CN114539312A - 一种铑催化不对称氢化制备α-或β-胺基膦酸酯衍生物的方法 - Google Patents
一种铑催化不对称氢化制备α-或β-胺基膦酸酯衍生物的方法 Download PDFInfo
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- CN114539312A CN114539312A CN202011326196.5A CN202011326196A CN114539312A CN 114539312 A CN114539312 A CN 114539312A CN 202011326196 A CN202011326196 A CN 202011326196A CN 114539312 A CN114539312 A CN 114539312A
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- rhodium
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- 238000000034 method Methods 0.000 title claims abstract description 28
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 title claims abstract description 21
- 239000010948 rhodium Substances 0.000 claims abstract description 46
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 32
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000003446 ligand Substances 0.000 claims abstract description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- KDPSKENBCWJPHJ-UHFFFAOYSA-N P.NP(O)O Chemical compound P.NP(O)O KDPSKENBCWJPHJ-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002184 metal Substances 0.000 claims abstract description 11
- 229910052751 metal Inorganic materials 0.000 claims abstract description 11
- 239000002243 precursor Substances 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 238000011065 in-situ storage Methods 0.000 claims abstract description 4
- 150000004696 coordination complex Chemical class 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- 125000000524 functional group Chemical group 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 239000000758 substrate Substances 0.000 claims description 10
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 150000003254 radicals Chemical class 0.000 claims description 8
- 239000012429 reaction media Substances 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000003708 ampul Substances 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- LYXHWHHENVLYCN-QMDOQEJBSA-N (1z,5z)-cycloocta-1,5-diene;rhodium;tetrafluoroborate Chemical compound [Rh].F[B-](F)(F)F.C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 LYXHWHHENVLYCN-QMDOQEJBSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims description 2
- 229910021604 Rhodium(III) chloride Inorganic materials 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 150000005840 aryl radicals Chemical class 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N binaphthyl group Chemical group C1(=CC=CC2=CC=CC=C12)C1=CC=CC2=CC=CC=C12 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003586 protic polar solvent Substances 0.000 claims description 2
- 238000002390 rotary evaporation Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- -1 catalytic antibodies Substances 0.000 description 24
- OLTSGVZGKOFTHZ-UHFFFAOYSA-N P.P.P.P.P.P.P.P.P Chemical compound P.P.P.P.P.P.P.P.P OLTSGVZGKOFTHZ-UHFFFAOYSA-N 0.000 description 23
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 230000003197 catalytic effect Effects 0.000 description 14
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 6
- 229910052698 phosphorus Inorganic materials 0.000 description 6
- 239000011574 phosphorus Substances 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000004679 31P NMR spectroscopy Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- YLFBFPXKTIQSSY-UHFFFAOYSA-N dimethoxy(oxo)phosphanium Chemical compound CO[P+](=O)OC YLFBFPXKTIQSSY-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 150000003283 rhodium Chemical class 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- IEEKUNHCBRVOCG-SSZFMOIBSA-N C(C1=CC=CC=C1)(=O)N\C(=C/P(=O)(OC)OC)\C1=CC=CC=C1 Chemical compound C(C1=CC=CC=C1)(=O)N\C(=C/P(=O)(OC)OC)\C1=CC=CC=C1 IEEKUNHCBRVOCG-SSZFMOIBSA-N 0.000 description 1
- KGICZIPOTPNZTA-UHFFFAOYSA-N CC(NOP(O)=O)=O Chemical class CC(NOP(O)=O)=O KGICZIPOTPNZTA-UHFFFAOYSA-N 0.000 description 1
- 241000819038 Chichester Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- BVMWIXWOIGJRGE-UHFFFAOYSA-N NP(O)=O Chemical class NP(O)=O BVMWIXWOIGJRGE-UHFFFAOYSA-N 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000003028 Stuttering Diseases 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- GEBLOQXLELCEEO-UHFFFAOYSA-N bis[(2-methylpropan-2-yl)oxy]-oxophosphanium Chemical compound CC(C)(C)O[P+](=O)OC(C)(C)C GEBLOQXLELCEEO-UHFFFAOYSA-N 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- OTYNBGDFCPCPOU-UHFFFAOYSA-N phosphane sulfane Chemical compound S.P[H] OTYNBGDFCPCPOU-UHFFFAOYSA-N 0.000 description 1
- 150000008300 phosphoramidites Chemical class 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
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Abstract
本发明提供一种铑催化不对称氢化制备α‑或β‑胺基膦酸酯衍生物的方法，由铑与双齿膦‑亚磷酰胺酯配体催化体系催化α‑或β‑胺基膦酸酯的反应，高效、高对映选择性地制备一系列手性α‑或β‑胺基膦酸酸衍生物的方法。该反应以铑金属前体和双齿膦‑亚磷酰胺酯配体在二氯甲烷等溶剂中原位生成的金属络合物为催化剂，在高压反应釜中室温条件下进行，是一条操作简单、高收率、高对映选择性的合成新路线。
Description
技术领域
本发明涉及有机合成领域，具体涉及一种铑催化不对称氢化制备α-或β-胺基膦酸酯衍生物的方法
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解，而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
光学活性的α-和β-胺基膦酸衍生物是相应氨基酸的生物立体异构体，在生物化学和药物中被广泛用作抗癌药物、酶活性物质抑制剂，催化抗体、除草剂、杀菌剂及抗菌药物等[(a)P.Kafarski,B.Lejczak,Phosphorus Sulfur Silicon Relat.Elem.1991,63,193；(b)Aminophosphonic and aminophosphinic acids:Chemistry and biologicalactivity(Eds.:V.P.Kukhar,H.R.Hudson),Wiley,Chichester,2000.]。因此，在过去几十年里对于α-和β-胺基膦酸衍生物的不对称合成已经有了较多的研究。近年来几种涉及不同类型键形成反应的催化不对称方法已经用于α-氨基膦酸衍生物的合成。但从原子经济性和反应效率上看，催化不对称氢化(APH)无疑是合成手性α-或β-胺基膦酸衍生物最有效的方法。目前通过该方法合成α-或β-胺基磷酸衍生物的研究仍然有限。自1985年
等首次报道基于Rh或Ru与双膦配体的催化体系用于乙酰氨基膦酸酯的不对称氢化反应以来[(c)U.
I.Hoppe,A.Thiele,LiebigsAnn.Chem.1985,555.]，催化不对称氢化制备α-氨基膦酸衍生物已取得巨大进展，许多催化剂体系适用于该反应[(d)M.J.Burk,T.A.Stammers,J.A.Straub,Org.Lett.1999,1,387；(e)I.D.Gridnev,M.Yasutake,T.Imamoto,I.P.Beletskaya,Proc.Natl.Acad.Sci.USA2004,101,5385；(f)D.Y.Wang,J.D.Huang,X.P.Hu,J.Deng,S.B.Yu,Z.C.Duan,Z.Zheng,J.Org.Chem.2008,73,2011；(gJ.Wassenaar,J.N.H.Reek,J.Org.Chem.2009,74,8403)。相反，以催化不对称氢化方法直接获得β-氨基膦酸衍生物的研究较少。其中Rh或Ir与双膦配体的催化体系催化氢化β-芳基取代的β-烯胺基膦酸酯已经取得了一定成效[(h)R.Kadyrov,J.Holz,B.Schaffner,O.Zayas,J.Almena,A.Borner,Tetrahedron:Asymmetry.2008,19,1189.(i)S.Doherty,J.G.Knight,A.L.Bell,S.El-Menabawey,C.M.Vogels,A.Decken,S.A.Westcott,Tetrahedron:Asymmetry.2009,20,1437.(j)S.E.Lyubimov,E.A.Rastorguev,T.A.Verbitskaya,E.G.Rys,V.N.Kalinin,V.A.Davankov,Russ.J.Phys.Chem.B.2010,4,1241.]。虽然丁奎玲课题组实现了单齿亚磷酰胺酯配体与铑催化体系对α-或β-烯酰胺膦酸酯的不对称氢化反应[(k)J.Z.Zhang,Y.Li,Z.Wang,K.L.Ding,Angew.Chem.Int.Ed.2011,50,11743.]，但目前同时适用于α-和β-胺基磷酸衍生物的催化不对称氢化合成的催化剂体系还非常少，因此开发一种有效的通用催化体系同时适用于α-或β-胺基磷酸衍生物的不对称催化氢化合成仍具有积极的科学和现实意义。
发明内容
本发明的目的是提供一种由铑与双齿膦-亚磷酰胺酯配体催化体系催化α-或β-烯酰胺膦酸酯的反应，高效制备一系列α-或β-胺基膦酸衍生物的方法。该反应以铑金属前体和双齿膦-亚磷酰胺酯配体在二氯甲烷等溶剂中原位生成的金属络合物为催化剂，在高压反应釜中室温条件下进行，是一条操作简单、高收率、高区域选择性的合成新路线。
具体地，本发明的技术方案如下所述：
本发明提供了一种α-或β-胺基膦酸衍生物的制备方法，所述方法包括以铑与双齿膦-亚磷酰胺酯配体催化体系以催化不对称氢化方式催化α-或β-烯酰胺膦酸酯(其结构如式I、II所示)的反应，高效、高对映选择性地制备一系列手性α-或β-胺基膦酸衍生物(其结构如式III、IV所示)的方法
其中，R选自氢、C1-C40烷基、C1-C40烷氧基、C3-C12环烷基、苯基、苄基、苯氧基、卤素、硝基、酰胺基、羟基、羧基、酯基或氰基等中的一种或多种，所述取代基个数为1-5个；
R1选自甲酰基、乙酰基、苯甲酰基等酰基及甲氧羰基、乙氧羰基、叔丁氧羰基、苄氧基羰基等酰氧基团；
R2为C1-C40烷基、C3-C12环烷基、苯基或取代苯基、苄基或取代苄基、萘基或取代萘基、杂环芳香基团或取代杂环芳香基团；所述取代苯基、取代萘基、取代杂环芳香基团的取代基选自C1-C40烷基、C1-C40烷氧基、卤素、硝基、酯基或氰基中的一种或多种；所述杂环芳香基团是指含一种或多种N、O、S等杂原子的五元或六元芳香基团；
在本发明中所述的C1-C40烷基尤其指C1-C5烷基，以及，所述C1-C40烷氧基尤其指C1-C5烷氧基。
在本发明中，如无特殊说明，本发明所述的α-或β-烯酰胺膦酸酯以及手性α-或β-胺基膦酸衍生物均如此处所定义
在本发明中，所述催化剂为铑金属络合物，其以铑金属前体和双齿膦-亚磷酰胺酯配体原位生成。
其中，所述铑金属前体为铑盐，选自无水无水RhCl3、水合RhCl3、[Rh(COD)Cl]2、[Rh(NBD)Cl]2、[Rh(NBD)2]BF4、[Rh(COD)2]BF4、[Rh(COD)2]SbF6、[Rh(NBD)2]SbF6中的一种。
所述双齿膦-亚磷酰胺酯配体具有式L所示结构：
其中，R3为H、烷基和环烷基等C1～C40内的含或不含N、S、O、P等官能团的脂肪基团；苄基等C7-C60在内的含或不含N、S、O、P等官能团的芳香基团与脂肪基的组合基团；芳基等C6-C60内的含或不含N、S、O、P等官能团的芳香基团；R3优势结构为H、CH3。R4为H，C1-C40内的烷基或C6-C60在内的芳基，其优势结构为H、CH3；
Ar为C6-C60内的含或不含N、S、O、P等官能团的芳香基团；其优势结构为苯基；
X基团为：手性或非手性的含或不含N、S、O、P等官能团的脂肪基团；含或不含N、S、O、P等官能团的芳香基团；手性或非手性的含或不含N、S、O、P等官能团的联苯或联萘类芳香基团；其优势结构为以下含轴手性、螺旋手性结构的联苯、联萘结构：
在本发明中，所述Rh金属前体优选为[Rh(COD)2]BF4，以此金属前体制备得到的铑催化剂的催化活性较好，收率较高。
在本发明中，所述膦-亚磷酰胺酯配体中R3为CH3，R4为CH3，Ar为苯基，X为下图结构(X-1)时，以此结构的配体(L-1)制备得到的铑催化剂的催化活性较好，以此催化剂催化的反应收率较高。
在本发明中，所述铑盐与膦-亚磷酰胺酯配体的摩尔比1:0.1-10，优选为1:1-5，更优选为1:1.1。
在本发明中，所述α-或β-胺基膦酸衍生物的制备方法包括以下步骤：
1)氮气保护下，将铑盐与膦-亚磷酰胺酯配体按摩尔比1:0.1-1:10在反应介质中搅拌0.5-2小时制得铑催化剂溶液；
2)在氮气保护下，将上述制备的手性铑催化剂溶液转移至装有α-或β-烯酰胺膦酸酯的安培瓶中，将安培瓶放入反应釜，用氢气置换三次后保持反应釜氢气压力为25-100bar。室温搅拌0.5-48小时；反应完毕后，减压旋蒸除去溶剂，柱层析分离，得到手性α-或β-胺基膦酸衍生物；
在本发明中，所述反应介质选自质子性溶剂和/或非质子性溶剂。
在本发明的所述反应介质选自甲醇、乙醇、甲苯、乙腈和二氯甲烷中的一种或多种；尤其当反应介质为二氯甲烷时，反应更容易进行。(上述反应介质均为无水介质)。
在本发明中，所述铑催化剂与底物的摩尔比为0.001-1：1，优选为0.01:1。
氢气压力：25-100bar，优先为50-60bar。
时间：0.5-48小时，优先反应时间为24小时。
在本发明中，所述手性α-或β-烯酰胺膦酸酯的制备方法按以下反应路线进行：
所述方法包括：在反应瓶中加入金属前体[Rh]及配体L，氮气保护下加入DCM，室温搅拌，得到铑催化剂溶液；然后将该催化剂溶液在氮气保护下加入到含底物的安培瓶中，氢气高压反应釜中室温搅拌反应，反应完毕后减压浓缩至基本无溶剂，硅胶柱层析分离，减压浓缩，真空干燥的步骤。
与现有技术相比，本发明具有以下优点：
1、反应底物来源丰富、廉价易得；
2、配体和催化剂易制备，活性高，对映选择性好；
3、反应条件温和，操作简便；
4、底物适用范围广，对于所述的各类α-或β-烯酰胺膦酸酯都能进行反应并得到理想效果。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。以下，结合附图来详细说明本发明的实施方案，其中：
图1为实施例1制备的手性(2-苯甲酰胺基-2-苯基乙基)膦酸二甲酯III-1的核磁共振氢谱；
图2为实施例1制备的手性(2-苯甲酰胺基-2-苯基乙基)膦酸二甲酯III-1的核磁共振磷谱；
图3为实施例4制备的手性产物(2-乙酰氨基-2-苯基乙基)膦酸二乙酯III-2的核磁共振氢谱；
图4为实施例4制备的手性产物(2-乙酰氨基-2-苯基乙基)膦酸二乙酯III-2的核磁共振磷谱；
图5为实施例5制备的手性产物(2-乙酰氨基-2-苯基乙基)膦酸二叔丁酯III-3的核磁共振氢谱；
图6为实施例5制备的手性产物(2-乙酰氨基-2-苯基乙基)膦酸二叔丁酯III-3的核磁共振磷谱；
图7为实施例6制备的手性产物(R)-二甲基(2-苯甲酰胺基-2-(4-氯苯基)乙基)膦酸酯III-4的核磁共振氢谱；
图8为实施例6制备的手性产物(R)-二甲基(2-苯甲酰胺基-2-(4-氯苯基)乙基)膦酸酯III-4的核磁共振磷谱
图9为实施例7制备的手性产物(1-乙酰氨基-2-(4-氟苯基)乙基)膦酸二甲酯IV-1的核磁共振氢谱；
图10为实施例7制备的手性产物(1-乙酰氨基-2-(4-氟苯基)乙基)膦酸二甲酯IV-1的核磁共振磷谱。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。本发明所使用的试剂或原料均可通过常规途径购买获得，如无特殊说明，本发明所使用的试剂或原料均按照本领域常规方式使用或者按照产品说明书使用。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。本发明实施例的核磁共振是通过Bruker 400核磁共振仪测定，高效液相色谱(HPLC)是通过Agilent 1100系列高效液相色谱测定。
实施例1[Rh(COD)2]BF4和L-1络合作为催化剂催化氢化(Z)-(2-苯甲酰胺基-2-苯基乙烯基)膦酸二甲酯(I-1)反应，生成手性(2-苯甲酰胺基-2-苯基乙基)膦酸二甲酯(III-1)。
氮气保护下，将[Rh(COD)2]BF4(0.00125mmol,1mol％)，手性膦-亚磷酰胺配体L-1(0.001375mmol,1.1mol％)溶于二氯甲烷(1.0mL)中，室温(25℃)下搅拌1小时，加入底物(Z)-(2-苯甲酰胺基-2-苯基乙烯基)膦酸二甲酯I-1(0.125mmol)的二氯甲烷(1.0mL)溶液，将其置于高压反应釜中，氢气置换3次，然后通入55bar氢气，室温(25℃)下反应24小时。慢慢释放氢气，除去溶剂后用硅胶柱分离得到(S)-(2-苯甲酰胺基-2-苯基乙基)膦酸二甲酯III-1。转化率99％。91％ee was determinedby chiral HPLC(chiralcel OD-H,n-hexane/i-PrOH＝80/20,0.8mL/min,220nm,40℃):tR(major)＝11.1min,tR(minor)＝14.5min.1HNMR(400MHz,CDCl3)δ8.14(d,J＝7.2Hz,1H),7.94(t,J＝9.3Hz,2H),7.53–7.46(m,1H),7.43(t,J＝7.3Hz,2H),7.40–7.30(m,4H),7.28–7.22(m,1H),5.61(ddd,J＝25.9,13.1,6.7Hz,1H),3.71(t,J＝10.7Hz,3H),3.39(d,J＝11.1Hz,3H),2.56–2.32(m,2H).31PNMR(162MHz,CDCl3)δ30.74.产物的核磁共振氢谱、磷谱如图1、图2所示。
实施例2
将实施例1中的配体L-1用配体L-2代替，其余同实施例1。反应得到化合物I-1，收率99％，96％ee。
L-2的结构式如下：
实施例3
将实施例1中的配体L-1用配体L-3代替，其余同实施例1。反应得到化合物I-1，收率99％，98％ee。
L-3的结构式如下：
实施例4
将实施例1中底物用(Z)-(2-乙酰氨基-2-苯基乙烯基)膦酸二乙酯I-2代替，其余同实施例1。得到手性产物(2-乙酰氨基-2-苯基乙基)膦酸二乙酯III-2。转化率为98％。91％ee was determinedby chiral HPLC(chiralcel OD-H,n-hexane/i-PrOH＝85/15,0.8mL/min,254nm,40℃):tR(major)＝7.59min,tR(minor)＝9.36min.1H NMR(400MHz,CDCl3)δ7.38–7.29(m,4H),7.24(ddd,J＝8.7,5.8,3.3Hz,1H),7.18–7.05(m,1H),5.59–5.18(m,1H),4.05(p,J＝7.2Hz,3H),3.97–3.55(m,3H),2.56–2.17(m,3H),2.04(s,4H),1.30(t,J＝7.0Hz,4H),1.06(t,J＝7.0Hz,4H).31PNMR(162MHz,CDCl3)δ27.59。产物的核磁共振氢谱、磷谱如图3、图4所示。
实施例5
将实施例1中底物用(Z)-(2-乙酰氨基-2-苯基乙烯基)膦酸二叔丁酯I-3代替，其余同实施例1。得到手性产物(2-乙酰氨基-2-苯基乙基)膦酸二叔丁酯III-3。转化率为98％。99％ee was determinedby chiral HPLC(chiralcel OD-H,n-hexane/i-PrOH＝85/15,0.8mL/min,254nm,40℃):tR(major)＝4.91min,tR(minor)＝3.93min.1HNMR(400MHz,CDCl3)δ7.36–7.27(m,4H),7.25–7.19(m,1H),7.17(d,J＝6.9Hz,1H),5.38–5.04(m,1H),2.18(dd,J＝16.9,6.7Hz,2H),2.03(s,3H),1.51(s,9H),1.32(s,9H).31PNMR(162MHz,CDCl3)δ19.06.产物的核磁共振氢谱、磷谱如图5、图6所示。
实施例6I
将实施例1中底物用(Z)-二甲基(2-苯甲酰胺基-2-(4-氯苯基)乙烯基)膦酸酯I-4代替，其余同实施例1。得到手性产物(R)-二甲基(2-苯甲酰胺基-2-(4-氯苯基)乙基)膦酸酯III-4。转化率为98％。93％ee was determinedby chiral HPLC(chiralcel OD-H,n-hexane/i-PrOH＝80/20,0.8mL/min,220nm,40℃):tR(major)＝9.13min,tR(minor)＝16.07min.1H NMR(400MHz,CDCl3)δ8.23(d,J＝7.2Hz,1H),7.96–7.88(m,2H),7.54–7.40(m,3H),7.35–7.27(m,4H),5.55(ddd,J＝25.8,12.6,7.0Hz,1H),3.71(d,J＝11.0Hz,3H),3.46(d,J＝11.1Hz,3H),2.49–2.31(m,2H).31PNMR(162MHz,CDCl3)δ30.35.产物的核磁共振氢谱、磷谱如图7、图8所示。
实施例7
将实施例1中底物用(1-乙酰氨基-2-(4-氟苯基)乙烯基)膦酸二甲酯II-1代替，其余同实施例1。得到手性产物(1-乙酰氨基-2-(4-氟苯基)乙基)膦酸二甲酯IV-1。转化率为98％。96％ee was determined by chiral HPLC(chiralcel AD-H,n-hexane/i-PrOH＝95/5,0.8mL/min,220nm,40℃):tR(major)＝18.5min,tR(minor)＝24.6min.1H NMR(400MHz,CDCl3)δ7.26–7.12(m,2H),6.97(ddd,J＝10.7,5.9,2.5Hz,2H),6.78(d,J＝9.9Hz,1H),4.85–4.65(m,1H),3.76(dd,J＝10.7,3.5Hz,6H),3.21–3.08(m,1H),2.90(dt,J＝14.4,10.6Hz,1H),1.90(d,J＝1.0Hz,3H).31P NMR(162MHz,CDCl3)δ26.59。产物的核磁共振氢谱、磷谱如图9、图10所示。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，尽管参照前述实施例对本发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种铑催化不对称氢化制备α-或β-胺基膦酸酯衍生物的方法，其特征在于，所述方法为以铑与双齿膦-亚磷酰胺酯配体形成的铑催化剂，来催化α-或β-胺基膦酸酯的不对称氢化反应，制备手性α-或β-胺基磷酸衍生物。
2.根据权利要求1所述铑催化不对称氢化制备α-或β-胺基膦酸酯衍生物的方法，其特征在于，所述α-或β-胺基膦酸酯结构式如下：
所述手性α-或β-胺基磷酸衍生物结构式如下：
其中，R选自氢、C1-C40烷基、C1-C40烷氧基、C3-C12环烷基、苯基、苄基、苯氧基、卤素、硝基、酰胺基、羟基、羧基、酯基或氰基等中的一种或多种，所述取代基个数为1-5个；
R1选自甲酰基、乙酰基、苯甲酰基等酰基及甲氧羰基、乙氧羰基、叔丁氧羰基、苄氧基羰基等酰氧基团；
R2为C1-C40烷基、C3-C12环烷基、苯基或取代苯基、苄基或取代苄基、萘基或取代萘基、杂环芳香基团或取代杂环芳香基团；所述取代苯基、取代萘基、取代杂环芳香基团的取代基选自C1-C40烷基、C1-C40烷氧基、卤素、硝基、酯基或氰基中的一种或多种；所述杂环芳香基团是指含一种或多种N、O、S等杂原子的五元或六元芳香基团。
3.根据权利要求1所述铑催化不对称氢化制备α-或β-胺基膦酸酯衍生物的方法，其特征在于，所述铑催化剂为金属络合物，其以铑金属前体和双齿膦-亚磷酰胺酯配体原位生成；
其中，所述铑金属前体为铑盐，选自无水无水RhCl3、水合RhCl3、[Rh(COD)Cl]2、[Rh(NBD)Cl]2、[Rh(NBD)2]BF4、[Rh(COD)2]BF4、[Rh(COD)2]SbF6、[Rh(NBD)2]SbF6中的一种；
所述双齿膦-亚磷酰胺酯配体具有式L所示结构：
其中，R3为H、烷基和环烷基等C1～C40内的含或不含N、S、O、P等官能团的脂肪基团；苄基等C7-C60在内的含或不含N、S、O、P等官能团的芳香基团与脂肪基的组合基团；芳基等C6-C60内的含或不含N、S、O、P等官能团的芳香基团；R3优势结构为H、CH3。R4为H，C7-C60在内的烷基或芳基，其优势结构为H、CH3；
Ar为C6-C60内的含或不含N、S、O、P等官能团的芳香基团；其优势结构为苯基；
X基团为：手性或非手性的含或不含N、S、O、P等官能团的脂肪基团；含或不含N、S、O、P等官能团的芳香基团；手性或非手性的含或不含N、S、O、P等官能团的联苯或联萘类芳香基团；其优势结构为以下含轴手性、螺旋手性结构的联苯、联萘结构：
4.根据权利要求3所述铑催化不对称氢化制备α-或β-胺基膦酸酯衍生物的方法，其特征在于，所述铑金属前体与膦-亚磷酰胺酯配体的摩尔比1:0.1-10。
5.根据权利要求1所述铑催化不对称氢化制备α-或β-胺基膦酸酯衍生物的方法，其特征在于，方法包括：
催化剂制备：氮气保护下，将铑金属前体与膦-亚磷酰胺酯配体按摩尔比1:0.1-1:10在反应介质中搅拌0.5-2小时制得手性铑催化剂溶液；
手性α-或β-胺基膦酸衍生物的制备：氮气保护下，将上述制备的手性铑催化剂溶液转移至装有α-或β-胺基膦酸酯的安瓿瓶中，将安瓿瓶放入反应釜，用氢气置换三次后保持反应釜氢气压力为25-100bar，室温搅拌0.5-48小时；反应完毕后，减压旋蒸除去溶剂，柱层析分离，得到手性α-或β-胺基膦酸衍生物。
6.根据权利要求5所述铑催化不对称氢化制备α-或β-胺基膦酸酯衍生物的方法，其特征在于，所述反应介质选自质子性溶剂和/或非质子性溶剂。
7.根据权利要求6所述铑催化不对称氢化制备α-或β-胺基膦酸酯衍生物的方法，其特征在于，所述反应介质选自甲醇、乙醇、甲苯、乙腈和二氯甲烷中的一种或多种。
8.根据权利要求1或5所述铑催化不对称氢化制备α-或β-胺基膦酸酯衍生物的方法，其特征在于，所述铑催化剂与底物α-或β-胺基膦酸酯的摩尔比为0.001-1：1。
9.根据权利要求5所述铑催化不对称氢化制备α-或β-胺基膦酸酯衍生物的方法，其特征在于，氢气压力：25-100bar；时间：0.5-48小时。
10.根据权利要求1或5所述铑催化不对称氢化制备α-或β-胺基膦酸酯衍生物的方法，其特征在于，所述方法还包括反应完毕后减压浓缩至基本无溶剂，硅胶柱层析分离，减压浓缩，真空干燥的步骤。
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