CN104447439B - One has optically active fluorine-containing alkylallyl amine compounds and preparation method - Google Patents

One has optically active fluorine-containing alkylallyl amine compounds and preparation method Download PDF

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CN104447439B
CN104447439B CN201410593856.4A CN201410593856A CN104447439B CN 104447439 B CN104447439 B CN 104447439B CN 201410593856 A CN201410593856 A CN 201410593856A CN 104447439 B CN104447439 B CN 104447439B
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CN104447439A (en
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刘振江
吴范宏
刘朋
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Shanghai Chempartner Co Ltd
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Shanghai Institute of Technology
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Abstract

The present invention provides one and has optically active fluorine-containing alkylallyl amine compounds, additionally provide the preparation method of above-mentioned fluorine-containing alkylallyl amine compounds, by the �� of organolithium reagent and optical purity, ��-unsaturated fluorine alkyl-tert-butyl sulfinyl ketoimine carries out regioselectivity ground addition reaction, easily transforms the fluorine-containing alkylallyl amine compounds with the chirality of derivatize with high receipts rate and outstanding diastereoselective synthesis one class. Cheaper starting materials required for the present invention is easy to get, synthetic method is simple to operate, and the reaction times is short, and the receipts rate of product and optical purity are all higher, it is a kind of method that general synthesis contains the alpha-fluoroalkyl allyl amine compounds of quaternary carbon chiral centre, there is good application prospect.

Description

One has optically active fluorine-containing alkylallyl amine compounds and preparation method
Technical field
The invention belongs to chemical field, particularly relate to a kind of fluorine-containing medicines, pesticide intermediate and its preparation method, one has optically active fluorine-containing alkylallyl amine compounds and preparation method specifically.
Background technology
Chirality allyl amine compounds is not only present in natural product and bioactive molecules widely, and as the important synthetic intermediate of a class, also have a wide range of applications ((a) St �� tz in organic synthesis field, A.Angew.Chem., Int.Ed.Engl.1987,26,320. (b) Dai, C.; Stephenson, C.R.J.Org.Lett.2010,12,3453. (c) Nakamura, Y.; Burke, A.M.; Kotani, S.; Ziller, J.W.; Rychnovsky, S.D.Org.Lett.2009,12,72. (d) Krishnan, S.; Bagdanoff, J.T.; Ebner, D.C.; Ramtohul, Y.K.; Tambar, U.K.; Stoltz, B.M.J.Am.Chem.Soc.2008,130,13745. (e) Jakobsche, C.E.; Gorka, P.; Miller, S.J.Angew.Chem.Int.Ed.2008,47,6707. (f) S.OtsukaandK.Tani, Synthesis1991,665.). In addition by the functionalization of its double bond being obtained diversified useful compound, such as ((a) Hayashi, the T. such as derivative of ��-and beta-amino acids, various alkaloid and sugar;Yamamoto, A.; Ito, Y.; Nishioka, E.; Miura, H.; Yanagi, K.J.Am.Chem.Soc.1989,111,6301. (b) Jumnah, R.; Williams, J.M.J.; Williams, A.C.TetrahedronLett.1993,34,6619. (c) Bower, J.F.; Jumnah, R.; Williams, J.M.J.J.Chem.Soc., PerkinTrans.11997,1411. (d) Burgess, K.; Liu, L.T.; Pal, B.J.Org.Chem.1993,58,4758. (e) Magnus, P.; Lacour, J.; Coldham, I.; Mugrage, B.; Bauta, W.B.Tetrahedron1995,51,11087. (f) Trost, B.M.; VanVranken, D.L.J.Am.Chem.Soc.1993,115,444.), therefore their asymmetric synthesis causes chemists' interest widely. On the other hand, a large amount of experimental facts shows the character due to fluorine atom uniqueness, introduces the physiologically active that fluorine atom often can change molecule effectively in the molecule. So fluorochemicals is more and more paid attention in the fields such as biological, medicine and agricultural chemicals, application also more and more extensive ((a) Prous, J.R.DrugsFut.1995,20,827. (b) James, K.D.; Ekwunbe, N.N.Synthesis2002,850. (c) James, K.D.; Ekwunbe, N.N.Tetrahedron2002,58,5905. (d) Price, M.L.P.; Jorgensen, W.L.J.Am.Chem.Soc.2000,122,9455. (e) Balzarini, J.; Baba, M.; Pauwells, R.; Herdewijn, P.; DeClercq, E.Biochem.Pharmacol.1988,37,2847. (f) Hertel, L.W.; Kroin, J.S.; Misner, J.W.; Tustin, J.M.J.Org.Chem.1988,53,2406. (g) Giovanni, M.; Daniela, U.; Raul, S.; Massimo, P.; Silvio, S.Antimicrob.Agents&Chemother.2000,44,1186.). In the middle of numerous fluorinated organic compound, chirality fluorine-containing alkylallyl amine compounds is a very important class. Although the synthesis report of the chirality allyl amine compounds replaced for non-fluorine alkyl on document is more, but the synthesis report for the chirality allyl amine compounds of alpha-fluoroalkyl replacement is relatively less, and the report of major part is only confined to ((a) Kawatsura, M. in the synthesis of the secondary fluoroalkyl vinyl propyl group aminated compounds of chirality; Terasaki, S.; Minakawa, M.; Hirakawa, T.; Ikeda, K.; Itoh, T.Org.Lett.2014,16,2442. (b) Liu, Z.-J.; Liu, J.-T.Chem.Commun.2008,5233. (c) Prakash, G.K.S.; Mandal, M.; Olah, G.A.Org.Lett.2001,3,2847. (d) Tam, N.T.N.; Magueur, G.; Our �� vitch, M.; Crousse, B.; B �� gu ��, J.-P.; Bonnet-Delpon, D.J.Org.Chem.2005,70,699. (e) Kuduk, S.D.; Marco, C.N.D.; Pitzenberger, S.M.; Tsou, N.TetrahedronLett.2006,47,2377. (f) Fries, S.; Pytkowiz, J.; Brigaud, T.TetrahedronLett.2005,46,4761. (g) Fustero, S.; Garc �� aSoler, J.; Bartolom ��, A.; S �� nchezRosell ��, M.Org.Lett.2003,5,2707. (h) Magueur, G.;Crousse, B.; Bonnet-Delpon, D.Eur.J.Org.Chem.2008,1527.). The method simultaneously effectively building fluorine-containing alkyl quaternary carbon chiral centre owing to lacking, therefore the method for the alpha-fluoroalkyl allyl amine compounds that synthesis contains quaternary carbon chiral centre is very limited at present.
The people such as Hu Jinbo in 2010 report the method that the synthesis of a kind of method by difluoromethyl contains the alpha-difluoromethyl allyl amine compounds of quaternary carbon chiral centre, but the method is only confined to contain (Liu, J. in the synthesis of difluoromethyl aminated compounds; Hu, J.Chem.Eur.J.2010,16,11443.). The people such as people and Ohshima such as yellow flame roots in 2013 report again the method that a single example multistep synthesis contains the ��-trifluoromethyl allyl amine compounds of quaternary carbon chiral centre respectively, owing to needs synthesize through multistep, reactions steps is loaded down with trivial details, receipts rate is lower, and the limitation of substrate relatively big ((a) Yang, Y.; Huang, Y.; Qing, F.-L.TetrahedronLett.2013,54,3826. (b) Morisaki, K.; Sawa, M.; Nomaguchi, J.-y.; Morimoto, H.; Takeuchi, Y.; Mashima, K.; Ohshima, T.Chem.Eur.J.2013,19,8417.). The people such as Liu Jintao also once reported the synthesis with the ��-trifluoromethyl allyl amine compounds containing quaternary carbon chiral centre that special groups replaces, but the synthesis due to the compound that only can carry out special groups replacement, the scope of application of its substrate is very limited ((a) Zhang, F. also; Liu, Z.-J.; Liu, J.-T.Org.Biomol.Chem.2011,9,3625. (b) Yuan, X.-M.; Xu, J.; Liu, Z.-J.; Yang, X.-J.; Wang, L.-M.; Zhang, Y.; Yang, X.-Y.; He, X.-P.; Liu, J.-T.J.FluorineChem.2012,144,102.). And the synthesis of the allyl amine compounds replaced for other alpha-fluoroalkyls containing quaternary carbon chiral centre there is not yet document report.
Summary of the invention
For above-mentioned technical problem of the prior art, the present invention provides one and has optically active fluorine-containing alkylallyl amine compounds and preparation method, and this described kind has optically active fluorine-containing alkylallyl amine compounds and preparation method solves the technical problem synthesizing the alpha-fluoroalkyl allyl amine compounds difficulty containing quaternary carbon chiral centre in prior art.
One of the present invention has optically active fluorine-containing alkylallyl amine compounds, and its structural formula is as follows:
Wherein, R1For alkyl, aryl, heteroaryl, alkene base, alkynes base, benzyl or naphthyl; R2For alkyl, aryl, heteroaryl, alkene base, alkynes base, benzyl or naphthyl; RfFor fluorine-containing alkyl.
Further, described alkyl is C1-20Alkyl or C1-20Haloalkyl; Described aryl is phenyl or substituted-phenyl; Substituting group in described substituted-phenyl be adjacent, para-orientation or polysubstituted methyl, ethyl, phenyl, methoxyl group, oxyethyl group, benzyloxy, trifluoromethyl, difluoromethyl, a methyl fluoride, fluorine, chlorine, bromine, ethanoyl or dimethylamino; Described heteroaryl is furyl, thienyl, pyridyl, pyrazolyl, pyrryl, thiazolyl, azoles base, quinolyl, isoquinolyl, indyl, indazolyl, benzofuryl, benzothienyl, benzothiazolyl or benzoxazolyl group; Described alkene base is vinyl, styryl or substituted phenylethylene base, and the double bond of alkene is cis or trans;Described alkynes base is phenylacetylene base or substitutedphenylethynyl base; Described benzyl is phenmethyl; Described naphthyl is 1-naphthyl or 2-naphthyl; Described fluorine-containing alkyl is the C that trifluoromethyl, difluoromethyl, a methyl fluoride, single fluorine or many fluorine replace1-20Alkyl or C1-20Haloalkyl.
Further, described PG is carbobenzoxy-(Cbz) (Cbz), tertiary butoxy carbonyl (Boc), tablet held before the breast by officials methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyl ethoxycarbonyl (Teoc), first (or second) oxygen carbonyl, phthaloyl (Pht), tolysulfonyl base (Tos), trifluoroacetyl base, adjacent (to) nitrobenzenesulfonyl (Ns), pivaloyl base, benzoyl (Bz), trityl (Trt), 2, 4-dimethoxy-benzyl (Dmb), to methoxy-benzyl (PMB), or benzyl (Bn).
Present invention also offers above-mentioned a kind of preparation method with optically active fluorine-containing alkylallyl amine compounds, with the �� of high chiral purity, ��-unsaturated fluorine alkyl-tert-butyl sulfinyl ketoimine is raw material, described ��, the structural formula of ��-unsaturated fluorine alkyl-tert-butyl sulfinyl ketoimine is as follows, olefinic double bonds is cis or trans
Under protection of inert gas; by ��; ��-unsaturated fluorine alkyl-tert-butyl sulfinyl ketoimine adds in organic solvent; organolithium reagent is slowly joined in above-mentioned reaction system under-78 DEG C��room temperature condition; described ��; the mol ratio of ��-unsaturated fluorine alkyl-tert-butyl sulfinyl ketoimine and organolithium reagent is 1: 1-10; then clear-cutting forestland is to room temperature; react 2-5 hour; cancellation is reacted; separatory, extraction, drying, steaming, except solvent, purification, obtain and have optically active fluorine-containing alkylallyl amine compounds.
Further, above-mentioned acquisition had that optically active fluorine-containing alkylallyl amine compounds is de-in acid condition can obtain as follows having optically active alpha-fluoroalkyl allyl amine compounds except sulfoxide prothetic group,
Further, the compound of above-mentioned acquisition can be obtained as follows having optically active alpha-fluoroalkyl allyl amine compounds by upper amido protecting group again,
Further, described organic solvent is removed the ether of moisture, tetrahydrofuran (THF), methyl tertiary butyl ether, glycol dimethyl ether, isopropyl ether, dioxane, methylene dichloride, normal hexane or toluene, it is preferable that be ether.
Further, the structure of described organolithium reagent is R1Li structure, wherein said R1For alkyl, aryl, heteroaryl, alkene base, alkynes base, benzyl or naphthyl.
Further, add saturated aqueous ammonium chloride after reaction or shrend is gone out reaction, it is preferable that be saturated aqueous ammonium chloride.
Further, obtain and there is optically active fluorine-containing alkylallyl amine compounds adopt solvent extraction, column chromatographic isolation and purification, described extraction solvent is ether, ethyl acetate, methylene dichloride, tetrahydrofuran (THF), normal hexane or toluene, it is preferable that be ethyl acetate.
Further, described rare gas element is nitrogen or argon gas, it is preferable that be argon gas.
Further, the siccative that drying process adopts is anhydrous sodium sulphate or anhydrous magnesium sulfate, it is preferable that be anhydrous sodium sulphate.
Further, described ��, ��-unsaturated fluorine alkyl-tert-butyl sulfinyl ketoimine and organolithium reagent mol ratio are 1: 3-5.
The reaction formula of the present invention is as follows:
Sequence number R1 Rf R2 Product rate % Dr
1 C6H5- CF3 C6H5- 90 98��2
2 2-MeC6H4- CF3 C6H5- 82 99��1
3 3-MeC6H4- CF3 C6H5- 90 97��3
4 4-MeC6H4- CF3 C6H5- 87 96��4
5 4-ClC6H4- CF3 C6H5- 99 98��2
6 4-FC6H4- CF3 C6H5- 99 95��5
7 4-MeOC6H4- CF3 C6H5- 48 96��4
8 n-Bu- CF3 C6H5- 82 > 99: 1
9 1-Naphthyl- CF3 C6H5- 91 > 99: 1
10 C6H5C��C- CF3 C6H5- 95 85��15
11 C6H5- CF3 C6H5(CH2)3- 82 98��2
12 C6H5- CF3 2-Furyl 81 98��2
13 C6H5- CF2H C6H5- 99 90��10
14 C6H5- CF2Cl C6H5- 91 > 99: 1
15 C6H5- C3F7 C6H5- 87 97��3
16 C6H5- C5F11 C6H5- 78 98��2
Wherein, Naphthyl is naphthyl, and Fruyl is furyl.
Compound 1,2,3,4 takes off except sulfoxide prothetic group can obtain optically active alpha-fluoroalkyl allyl amine compounds 5,6 in acid condition; 5,6 can obtain compound 7,8 by upper amido protecting group.
The present invention is by the �� of organolithium reagent and optical purity, ��-unsaturated fluorine alkyl-tert-butyl sulfinyl ketoimine carries out regioselectivity ground addition reaction, easily transforms the fluorine-containing alkylallyl amine compounds with the chirality of derivatize with high receipts rate and outstanding diastereoselective synthesis one class.
The present invention compares with prior art, and its technical progress is significant. The present invention provides a kind of convenience and high-efficiency and universally synthesizes the method for the alpha-fluoroalkyl allyl amine compounds containing quaternary carbon chiral centre. Cheaper starting materials required for the present invention is easy to get, and synthetic method is simple to operate, and the reaction times is short, and the receipts rate of product and optical purity are all higher, has good application prospect.
Embodiment
Utilize following embodiment will contribute to understanding the present invention, but do not limit the content of the present invention.
Embodiment 1
Under argon gas shielded, reaction tubes adds 1mL anhydrous diethyl ether and unsaturated imines(75.8mg, 0.25mmol), is cooled to-40 DEG C, slowly drips and adds lithium reagentDiethyl ether solution (0.75mmol), after dropwising, returns to room temperature, stirs, and TLC follows the tracks of reaction to completely. Add 5ml saturated aqueous ammonium chloride, separatory, extraction into ethyl acetate, anhydrous sodium sulfate drying. Rotary evaporation is except desolventizing, and rapid column chromatography obtains product85.9mg, product rate 90%.
[��]D 20-100.92 (c=1.29, CHCl3); FT-IR (KBr, cm-1): �� 3329,3061,2926,2868,1713,1652,1578,1540,1450,1248,1074,9 62,750;1HNMR(CDCl3): �� 7.67 (d, J=7.3Hz, 2H), 7.46-7.22 (m, 8H), 6.62 (d, J=16.4Hz, 1H), 6.55 (d, J=16.4Hz, 1H), 4.13 (s, 1H), 1.29 (s, 9H).;19FNMR(CDCl3): ��-73.07 (s, 3F);13CNMR(CDCl3): �� 137.04,136.46,135.54,129.07,128.72,128.68,128.66,128.33,127.07,125.37 (q, J=286.0Hz), 124.45,68.79 (q, J=27.0Hz), 57.08,22.62.
Embodiment 2:
Under argon gas shielded, reaction tubes adds 1mL anhydrous diethyl ether and unsaturated imines(75.8mg, 0.25mmol), is cooled to-40 DEG C, slowly drips and adds the lithium reagent preparedDiethyl ether solution (0.75mmol), after dropwising, returns to room temperature, stirs, and TLC follows the tracks of reaction to completely. Add 5ml saturated aqueous ammonium chloride, separatory, extraction into ethyl acetate, anhydrous sodium sulfate drying. Rotary evaporation is except desolventizing, and rapid column chromatography obtains product81.1mg, product rate 82%.
[��]D 27-145.59 (c=0.88, CHCl3); FT-IR (KBr, cm-1): �� 3372,3253,3061,2960,1713,1652,1506,1449,1364,1153,940,75 1;1HNMR (400MHz, CDCl3) �� 7.65 (d, J=8.0Hz, 1H), 7.43 (d, J=7.1Hz, 2H), 7.38-7.23 (m, 6H), 6.81 (d, J=16.3Hz, 1H), 6.50 (d, J=16.3Hz, 1H), 4.01 (s, 1H), 2.51 (s, 3H), 1.29 (s, 9H).;19FNMR (376MHz, CDCl3) ��-71.09 (s, 3F);13CNMR (101MHz, CDCl3) �� 137.87,135.85,135.81,134.93,133.85,129.30,128.76,128.69,128.64,126.98,125.86,125.73 (q, J=287.0Hz), (125.44,68.98 q, J=26.9Hz), 57.23,23.11,22.65.
Embodiment 3:
Under argon gas shielded, reaction tubes adds 1mL anhydrous diethyl ether and unsaturated imines(75.8mg, 0.25mmol), is cooled to-40 DEG C, slowly drips and adds the lithium reagent preparedDiethyl ether solution (0.75mmol), after dropwising, returns to room temperature, stirs, and TLC follows the tracks of reaction to completely.Add 5ml saturated aqueous ammonium chloride, separatory, extraction into ethyl acetate, anhydrous sodium sulfate drying. Rotary evaporation is except desolventizing, and rapid column chromatography obtains product90mg, product rate 90%.
[��]D 27-94.32 (c=0.97, CHCl3); FT-IR (KBr, cm-1): �� 3347,3208,3058,2958,1713,1648,1578,1450,1364,1169,973,75 1;1HNMR (400MHz, CDCl3) �� 7.50-7.42 (m, 4H), 7.39-7.27 (m, 4H), 7.23 (d, J=7.6Hz, 1H), 6.66 (d, J=16.4Hz, 1H), 6.56 (d, J=16.4Hz, 1H), 4.12 (s, 1H), 2.40 (s, 3H), 1.31 (s, 9H);19FNMR (376MHz, CDCl3) ��-72.85 (s, 3F);13CNMR (101MHz, CDCl3) �� 137.94,136.26,136.05,135.22,129.39,128.42,128.24, (128.22,128.09,126.65,124.97 q, J=286.1Hz), 124.96, (124.28,68.25 q, J=27.0Hz), 56.61,22.17,21.22.
Embodiment 4:
Under argon gas shielded, reaction tubes adds 1mL anhydrous diethyl ether and unsaturated imines(75.8mg, 0.25mmol), is cooled to-40 DEG C, slowly drips and adds the lithium reagent preparedDiethyl ether solution (0.75mmol), after dropwising, returns to room temperature, stirs, and TLC follows the tracks of reaction to completely. Add 5ml saturated aqueous ammonium chloride, separatory, extraction into ethyl acetate, anhydrous sodium sulfate drying. Rotary evaporation is except desolventizing, and rapid column chromatography obtains product86mg, product rate 87%.
[��]D 25-90.54 (c=1.04, CHCl3); FT-IR (KBr, cm-1): �� 3344,3207,3060,2958,2925,1713,1647,1540,1449,1364,1160,9 74,749;1HNMR (400MHz, CDCl3) �� 7.57 (d, J=8.1Hz, 2H), 7.45 (d, J=7.0Hz, 2H), 7.38-7.21 (m, 5H), 6.65 (d, J=16.3Hz, 1H), 6.57 (d, J=16.3Hz, 1H), (4.12 s, 1H), 2.39 (s, 3H), 1.30 (s, 9H);19FNMR (376MHz, CDCl3) ��-73.16 (s, 3F);13CNMR (101MHz, CDCl3) �� 139.07,136.88,135.70,133.56,129.40,128.72,128.71,128.29,127.12,125.50 (q, J=286.0Hz), 124.74,68.64 (q, J=27.1Hz), 57.06,22.65,21.05.
Embodiment 5:
Under argon gas shielded, reaction tubes adds 1mL anhydrous diethyl ether and unsaturated imines(75.8mg, 0.25mmol), is cooled to-40 DEG C, slowly drips and adds the lithium reagent preparedDiethyl ether solution (0.75mmol), after dropwising, returns to room temperature, stirs, and TLC follows the tracks of reaction to completely. Add 5ml saturated aqueous ammonium chloride, separatory, extraction into ethyl acetate, anhydrous sodium sulfate drying. Rotary evaporation is except desolventizing, and rapid column chromatography obtains product102.9mg, product rate 99%.
[��]D 24-105.84 (c=1.11, CHCl3); FT-IR (KBr, cm-1): �� 3344,3215,3060,2059,2926,1714,1647,1540,1448,1364,1166,9 85,751;1HNMR (400MHz, CDCl3) �� 7.64 (d, J=8.5Hz, 2H), 7.46-7.38 (m, 4H), 7.38-7.27 (m, 3H), 6.59-6.47 (m, 2H), 4.08 (s, 1H), 1.29 (s, 9H);19FNMR (376MHz, CDCl3) ��-73.43 (s, 3F);13CNMR (101MHz, CDCl3) �� 137.70,135.34,135.31,134.92,130.07,130.05,128.95,128.88,128.76,127.14,125.26 (q, J=286.84Hz), 123.84,68.81 (q, J=27.2Hz), 57.18,22.63.
Embodiment 6:
Under argon gas shielded, reaction tubes adds 1mL anhydrous diethyl ether and unsaturated imines(75.8mg, 0.25mmol), is cooled to-40 DEG C, slowly drips and adds the lithium reagent preparedDiethyl ether solution (0.75mmol), after dropwising, returns to room temperature, stirs, and TLC follows the tracks of reaction to completely.Add 5ml saturated aqueous ammonium chloride, separatory, extraction into ethyl acetate, anhydrous sodium sulfate drying. Rotary evaporation is except desolventizing, and rapid column chromatography obtains product98.9mg, product rate 99%.
[��]D 25-78.62 (c=0.99, CHCl3); FT-IR (KBr, cm-1): �� 3343,3197,3061,2960,2927,1714,1652,1605,1540,1449,1364,1 164,974,749;1HNMR (400MHz, CDCl3) �� 7.68 (dd, J=8.5,5.2Hz, 2H), 7.46-7.39 (m, 2H), 7.39-7.30 (m, 3H), 7.12 (t, J=8.6Hz, 2H), 6.57 (d, J=16.0Hz, 1H), 6.52 (d, J=16.0Hz, 1H), 4.07 (s, 1H), 1.30 (s, 9H);19FNMR (376MHz, CDCl3) ��-73.50 (s, 3F) ,-112.40--112.49 (m, 1F);13CNMR (101MHz, CDCl3) �� 162.96 (d, J=249.6Hz), 137.48,135.37,132.20 (d, J=3.4Hz), 130.61 (d, J=8.3Hz), 128.90,128.76,127.13, (125.32 q, J=285.7Hz), 124.15,115.64 (d, J=21.5Hz), 68.69 (q, J=27.2Hz), 57.15,22.63.
Embodiment 7:
Under argon gas shielded, reaction tubes adds 1mL anhydrous diethyl ether and unsaturated imines(75.8mg, 0.25mmol), is cooled to-40 DEG C, slowly drips and adds the lithium reagent preparedDiethyl ether solution (0.75mmol), after dropwising, returns to room temperature, stirs, and TLC follows the tracks of reaction to completely. Add 5ml saturated aqueous ammonium chloride, separatory, extraction into ethyl acetate, anhydrous sodium sulfate drying. Rotary evaporation is except desolventizing, and rapid column chromatography obtains product49.4mg, product rate 48%.
[��]D 24-38.44 (c=1.99, CHCl3); FT-IR (KBr, cm-1): �� 3343,3208,3060,2959,2868,1713,1647,1539,1463,1364,1160,9 74,750;1HNMR (400MHz, CDCl3) �� 7.59 (d, J=8.8Hz, 2H), 7.43 (d, J=7.0Hz, 2H), 7.37-7.27 (m, 3H), (6.95 d, J=9.0Hz, 2H), 6.63 (d, J=16.3Hz, 1H), 6.55 (d, J=16.3Hz, 1H), 4.08 (s, 1H), 3.83 (s, 3H), 1.29 (s, 9H);19FNMR (376MHz, CDCl3) ��-73.36 (s, 3F);13CNMR (101MHz, CDCl3) �� 159.97,136.86,135.66,129.81,129.79,128.72,128.30,127.11,125.51 (q, J=284.83Hz), 124.82,113.97,68.49 (q, J=27.1Hz), 57.05,55.31,22.65.
Embodiment 8:
Under argon gas shielded, reaction tubes adds 1mL anhydrous diethyl ether and unsaturated imines(75.8mg, 0.25mmol), is cooled to-40 DEG C, slowly drips the hexane solution (0.75mmol) adding n-Butyl Lithium, after dropwising, returns to room temperature, stirs, and TLC follows the tracks of reaction to completely. Add 5ml saturated aqueous ammonium chloride, separatory, extraction into ethyl acetate, anhydrous sodium sulfate drying. Rotary evaporation is except desolventizing, and rapid column chromatography obtains product74.1mg, product rate 82%.
[��]D 25-45.50 (c=0.95, CHCl3); FT-IR (KBr, cm-1): �� 3329,3228,3060,2959,2872,1715,1652,1578,1457,1364,1148,9 74,748;1HNMR (400MHz, CDCl3) �� 7.42 (d, J=7.1Hz, 2H), 7.37-7.26 (m, 3H), 6.79 (d, J=16.4Hz, 1H), (6.24 d, J=16.4Hz, 1H), 3.64 (s, 1H), 2.09-1.91 (m, 2H), 1.48-1.28 (m, 4H), 1.26 (s, 9H), 0.91 (t, J=7.1Hz, 3H);19FNMR (376MHz, CDCl3) ��-76.44 (s, 3F);13CNMR (101MHz, CDCl3) �� 135.72,134.51,128.72,128.56,126.86,125.82 (q, J=286.4Hz), 124.12,64.64 (q, J=26.5Hz), 57.02,33.67,24.85,22.87,22.64,13.82.
Embodiment 9:
Under argon gas shielded, reaction tubes adds 1mL anhydrous diethyl ether and unsaturated imines(75.8mg, 0.25mmol), is cooled to-40 DEG C, slowly drips and adds the lithium reagent preparedDiethyl ether solution (0.75mmol), after dropwising, returns to room temperature, stirs, and TLC follows the tracks of reaction to completely. Add 5ml saturated aqueous ammonium chloride, separatory, extraction into ethyl acetate, anhydrous sodium sulfate drying. Rotary evaporation is except desolventizing, and rapid column chromatography obtains product98.2mg, product rate 91%.
[��]D 27-155.55 (c=0.73, CHCl3); FT-IR (KBr, cm-1): �� 3358,32159,3055,2960,2868,1712,1646,1540,1448,1363,1155,971,750;1HNMR (400MHz, CDCl3) �� 8.54 (d, J=8.6Hz, 1H), 7.97-7.86 (m, 3H), 7.56-7.44 (m, 3H), 7.36 (dd, J=7.9,1.3Hz, 2H), 7.32-7.23 (m, 3H), 7.02 (d, J=16.2Hz, 1H),, 6.42 (d, J=16.2Hz, 1H), 4.33 (s, 1H), 1.26 (s, 9H);19FNMR (376MHz, CDCl3) ��-70.89 (s, 3F);13CNMR (101MHz, CDCl3) �� 136.82,135.76,135.21,131.18,131.08,129.79,129.34,128.63,128.56,127.76,127.63 (q, J=3.38Hz), 127.01,126.27,125.79,125.72 (q, J=287.86Hz) 125.64,124.44,69.44 (q, J=26.9Hz), 57.29,22.65.
Embodiment 10:
Under argon gas shielded, reaction tubes adds 1mL anhydrous diethyl ether and unsaturated imines(75.8mg, 0.25mmol), is cooled to-40 DEG C, slowly drips and adds the lithium reagent preparedDiethyl ether solution (0.75mmol), after dropwising, returns to room temperature, stirs, and TLC follows the tracks of reaction to completely. Add 5ml saturated aqueous ammonium chloride, separatory, extraction into ethyl acetate, anhydrous sodium sulfate drying. Rotary evaporation is except desolventizing, and rapid column chromatography obtains product96.3mg, product rate 95%.
[��]D 24-145.19 (c=0.99, CHCl3); FT-IR (KBr, cm-1): �� 3411,3192,3060,2959,2927,1712,1651,1578,1445,1364,1193,9 70,754;1HNMR (400MHz, CDCl3) �� 7.61 (dd, J=7.7,1.8Hz, 2H), 7.49 (d, J=7.0Hz, 2H), 7.40-7.30 (m, 7H), 6.25 (d, J=15.7Hz, 1H), 4.01 (s, 1H), 1.27 (s, 9H).;19FNMR (376MHz, CDCl3) ��-78.24 (s, 3F);13CNMR (101MHz, CDCl3) �� 138.86,135.08,132.13,129.46,129.13,128.80,128.43,127.39,123.76 (q, J=292.8Hz), 121.22,120.36,90.34,81.96,62.27 (q, J=30.8Hz), 56.96,22.42.
Embodiment 11:
Under argon gas shielded, reaction tubes adds 1mL anhydrous diethyl ether and unsaturated imines(86mg, 0.25mmol), is cooled to-40 DEG C, slowly drips and adds the lithium reagent preparedDiethyl ether solution (0.75mmol), after dropwising, returns to room temperature, stirs, and TLC follows the tracks of reaction to completely.Add 5ml saturated aqueous ammonium chloride, separatory, extraction into ethyl acetate, anhydrous sodium sulfate drying. Rotary evaporation is except desolventizing, and rapid column chromatography obtains product86.5mg, product rate 82%.
[��]D 26-63.35 (c=1.12, CHCl3); FT-IR (KBr, cm-1): �� 3346,3212,3061,2929,2860,1663,1603,1496,1450,1365,1252,9 76,700;1HNMR (400MHz, CDCl3) �� 7.64 (d, J=7.4Hz, 2H), 7.47-7.36 (m, 3H), 7.31-7.23 (m, 2H), 7.22-7.09 (m, 3H), 5.92 (d, J=15.8Hz, 1H), 5.75-5.61 (m, 1H), 4.02 (s, 1H), 2.63 (t, J=7.7Hz, 2H), 2.26-2.11 (m, 2H), 1.81-1.66 (m, 2H), 1.28 (s, 9H);19FNMR (376MHz, CDCl3) ��-73.39 (s, 3F);13CNMR (101MHz, CDCl3) �� 142.05,139.64,136.87,128.78,128.52,128.48,128.36, (q, J=285.9Hz), 128.33,125.80,125.52,125.49 68.72 (q, J=26.8Hz), 56.91,35.26,32.17,30.33,22.69.
Embodiment 12:
Under argon gas shielded, reaction tubes adds 1mL anhydrous diethyl ether and unsaturated imines(88mg, 0.3mmol), is cooled to-40 DEG C, slowly drips and adds the lithium reagent preparedDiethyl ether solution (0.9mmol), after dropwising, returns to room temperature, stirs, and TLC follows the tracks of reaction to completely. Add 5ml saturated aqueous ammonium chloride, separatory, extraction into ethyl acetate, anhydrous sodium sulfate drying. Rotary evaporation is except desolventizing, and rapid column chromatography obtains product90.5mg, product rate 81%.
[��]D 23-141.10 (c=1.03, CHCl3); FT-IR (KBr, cm-1): �� 3206,2960,2927,2869,1713,1654,1474,1448,1365,1249,1158,9 29,741,701;1HNMR (400MHz, CDCl3) �� 7.68 (d, J=7.5Hz, 2H), 7.46-7.36 (m, 4H), 6.54 (d, J=16.1Hz, 1H), 6.36 (dd, J=3.2,1.8Hz, 1H), 6.34-6.27 (m, 2H), 4.12 (s, 1H), 1.28 (s, 9H);19FNMR (376MHz, CDCl3) ��-73.33 (s, 3F);13CNMR (101MHz, CDCl3) �� 151.13,143.12,136.36,129.05,128.70,128.44,125.46,125.42 (q, J=286.1Hz), 122.19,111.62,110.95,68.98 (q, J=27.2Hz), 57.12,22.65.
Embodiment 13
Under argon gas shielded, reaction tubes adds 1mL anhydrous diethyl ether and unsaturated imines(85.6mg, 0.3mmol), is cooled to-40 DEG C, slowly drips and adds the lithium reagent preparedDiethyl ether solution (0.9mmol), after dropwising, returns to room temperature, stirs, and TLC follows the tracks of reaction to completely. Add 5ml saturated aqueous ammonium chloride, separatory, extraction into ethyl acetate, anhydrous sodium sulfate drying. Rotary evaporation is except desolventizing, and rapid column chromatography obtains product108.1mg, product rate 99%.
[��]D 26-59.53 (c=0.99, CHCl3); FT-IR (KBr, cm-1): �� 3199,3059,2959,2868,1711,1559,1578,11496,1448,1365,1068,973,746,696;1HNMR (400MHz, CDCl3) �� 7.55 (d, J=7.3Hz, 2H), 7.45-7.25 (m, 8H), 6.64 (d, J=16.0Hz, 1H), 6.49 (d, J=15.1Hz, 1H), 6.64-6.33 (t, J=53.4Hz, 1H), 4.13 (s, 1H), 1.28 (s, 9H);19FNMR (376MHz, CDCl3) ��-125.06 ,-129.74 (ABd, JAB=277.8, J1=54.3Hz, 2F);13CNMR (101MHz, CDCl3) �� 136.51,135.88,134.32,128.78,128.71,128.69, (t, J=2.5Hz), 128.44,128.28,126.93,126.36 116.16 (t, J=250.02Hz), 67.05 (t, J=20.7Hz), 56.75,22.82.
Embodiment 14
Under argon gas shielded, reaction tubes adds 2mL anhydrous diethyl ether and unsaturated imines(159.9mg, 0.5mmol), is cooled to-40 DEG C, slowly drips and adds the lithium reagent preparedDiethyl ether solution (1.0mmol), after dropwising, returns to room temperature, stirs, and TLC follows the tracks of reaction to completely. Add 5ml saturated aqueous ammonium chloride, separatory, extraction into ethyl acetate, anhydrous sodium sulfate drying. Rotary evaporation is except desolventizing, and rapid column chromatography obtains product180.9mg, product rate 91%.
[��]D 25-115.09 (c=1.04, CHCl3); FT-IR (KBr, cm-1): �� 3344,3215,3060,2059,2926,1714,1647,1540,1448,1364,1166,9 85,751;1HNMR (400MHz, CDCl3): �� 7.73 (d, J=7.0Hz, 2H), 7.46-7.26 (m, 8H), 6.62 (d, J=16.2Hz, 1H), 6.49 (d, J=16.2Hz, 1H),, 4.31 (s, 1H), 1.31 (s, 9H);19FNMR (376MHz, CDCl3) ��-57.62,59.32 (AB, JAB=160.9Hz, 2F);13CNMR (101MHz, CDCl3) �� 138.59,137.10,135.60,131.25 (t, J=302.8Hz), 128.96,128.91,128.78,128.69,128.50,127.14,124.37,73.00 (t, J=23.7Hz), 57.19,22.79.
Embodiment 15
Under argon gas shielded, reaction tubes adds 2mL anhydrous diethyl ether and unsaturated imines(201.6mg, 0.5mmol), is cooled to-40 DEG C, slowly drips and adds the lithium reagent preparedDiethyl ether solution (1.0mmol), after dropwising, returns to room temperature, stirs, and TLC follows the tracks of reaction to completely. Add 5ml saturated aqueous ammonium chloride, separatory, extraction into ethyl acetate, anhydrous sodium sulfate drying. Rotary evaporation is except desolventizing, and rapid column chromatography obtains product209.6mg, product rate 87%.
[��]D 24-143.74 (c=1.03, CHCl3); FT-IR (KBr, cm-1): �� 3371,3219,3062,2960,2870,1715,1647,1540,1448,1364,1213,9 74,744;1HNMR (300MHz, CDCl3) �� 7.72 (d, J=6.0Hz, 2H), 7.55-7.29 (m, 8H), (6.66 d, J=15.9Hz, 1H), 6.40 (d, J=15.9Hz, 1H), 4.38 (s, 1H), 1.31 (s, 9H);16FNMR (282MHz, CDCl3) ��-81.17 (m, 3F) ,-109.05 ,-113.17 (ABm, JAB=274.95Hz, 2F) ,-117.86 ,-122.73 (ABm, JAB=284.48Hz, 2F);13CNMR (101MHz, CDCl3) �� 139.17,135.60,135.49,129.04,128.85,128.69,128.58,128.50,127.17,123.71,71.01-69.19,57.07,22.70.
Embodiment 16
Under argon gas shielded, reaction tubes adds 2mL anhydrous diethyl ether and unsaturated imines(251.5mg, 0.5mmol), is cooled to-40 DEG C, slowly drips and adds the lithium reagent preparedDiethyl ether solution (1.0mmol), after dropwising, returns to room temperature, stirs, and TLC follows the tracks of reaction to completely.Add 5ml saturated aqueous ammonium chloride, separatory, extraction into ethyl acetate, anhydrous sodium sulfate drying. Rotary evaporation is except desolventizing, and rapid column chromatography obtains product226.8mg, product rate 78%.
[��]D 24-119.10 (c=0.9, CHCl3); FT-IR (KBr, cm-1): �� 3373,3245,3062,2061,2870,1716,1646,1540,1448,1361,1236,9 75,745;1HNMR (300MHz, CDCl3) �� 7.72 (d, J=7.0Hz, 2H), 7.36 (m, 7H), 6.66 (d, J=16.1Hz, 1H), 6.40 (d, J=16.1Hz, 1H), 4.39 (s, 1H), 1.31 (s, 9H);19FNMR (282MHz, CDCl3) ��-80.78 (t, J=10.0Hz) ,-108.16 ,-112.99 (ABm, JAB=277.77Hz, 2F) ,-114.44 ,-118.55 (ABm, JAB=294.69Hz, 2F) ,-122.66 ,-125.98 (ABm, JAB=104.34Hz, 4F);13CNMR (101MHz, CDCl3) �� 139.20,135.55,135.48,129.05,128.85,128.69,128.58,128.50,127.18,123.80,71.04 (t, J=21.72Hz), 57.06,22.70.
Embodiment 17:
By raw material(80mg, 0.2mmol) is dissolved in 5ml methyl alcohol, adds the diethyl ether solution (2ml of hydrochloric acid under room temperature, 2.0M), stir 1 hour at this temperature, in reaction system, add saturated sodium bicarbonate aqueous solution, adjust pH to 7-8, separatory, extraction into ethyl acetate, anhydrous sodium sulfate drying, rotary evaporation is except desolventizing, without the need to purifying, obtain product55.5mg, product rate > 99%.
[��]D 27106.52 (c=1.002, MeOH);1HNMR (400MHz, CDCl3) �� 7.74 (d, J=7.8Hz, 2H), 7.53-7.31 (m, 8H), 6.96 (d, J=16.1Hz, 1H), 6.74 (d, J=16.1Hz, 1H), 2.08 (s, 2H);19FMR (376MHz, CDCl3) ��-76.63 (s, 3F);13CNMR (101MHz, CDCl3) �� 138.59,136.17,132.12,128.79,128.52,128.42,128.36,128.27,127.25,126.88,126.77 (q, J=285.8Hz), 63.28 (q, J=26.8Hz).
Embodiment 18:
By raw material(180mg, 0.65mmol) it is dissolved in 6ml1, in 4-dioxane, under room temperature, add Benzoyl chloride (275mg, 1.95mmol), triethylamine (66mg, 0.65mmol), salt of wormwood (90mg, 0.65mmol), it is heated to 70 degrees Celsius, stir at this temperature and spend the night, be cooled to room temperature, add 10ml deionized water, separatory, extraction into ethyl acetate, anhydrous sodium sulfate drying, rotary evaporation is except desolventizing, (sherwood oil: ethyl acetate=5: 1), obtains product to rapid column chromatography215mg, product rate 90%.
Whitesolid; Mp:114-116 DEG C; [��]D 24-4.43 (c=1.48, CHCl3); FT-IR (KBr, cm-1): �� 3447,3299,3060,3028,1960,1882,1802,1685,1559,1487,1449,1 287,1246,1159,970,746,693;1HNMR (400MHz, CDCl3) �� 7.91-7.84 (m, 2H), 7.69-7.24 (m, 13H), 6.98 (d, J=16.2Hz, 1H), 6.89-6.79 (m, 2H);19FNMR (376MHz, CDCl3) ��-74.29 (s, 3F);13CNMR (101MHz, CDCl3) �� 165.91,135.96,134.81,134.49,134.25,132.20,128.87,128.75,128.65,128.47,127.68,127.67,127.12, (q, J=285.8Hz), 127.01,125.21 123.33,66.93 (q, J=26.8Hz).

Claims (4)

1. one kind has the preparation method of optically active fluorine-containing alkylallyl amine compounds, it is characterized in that: with the �� of high chiral purity, ��-unsaturated fluorine alkyl-tert-butyl sulfinyl ketoimine for raw material, described ��, the structural formula of ��-unsaturated fluorine alkyl-tert-butyl sulfinyl ketoimine is as follows
Wherein said R2For phenyl or furyl; RfFor the C that single fluorine or many fluorine replace1-20Alkyl; under protection of inert gas, ��, ��-unsaturated fluorine alkyl-tert-butyl sulfinyl ketoimine is added in organic solvent; slowly being joined by organolithium reagent in above-mentioned reaction system under-78 DEG C��room temperature condition, the structure of described organolithium reagent is R1Li structure, wherein said R1For phenyl, substituted-phenyl, naphthyl or phenylacetylene base, described ��, the mol ratio of ��-unsaturated fluorine alkyl-tert-butyl sulfinyl ketoimine and organolithium reagent is 1:1��10, then clear-cutting forestland is to room temperature, react 2��5 hours, cancellation is reacted, and separatory, extraction, drying, steaming, except solvent, purification, obtain and have optically active fluorine-containing alkylallyl amine compounds; Can obtain as follows there is optically active alpha-fluoroalkyl allyl amine compounds by de-in acid condition for the compound of above-mentioned acquisition except sulfoxide prothetic group,
The compound of above-mentioned acquisition is obtained as follows having optically active alpha-fluoroalkyl allyl amine compounds by upper amido protecting group again,
2. a kind of preparation method with optically active fluorine-containing alkylallyl amine compounds according to claim 1, it is characterised in that: described organic solvent is ether, tetrahydrofuran (THF), methyl tertiary butyl ether, glycol dimethyl ether, isopropyl ether, dioxane, methylene dichloride, normal hexane or toluene.
3. a kind of preparation method with optically active fluorine-containing alkylallyl amine compounds according to claim 1, it is characterised in that: add saturated aqueous ammonium chloride after reaction or shrend is gone out reaction.
4. a kind of preparation method with optically active fluorine-containing alkylallyl amine compounds according to claim 1, it is characterised in that: obtain and there is optically active fluorine-containing alkylallyl amine compounds employing solvent extraction, column chromatographic isolation and purification.
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