CN109422602A - 一种不对称氢化亚胺制备手性胺的方法 - Google Patents
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- 150000002466 imines Chemical class 0.000 title claims abstract description 39
- 238000000034 method Methods 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 title claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 31
- 238000011065 in-situ storage Methods 0.000 claims abstract description 20
- -1 ferrocene phosphine-diformamidine imine Chemical class 0.000 claims abstract description 18
- 150000001412 amines Chemical class 0.000 claims abstract description 16
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 14
- 239000003446 ligand Substances 0.000 claims abstract description 13
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 12
- 229910052741 iridium Inorganic materials 0.000 claims abstract description 11
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 229910052751 metal Inorganic materials 0.000 claims abstract description 7
- 239000002184 metal Substances 0.000 claims abstract description 7
- 239000002243 precursor Substances 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000011630 iodine Substances 0.000 claims abstract description 5
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 5
- 150000007513 acids Chemical class 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 150000002576 ketones Chemical class 0.000 claims description 9
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-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
- 239000001257 hydrogen Substances 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 5
- 230000000996 additive effect Effects 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- JJVKJJNCIILLRP-UHFFFAOYSA-N 2-ethyl-6-methylaniline Chemical compound CCC1=CC=CC(C)=C1N JJVKJJNCIILLRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000008365 aromatic ketones Chemical class 0.000 claims description 4
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- NKYZMZNNAWWQCF-UHFFFAOYSA-N 2,4-dimethylthiophen-3-amine Chemical compound CC1=CSC(C)=C1N NKYZMZNNAWWQCF-UHFFFAOYSA-N 0.000 claims description 3
- CWKLZLBVOJRSOM-UHFFFAOYSA-N methyl pyruvate Chemical compound COC(=O)C(C)=O CWKLZLBVOJRSOM-UHFFFAOYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 150000001448 anilines Chemical class 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- CUZLJOLBIRPEFB-UHFFFAOYSA-N 1-methoxypropan-2-one Chemical compound COCC(C)=O CUZLJOLBIRPEFB-UHFFFAOYSA-N 0.000 claims 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims 1
- 150000004982 aromatic amines Chemical class 0.000 claims 1
- 235000019253 formic acid Nutrition 0.000 claims 1
- 125000005842 heteroatom Chemical class 0.000 claims 1
- 229930192474 thiophene Natural products 0.000 claims 1
- WVQBLGZPHOPPFO-UHFFFAOYSA-N 2-chloro-N-(2-ethyl-6-methylphenyl)-N-(1-methoxypropan-2-yl)acetamide Chemical compound CCC1=CC=CC(C)=C1N(C(C)COC)C(=O)CCl WVQBLGZPHOPPFO-UHFFFAOYSA-N 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 8
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000000758 substrate Substances 0.000 description 7
- 208000012839 conversion disease Diseases 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 4
- WVQBLGZPHOPPFO-LBPRGKRZSA-N (S)-metolachlor Chemical compound CCC1=CC=CC(C)=C1N([C@@H](C)COC)C(=O)CCl WVQBLGZPHOPPFO-LBPRGKRZSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 3
- 239000005617 S-Metolachlor Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 229940017219 methyl propionate Drugs 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- VSIMNRRKKQUGMF-UHFFFAOYSA-N 1,1-dimethoxy-n-methylmethanamine Chemical compound CNC(OC)OC VSIMNRRKKQUGMF-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- 229910021638 Iridium(III) chloride Inorganic materials 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- BXMJNGVLZAWGJH-UHFFFAOYSA-N [Ir].C1CCC=CC=CC1 Chemical compound [Ir].C1CCC=CC=CC1 BXMJNGVLZAWGJH-UHFFFAOYSA-N 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000002790 naphthalenes Chemical class 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- DANYXEHCMQHDNX-UHFFFAOYSA-K trichloroiridium Chemical compound Cl[Ir](Cl)Cl DANYXEHCMQHDNX-UHFFFAOYSA-K 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
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- C07B53/00—Asymmetric syntheses
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
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- C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
- C07C209/52—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of imines or imino-ethers
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- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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Abstract
本发明公开了一种不对称氢化亚胺制备手性胺的方法：以手性二茂铁膦‑二甲脒亚胺与金属铱前驱体反应原位制备配合物为催化剂，在碘盐或单质碘存在下、在酸共同作用下，亚胺不对称加氢制备手性胺。适宜的催化剂用量(以摩尔计)为：原料亚胺/催化剂(S/C)等于100000‑1000000。本发明配体制备简单，催化剂用量低，操作简便，且可实现连续操作，适于大规模制备手性胺，产物的对映体过量值(ee值)达80％以上，可满足作为农药中间体的要求。本发明对于精异丙甲草胺中间体的合成得到较理想的结果，具有很好的工业实用性。
Description
技术领域
本发明属于有机合成领域，具体涉及一种高活性、高选择性不对称氢化亚胺制备手性胺化合物的方法。
背景技术
手性胺化合物是重要的有机合成中间体，可用于制备具有生物活性的各种天然及非天然化合物。近年来，国内外有机化学家通过合成不同骨架的手性配体来调控亚胺的不对称催化氢化反应制备手性胺化合物做了许多工作，并取得了很大成功(Tang.W.,Zhang.X.etc.Chem.Rev.,2003,103,3029.)。但这些催化剂存在着诸如反应活性低、底物范围窄、反应条件苛刻等问题。专利(EP0691949B1)报道了一种较好的催化体系，利用手性配体{(R)-1-[(S)-2-二苯基膦基茂铁基]}乙基-二-(3,5-二甲基苯基)膦与铱-环辛二烯络合物原位形成催化剂，在酸和四丁基碘化铵存在下于50度和80大气压氢气，催化氢化MEA-亚胺制备精异丙甲草胺中间体，最高对映体过量值(ee)为76％，但是，该反应体系所应用的配体合成困难。因此，发展高活性、高立体选择性、底物适用范围广的亚胺的不对称氢化方法，具有十分重要的意义。
发明内容
本发明的目的在于提供一种操作简便，配体合成容易，可以工业化规模应用的亚胺不对称催化加氢的方法，以满足不对称氢化制备手性农药中间体，特别是精异丙甲草胺中间体的合成。
本发明的技术方案如下：以手性二茂铁膦-二甲脒亚胺与金属铱前驱体反应原位制备配合物为催化剂，在碘盐或单质碘存在下、在酸共同作用下，亚胺不对称加氢制备手性胺。适宜的催化剂用量(以摩尔计)为：原料亚胺/催化剂(S/C)等于100000-1000000。反应底物亚胺可以在反应时直接加入相应的胺和酮原位生成。
本发明中用于原位合成亚胺的胺选自C1-C8的脂肪胺，有/无取代基的苯或萘环芳香胺；所述的取代基选自1-3个C1-C4烷基。进一步优选1-2个C1-C2烷基的一取代苯胺、二取代苯胺或杂环芳香胺，如2-甲基-6-乙基苯胺、2,6-二甲基苯胺或2,4-二甲基-3-氨基噻吩；用于原位合成亚胺的酮选自脂肪酮、有/无取代基的芳香酮，所述的取代基选自一个C1-C2烷基、烷氧基或2个C1-C2烷基组成的邻、间或对位取代芳香酮，进一步优选C3-C6脂肪酮，如甲氧基丙酮和丙酮酸甲酯。
本发明所用的催化剂体系，包括以下二个组成部分：
(i)一种铱化合物
(ii)二茂铁膦-二甲脒亚胺配体，其结构如下：
根据本发明提供的催化剂体系，所述金属铱前驱体选自[Ir(COD)Cl]2、IrCl3·3H2O或[Ir(OMe)(COD)]2中的一种。
根据本发明提供的催化剂体系，所述溶剂选自二氯甲烷、二氯乙烷或甲苯中的一种。
根据本发明提供的催化剂体系，所述铱浓度为0.0001-0.01mol/L。
根据本发明提供的催化剂体系，所述配体与铱的摩尔比(mol/mol)为1-2/1。
根据本发明提供的催化剂体系，所述底物与催化剂的摩尔比(mol/mol)为105-106/1。
根据本发明提供的催化剂体系，所述反应温度40-100℃。
根据本发明提供的催化剂体系，所述反应压力为20-60bar。
本发明中所述添加剂选自碘化钾、碘化钠、四丁基碘化铵或单质碘中的一种。所述添加剂用量(以摩尔计)为：原料亚胺/添加剂(S/A)等于1000-10000。
本发明中亚胺在催化不对称氢化反应时可直接加入体系，也可在反应体系中由上所述的胺和酮脱水缩合原位生成。在有或无溶剂的条件下，在上述催化剂的存在下不对称加氢合成手性胺，反应式如下：
应用本发明的方法优选制备由2-甲基-6-乙基苯胺或2,4-二甲基-3-氨基噻吩与甲氧基丙酮生成的亚胺和2,6-二甲基苯胺与丙酮酸甲酯生成的亚胺的不对称氢化得到的手性胺化合物，见反应式如下：
本发明提供的以二茂铁膦-二甲脒亚胺为配体、铱为中心金属前体原位配位的催化剂体系高活性、高立体选择性氢化制备手性胺化合物，其特征在于，包括以下步骤：
(1)在200ml高压釜中，对高压釜干燥，氮气置换，然后向高压釜中注入底物及添加剂。
(2)将上述配体和铱化合物原位配合的溶液注入高压釜中，用氢气置换三次，然后向反应釜中通入氢气并调节釜内压力，加热至设定的温度。直至压力不降，降温，开釜，产品用GC分析含量，HPLC检测产品的ee值。
本发明的有益效果是：
本发明中二茂铁膦-二甲基脒亚胺配体合成简洁，提供了以铱为中心金属前体、二茂铁膦-二甲基脒亚胺为配体的高活性、高立体选择性氢化亚胺制备手性胺化合物的催化剂体系；操作简便，且可实现连续操作，适于大规模制备农药，如：精异丙甲草胺中间体，因而具有很好的工业应用价值。
具体实施方式
下面的实施例将对本发明予以进一步的说明，但并不因此而限制本发明。
核磁共振是通过Bruker核磁共振仪测定，高效液相色谱(HPLC)是通过Agilent1100系列高效液相色谱测定。反应转化率通过GC分析，条件如下：
色谱柱：SE-54
进样口温度：250℃
检测器温度：250℃
柱温:50℃保持2分钟，然后10℃/分钟升至250℃，再保持5分钟。
实施例1
1制备配体二茂铁膦-二甲基脒亚胺
将(R)-1-[(α-氨基)乙基]-(S)-2-(二苯基膦)二茂铁(10mmol)溶于15ml N,N-二甲基甲酰胺二甲基缩醛中，室温搅拌反应至原料点基本消失(TLC检测)，减压脱去挥发性组分后，再用正己烷重结晶，得橙色方形片状晶体。二茂铁膦-二甲基脒亚胺结构式如下：
二茂铁膦-二甲基脒亚胺的核磁共振谱：
1H NMR(400MHz,CDCl3):δ7.52-7.07(m,11H),4.60(s,1H),4.56(m,1H),4.25(s,1H),3.97(s,5H),3.70(s,1H),2.21(s,6H),1.56(d,J＝6.8Hz,3H)；31P NMR(162MHz，CDCl3):δ-22.8。
2催化剂的制备
将6.717g的金属前躯体[Ir(COD)Cl]2及9.367g的配体加入20L的二氯乙烷中，室温搅拌2h，原位配位生成催化剂(10-3mol/l)。
3氢化反应
氢化反应在200ml高压釜中进行。先将反应釜用氮气置换三次，然后往反应釜中注入52g亚胺(由2-甲基-6-乙基苯胺与甲氧基丙酮生成，具体结构如下：)、10ml乙酸、0.5ml原位配位好的上述催化剂(S/C＝3×105)及0.05g四丁基碘化铵。再用氢气将反应釜置换三次后，通氢气加压至20bar,加热至40℃反应3h，泄压，开釜，GC分析反应转化率大于99％，减压蒸馏，得(S)-NAA 50g 95％yield，HPLC分析83％ee。
(S)-NAA的结构式如下：
HPLC(chiralcel OJ-H,n-hexane/i-PrOH＝98/2,1.0ml/min,254nm,40℃):tR(minor)＝4.0min,tR(major)＝4.4min.1H NMR(400MHz,CDCl3):δ7.00(dd,J＝7.6,15.2Hz,2H),6.87(t,J＝7.6Hz,1H),3.34-3.38(m,6H),2.65(q,J＝7.6Hz,2H),2.29(s,3H),1.23(t,J＝7.6Hz,3H),1.18(d,J＝5.6Hz,3H)。
实施例2
反应压力为10bar，其它条件与实例1相同，GC分析反应转化率大于95％，HPLC分析80％ee。
实施例3
反应温度为25℃，其它条件与实例1相同，GC分析反应转化率90％，HPLC分析81％ee。
实施例4
反应底物为(E)-2-乙基-6-甲基-N-(1-苯基亚丙基)苯胺，其它条件与实施例1相同，GC分析反应转化率大于99％，HPLC分析96％ee。
2-乙基-6-甲基-N-(1-苯基丙基)苯胺结构式如下：
HPLC(OJ-H,n-hexane/i-PrOH＝90/10,1.0ml/min,254nm,40℃):tR(major)＝4.5min,tR(minor)＝4.9min.1H NMR(400MHz,CDCl3):δ7.26-7.32(m,5H)，6.98(d,J＝7.2Hz,2H),6.88(t,J＝7.2Hz,1H),4.29-4.31(m,1H),3.25(br,1H),2.54(q,J＝7.2Hz,2H),2.21(s,6H),1.53(d,J＝5.6Hz,3H),1.53(d,J＝5.6Hz,3H),δ＝1.19(t,J＝7.2Hz,3H)。
实施例5
反应底物为N-(1-甲氧基-2-亚丙基)-2,6-二甲基苯胺，其它条件与实施例1相同，GC分析反应转化率大于99％，HPLC分析96％ee。
N-(1-甲氧基-2-丙基)-2,6-二甲基苯胺结构式如下：
GC(β-DEX 120column,column temp.:85℃,carrier gas:N2):tR(major)＝69.8min,tR(minor)＝71.4min.1H NMR(400MHz,CDCl3):δ6.99(d,J＝7.2Hz,2H),6.82(t,J＝7.2Hz,1H),3.35-3.80(m,7H),2.30(s,6H),1.20(d,J＝6.0Hz,3H)ppm；13C NMR(100MHz,CDCl3):δ145.0,129.4,128.8,121.5,76.3,59.0,52.4,18.7,18.6。
实施例6
将实施例1中的底物改为2-(2,6-二甲基苯基亚氨基)丙酸甲酯，其余同实施例1，反应得产物2-(2,6-二甲基苯基氨基)丙酸甲酯。94％yield，HPLC分析88％ee。
2-(2,6-二甲基苯基氨基)丙酸甲酯结构式如下：
HPLC(chiralcel OD-H,n-hexane/i-PrOH＝99/1,1.0ml/min,254nm,40℃):tR(minor)＝6.9min,tR(major)＝7.7min.1H NMR(400MHz,CDCl3):δ＝6.97(d,J＝7.6Hz,2H),6.81(t,J＝7.6Hz,1H),4.00(q,J＝7.2Hz,1H),3.68(s,3H),2.31(s,6H),1.38(d,J＝7.2Hz,3H)。
Claims (13)
1.一种不对称氢化亚胺制备手性胺的方法：以手性二茂铁膦-二甲脒亚胺与金属铱前驱体反应原位制备配合物为催化剂，在碘盐和/或单质碘存在下、在酸共同作用下，亚胺不对称加氢制备手性胺。
2.根据权利要求1所述的方法，其特征在于：适宜的催化剂用量(以摩尔计)为：原料亚胺/催化剂(S/C)等于100000-1000000。
3.根据权利要求1所述的方法，其特征在于：所述金属铱前驱体选自[Ir(COD)Cl]2、IrCl3.3H2O或[Ir(OMe)(COD)]2中的一种或二种以上；
所述配体手性二茂铁膦-二甲脒亚胺结构如下：
4.根据权利要求1所述的催化剂体系，其特征在于：所述原位制备配合物采用的溶剂选自二氯甲烷、二氯乙烷、或甲苯中的一种或二种以上。
5.根据权利要求1、3或4所述的催化剂体系，其特征在于：所述铱浓度为0.0001-0.01mol/L；所述手性配体与铱的摩尔比(mol/mol)为1-2/1。
6.根据权利要求1所述的催化剂体系，其特征在于：所述催化剂用量(以摩尔计)优选为：原料亚胺/催化剂(S/C)等于200000-500000。
7.根据权利要求1所述的方法，其特征在于：所述碘盐选自碘化钾、碘化钠、四丁基碘化铵中的一种或二种以上；所述添加剂碘盐和/或单质碘用量(以摩尔计)为：原料亚胺/添加剂(S/A)等于1000-10000；
所述酸为甲酸、乙酸、对甲苯磺酸中的一种或二种以上；所述酸的用量为：原料/酸(mol/mol)等于1000-10。
8.根据权利要求1所述的方法，其特征在于：亚胺既可以在氢化反应时直接加入，或也可以通过相应的胺与酮反应原位生成；
用于原位合成亚胺的胺选自C1-C8的脂肪胺，取代苯环芳香胺、取代萘环芳香胺、含杂原子的芳香胺；苯环或萘环上的所述的取代基选自1-3个C1-C4的烷基；
用于原位合成亚胺的酮选自脂肪酮、芳香酮、有取代基的芳香酮，所述的取代基选自一个C1-C2烷基、烷氧基或2个C1-C2烷基组成的邻、间或对位取代芳香酮。
9.根据权利要求8所述的方法，其特征在于：用于原位合成亚胺的胺选自1-2个C1-C2烷基的一取代苯胺、二取代苯胺或呋喃、噻吩芳香胺。
10.根据权利要求8所述的方法，其特征在于：用于原位合成亚胺的胺选自2-甲基-6-乙基苯胺、2,6-二甲基苯胺或2,4-二甲基-3-氨基噻吩。
11.根据权利要求8所述的方法，其特征在于：用于原位合成亚胺的酮选自C3-C6脂肪酮。
12.根据权利要求8所述的方法，其特征在于：用于原位合成亚胺的酮选自甲氧基丙酮和丙酮酸甲酯。
13.根据权利要求1所述的方法，其特征在于：用于反应所述温度在40-100℃，所述氢气压力为20-60bar。
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