技术领域technical field
本发明属于有机合成领域，尤其涉及一种含氟医药、农药、化工中间体及其合成方法，具体地说是一种含有四取代碳手性中心的α-氟烷基-α-氨基酸类化合物及其制备方法。The invention belongs to the field of organic synthesis, in particular to a fluorine-containing medicine, pesticide, chemical intermediate and its synthesis method, in particular to an α-fluoroalkyl-α-amino acid compound containing a four-substituted carbon chiral center and its preparation method.
背景技术Background technique
含氟氨基酸是一类非常重要的非天然氨基酸，由于含氟基团本身具有较强的吸电子能力、较高的亲脂性和较大的立体位阻等特性，使得含氟氨基酸表现出一些特殊的生理活性。目前许多含氟氨基酸已被用作跟踪生化反应的探针((a)Vocadlo,D.J.；Mayer,C.；He,S.M.；Withers,S.G.Biochemistry 2000,39,117-126；(b)Namchuk,M.N.；McCarter,J.D.；Becalski,A.；Andrews,T.；Withers,S.G.J.Am.Chem.Soc.2000,122,1270-1277.(c)Dubios,J.；Dugave,C.；Foures,C.；Kaminsky,M.；Tabet,J.C.；Bory,S.；Gaudry,M.；Marquet,A.Biochemistry 1991,30,10506-10512.)、酶抑制剂(Kollonitsch,J.；Patchett,A.A.；Marburg,S.；Maycock,A.L.；Perkins,L.M.；Doldouras,G.A.；Duggan,D.E.；Aster,S.D.Nature 1978,24,906-908.)和抗肿瘤药物(Tsushima,T.；Kawada,K.；Ishihara,S.；Uchida,N.；Shiratori,O.；Higaki,J.；Hirata,M.Tetrahedron 1998,44,5375-5387.)等，在生物、医药、农药等领域得到了广泛的应用((a)Kukhar,V.P.；Soloshonok,V.A.(eds.),Fluorine-containing Amino Acids:Synthesis and Properties,Wiley,Chichester,1995；(b)Zanda,M.New J.Chem.2004,28,1401；(c)Koksch,B.；Sewald,N.；Hakubke,H.D.；Burger,K.；in:Biomedical Frontiers of Fluorine Chemistry,(Eds.:Ojima,I.；McCarthy,J.R.；Welch,J.T.),ACS Series 639Washington D.C.,1996,42；(d)Welch,J.T.；Eswarakrishnan,S.Fluorine in Bioorganic Chemistry；Wiley:New York,1991；(e)Filler,R.；Kobayashi,Y.；Yagupolskii,L.M..Biomedical Aspects of Fluorine Chemistry:Elsevier:Amsterdam,1993.)在各种类型的含氟氨基酸中，α-氟烷基-α-氨基酸是其中重要的一类，由于其潜在的生理活性更是引起了化学家和生物学家们的广泛合成兴趣，然而现有文献上对于α-氟烷基-α-氨基酸的合成报道主要集中在具有三取代碳手性中心的α-氟烷基-α-氨基酸的合成方面((a)Sutherland,A.；Willis,C.L.Nat.Prod.Rep.2000,17,621；(b)Qiu,X.-L.；Meng,W.-D.；Qing,F.-L.Tetrahedron 2004,60,6711；(c)Smits,R.；Cadicamo,C.D.；Burger,K.；Koksch,B.Chem.Soc.Rev. 2008,37,1727；(d)Czekelius,C.；Tzschucke,C.C.Synthesis 2010,543；(e)Sorochinsky,A.E.；Soloshonok,V.A.J.Fluorine Chem.2010,131,127.)，而对于具有四取代碳手性中心的α-氟烷基-α-氨基酸的合成报道却相对较少，已有的报道也仅局限在具有四取代碳手性中心的α-三氟甲基-α-氨基酸的合成上((a)Wang,H.；Zhao,X.；Li,Y.；Lu,L.Org.Lett.2006,8,1379；(b)Min,Q.-Q.；He,C.-Y.；Zhou,H.；Zhang,X.Chem.Commun.2010,46,8029；(c)Enders,D.；Gottfried,K.；Raabe,G.Adv.Synth.Catal.2010,352,3147；(d)Huguenot,F.；Brigaud,T.J.Org.Chem.2006,71,7075；(e)Martin,T.；Massif,C.；Wermester,N.；Linol,J.；Tisse,S.；Cardinael,P.；Coquerel,G.；Bouillon,J.-P.Tetrahedron:Asymmetry 2011,22,12；(f)Simon,J.；Nguyen,T.T.；Chelain,E.；Lensen,N.；Pytkowicz,J.；Chaume,G.；Brigaud,T.Tetrahedron:Asymmetry 2011,22,309；(g)Asensio,A.；Bravo,P.；Crucianelli,M.；Farina,A.；Fustero,S.；Soler,J.G.；Meille,S.V.；Panzeri,W.；Viani,F.；Volonterio,A.；Zanda,M.Eur.J.Org.Chem.2001,1449；(h)Blocker,M.；Immaneni,S.；Shaikh,A.Tetrahedron Lett.2014,55,5572；(i)Yang,J.；Min,Q.-Q.；He,Y.；Zhang,X.Tetrahedron Lett.2011,52,4675；(j)Morisaki,K.；Sawa,M.；Nomaguchi,J.-y.；Morimoto,H.；Takeuchi,Y.；Mashima,K.；Ohshima T.Chem.Eur.J.2013,19,8417.)和α-二氟甲基-α-氨基酸((a)Liu,Y.-L.；Shi,T.-D.；Zhou,F.；Zhao,X.-L.；Wang,X.；Zhou,J.Org.Lett.2011,13,3826；(b)Liu,J.；Hu,J.Chem.Eur.J.2010,16,11443.)，对于具有四取代碳手性中心的其他α-氟烷基取代的α-氨基酸类化合物的合成至今尚未见文献报道。Fluorine-containing amino acids are a very important class of unnatural amino acids. Due to the strong electron-withdrawing ability, high lipophilicity and large steric hindrance of the fluorine-containing groups, the fluorine-containing amino acids show some special characteristics. physiological activity. Many fluorine-containing amino acids have been used as probes to track biochemical reactions ((a) Vocadlo, D.J.; Mayer, C.; He, S.M.; Withers, S.G. Biochemistry 2000, 39, 117-126; (b) Namchuk, M.N.; McCarter , J.D.; Becalski, A.; Andrews, T.; Withers, S.G.J.Am.Chem.Soc.2000, 122, 1270-1277.(c) Dubios, J.; Dugave, C.; M.; Tabet, J.C.; Bory, S.; Gaudry, M.; Marquet, A. Biochemistry 1991, 30, 10506-10512.), enzyme inhibitors (Kollonitsch, J.; Patchett, A.A.; Marburg, S.; Maycock, A.L.; Perkins, L.M.; Doldouras, G.A.; Duggan, D.E.; Aster, S.D. Nature 1978, 24, 906-908.) and antineoplastic agents (Tsushima, T.; Kawada, K.; Ishihara, S.; Uchida, N. .; Shiratori, O.; Higaki, J.; Hirata, M. Tetrahedron 1998, 44, 5375-5387.), etc., have been widely used in the fields of biology, medicine, and pesticides ((a) Kukhar, V.P.; Soloshonok , V.A. (eds.), Fluorine-containing Amino Acids: Synthesis and Properties, Wiley, Chichester, 1995; (b) Zanda, M.New J.Chem.2004, 28, 1401; (c) Koksch, B.; Sewald , N.; Hakubke, H.D.; Burger, K.; in: Biomedical Frontiers of Fluorine Chemistry, (Eds.: Ojima, I.; McCarthy, J.R.; Welch, J.T.), ACS Series 639 Washington D.C., 1996, 42; (d ) Welch, J.T.; Eswarakrishnan, S. Fluorine in Bioorganic Chemistry; Wiley: New York, 1991; (e) Filler, R .; Kobayashi, Y.; Yagupolskii, L.M.. Biomedical Aspects of Fluorine Chemistry: Elsevier: Amsterdam, 1993.) Among various types of fluorine-containing amino acids, α-fluoroalkyl-α-amino acids are an important class, Due to its potential physiological activity, chemists and biologists have attracted extensive synthetic interest. However, the existing reports on the synthesis of α-fluoroalkyl-α-amino acids mainly focus on the three-substituted carbon chiral center. Synthetic aspects of α-fluoroalkyl-α-amino acids ((a) Sutherland, A.; Willis, C.L. Nat. Prod. Rep. 2000, 17, 621; (b) Qiu, X.-L.; Meng, W. -D.; Qing, F.-L. Tetrahedron 2004, 60, 6711; (c) Smits, R.; Cadicamo, C.D.; Burger, K.; ; (d) Czekelius, C.; Tzschucke, C.C.Synthesis 2010,543; (e) Sorochinsky, A.E.; Soloshonok, V.A.J.Fluorine Chem.2010,131,127.), and for α-fluoroalkanes with four substituted carbon chiral centers However, there are relatively few reports on the synthesis of α-amino acids, and the existing reports are limited to the synthesis of α-trifluoromethyl-α-amino acids with four-substituted carbon chiral centers ((a) Wang, H. ; Zhao, X.; Li, Y.; Lu, L. Org. Lett. 2006, 8, 1379; (b) Min, Q.-Q.; , X. Chem. Commun. 2010, 46, 8029; (c) Enders, D.; Gottfried, K.; Raabe, G. Adv. Synth. Catal. 2010, 352, 3147; (d) Huguenot, F.; Brigaud, T. J. Org. Chem. 2006, 71, 7075; (e) Martin, T.; Massif, C.; Wermester, N.; Linol, J.; ; Bouillon, J.-P. Tetrahedron: Asymmetry 2011, 22, 12; (f) Simon, J.; Nguyen, T.T.; Chelain, E.; z, J.; Chaume, G.; Brigaud, T. Tetrahedron: Asymmetry 2011, 22, 309; (g) Asensio, A.; Bravo, P.; Crucianelli, M.; Farina, A.; Fustero, S.; Soler , J.G.; Meille, S.V.; Panzeri, W.; Viani, F.; Volonterio, A.; Zanda, M. Eur. J. Org. Chem. 2001, 1449; (h) Blocker, M.; ; Shaikh, A. Tetrahedron Lett.2014, 55, 5572; (i) Yang, J.; Min, Q.-Q.; He, Y.; Zhang, X. Tetrahedron Lett.2011, 52, 4675; ) Morisaki, K.; Sawa, M.; Nomaguchi, J.-y.; Morimoto, H.; Takeuchi, Y.; Mashima, K.; Ohshima T. Chem. Eur. J. 2013, 19, 8417.) and α-difluoromethyl-α-amino acids ((a) Liu, Y.-L.; Shi, T.-D.; Zhou, F.; Zhao, X.-L.; Wang, X.; Zhou , J.Org.Lett.2011,13,3826; (b) Liu,J.; Hu,J.Chem.Eur.J.2010,16,11443.), for other α The synthesis of α-amino acid compounds substituted with -fluoroalkyl has not been reported in the literature so far.
此外，由于含有四取代碳手性中心的α-氟烷基-α-氨基酸具有紧凑的结构和较强的亲脂性，将其引入多肽类药物，可以显著地提高该类药物的生物活性，使得其在体内不易被酶催化分解，同时增强其在体内的穿透能力，有利于药物在体内的吸收。因此，发展一种通用地、简便高效地、高立体选择性地合成结构多样的、具有不同含氟基团取代的含有四取代碳手性中心的α-氟烷基-α-氨基酸类化合物的方法就变得十分重要和非常有意义。In addition, due to the compact structure and strong lipophilicity of α-fluoroalkyl-α-amino acids containing four-substituted carbon chiral centers, introducing them into polypeptide drugs can significantly improve the biological activity of such drugs, making It is not easily decomposed by enzymes in the body, and at the same time enhances its penetration ability in the body, which is beneficial to the absorption of drugs in the body. Therefore, the development of a general, simple and efficient, high stereoselective synthesis of α-fluoroalkyl-α-amino acid compounds with different fluorine-containing group substitutions containing four-substituted carbon chiral centers The method becomes very important and very meaningful.
发明内容Contents of the invention
针对现有技术中的上述技术问题，本发明提供了一种含有四取代碳手性中心的α-氟烷基-α-氨基酸类化合物及其制备方法，所述的这种具有四取代碳手性中心的α-氟烷基-α-氨基酸类化合物及其制备方法解决了现有技术中无法获得四取代碳手性中心的α-氟烷基-α-氨基酸类化合物的技术问题。Aiming at the above-mentioned technical problems in the prior art, the present invention provides an α-fluoroalkyl-α-amino acid compound containing a tetrasubstituted carbon chiral center and a preparation method thereof. The α-fluoroalkyl-α-amino acid compound with a sex center and the preparation method thereof solve the technical problem that the α-fluoroalkyl-α-amino acid compound with a tetrasubstituted carbon chiral center cannot be obtained in the prior art.
本发明提供了一种含有四取代碳手性中心的α-氟烷基-α-氨基酸类化合物，其结构式如下：The present invention provides an α-fluoroalkyl-α-amino acid compound containing a tetrasubstituted carbon chiral center, the structural formula of which is as follows:
其中，R1为烷基、芳基、杂芳基、苄基、或者萘基；R2为氢、烷基、芳基、杂芳基、或者萘基；Rf为含氟烷基；所述的烷基为C1-20烷基或C1-20卤代烷基；所述的芳基为苯基或取代苯基；所述的取代苯基中的取代基为邻、间、对位取代或者多取代的甲基、乙基、苯基、甲氧基、乙氧基、苄氧基、三氟甲基、二氟甲基、一氟甲基、氟、氯、溴、乙酰基或二甲氨基；所述的杂芳基为呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、噻唑基、噁唑基、喹啉基、异喹啉基、吲哚基、吲唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基或苯并噁唑基；所述的苄基为苯甲基；所述的萘基为1-萘基或2-萘基；所述的含氟烷基为三氟甲基，二氟甲基，一氟甲基，单氟或者多氟取代的C1-20烷基或C1-20卤代烷基；PG为苄氧羰基(Cbz)、叔丁氧羰基(Boc)、笏甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、甲(或乙)氧羰基、邻苯二甲酰基(Pht)、对甲苯磺酰基(Tos)、三氟乙酰基(Tfa)、邻(对)硝基苯磺酰基(Ns)、特戊酰基、苯甲酰基(Bz)、三苯甲基(Trt)、2,4-二甲氧基苄基(Dmb)、对甲氧基苄基(PMB)、或者苄基(Bn)。Wherein, R is alkyl, aryl, heteroaryl, benzyl, or naphthyl; R ishydrogen , alkyl, aryl, heteroaryl, or naphthyl; R isfluorine -containing alkyl; The alkyl is C1-20 alkyl or C1-20 haloalkyl; the aryl is phenyl or substituted phenyl; the substituent in the substituted phenyl is adjacent, meta, para-substituted or polysubstituted methyl, ethyl, phenyl, methoxy, ethoxy, benzyloxy, trifluoromethyl, difluoromethyl, monofluoromethyl, fluoro, chloro, bromo, acetyl or di Methylamino; the heteroaryl is furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, quinolinyl, isoquinolyl, indolyl, indazolyl, Benzofuryl, benzothienyl, benzothiazolyl or benzoxazolyl; said benzyl is benzyl; said naphthyl is 1-naphthyl or 2-naphthyl; said The fluorine-containing alkyl group is trifluoromethyl, difluoromethyl, monofluoromethyl, C1-20 alkyl or C1-20 haloalkyl substituted by monofluorine or polyfluorine; PG is benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), Wat methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilethoxycarbonyl (Teoc), methyl (or ethyl) oxycarbonyl, phthaloyl (Pht ), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o (p) nitrobenzenesulfonyl (Ns), pivaloyl, benzoyl (Bz), trityl (Trt), 2,4-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB), or benzyl (Bn).
本发明还提供了上述的一种含有四取代碳手性中心的α-氟烷基-α-氨基酸类化合物的制备方法，包括如下步骤：The present invention also provides a method for preparing the above-mentioned α-fluoroalkyl-α-amino acid compound containing a tetrasubstituted carbon chiral center, comprising the following steps:
1)一个制备α，β-不饱和氟烷基亚磺酰酮亚胺的步骤，在有机溶剂中，以含氟烷基不饱和酮和手性辅基亚磺酰胺为起始原料，所述的含氟烷基不饱和酮和手性辅基亚磺酰胺的摩尔比为1:1～3，将四乙氧基钛和上述原料一起溶于有机溶剂中，所述的含氟烷基不饱和酮和四乙氧基钛的摩尔比为1:2～6，通过加热回流、分液、萃取得到α，β-不饱和氟烷基亚磺酰酮亚胺；1) A step for preparing α, β-unsaturated fluoroalkyl sulfinyl ketimine, in an organic solvent, using fluorine-containing alkyl unsaturated ketone and chiral prosthetic sulfinamide as starting materials, said The molar ratio of the fluorine-containing alkyl unsaturated ketone to the chiral prosthetic sulfenamide is 1:1-3, and the tetraethoxytitanium and the above-mentioned raw materials are dissolved in an organic solvent, and the fluorine-containing alkyl is not The molar ratio of saturated ketone and tetraethoxytitanium is 1:2~6, and α, β-unsaturated fluoroalkylsulfinylketimine is obtained by heating to reflux, liquid separation and extraction;
2)在惰性气体保护下，温度控制在-10℃以下，α，β-不饱和氟烷基亚磺酰酮亚胺与有机金属试剂在有机溶剂中进行加成反应，所述的α，β-不饱和氟烷基亚磺酰酮亚胺与有机金属试剂的摩尔比为1:2～4，反应结束后进行分液、萃取得到新的加成产物；2) Under the protection of an inert gas, the temperature is controlled below -10°C, and the α, β-unsaturated fluoroalkylsulfinylketimine and the organometallic reagent undergo an addition reaction in an organic solvent, and the α, β - The molar ratio of the unsaturated fluoroalkylsulfinylketimine to the organometallic reagent is 1:2-4, after the reaction is completed, liquid separation and extraction are carried out to obtain a new addition product;
3)一个脱除手性辅基亚磺酰胺的步骤，将步骤2)获得的加成反应物溶于有机溶剂中，在常 温下加入过量的氯化氢水溶液，搅拌，旋干溶剂，得到脱除了手性辅基亚磺酰胺的化合物；3) A step for removing the chiral prosthetic sulfinamide, dissolving the addition reactant obtained in step 2) in an organic solvent, adding an excessive amount of aqueous hydrogen chloride solution at normal temperature, stirring, and spinning the solvent to obtain the removed Compounds with chiral prosthetic sulfenamides;
4)一个氨基保护的步骤，将步骤3)获得的化合物溶于有机溶剂中，加入三乙胺，碳酸钾，苯甲酰氯，步骤3)获得的化合物与三乙胺、碳酸钾和苯甲酰氯的摩尔比为1:1～2:1～2：2～4，60～90℃加热反应过夜，冷却至室温，分液，萃取，干燥，得到新的产物；4) An amino protection step, the compound obtained in step 3) is dissolved in an organic solvent, triethylamine, potassium carbonate, and benzoyl chloride are added, and the compound obtained in step 3) is mixed with triethylamine, potassium carbonate, and benzoyl chloride The molar ratio is 1:1～2:1～2:2～4, heated and reacted overnight at 60～90°C, cooled to room temperature, separated, extracted and dried to obtain a new product;
5)一个双键的氧化步骤，步骤4)获得的化合物溶于有机溶剂中，-50℃以下的温度下向体系内通入臭氧气体至体系变蓝，TLC跟踪反应完全，加入三苯基磷，步骤4)获得的化合物与三苯基磷的摩尔比为1:1～3，室温搅拌反应3小时，旋干溶剂，将所得产物溶于有机溶剂中，并向体系中加入2-甲基2-丁烯，水，亚氯酸钠，磷酸二氢钠，步骤4)获得的化合物与2-甲基2-丁烯、水、亚氯酸钠、磷酸二氢钠的摩尔比为1:0.04～0.06:5～10：3～5:3～5，TLC跟踪至反应完全，加入氢氧化钠水溶液调溶液pH＝9，旋除溶剂，水相用稀盐酸中和至pH＝3，萃取，合并有机相，干燥，旋干溶剂制得具有四取代碳手性中心的α-氟烷基-α-氨基酸类化合物；5) A double bond oxidation step, the compound obtained in step 4) is dissolved in an organic solvent, and ozone gas is introduced into the system at a temperature below -50°C until the system turns blue, TLC traces the reaction is complete, and triphenylphosphine is added , Step 4) The molar ratio of the obtained compound to triphenylphosphine is 1:1～3, stirred and reacted at room temperature for 3 hours, spin-dried the solvent, dissolved the obtained product in an organic solvent, and added 2-methyl 2-butene, water, sodium chlorite, sodium dihydrogen phosphate, the mol ratio of the compound obtained in step 4) and 2-methyl 2-butene, water, sodium chlorite, sodium dihydrogen phosphate is 1: 0.04～0.06:5～10:3～5:3～5, TLC tracking until the reaction is complete, add aqueous sodium hydroxide solution to adjust the pH=9, spin off the solvent, neutralize the aqueous phase with dilute hydrochloric acid to pH=3, extract , combining the organic phases, drying, and spin-drying the solvent to obtain an α-fluoroalkyl-α-amino acid compound with a four-substituted carbon chiral center;
6)一个脱氨基保护基的步骤，将步骤5)获得的化合物加入过量浓盐酸并于封管中加热至90～105℃反应过夜，冷却至室温后，过滤，滤液旋干得脱除保护基团的具有四取代碳手性中心的α-氟烷基-α-氨基酸类化合物；6) A step of deamination protecting group, adding excess concentrated hydrochloric acid to the compound obtained in step 5) and heating to 90-105°C in a sealed tube to react overnight, cooling to room temperature, filtering, and spinning the filtrate to remove the protecting group α-fluoroalkyl-α-amino acid compounds with four substituted carbon chiral centers;
7)一个氨基酸酯化的步骤，将步骤6)获得的化合物溶于醇中，冰盐浴冷却，滴加氯化亚砜，步骤6)获得的化合物与氯化亚砜的摩尔比为1:4～8，加毕恢复至室温后加热回流，15～30小时，旋除溶剂，加入饱和碳酸氢钠水溶液，搅拌，分液，萃取，干燥，旋干溶剂得具有四取代碳手性中心的α-氟烷基-α-氨基酸酯类化合物。7) An amino acid esterification step, dissolving the compound obtained in step 6) in alcohol, cooling in an ice-salt bath, and adding thionyl chloride dropwise, the molar ratio of the compound obtained in step 6) to thionyl chloride is 1: 4 to 8, return to room temperature after addition and heat to reflux, 15 to 30 hours, spin off the solvent, add saturated aqueous sodium bicarbonate, stir, separate, extract, dry, and spin dry the solvent to obtain a compound with a tetrasubstituted carbon chiral center. α-fluoroalkyl-α-amino acid esters.
进一步的，所述的含氟烷基不饱和酮的结构式为，Further, the structural formula of the fluorine-containing alkyl unsaturated ketone is:
其中所述R3为烷基、芳基、杂芳基、苄基、或者萘基。 Wherein said R3 is alkyl, aryl, heteroaryl, benzyl, or naphthyl.
进一步的，所述的手性辅基亚磺酰胺的结构式为：Further, the structural formula of the chiral prosthetic sulfinamide is:
其中所述R4为烷基、芳基、杂芳基、苄基、或者萘基。 Wherein said R4 is alkyl, aryl, heteroaryl, benzyl, or naphthyl.
进一步的，步骤1)中所述的溶剂为乙醚、四氢呋喃、甲基叔丁基醚、乙二醇二甲醚、异丙醚、二氧六环、二氯甲烷、正己烷或甲苯。Further, the solvent described in step 1) is diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, isopropyl ether, dioxane, dichloromethane, n-hexane or toluene.
进一步的，所述的有机金属试剂为有机锂试剂，所述的有机锂试剂具有R1Li的结构，步骤2)中所用的溶剂为乙醚、四氢呋喃、甲基叔丁基醚、乙二醇二甲醚、异丙醚、二氧六环、正己烷或甲苯。Further, the organometallic reagent is an organolithium reagent, and the organolithium reagent has a structure of R1 Li, and the solvent used in step 2) is diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethylene glycol di Methyl ether, isopropyl ether, dioxane, n-hexane or toluene.
进一步的，在一个脱除手性辅基亚磺酰胺的步骤中所用的试剂为氯化氢的水溶液、氯化氢的乙醚溶液、氯化氢的甲醇溶液或者氯化氢的二氧六环溶液，所用有机溶剂为乙醚、四氢呋喃、二氯甲烷、三氯甲烷、甲醇、或者二氧六环。Further, the reagent used in the step of removing chiral prosthetic sulfinamide is aqueous solution of hydrogen chloride, ether solution of hydrogen chloride, methanol solution of hydrogen chloride or dioxane solution of hydrogen chloride, and the organic solvent used is ether, tetrahydrofuran , dichloromethane, chloroform, methanol, or dioxane.
进一步的，在一个氨基保护的步骤中，采用苄氧羰基(Cbz)、叔丁氧羰基(Boc)、笏甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、甲(或乙)氧羰基、邻苯二甲酰基(Pht)、对甲苯磺酰基(Tos)、三氟乙酰基(Tfa)、邻(对)硝基苯磺酰基(Ns)、特戊酰基、苯甲酰基(Bz)、三苯甲基(Trt)、2,4-二甲氧基苄基(Dmb)、对甲氧基苄基(PMB)、或者苄基(Bn)对氨基进行保护。Further, in an amino protection step, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), Watt methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methyl (or ethyl) oxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o (p) nitrobenzenesulfonyl (Ns), pivaloyl, benzoyl (Bz), trityl (Trt), 2,4-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB), or benzyl (Bn) p- Amino groups are protected.
进一步的，所述的双键氧化所用方法为臭氧氧化、高锰酸钾氧化、高碘酸钠氧化、或者三氧化钌氧化。Further, the method used for the double bond oxidation is ozone oxidation, potassium permanganate oxidation, sodium periodate oxidation, or ruthenium trioxide oxidation.
进一步的，还包括一个分离纯化的步骤，采用溶剂萃取、硅胶柱层析分离纯化或者离子交换柱层析进行分离纯化。Further, a separation and purification step is also included, using solvent extraction, silica gel column chromatography for separation and purification or ion exchange column chromatography for separation and purification.
本发明提供了一种通用地、简便高效地、高立体选择性地合成结构多样的、具有不同含氟基团取代的含有四取代碳手性中心的α-氟烷基-α-氨基酸的方法。The present invention provides a method for synthesizing α-fluoroalkyl-α-amino acids with four-substituted carbon chiral centers with various structures, substituted with different fluorine-containing groups, in a general, simple, efficient, and highly stereoselective manner .
本发明通过手性辅基亚磺酰胺的诱导作用，首先合成出具有高光学纯的、结构多样的含有α-四取代碳手性中心的不同氟烷基烯丙基胺类化合物，然后通过双键氧化制备出结构多样的、具有不同含氟基团取代的含有四取代碳手性中心的α-氟烷基-α-氨基酸类化合物。The present invention firstly synthesizes different fluoroalkyl allylamine compounds with high optical purity and various structures containing α-tetrasubstituted carbon chiral centers through the induction of chiral prosthetic sulfenamides, and then through double The α-fluoroalkyl-α-amino acid compounds with four-substituted carbon chiral centers with various structures and substituted fluorine-containing groups were prepared by bond oxidation.
本发明利用廉价易得的含氟烷基不饱和酮和手性辅基亚磺酰胺为起始原料，依次通过α，β-不饱和氟烷基亚磺酰酮亚胺的制备，有机金属试剂与手性α，β-不饱和亚胺的选择性加成，手性辅基的脱除，氨基的保护，最后通过双键的简单氧化就可以以高的对映纯度得到含有四取代碳手性中心的α-氟烷基-α-氨基酸类化合物。The present invention uses cheap and easy-to-obtain fluorine-containing alkyl unsaturated ketones and chiral prosthetic sulfenamides as starting materials, and sequentially prepares α, β-unsaturated fluoroalkyl sulfinyl ketimines, organometallic reagents Selective addition to chiral α,β-unsaturated imines, removal of chiral prosthetic groups, protection of amino groups, and finally simple oxidation of double bonds can give tetrasubstituted carbon chiral compounds with high enantiopurity. Sex center α-fluoroalkyl-α-amino acid compounds.
本发明与已有技术相比，其技术进步是显著的。本发明所用原料廉价易得，合成方法操作简单，选择性好，产率高，反应具有普遍适用性，是一种通用的合成含有四取代碳手性中心的α-氟烷基-α-氨基酸类化合物的方法，具有很好的应用前景。Compared with the prior art, the technical progress of the present invention is remarkable. The raw materials used in the present invention are cheap and easy to obtain, the synthesis method is simple to operate, good in selectivity, high in yield, and the reaction has universal applicability. The compound-like method has a good application prospect.
具体实施方式：Detailed ways:
为对本发明进行更好地说明，列举下述实施例，但并不限制本发明的内容。In order to better illustrate the present invention, the following examples are cited, but the content of the present invention is not limited.
实施例1Example 1
将含氟烷基不饱和酮1，手性亚磺酰胺，四乙氧基钛溶于有机溶剂中，加热回流24小时，淬灭反应，过滤，分液萃取，干燥，柱层析得产物2。Dissolve fluorine-containing alkyl unsaturated ketone 1, chiral sulfenamide, and tetraethoxytitanium in an organic solvent, heat to reflux for 24 hours, quench the reaction, filter, separate and extract, dry, and column chromatography to obtain product 2 .
进一步的，将产物2溶于有机溶剂中，惰性气体保护，-40℃条件下，加入有机锂试剂，反应结束后，淬灭反应，分液，萃取，干燥，柱层析得产物3。Further, the product 2 was dissolved in an organic solvent, under the protection of an inert gas, and an organolithium reagent was added under the condition of -40°C. After the reaction was completed, the reaction was quenched, liquid separation, extraction, drying, and column chromatography were performed to obtain the product 3.
进一步的，将产物3溶于有机溶剂中，室温条件下加入氯化氢的水溶液，室温搅拌2小时，旋干溶剂，得产物4。Further, the product 3 was dissolved in an organic solvent, an aqueous solution of hydrogen chloride was added at room temperature, stirred at room temperature for 2 hours, and the solvent was spin-dried to obtain product 4.
进一步的，将产物4溶于有机溶剂中，加入三乙胺，碳酸钾，苯甲酰氯，加热过夜反应，冷却至室温，淬灭反应，分液，萃取，干燥，蒸除溶剂，柱层析提纯，所得产物5。Further, dissolve the product 4 in an organic solvent, add triethylamine, potassium carbonate, and benzoyl chloride, heat overnight for reaction, cool to room temperature, quench the reaction, separate liquids, extract, dry, evaporate the solvent, and perform column chromatography Purification, the resulting product 5.
进一步的，将产物5溶于有机溶剂中，-78℃条件下向体系内通入臭氧气体至体系变蓝，TLC跟踪反应完全，加入三苯基磷，室温搅拌反应3小时，旋干溶剂，得产物6。Further, the product 5 was dissolved in an organic solvent, ozone gas was introduced into the system at -78°C until the system turned blue, TLC followed the complete reaction, triphenylphosphine was added, the reaction was stirred at room temperature for 3 hours, and the solvent was spin-dried. Product 6 was obtained.
进一步的，所得产物6溶于有机溶剂中，向体系中加入2-甲基2-丁烯，水，亚氯酸钠，磷酸二氢钠，TLC跟踪至反应完全，加入氢氧化钠水溶液调溶液pH＝9，旋除溶剂，水相用稀盐酸中和至pH＝3，萃取，合并有机相，干燥，旋干溶剂得产物7。Further, the obtained product 6 is dissolved in an organic solvent, 2-methyl-2-butene, water, sodium chlorite, sodium dihydrogen phosphate are added to the system, TLC is followed until the reaction is complete, and an aqueous solution of sodium hydroxide is added to adjust the solution pH = 9, the solvent was removed by spinning, the aqueous phase was neutralized to pH = 3 with dilute hydrochloric acid, extracted, the organic phases were combined, dried, and the solvent was spin-dried to obtain product 7.
进一步的，将产物7和浓盐酸加热过夜，恢复至室温，过滤，滤液旋干，得浅黄色固体8。Further, the product 7 and concentrated hydrochloric acid were heated overnight, returned to room temperature, filtered, and the filtrate was spin-dried to obtain 8 as a light yellow solid.
进一步的，将产物8溶于有机溶剂中，冰盐浴冷却缓慢滴加氯化亚砜，加毕恢复至室温后加热回流24小时，旋除溶剂，加入饱和碳酸氢钠水溶液，搅拌半小时，分液，萃取，干燥，旋干溶剂得产物9。Further, dissolve the product 8 in an organic solvent, cool in an ice-salt bath and slowly add thionyl chloride dropwise, return to room temperature after the addition and heat to reflux for 24 hours, spin off the solvent, add saturated aqueous sodium bicarbonate solution, and stir for half an hour. Liquid separation, extraction, drying, and spin-drying of the solvent gave product 9.
进一步的，所述的有机溶剂为四氢呋喃、乙醚、甲醇、二氧六环、二氯甲烷、叔丁醇、正己烷、甲基叔丁基醚、乙二醇二甲醚、异丙醚或甲苯。Further, the organic solvent is tetrahydrofuran, ether, methanol, dioxane, dichloromethane, tert-butanol, n-hexane, methyl tert-butyl ether, ethylene glycol dimethyl ether, isopropyl ether or toluene .
上述反应的过程如下描述：The process of the above reaction is described as follows:
进一步的，所述的含氟烷基不饱和酮，其特征是该化合物具有如下结构式：Further, the fluorine-containing alkyl unsaturated ketone is characterized in that the compound has the following structural formula:
进一步的，所述的手性辅基亚磺酰胺，其特征是该化合物具有如下结构式：Further, the chiral prosthetic sulfenamide is characterized in that the compound has the following structural formula:
进一步的，所述的淬灭反应所用试剂为饱和氯化铵水溶液、饱和氯化钠水溶液、饱和碳酸氢钠水溶液或者去离子水。Further, the reagents used in the quenching reaction are saturated ammonium chloride aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bicarbonate aqueous solution or deionized water.
进一步的，所述的萃取溶剂为乙醚，乙酸乙酯，二氯甲烷，四氢呋喃，正己烷或者甲苯。Further, the extraction solvent is diethyl ether, ethyl acetate, dichloromethane, tetrahydrofuran, n-hexane or toluene.
进一步的，所述的干燥剂为无水硫酸钠或者无水硫酸镁。Further, the desiccant is anhydrous sodium sulfate or anhydrous magnesium sulfate.
实施例2Example 2
反应瓶中依次加入1g666mg3g Ti(OEt)4，45ml四氢呋喃，80℃回流反应24小时，冷却至室温，加入30ml饱和氯化钠水溶液，过滤，滤饼用乙酸乙酯洗，合并滤液，分液，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤除去干燥剂，旋干溶剂，快速柱层析(PE：EA＝15：1)，得产物1.3g，产率86％。Add 1g to the reaction bottle 666mg 3g Ti(OEt)4 , 45ml tetrahydrofuran, reflux at 80°C for 24 hours, cool to room temperature, add 30ml saturated aqueous sodium chloride solution, filter, wash the filter cake with ethyl acetate, combine the filtrates, separate the liquids, extract with ethyl acetate, The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, spin-dried the solvent, and flash column chromatography (PE:EA=15:1) to obtain the product 1.3 g, 86% yield.
mp:55-56℃；[α]D20-985.76(c＝0.70,CHCl3)；FT-IR(KBr,cm-1):ν2964,2932,1617,1583,1451,1197,1144,1126,1079,977,762,698；1H NMR(400MHz,CDCl3):δ8.00(d,J＝16.8Hz,1H),7.44-7.47(m,2H),7.27-7.30(m,3H),7.23(d,J＝16.8Hz,1H),1.25(s,9H)；19F NMR(376MHz,CDCl3):δ-66.26(s,3F)；13C NMR(CDCl3):δ158.66(q,J＝32.9Hz),143.77(q,J＝2.7Hz),134.65,130.86,128.89,128.35,118.88(q,J＝282.4Hz),115.09,60.58,22.89. mp: 55-56°C; [α]D20 -985.76 (c=0.70, CHCl3 ); FT-IR (KBr, cm-1 ): ν2964, 2932, 1617, 1583, 1451, 1197, 1144, 1126, 1079,977,762,698;1 H NMR (400MHz, CDCl3 ): δ8.00(d, J=16.8Hz, 1H), 7.44-7.47(m, 2H), 7.27-7.30(m, 3H), 7.23(d, J=16.8Hz,1H),1.25(s,9H);19 F NMR(376MHz,CDCl3 ):δ-66.26(s,3F);13 C NMR(CDCl3 ):δ158.66(q,J= 32.9Hz), 143.77(q, J=2.7Hz), 134.65, 130.86, 128.89, 128.35, 118.88(q, J=282.4Hz), 115.09, 60.58, 22.89.
氩气保护下，反应管中加入1mL无水乙醚及不饱和亚胺(75.8mg，0.25mmol)，冷却至-40℃，缓慢滴加制备好的锂试剂乙醚溶液(0.75mmol)，滴加完毕后，恢复至室温，搅拌，TLC跟踪反应至完全。加入5ml饱和氯化铵水溶液。分液，乙醚萃取，无 水硫酸钠干燥。旋转蒸发除去溶剂，快速柱层析得产物85.9mg，产率90％。Under argon protection, add 1mL of anhydrous diethyl ether and unsaturated imine to the reaction tube (75.8mg, 0.25mmol), cooled to -40°C, slowly added the prepared lithium reagent dropwise Diethyl ether solution (0.75 mmol), after the dropwise addition, was returned to room temperature, stirred, and followed by TLC to complete the reaction. Add 5 ml of saturated aqueous ammonium chloride solution. Separation, extraction with ether, and drying over anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the product was obtained by flash column chromatography 85.9 mg, 90% yield.
[α]D20-100.92(c＝1.29,CHCl3)；FT-IR(KBr,cm-1):ν3329,3061,2926,2868,1713,1652,1578,1540,1450,1248,1074,962,750；1H NMR(400MHz,CDCl3):δ7.67(d,J＝7.3Hz,2H),7.46-7.22(m,8H),6.62,6.55(AB,JAB＝16.4Hz,2H),4.13(s,1H),1.29(s,9H)；19F NMR(376MHz,CDCl3):δ-73.07(s,3F)；13C NMR(101MHz,CDCl3):δ137.04,136.46,135.54,129.07,128.72,128.68,128.66,128.33,127.07,125.37(q,J＝286.0Hz),124.45,68.79(q,J＝27.0Hz),57.08,22.62.[α]D20 -100.92 (c=1.29, CHCl3 ); FT-IR (KBr, cm-1 ): ν3329, 3061, 2926, 2868, 1713, 1652, 1578, 1540, 1450, 1248, 1074, 962, 750 ;1 H NMR (400MHz, CDCl3 ): δ7.67 (d, J = 7.3Hz, 2H), 7.46-7.22 (m, 8H), 6.62, 6.55 (AB, JAB = 16.4Hz, 2H), 4.13 (s,1H),1.29(s,9H);19 F NMR(376MHz,CDCl3 ):δ-73.07(s,3F);13 C NMR(101MHz,CDCl3 ):δ137.04,136.46,135.54,129.07, 128.72, 128.68, 128.66, 128.33, 127.07, 125.37 (q, J=286.0Hz), 124.45, 68.79 (q, J=27.0Hz), 57.08, 22.62.
将115mg溶解于5ml甲醇中，室温下加入3ml氯化氢的水溶液(2mol/L)，室温搅拌3小时，加入饱和碳酸氢钠5ml，分液，乙醚萃取，无水硫酸钠干燥，旋转蒸发除去溶剂，得产物79.1mg，产率95％。115mg Dissolve in 5ml of methanol, add 3ml of hydrogen chloride aqueous solution (2mol/L) at room temperature, stir at room temperature for 3 hours, add 5ml of saturated sodium bicarbonate, separate liquid, extract with ether, dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain the product 79.1 mg, yield 95%.
[α]D26.5106.52(c＝1.002,MeOH)；FT-IR(KBr,cm-1):ν3329,3061,2927,2854,1865,1733,1646,1575,1489,1373,1153,972,743；1H NMR(400MHz,CDCl3):δ7.74(d,J＝7.8Hz,2H),7.53-7.31(m,8H),6.96,6.74(AB,JAB＝16.1Hz,2H),2.08(s,2H)；19F NMR(376MHz,CDCl3):δ-76.63(s,3F)；13C NMR(101MHz,CDCl3):δ138.59,136.17,132.12,128.79,128.52,128.42,128.36,128.27(d,J＝0.6Hz),127.25(d,J＝1.5Hz),126.88,126.77(q,J＝285.8Hz),63.28(q,J＝26.8Hz).[α]D26.5 106.52 (c=1.002, MeOH); FT-IR (KBr, cm-1 ): ν3329, 3061, 2927, 2854, 1865, 1733, 1646, 1575, 1489, 1373, 1153, 972, 743;1 H NMR (400MHz, CDCl3 ): δ7.74 (d, J = 7.8Hz, 2H), 7.53-7.31 (m, 8H), 6.96, 6.74 (AB, JAB = 16.1Hz, 2H), 2.08 (s , 2H);19 F NMR (376MHz, CDCl3 ): δ-76.63 (s, 3F);13 C NMR (101 MHz, CDCl3 ): δ 138.59, 136.17, 132.12, 128.79, 128.52, 128.42, 128.36, 128.27 (d , J=0.6Hz), 127.25(d, J=1.5Hz), 126.88, 126.77(q, J=285.8Hz), 63.28(q, J=26.8Hz).
将69mg溶于2.5ml二氧六环中，依次向体系中加入三乙胺25.3mg，碳酸钾34.6mg，苯甲酰氯105.4mg，加热至80℃，搅拌反应过夜，反应结束后冷却至室温，加入5ml去离子水，分液，乙醚萃取，合并有机相，无水硫酸镁干燥，旋干溶剂，快速柱层析 得产物85.8mg，产率90％。69mg Dissolve in 2.5ml of dioxane, add 25.3mg of triethylamine, 34.6mg of potassium carbonate, and 105.4mg of benzoyl chloride to the system in sequence, heat to 80°C, stir and react overnight, cool to room temperature after the reaction, add 5ml Deionized water, liquid separation, ether extraction, combined organic phases, dried over anhydrous magnesium sulfate, spin-dried solvent, flash column chromatography to obtain the product 85.8 mg, 90% yield.
mp:114-116℃；[α]D24-4.43(c＝1.48,CHCl3)；FT-IR(KBr,cm-1):ν3447,3299,3060,3028,1960,1882,1802,1685,1559,1487,1449,1287,1246,1159,970,746,693；1H NMR(400MHz,CDCl3):δ7.91-7.84(m,2H),7.69-7.24(m,13H),6.98(d,J＝16.2Hz,1H),6.89-6.79(m,2H)；19FNMR(376MHz,CDCl3):δ-74.29(s,3F)；13C NMR(101MHz,CDCl3):δ165.91,135.96,134.81,134.49(d,J＝1.1Hz),134.25,132.20,128.87,128.75,128.65,128.47,127.68,127.67,127.12,127.01,125.21(q,J＝285.8Hz),123.33,66.93(q,J＝26.8Hz).mp: 114-116°C; [α]D24 -4.43 (c=1.48, CHCl3 ); FT-IR (KBr, cm-1 ): ν3447, 3299, 3060, 3028, 1960, 1882, 1802, 1685, 1559,1487,1449,1287,1246,1159,970,746,693;1 H NMR (400MHz, CDCl3 ): δ7.91-7.84(m, 2H), 7.69-7.24(m, 13H), 6.98(d, J＝ 16.2Hz,1H),6.89-6.79(m,2H);19 FNMR(376MHz,CDCl3 ):δ-74.29(s,3F);13 C NMR(101MHz,CDCl3 ):δ165.91,135.96,134.81,134.49 (d,J=1.1Hz),134.25,132.20,128.87,128.75,128.65,128.47,127.68,127.67,127.12,127.01,125.21(q,J=285.8Hz),123.33,66.93(q,J=26.8Hz) .
将110mg溶于5ml二氯甲烷，2.5ml甲醇的混合溶液中，冷却至-78℃，体系中通入臭氧至体系变蓝，继续搅拌，TLC跟踪至反应结束，将90mg三苯基磷溶于1.5ml四氢呋喃中，并加入体系中，加毕后恢复室温，继续搅拌反应2小时，旋转蒸发除去溶剂，得产物82mg，产率95％。110mg Dissolve in a mixed solution of 5ml of dichloromethane and 2.5ml of methanol, cool to -78°C, inject ozone into the system until the system turns blue, continue to stir, follow TLC until the reaction is complete, dissolve 90mg of triphenylphosphine in 1.5ml In tetrahydrofuran, and added to the system, return to room temperature after the addition, continue to stir the reaction for 2 hours, and remove the solvent by rotary evaporation to obtain the product 82 mg, yield 95%.
mp:119-121℃；[α]D25-70.79(c＝0.96,CHCl3)；1H NMR(400MHz,CDCl3):δ9.63(s,1H),7.87(d,J＝6.9Hz,2H),7.73-7.31(m,9H)；19F NMR(376MHz,CDCl3):δ-71.79(s,3F).mp: 119-121°C; [α]D25 -70.79 (c=0.96, CHCl3 );1 H NMR (400MHz, CDCl3 ): δ9.63 (s, 1H), 7.87 (d, J=6.9Hz , 2H), 7.73-7.31 (m, 9H);19 F NMR (376MHz, CDCl3 ): δ-71.79 (s, 3F).
将75mg溶于3ml叔丁醇中，冰水浴条件下依次向反应体系中加入1ml2-甲基-2丁烯，5ml去离子水，108mg亚氯酸钠，144mg磷酸二氢钠，加毕保温反应半小时，恢复室温搅拌过夜，反应结束后，用2mol/L氢氧化钠溶液调pH＝9，旋转蒸发除去叔丁醇，二氯甲烷洗，合并水相，用稀盐酸中和至pH＝3，二氯甲烷萃取有机相，合并有机相，无水硫酸钠干燥，旋干溶剂得产物72mg，产率91％。75mg Dissolve in 3ml of tert-butanol, add 1ml of 2-methyl-2-butene, 5ml of deionized water, 108mg of sodium chlorite, 144mg of sodium dihydrogen phosphate to the reaction system in an ice-water bath, and keep warm for half an hour , return to room temperature and stir overnight, after the reaction, adjust pH=9 with 2mol/L sodium hydroxide solution, remove tert-butanol by rotary evaporation, wash with dichloromethane, combine water phases, neutralize to pH=3 with dilute hydrochloric acid, Extract the organic phase with methyl chloride, combine the organic phases, dry over anhydrous sodium sulfate, and spin the solvent to obtain the product 72 mg, yield 91%.
mp:143-144℃；[α]D26-40.30(c＝1.25,CHCl3)；FT-IR(KBr,cm-1):ν3443,3371,3227,3066,2922,2844,2601,1958,1892,1756,1677,1510,1262,1180,960,762,710；1H NMR(400MHz,CDCl3):δ8.51(s,2H),7.83(d,J＝7.6Hz,2H),7.64-7.27(m,8H)；19F NMR(376MHz, CDCl3):δ-71.79(s,3F)；13C NMR(101MHz,CDCl3):δ168.67,166.94,133.13,132.35,130.80,129.83,129.03,128.98,127.52,126.96,123.37(q,J＝286.3Hz),69.03(q,J＝28.2Hz).mp: 143-144°C; [α]D26 -40.30 (c=1.25, CHCl3 ); FT-IR (KBr, cm-1 ): ν3443, 3371, 3227, 3066, 2922, 2844, 2601, 1958, 1892, 1756, 1677, 1510, 1262, 1180, 960, 762, 710;1 H NMR (400MHz, CDCl3 ): δ8.51(s, 2H), 7.83(d, J=7.6Hz, 2H), 7.64-7.27(m ,8H);19 F NMR(376MHz, CDCl3 ):δ-71.79(s,3F);13 C NMR(101MHz,CDCl3 ):δ168.67,166.94,133.13,132.35,130.80,129.83,129.03,128.98,127.52 ,126.96,123.37(q,J=286.3Hz),69.03(q,J=28.2Hz).
将65mg和1ml浓盐酸加入反应管，100℃加热反应过夜，反应结束后，停止加热恢复室温，过滤除去固体，滤液旋干，得浅黄色固体42.5mg，产率83％。65mg Add 1ml of concentrated hydrochloric acid to the reaction tube, heat and react overnight at 100°C, after the reaction, stop heating and return to room temperature, filter to remove the solid, and spin the filtrate to obtain a light yellow solid 42.5 mg, 83% yield.
mp:>250℃；[α]D25+14.27(c＝1.21,H2O)；1H NMR(400MHz,D2O):δ7.32-7.36(m,5H)； 19F NMR(376MHz,D2O):δ-70.47(s,3F)；13C NMR(101MHz,D2O):δ166.48,130.74,129.55,129.37,127.08,123.20(q,J＝284.4Hz),67.90(q,J＝27.1Hz)。mp: >250℃; [α]D25 +14.27 (c=1.21, H2 O);1 H NMR (400MHz, D2 O): δ7.32-7.36 (m, 5H);19 F NMR (376MHz ,D2 O): δ-70.47(s,3F);13 C NMR (101MHz,D2 O): δ166.48,130.74,129.55,129.37,127.08,123.20(q,J＝284.4Hz),67.90(q, J = 27.1 Hz).
上述反应的过程描述如下：The process of the above reaction is described as follows:
。 .
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