善起来。2011年和2015年,现有技术1[Teverovskiy,G.;Surry,D.S.;Buchwald,S.L.,Angew.Chem.Int.Ed.2011,50,7312-7314.]和现有技术2[Yin,G.;Kalvet,I.;Schoenebeck,F.,Angew.Chem.Int.Ed.2015,54,6809-6813.]分别报道了钯催化的芳基卤代物的三氟甲硫基化方法,该方法需要使用昂贵的钯催化剂与配体,一定程度上限制了该方法的应用。现有技术3[Yin,W.;Wang,Z.;Huang,Y.,Adv.Synth.Catal.2014,356,2998-3006.]报道了钯催化C-H直接活化的三氟甲硫基化反应,但是需要有导向基的参与,反应才能顺利进行,因此底物的普适性方面受到一定程度的制约。其实早在1993年,我国的氟化学专家陈庆云院士就发现铜是一个适合三氟甲硫基的金属,通过“陈试剂”(FSO2CF2COOEt)与单质硫原位生成三氟甲硫基负离子,在碘化亚铜的作用下实现了芳基碘化物的三氟甲硫基化,参见现有技术4[Chen,Q.-Y.;Duan,J.-X.,J.Chem.Soc.,Chem.Commun.1993,918-919.]。2011年,现有技术5[Chen,C.;Xie,Y.;Chu,L.;Wang,R.-W.;Zhang,X.;Qing,F.-L.,Angew.Chem.Int.Ed.2012,51,2492-2495.]报道了硫氰酸亚铜催化的芳基硼酸的氧化三氟甲硫基化反应,该方法中配体1,10-菲啰啉的使用十分关键,它能稳定活性物质CuSCF3,进而提高反应效率。2013年,现有技术6[Weng,Z.;He,W.;Chen,C.;Lee,R.;Tan,D.;Lai,Z.;Kong,D.;Yuan,Y.;Huang,K.-W.,Angew.Chem.Int.Ed.2013,52,1548-1552.]分离出2-2’-联吡啶稳定的(bpy)Cu(SCF3)络合物,报道了该络合物对芳基碘化物的三氟甲硫基化。但是需要先制备相应的金属络合物,并且对芳基溴化物活性不高。现有技术7[Xu,J.;Mu,X.;Chen,P.;Ye,J.;Liu,G.,Org.Lett.2014,16,3942-3945.]报道了铜催化条件下导向基团诱导的芳基卤代物的三氟甲硫基化反应;但是和前面一样,导向基的存在使得底物的普适性受到影响。因此,开发一种更加经济、温和的实验条件来实现对活性稍差的芳基卤化物的方法十分重要。
发明内容
本发明所要解决的技术问题是提供一种芳基三氟甲基硫醚的合成方法,是从廉价并简单易得的芳基溴化物出发,通过简单温和的合成条件,直接制备出相应的芳杂基三氟甲基硫醚化合物。该方法解决了现有技术中成本昂贵、条件苛刻、底物普适性窄以及不适用于工业化应用等缺陷。
为解决上述技术问题,本发明提供以下技术方案:
一种芳基三氟甲基硫基醚化合物的合成方法,包括:将芳基卤化物、三氟甲烷硫醇银、铜盐催化剂、含氮有机配体与有机溶剂混合,在20~120℃搅拌反应1~60h;反应完毕后,得到芳基三氟甲基硫醚化合物;其中,芳基卤代物、三氟甲烷硫醇银和铜盐催化剂的投料摩尔比为1:(1-50):(0.01-2);铜盐催化剂与含氮有机配体的投料摩尔比(0.1-10):1;
所述芳基卤代物选自芳基溴化物或芳基碘化物,所述芳基选自苯基,萘环基,吡啶基,噻吩基,呋喃基,噁唑基,噻唑基,吡唑基,1,3,4-噁二唑基,哒嗪基,吡嗪基或嘧啶基;所述铜盐催化剂为一价铜盐;所述含氮有机配体选自吡啶,单取代或多取代的吡啶衍生物,乙二胺,或乙二胺衍生物;所述有机溶剂选自乙腈,四氢呋喃,甲苯,乙酸乙酯,1,4-二氧六环或N,N-二甲基甲酰胺中的至少一种。
在一种优选的实施方式中,所述苯基卤化物选自4-溴苯乙酮,4-碘苯乙酮,4-碘苯酚,4-溴苯酚,4-溴硝基苯,4-碘硝基苯,叔丁基N-(4-碘代苯基)氨基甲酸酯,4-溴碘苯,3-碘苯甲酸甲酯,3-溴苯甲酸甲酯,3-溴乙烯基,3-碘苯乙烯,3-溴苯腈,3-碘苯腈,3-溴苯丙酮,3-碘苯丙酮,4-溴-1,2-二硝基苯,4-碘-1,2-二硝基苯,5-溴-1H-苯并[d]咪唑或5-碘-1H-苯并[d]咪唑,6-碘-1,4-苯并二氧烷,2,4-二甲氧基碘苯,2-碘萘,5-溴-2-嘧啶甲酸甲酯,5-溴氰基吡啶,2-溴-5-硝基吡啶,2-溴-3-氟-4-甲基吡啶,2-溴噻唑-5-羧酸乙酯,4-溴噻唑-2-甲酸甲酯,5-溴噻唑-4-甲酸乙酯,2-溴噁唑-5-甲酸乙酯,5-溴呋喃-2-羧酸甲酯,5-溴噻吩-2-甲酸乙酯,4-溴-1-甲基-1H-吡唑-5-羧酸甲酯,2-溴-5-苯基-1,3,4-噁二唑,2-溴苯并噻唑,2-溴-6-甲氧基苯并[d]噻唑,2-溴-1-甲基苯并咪唑或2-溴喹喔啉。
在一种优选的实施方式中,所述芳基卤化物为4-碘苯酚,4-溴苯酚,4-溴硝基苯,4-碘硝基苯,叔丁基N-(4-碘代苯基)氨基甲酸酯或4-溴碘苯。通过本方法由该芳基卤化物高效合成的芳基三氟甲基硫醚是抗球虫药物妥曲珠利的关键中间体。
在一种优选的实施方式中,所述芳基卤化物为3-碘苯甲酸甲酯,3-溴苯甲酸甲酯,3-溴乙烯基,3-碘苯乙烯,3-溴苯腈,3-碘苯腈,3-溴苯丙酮或3-碘苯丙酮。通过本方法由该芳基卤化物高效合成的芳基三氟甲基硫醚是食欲减退药物替氟雷司的关键中间体。
在一种优选的实施方式中,所述芳基卤化物为4-溴-1,2-二硝基苯,4-碘-1,2-二硝基苯,5-溴-1H-苯并[d]咪唑或5-碘-1H-苯并[d]咪唑。通过本方法由该芳基卤化物高效合成的芳基三氟甲基硫醚是抗高血压药氯沙坦的关键中间体。
在一种优选的实施方式中,所述三氟甲烷硫醇银与芳基卤化物的摩尔投料比为(1-10):1;较佳的,所述三氟甲烷硫醇银与芳基卤化物的摩尔投料比为(1.1-5):1。
在一种优选的实施方式中,所述有机溶剂选自乙腈,1,4-二氧六环或N,N-二甲基甲酰胺中的至少一种。
在一种优选的实施方式中,所述有机溶剂与芳基卤化物的体积质量比为(5-100):1。较佳的,所述有机溶剂与芳基卤化物的体积质量比为(5-50):1;更佳的,所述有机溶剂与芳基卤化物的体积质量比为(5-15):1。
在一种优选的实施方式中,所述铜盐催化剂为碘化亚铜或溴化亚铜。
在一种优选的实施方式中,所述铜盐催化剂的用量为芳基卤化物的0.01-1摩尔当量。较佳的,铜盐催化剂的用量为芳基卤化合物的0.5-1摩尔当量。
在一种优选的实施方式中,所述含氮有机配体选自吡啶,1,10-菲啰啉,2-2’联吡啶,2,2':6',2”-三联吡啶、乙二胺、(1R,2R)-(-)-N,N-二甲基环己烷-1,2-二胺中的至少一种。
在一种优选的实施方式中,所述铜盐催化剂与含氮有机配体的投料摩尔比(0.5-5):1;较佳的,所述铜盐催化剂与含氮有机配体的投料摩尔比(0.5-2):1。
在一种优选的实施方式中,所述含氮有机配体与铜盐催化剂以制备成络合物的形式投料。所述铜盐催化剂和与含氮有机配体的络合物的制备过程中的反应温度为-20℃-60℃。
在一种优选的实施方式中,反应时间为16~60h;更优选的,反应时间为16~48h。
在一种优选的实施方式中,反应温度为80~120℃;更优选的,反应温度为100~120℃。
在一种优选的实施方式中,反应完毕后,浓缩,柱层析分析,得到芳基三氟甲基硫醚化合物。
本发明的制备方法的反应式如下:
其中,X为溴或者碘;Ar为苯基,萘环基,吡啶基,噻吩基,呋喃基,噁唑基,噻唑基,吡唑基,1,3,4-噁二唑基,哒嗪基,吡嗪基或嘧啶基;铜盐催化剂为一价铜盐;所述含氮有机配体选自吡啶,单取代或多取代的吡啶衍生物,乙二胺,或乙二胺衍生物;所述有机溶剂选自乙腈,四氢呋喃,甲苯,乙酸乙酯,1,4-二氧六环或N,N-二甲基甲酰胺中的至少一种。
通过本发明的方法合成的相关的芳基三氟甲基硫醚是制备医药妥曲珠利、替氟雷司、氯沙坦的关键中间体。
本发明的方法中,所涉及的原料是芳基溴化物或芳基碘化物,均有良好的反应活性,且原料易得。
本发明的方法具有简单高效、条件温和、便于操作、底物普适性广、以及不需要其他添加剂的优势,可通过本发明的方法制备得到具有各种取代基的芳基三氟甲基硫醚化合物。
本发明的方法解决了现有技术中成本昂贵、条件苛刻、底物普适性窄以及不适用于工业化应用等缺陷。
本发明是这样实现的:在有机溶剂中,在温度为20-120℃反应,芳基卤化物和三氟甲基硫化银在铜盐和配体的促进作用下,反应1-60小时以较高收率制备得到芳基-三氟甲基硫醚化合物。
本发明的方法里,使用各种芳基卤化物例如芳基碘化物和芳基溴化物均具有良好的反应效果,相对而言芳基碘化物的活性稍高;该方法底物普适性广,很多现有技术中反应活性极差的芳基卤化物底物(尤其是芳基溴化物)均能够顺利反应得到产物。
与现有方法相比较,例如现有技术6(使用的2-2’-联吡啶稳定的(bpy)Cu(SCF3)络合物的方法),仅对芳基碘化物有比较好的活性效果,其对芳基碘化物的收率与使用本发明的方法基本相当,但是对于芳基溴化物的适用性不强,以实例4-5,4-7,4-8,4-10为例,使用现有技术6的方法均无法得到相应的三氟甲基化产物;又例如现有技术7(导向基团诱导的芳基卤代物的三氟甲硫基化方法),仅适用于有诱导基的底物,该方法无法合成本发明中合成的很多化合物,以实例4-5,4-7,4-8,4-10为例。
本发明所涉及的铜盐与1,10-菲啰啉,2-2'联吡啶或2,2':6',2”-三联吡啶等等配体组成效果较佳。
具体实施方式
下面将对本发明的技术方案进行清楚、完整的描述,显然,所描述的实施例是本发明的一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
以2-2'联吡啶为配体,在碘化亚铜的参与下,4-溴硝基苯与三氟甲基硫化银的偶联反应。
在25mL的反应管中,以乙腈(5mL)作为溶剂,加入1-溴-4-硝基苯(0.5mmol)、三氟甲基硫化银(1.5mmol)和2-2'联吡啶(1.0mmol)在一价铜盐CuI(1.0mmol)作用下封管反应,110℃搅拌48小时,LCMS检测反应,反应完全。然后,加入饱和氯化铵淬灭,然后过滤、萃取、干燥后除去溶剂后柱层析分离得到相应的芳基三氟甲基硫醚化合物,产率为56%。
实施例2
以2-2'联吡啶为配体,在碘化亚铜的参与下,1-碘-4-硝基苯与三氟甲基硫化银的偶联反应。
在25mL的反应管中,以乙腈(5mL)作为溶剂,加入1-碘-4-硝基苯(0.5mmol)、三氟甲基硫化银(1.5mmol)和2-2'联吡啶(1.0mmol)在一价铜盐CuI(1.0mmol)作用下封管反应,110℃搅拌16小时,LCMS检测反应,反应完全。然后,加入饱和氯化铵淬灭,然后过滤、萃取、干燥后除去溶剂后柱层析分离得到相应的芳基三氟甲基硫醚化合物,产率为87%。相关数据如下:淡黄色液体,1H NMR(400MHz,CDCl3)δ=8.28(d,J=8.8Hz,2H),7.84(d,J=8.8Hz,2H).13C NMR(101MHz,CDCl3)δ=149.15,136.06,132.53(q,J=2.2Hz),128.94(q,J=310Hz),124.33.19F NMR(376MHz,CDCl3)δ=-41.38(s,3F).MS(ESI):M-NO2+H+,m/z:178.2。
可见,相同反应条件下芳基溴化物的反应活性(实施例1)明显低于芳基碘化物(实施例2)。因此,发展适用于芳基溴化物的方法挑战更大。
实施例3
具有不同取代基的芳基碘化物与三氟甲基硫化银在碘化亚铜参与下的偶联反应。本发明尝试了大量的芳基碘化物作为底物,均具有很好的反应活性,产物收率高。以下仅为部分代表性实施方式。
在25mL的反应管中,以乙腈(5mL)作为溶剂,加入取代的苯基卤化物(0.5mmol)、三氟甲基硫化银(1.5mmol)和2-2'联吡啶(1.0mmol)在一价铜盐CuI(1.0mmol)作用下封管反应,110℃搅拌16-60小时。LCMS检测反应,反应完全后,加入饱和氯化铵淬灭,然后过滤、萃取、干燥后除去溶剂后柱层析分离得到相应的芳基三氟甲基硫醚化合物。
3-1、当所述不同取代基的苯基卤化物为4-碘苯乙酮,所得的化合物为4'-(三氟甲硫基)苯乙酮(94mg),产率:85%。
相关数据为:淡黄色液体,1H NMR(400MHz,CDCl3)δ=7.97(d,J=8.6Hz,2H),7.80-7.67(d,J=8.6Hz,2H),2.62(s,3H).13C NMR(100MHz,CDCl3)δ=197.01,138.49,135.73,129.98(q,J=1.6Hz),129.27(q,J=310Hz),129.06,26.66.19F NMR(376MHz,CDCl3)δ=-41.83(s,3F).MS(ESI):M+H+,m/z:221.1.
3-2、当所述不同取代基的苯基卤化物为叔丁基N-(4-碘代苯基)氨基甲酸酯,所得的化合物为叔丁基N-(4-三氟甲硫苯基)氨基甲酸酯(125 mg),产率:85%。
相关数据为:灰白色固体,1H NMR(400MHz,CDCl3)δ=7.57(d,J=8.8Hz,2H),7.44(d,J=8.8Hz,2H),6.66(br s,1H),1.53(s,9H).13C NMR(101MHz,CDCl3)δ=152.31,141.14,137.58,129.57(q,J=310Hz),118.81,117.18,81.29,28.25.19F NMR(376MHz,CDCl3)δ=-43.58(s,3F).MS(ESI):M-t-Bu+H+,m/z:238.0.
3-3、当所述不同取代基的苯基卤化物为3-碘苯甲酸甲酯,所得的化合物为3-三氟甲硫基苯甲酸甲酯(90mg),产率:76%。
相关数据为:无色液体,1H NMR(400MHz,CDCl3)δ=8.33(s,1H),8.17(td,J=1.4,8.0Hz,1H),7.85(d,J=7.8Hz,1H),7.52(t,J=7.8Hz,1H),3.95(s,3H).13C NMR(100MHz,CDCl3)δ=165.75,140.42,137.27,131.93,131.67,129.60,129.39(q,J=310Hz),125.05(q,J=1.6Hz),52.48.19F NMR(376MHz,CDCl3)δ=-42.51(s,3F).MS(ESI):M+H+,m/z:237.1.
3-4、当所述不同取代基的苯基卤化物为2,4-二甲氧基碘苯,所得的化合物为(2,4-二甲氧基)苯基三氟甲基硫醚(106mg),产率:82%。
相关数据为:无色液体,1H NMR(400MHz,CDCl3)δ=7.54(d,J=8.6Hz,1H),6.57-6.48(m,2H),3.89(s,3H),3.86-3.83(m,3H).13C NMR(101MHz,CDCl3)δ=163.92,162.09,140.252,129.56(q,J=310Hz),105.60,103.22(q,J=2.4Hz),99.29,56.05,55.57.19F NMR(376MHz,CDCl3)δ=-43.66(s,3F).MS(ESI):M+H+,m/z:239.0.
3-5、当所述不同取代基的苯基卤化物为6-碘-1,4-苯并二氧烷,所得的化合物为6-三氟甲硫基-1,4-苯并二氧烷(120 mg),产率:97%。
相关数据为:无色液体,1H NMR(400MHz,CDCl3)δ=7.21-7.18(m,1H),7.13(dd,J=2.0,8.4Hz,1H),6.90(d,J=8.4Hz,1H),4.33-4.26(m,4H).13C NMR(101MHz,CDCl3)δ=146.24,143.83,130.07,129.61(q,J=310Hz),125.54,118.19,115.45(q,J=2.4Hz),64.44,64.11.19F NMR(376MHz,CDCl3)δ=-43.66(s,3F).MS(ESI):M+H+,m/z:237.0.
3-6、当所述不同取代基的苯基卤化物为2-碘萘,所得的化合物为2-萘三氟甲硫基醚(94mg),产率:82%。
相关数据为:无色液体,1H NMR(400MHz,CDCl3)δ=8.25-8.20(m,1H),7.93-7.85(m,3H),7.70(dd,J=1.2,8.6Hz,1H),7.63-7.56(m,2H).13C NMR(101MHz,CDCl3)δ=137.07,133.92,133.42,131.83,129.80(q,J=310Hz),129.26,128.22,127.97,127.82,127.04,121.54(q,J=1.6Hz).19F NMR(376MHz,CDCl3)δ=-42.44(s,3F).
实施例4
具有不同取代基的芳(杂)基溴化物与三氟甲基硫化银在碘化亚铜参与下的偶联反应。本发明尝试了大量的芳(杂)基溴化物作为底物,均具有良好的反应活性,产物收率较高。以下仅为部分代表性实施方式。
在25mL的反应管中,以乙腈(5mL)作为溶剂,加入不同取代基的芳(杂)基溴化物(0.5mmol)、三氟甲基硫化银(1.5mmol)和2-2'联吡啶(1.0mmol)在一价铜盐CuI(1.0mmol)作用下下封管反应,110℃搅拌16-60小时。LCMS检测反应,反应完全后,加入饱和氯化铵淬灭,然后过滤、萃取、干燥后除去溶剂后柱层析分离得到相应的芳基三氟甲基硫醚化合物。
4-1、当所述不同取代基的芳(杂)基溴化物为2-溴嘧啶时,所得的化合物为2-三氟甲硫基嘧啶(68mg),产率:75%。
相关数据为:淡黄色液体,1H NMR(400MHz,CDCl3)δ=8.66(br d,J=4.4Hz,2H),7.22-7.17(m,1H).19F NMR(376MHz,CDCl3)δ=-41.05(s,3F).MS(ESI):M+H+,m/z:181.1.
4-2、当所述不同取代基的芳(杂)基溴化物为5-溴-2-嘧啶甲酸甲酯时,所得的化合物为5-三氟甲硫基-2-嘧啶甲酸甲酯(103 mg),产率:86%。
相关数据为:白色固体,1H NMR(400MHz,CDCl3)δ=9.14(s,2H),4.11(s,3H)
13C NMR(101MHz,CDCl3)δ=163.15,162.89,157.14,128.27(q,J=310Hz),124.32,53.94.19F NMR(376MHz,CDCl3)δ=-40.99(s,3F).MS(ESI):M+H+,m/z:239.1.
4-3、当所述不同取代基的芳(杂)基溴化物为2-氰基-5-溴吡啶时,所得的化合物为2-氰基-5-三氟甲硫基吡啶(100mg),产率:92%。
相关数据为:白色固体,1H NMR(400MHz,CDCl3)δ=8.92(d,J=1.8Hz,1H),8.15(dd,J=2.0,8.0Hz,1H),7.84-7.76(m,1H).13C NMR(101MHz,CDCl3)δ=156.01,143.90,135.47,128.66,128.59(q,J=310Hz),126.72(q,J=2.4Hz),116.25.19F NMR(376MHz,CDCl3)δ=-41.10(s,3F).MS(ESI):M+H+,m/z:205.1.
4-4、当所述不同取代基的芳(杂)基溴化物为2-溴-5-硝基吡啶时,所得的化合物为2-三氟甲硫基-5-硝基吡啶(85 mg),产率:76%。
相关数据为:淡黄色液体,1H NMR(400MHz,CDCl3)δ=9.37(d,J=2.8Hz,1H),8.49(dd,J=2.8,8.8Hz,1H),7.64(d,J=8.8Hz,1H).13C NMR(101MHz,CDCl3)δ=158.34,145.51,143.06,132.32,128.39(q,J=310Hz),124.16.19F NMR(376MHz,CDCl3)δ=-39.67(s,3F).MS(ESI):M+H+,m/z:225.0.
4-5、当所述不同取代基的芳(杂)基溴化物为2-溴噻唑-5-羧酸乙酯时,所得的化合物为2-三氟甲硫基-噻唑-5-羧酸乙酯(85mg),产率:66%。此外,发明人尝试了以2-溴噻唑-5-羧酸乙酯为底物,并采现有技术6公开的方法来进行制备,结果发现反应活性很差,未得到产物。现有技术7的方法也无法得到该产物。
相关数据为:淡黄色液体,1H NMR(400MHz,CDCl3)δ=8.47(s,1H),4.40(q,J=7.2Hz,2H),1.40(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ=159.99,155.22,149.14,135.73,127.86(q,J=310Hz),62.30,14.21.19F NMR(376MHz,CDCl3)δ=-40.97(s,3F).MS(ESI):M+H+,m/z:258.0.
4-6、当所述不同取代基的芳(杂)基溴化物为4-溴噻唑-2-甲酸甲酯时,所得的化合物为4-三氟甲硫基-噻唑-2-甲酸甲酯(87 mg),产率:72%。
相关数据为:灰白色固体,1H NMR(400MHz,CDCl3)δ=8.02(s,1H),4.04(s,3H).13CNMR(101MHz,CDCl3)δ=159.62,159.36,139.46,133.64,128.62(q,J=310Hz),53.67.19FNMR(376MHz,CDCl3)δ=-41.77(s,3F).MS(ESI):M+H+,m/z:244.0.
4-7、当所述不同取代基的芳(杂)基溴化物为5-溴噻唑-4-甲酸乙酯时,所得的化合物为5-三氟甲硫基-噻唑-4-甲酸乙酯(71mg),产率:55%。此外,发明人尝试了以5-溴噻唑-4-甲酸乙酯为底物,并采现有技术6公开的方法来进行制备,结果发现反应活性很差,未得到产物。现有技术7的方法也无法得到该产物。
相关数据为:灰白色固体,1H NMR(400MHz,CDCl3)δ=8.94(s,1H),4.48(q,J=7.2Hz,2H),1.45(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ=160.21,154.88,147.02,127.31(q,J=310Hz),61.31,13.19.19F NMR(376MHz,CDCl3)δ=-43.17(s,3F).MS(ESI):M+H+,m/z:258.1.
4-8、当所述不同取代基的芳(杂)基溴化物为2-溴噁唑-5-甲酸乙酯时,所得的化合物为2-三氟甲硫基-噁唑-5-甲酸乙酯(78mg),产率:65%。此外,发明人尝试了以2-溴噁唑-5-甲酸乙酯为底物,并采现有技术6公开的方法来进行制备,结果发现反应活性很差,未得到产物。现有技术7的方法也无法得到该产物。
相关数据为:无色液体,1H NMR(400MHz,CDCl3)δ=7.86(s,1H),4.43(q,J=7.2Hz,2H),1.41(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ=155.60,151.67,145.48,134.36,126.36(q,J=310Hz),61.12,13.15.19F NMR(376MHz,CDCl3)δ=-38.95(s,3F).MS(ESI):M+H+,m/z:242.1.
4-9、当所述不同取代基的芳(杂)基溴化物为5-溴呋喃-2-甲酸乙酯时,所得的化合物为5-三氟甲硫基-呋喃-2-羧酸乙酯(84mg),产率:83%。
相关数据为:淡黄色液体,1H NMR(400MHz,CDCl3)δ=7.15(d,J=3.6Hz,1H),6.91(d,J=3.6Hz,1H),3.85(s,3H).13C NMR(101MHz,CDCl3)δ=158.09,-149.24,139.40,-127.65(q,J=310Hz),124.54,118.95,52.33.19F NMR(376MHz,CDCl3)δ=-42.49(s,3F).MS(ESI):M+H+,m/z:227.1.
4-10、当所述不同取代基的芳(杂)基溴化物为5-溴噻吩-2-甲酸乙酯时,所得的化合物为5-三氟甲硫基-噻吩-2-羧酸乙酯(85mg),产率:63%。此外,发明人尝试了以5-溴噻吩-2-甲酸乙酯为底物,并采现有技术6公开的方法来进行制备,结果发现反应活性很差,未得到产物。现有技术7的方法也无法得到该产物。
相关数据为:无色液体,1H NMR(400MHz,CDCl3)δ=7.74(d,J=4.0Hz,1H),7.37(s,1H),4.37(q,J=7.2Hz,2H),1.38(t,J=7.2Hz,3H).19F NMR(376MHz,CDCl3)δ=-44.31(s,3F).13C NMR(101MHz,CDCl3)δ=160.92,141.24,139.24,133.24,128.13(q,J=310Hz),127.67(t,J=2.5Hz),61.75,14.20.MS(ESI):M+H+,m/z:257.0.
4-11、当所述不同取代基的芳(杂)基溴化物为2-溴-5-苯基-1,3,4-噁二唑时,所得的化合物为2-三氟甲硫基-5-苯基-1,3,4-噁二唑(80mg),产率:81%。
相关数据为:无色液体,1H NMR(400MHz,CDCl3)δ=8.09-8.03(m,2H),7.74-7.68(m,1H),7.68-7.62(m,2H).13C NMR(101MHz,CDCl3)δ=168.37,154.82(q,J=3.2Hz),133.55,130.78(q,J=310Hz),130.17,127.42,122.76.19F NMR(376MHz,CDCl3)δ=-39.59(s,3F).MS(ESI):M+H+,m/z:247.1.
4-12、当所述不同取代基的芳(杂)基溴化物为4-溴-1-甲基-1H-吡唑-5-羧酸甲酯时,所得的化合物为4-三氟甲硫基-1-甲基-1H-吡唑-5-羧酸甲酯(100mg),产率:76%。此外,发明人尝试了以5-溴噻吩-2-甲酸乙酯为底物,并采现有技术6公开的方法来进行制备,结果发现反应活性很差,未得到产物。现有技术7的方法也无法得到该产物。
相关数据为:黄色液体,1H NMR(400MHz,CDCl3)δ=7.67(s,1H),4.20(s,3H),3.98(s,3H).19F NMR(376MHz,CDCl3)δ=-43.58(s,3F).MS(ESI):M+H+,m/z:241.1.
4-13、当所述不同取代基的芳(杂)基溴化物为2-溴苯并噻唑时,所得的化合物为2-三氟甲硫基苯并噻唑(100mg),产率:81%。
相关数据为:无色液体,1H NMR(400MHz,CDCl3)δ=8.15(d,J=8.0Hz,1H),7.91(d,J=8.0Hz,1H),7.60-7.54(m,1H),7.53-7.46(m,1H).13C NMR(100MHz,CDCl3)δ=153.09,151.69(q,J=2.8Hz),137.88,128.23(q,J 310Hz),126.97,126.69,124.11,121.29.19FNMR(376MHz,CDCl3)δ=-40.18(s,3F).
MS(ESI):M+H+,m/z:235.9.
4-14、当所述不同取代基的芳(杂)基溴化物为2-溴-6-甲氧基苯并[d]噻唑时,所得的化合物为2-三氟甲硫基-6-甲氧基苯并[d]噻唑(125mg),产率:93%。
相关数据为:白色固体,1H NMR(400MHz,CDCl3)δ=8.03(d,J=9.0Hz,1H),7.33(d,J=2.4Hz,1H),7.17(dd,J=2.4,9.0Hz,1H),3.91(s,3H).13C NMR(100MHz,CDCl3)δ=157.87,146.79,146.52(q,J=3.0Hz),138.93,127.20(q,J=310Hz),123.77,115.98,102.04,54.73.19F NMR(376MHz,CDCl3)δ=-40.67(s,3F).MS(ESI):M+H+,m/z:265.9.
4-15、当所述不同取代基的芳(杂)基溴化物为2-溴-1-甲基苯并咪唑时,所得的化合物为2-三氟甲硫基-1-甲基苯并咪唑(83mg),产率:71%。
相关数据为:白色固体,1H NMR(400MHz,CDCl3)δ=7.76(d,J=8.0Hz,1H),7.34-7.21(m,3H),3.83(s,3H).13C NMR(100MHz,CDCl3)δ=143.17,137.50(q,J=2.4Hz),136.62,128.19(q,J=310Hz),124.94,123.39,120.88,110.36,31.29.19F NMR(376MHz,CDCl3)δ=-40.24(s,3F).MS(ESI):M+H+,m/z:233.0.
4-16、当所述不同取代基的芳(杂)基溴化物为2-溴喹喔啉时,所得的化合物为2-三氟甲硫基喹喔啉(95mg),产率:76%。
相关数据为:白色固体,1H NMR(400MHz,CDCl3)δ=8.92(s,1H),8.16-8.05(m,2H),7.86-7.78(m,2H).13C NMR(101MHz,CDCl3)δ=146.23(q,J=2.5Hz),146.01(q,J=1.8Hz),142.65,141.44,131.23,131.20,129.40,129.35,128.92(q,J=310Hz).19F NMR(376MHz,CDCl3)δ=-38.72(s,3F).MS(ESI):M+H+,m/z:231.1.
综上所述,上述各实施例仅为本发明的较佳实施例而已,并不用以限定本发明的保护范围,凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,皆应包含在本发明的保护范围内。
Claims (10)
1.一种芳基三氟甲基硫基醚化合物的合成方法,其特征在于,所述方法包括:
将芳基卤化物、三氟甲烷硫醇银、铜盐催化剂、含氮有机配体与有机溶剂混合,在20~120℃搅拌反应1~60h;反应完毕后,得到芳基三氟甲基硫醚化合物;
其中,芳基卤代物、三氟甲烷硫醇银和铜盐催化剂的投料摩尔比为1:(1-50):(0.01-2);铜盐催化剂与含氮有机配体的投料摩尔比(0.1-10):1;
所述芳基卤代物选自芳基溴化物或芳基碘化物,所述芳基选自苯基,萘环基,吡啶基,噻吩基,呋喃基,噁唑基,噻唑基,吡唑基,1,3,4-噁二唑基,哒嗪基,吡嗪基或嘧啶基;
所述铜盐催化剂为一价铜盐;
所述含氮有机配体选自吡啶,单取代或多取代的吡啶衍生物,乙二胺,或乙二胺衍生物;
所述有机溶剂选自乙腈,四氢呋喃,甲苯,乙酸乙酯,1,4-二氧六环或N,N-二甲基甲酰胺中的至少一种。
2.如权利要求1所述的方法,其特征在于,所述苯基卤化物选自4-溴苯乙酮,4-碘苯乙酮,4-碘苯酚,4-溴苯酚,4-溴硝基苯,4-碘硝基苯,叔丁基N-(4-碘代苯基)氨基甲酸酯,4-溴碘苯,3-碘苯甲酸甲酯,3-溴苯甲酸甲酯,3-溴乙烯基,3-碘苯乙烯,3-溴苯腈,3-碘苯腈,3-溴苯丙酮,3-碘苯丙酮,4-溴-1,2-二硝基苯,4-碘-1,2-二硝基苯,5-溴-1H-苯并[d]咪唑或5-碘-1H-苯并[d]咪唑,6-碘-1,4-苯并二氧烷,2,4-二甲氧基碘苯,2-碘萘,5-溴-2-嘧啶甲酸甲酯,5-溴氰基吡啶,2-溴-5-硝基吡啶,2-溴-3-氟-4-甲基吡啶,2-溴噻唑-5-羧酸乙酯,4-溴噻唑-2-甲酸甲酯,5-溴噻唑-4-甲酸乙酯,2-溴噁唑-5-甲酸乙酯,5-溴呋喃-2-羧酸甲酯,5-溴噻吩-2-甲酸乙酯,4-溴-1-甲基-1H-吡唑-5-羧酸甲酯,2-溴-5-苯基-1,3,4-噁二唑,2-溴苯并噻唑,2-溴-6-甲氧基苯并[d]噻唑,2-溴-1-甲基苯并咪唑或2-溴喹喔啉。
3.如权利要求1所述的方法,其特征在于,所述三氟甲烷硫醇银与芳基卤化物的摩尔投料比为(1-10):1;较佳的,所述三氟甲烷硫醇银与芳基卤化物的摩尔投料比为(1.1-5):1。
4.如权利要求1所述的方法,其特征在于,所述有机溶剂选自乙腈,1,4-二氧六环或N,N-二甲基甲酰胺中的至少一种。
5.如权利要求1所述的方法,其特征在于,所述有机溶剂与芳基卤化物的体积质量比为(5-100):1;较佳的,所述有机溶剂与芳基卤化物的体积质量比为(5-50):1;更佳的,所述有机溶剂与芳基卤化物的体积质量比为(5-15):1。
6.如权利要求1所述的方法,其特征在于,所述铜盐催化剂为碘化亚铜或溴化亚铜。
7.如权利要求1所述的方法,其特征在于,所述铜盐催化剂的用量为芳基卤化物的0.01-1摩尔当量;较佳的,铜盐催化剂的用量为芳基卤化合物的0.5-1摩尔当量。
8.如权利要求1所述的方法,其特征在于,所述含氮有机配体选自吡啶,1,10-菲啰啉,2-2’联吡啶,2,2':6',2”-三联吡啶、乙二胺、(1R,2R)-(-)-N,N-二甲基环己烷-1,2-二胺中的至少一种。
9.如权利要求1所述的方法,其特征在于,所述铜盐催化剂与含氮有机配体的投料摩尔比(0.5-5):1;较佳的,所述铜盐催化剂与含氮有机配体的投料摩尔比(0.5-2):1。
10.如权利要求1所述的方法,其特征在于,所述含氮有机配体与铜盐催化剂以制备成络合物的形式投料。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110238774.8A CN112939829B (zh) | 2021-03-04 | 2021-03-04 | 芳基三氟甲基硫醚的合成方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110238774.8A CN112939829B (zh) | 2021-03-04 | 2021-03-04 | 芳基三氟甲基硫醚的合成方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112939829A true CN112939829A (zh) | 2021-06-11 |
CN112939829B CN112939829B (zh) | 2023-02-21 |
Family
ID=76247571
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110238774.8A Active CN112939829B (zh) | 2021-03-04 | 2021-03-04 | 芳基三氟甲基硫醚的合成方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN112939829B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114890908A (zh) * | 2022-05-26 | 2022-08-12 | 华中科技大学 | 一种γ位三氟甲基氨基酸衍生物及制备方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4788012A (en) * | 1986-05-28 | 1988-11-29 | Rhone-Poulenc Chimie | Process for the preparation of benzyl trifluoromethyl sulfide |
CN104557358A (zh) * | 2015-02-02 | 2015-04-29 | 中国科学院上海有机化学研究所 | 一种烷基三氟甲基硫醚化合物及其制备方法 |
CN105669503A (zh) * | 2016-01-12 | 2016-06-15 | 中山大学 | 三氟甲硫基试剂及其制备方法与在不对称三氟甲硫基化反应中的应用 |
-
2021
- 2021-03-04 CN CN202110238774.8A patent/CN112939829B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4788012A (en) * | 1986-05-28 | 1988-11-29 | Rhone-Poulenc Chimie | Process for the preparation of benzyl trifluoromethyl sulfide |
CN104557358A (zh) * | 2015-02-02 | 2015-04-29 | 中国科学院上海有机化学研究所 | 一种烷基三氟甲基硫醚化合物及其制备方法 |
CN105669503A (zh) * | 2016-01-12 | 2016-06-15 | 中山大学 | 三氟甲硫基试剂及其制备方法与在不对称三氟甲硫基化反应中的应用 |
Non-Patent Citations (2)
Title |
---|
JIABIN XU ET AL.: "Copper-Catalyzed Trifluoromethylthiolation of Aryl Halides with Diverse Directing Groups", 《ORG. LETT.》 * |
PERUMAL SARAVANAN ET AL.: "Copper-Catalyzed Trifluoromethylthiolation of Di(hetero)aryl-l 3 -iodanes: Mechanistic Insight and Application to Synthesis of (Hetero)Aryl Trifluoromethyl Sulfides", 《ADV. SYNTH. CATAL.》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114890908A (zh) * | 2022-05-26 | 2022-08-12 | 华中科技大学 | 一种γ位三氟甲基氨基酸衍生物及制备方法 |
Also Published As
Publication number | Publication date |
---|---|
CN112939829B (zh) | 2023-02-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107880079B (zh) | 环状氮杂环双卡宾钯配合物及其制备方法与用途 | |
Li et al. | Rh (II)-catalyzed [2, 3]-sigmatropic rearrangement of sulfur ylides derived from N-tosylhydrazones and sulfides | |
CN111393480B (zh) | 一种含双膦邻位碳硼烷配体的金配合物及其制备方法和应用 | |
Ma et al. | Direct CH bond (Hetero) arylation of thiazole derivatives at 5-position catalyzed by N-heterocyclic carbene palladium complexes at low catalyst loadings under aerobic conditions | |
CN112939829B (zh) | 芳基三氟甲基硫醚的合成方法 | |
CN102225944A (zh) | 一种手性锌配合物 | |
CN108689895A (zh) | 一种硫代酰胺衍生物及其制备方法 | |
CN103880762B (zh) | 一种1,2,3-三氮唑类化合物的制备方法 | |
CN112574081B (zh) | 制备芳基硫代酰胺类化合物的方法 | |
CN108017548B (zh) | 一种以氘代甲醇合成氘代二甲胺盐的方法 | |
CN105934423B (zh) | 2,3,6-三甲基苯酚的生产工艺 | |
CN102382058A (zh) | 一种n-芳基-氮杂环类化合物的制备方法 | |
JP2015172005A (ja) | 鉄触媒によるカップリング化合物の製造方法 | |
CN113735777B (zh) | 一种制备环硫脲化合物的方法 | |
CN103130810A (zh) | 一种吡唑并[1,5-c]喹唑啉类化合物的合成方法 | |
CN113735752B (zh) | 一种基于取代碘苯制备异硫脲化合物的方法 | |
CN113004248B (zh) | 一种钴催化碳氢胺化反应合成咔唑类化合物的方法 | |
CN113024611B (zh) | 一种氮杂环卡宾环钯化合物及其制备方法和应用 | |
CN102786466B (zh) | 一种手性Salan配体的合成方法 | |
CN105330565A (zh) | 一种由铜催化合成苯甲腈衍生物的新型方法 | |
Tùng et al. | Efficient Synthesis of Substituted Selenophenes Based on the First Palladium (0)‐Catalyzed Cross‐Coupling Reactions of Tetrabromoselenophene | |
CN106146417B (zh) | 一种利用醛亚硫酸氢钠加合物制备4-芳基-nh-1,2,3-三唑的方法 | |
CN102358715B (zh) | 一种由芳基硼酸合成芳腈的方法 | |
CN104311474B (zh) | 一种3‑炔基吡啶类化合物的合成方法 | |
CN114213298B (zh) | 一种由硫酚直接氧化制备硫代磺酸酯类化合物的方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |