CN102304007B - Asymmetric catalytic hydrogenation reaction method of intra-annular N-alkylimine - Google Patents

Asymmetric catalytic hydrogenation reaction method of intra-annular N-alkylimine Download PDF

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CN102304007B
CN102304007B CN201110198209.XA CN201110198209A CN102304007B CN 102304007 B CN102304007 B CN 102304007B CN 201110198209 A CN201110198209 A CN 201110198209A CN 102304007 B CN102304007 B CN 102304007B
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范青华
陈飞
何艳梅
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Abstract

The invention discloses an asymmetric catalytic hydrogenation reaction method, comprising the following step of: subjecting intra-annular N-alkylimine shown as formula III in the specification and hydrogen gas in the presence of a chiral catalyst shown as formula II to an addition reaction to obtain an intra-annular chiral amine product. In the method, the intra-annular N-alkylimine is catalytically hydrogenated with the chiral catalyst formed by chiral diamine ligand and transitional metals to obtain the intra-annular chiral amine product, with high yield and high enantioselectivity; and the enantiomeric excess of the intra-annular N-alkylimine can reach to 98% ee. Prepared by the method provided by the invention, the intra-annular N-alkylimine is used as an important chiral intermediate in the preparation process of medicine and material. Therefore, the method is important to the industrial application.

Description

The method of the asymmetric catalytic hydrogenation of N-alkyl imines reaction in ring
Technical field
The present invention relates to encircle the method for asymmetric synthesis of interior Chiral Amine, particularly relate to a kind of method with the asymmetric hydrogenation of N-alkyl imines in the ring of chiral diamine metal catalyst catalysis.
Background technology
Asymmetric efficient the synthesizing of high enantioselectivity chipal compounds, in chemical industry, agricultural, herding and each field of medicine, be day by day subject to common concern, especially at pharmaceutical industry, the research and development of chiral drug, production and selling have become the main flow (A.M.Rouhi of global medicine industry development, " Chiral chemistry ", Chem.Eng.News 2004,82, and 47).And asymmetric catalytic hydrogenation is one of main method of efficiently preparing chipal compounds.Asymmetric catalytic hydrogenation reaction refers at chiral catalyst and (is generally the title complex that chiral ligand and transition metal form, X. Zhang, " New Chiral Phosphorus Ligands for Enantioselective Hydrogenation ", Chem.Rev.2003,103,3029), under effect, the addition reaction of hydrogen to unsaturated link(age) in unsaturated prochirality compound (being called substrate), generates chiral product.Unsaturated prochirality compound generally comprises the compounds such as prochiral olefin (C=C), ketone (C=O), imines (C=N).Asymmetric catalytic hydrogenation reaction is because using hydrogen cheap and easy to get, and little to the pollution of environment, chiral product has again high enantioselectivity, so be subject to the generally attention of industry member.As far back as the seventies in last century, About Monsanto Chemicals just utilizes asymmetric catalytic hydrogenation technology successfully to develop and treats the suitability for industrialized production (H.-U.Blaser of Parkinsonian L-3,4 dihydroxyphenylalanine, F. Spindler, M.Studer, " Enantioselective catalysis in fine chemicals production ", Appl.Catal.A:General 2001,221, and 119; W.S.Knowles, " Application of Organometallic Catalysis to the Commercial Production of L-DOPA ", J.Chem.Educ.1986,63,222; W. S.Knowles, " Asymmetric hydrogenations ", Adv.Synth.Catal.2003,345,3).
Chiral Amine is the skeleton structure of many bioactive compoundss and chiral drug, for example: nicotine (T.Spangenberg in formula I, B.Breit, A.Mann, " Hydroformylation of Homoallylic Azides:A Rapid Approach toward Alkaloids ", Org.Lett.2009,11,261) there is analgesic activity, and can be used for treating tobacco dependence.Compd B MS-394136 (J.Lloyd, H.J.Finlay, W.Vacarro, T.Hyunh, A.Kover, R.Bhandaru, L.Yan, K.Atwal, M.L. Conder, T.Jenkins-West, H. Shi, C.Huang, D.Li, H.Sun, P.Levesque, " Pyrrolidine amides of pyrazolodihydropyrimidines as potent and selective Kv1.5blockers " Bioorg.Med.Chem.Lett.2010,20,1436) can be used to Cardiovarscular.Compound L Y-394681 (A.K.Amegadzie, K.M.Gardinier, E.J.Hembre, P.A.Hipskind, L. N.Jungheim, B.S.Muehl, K.A.Savin, K.J.Thrasher, S.A.Boyd, " Tachykinin receptor antagonists ", (Lilly), Patent WO 2005000821A1,2005) as a kind of tachykinin receptor, can be used for treating the central nervous system vegetative nervous system disease of unifying.The asymmetric catalytic hydrogenation reaction of imines (containing the two keys of C=N) compounds is the easiest method (T.C.Nugent of preparation Chiral Amine analog derivative, Chiral Amine Synthesis:Methods, Developments and Applications (Ed.:T.C.Nugent), Wiley-VCH, Weinheim, 2010).Imines asymmetric catalytic hydrogenation has been successfully applied to large-scale industrial production, wherein, the most successful industrialization example is the suitability for industrialized production (H.-U.Blaser of chirality weedicide (S)-metolachlor of successfully developing of Syngenta company, " The Chiral Switch of (S)-Metolachlor:A Personal Account of an Industrial Odyssey in Asymmetric Catalysis ", Adv.Synth.Catal.2002,344,17).They adopt the asymmetric hydrogenation of iridium-chiral diphosphine ligand catalyzer (Ir-xyliphos) catalysis imines key intermediate as gordian technique, and efficient (turn over number TON reaches 2,000,000, and transformation frequency TOF reaches 400,000h -1), highly selective realized current known largest asymmetric catalytic hydrogenation process with the output of 10,000 tons/year.In addition, Japanese Daiichi company and DOW Chemical (Dowpharma) have also successfully realized respectively the suitability for industrialized production of broad-spectrum antibacterials levofloxacins ((S)-levonoxacin) and treatment Alzheimer's disease medicine (S)-18986 by the asymmetric catalytic hydrogenation gordian technique of imines.
Figure BDA0000076035040000021
(formula I)
Summary of the invention
The object of this invention is to provide a kind of method that interior N-alkyl imines carries out asymmetric catalytic hydrogenation reaction of encircling.
The method of asymmetric catalytic hydrogenation reaction provided by the invention, under the condition that comprises the steps: to exist at chiral catalyst shown in formula II, carries out addition reaction with hydrogen to N-alkyl imines in ring shown in formula III, obtains Chiral Amine product;
Figure BDA0000076035040000022
wherein:
Figure BDA0000076035040000023
(formula II)
In described formula II general structure, M is metal Ru Ru, rhodium Rh or iridium Ir;
Described L 1* for containing single sulphonyl substituting group (SO 2r ') chiral diamine L 1(L 1general structure be: NHR "-chirality connecting arm-NHSO 2r ') with the reacted chiral diamine ligands of metal precursor, the alkyl that R ' in described chiral diamine ligands is 1-10 for the total number of carbon atoms, trifluoromethyl, phenyl, naphthyl, contain substituent phenyl or contain substituent naphthyl, the described substituent phenyl and containing in substituent naphthyl of containing, described substituting group is selected from least one in alkyl, methoxyl group, fluorine, chlorine, bromine, nitro and the trifluoromethyl that the total number of carbon atoms is 1-10;
Described R " is selected from least one in the alkyl that H, benzyl and the total number of carbon atoms are 1-10;
Described L 2for η 6-benzene dentate, η 5-luxuriant dentate, contain substituent η 6-benzene dentate or contain substituent η 5-luxuriant dentate, described in contain substituent η 6-benzene dentate and contain substituent η 5in-luxuriant dentate, described substituting group is selected from least one in the alkyl that the total number of carbon atoms is 1-10, and described substituting group is selected from least one in the alkyl that the total number of carbon atoms is 1-10;
Described X is Cl -, Br -, I -, OAc -, NO 3 -, HSO 4 -, H 2pO 4 -, [OTf] -(trifluoro formic acid negative ion), [BF 4] -(tetrafluoride boron anion), [SbF 6] -(antimony hexafluoride negative ion), [PF 6] -(phosphorus hexafluoride negative ion), [NTf 2] -(two (fluoroform sulphonyl) imines negative ion), four aryl boron anion (BAr 4 -) or the derivative phosphoric acid negative ion of dibenzyl diphenol;
(formula III)
In described formula III general structure, R is alkyl, cycloalkyl, aryl, fragrant benzyl, contains substituent alkyl, contains substituent cycloalkyl or contain substituent aryl, wherein, the described substituent cycloalkyl and containing in substituent aryl of containing, described substituting group is all selected from least one in fluorine, chlorine, bromine, nitro, methyl, methoxyl group, trifluoromethyl, hydroxyl and kharophen;
N is 1,2 or 3.
In aforesaid method, in described formula II general structure, described in contain the substituent chiral diamine L of single sulphonyl 1be preferably (R, R) mono-sulphonyl-1 of-N-, 2-diaryl quadrol (shown in IVa), (S, S) mono-sulphonyl-1 of-N-, 2-diaryl quadrol (shown in IVb), (R, R) mono-sulphonyl-1 of-N-, 2-cyclohexanediamine (shown in Va), (S, S) mono-sulphonyl-1 of-N-, 2-cyclohexanediamine (shown in Vb), (R, R) the mono-sulphonyl-1-of-N-substituted azole-3, 4-diamines (shown in VIa), (S, S) the mono-sulphonyl-1-of-N-substituted azole-3, 4-diamines (shown in VIb), (R) mono-sulphonyl-2 of-N-, 2 '-diaminostilbene, 1 '-dinaphthalene (shown in VIIa) or mono-sulphonyl-2 of (S)-N-, 2 '-diaminostilbene, 1 '-dinaphthalene (shown in VIIb),
Figure BDA0000076035040000031
(formula IVa) (formula Va) (formula VIa) (formula VIIa)
Figure BDA0000076035040000032
(formula IVb) (formula Vb) (formula VIb) (formula VIIb)
Described L 2be preferably η 6-benzene dentate, η 6-Isosorbide-5-Nitrae-dimethyl benzene dentate, η 6-1-methyl-4-isopropyl benzene dentate, η 6-1,3,5 ,-Three methyl Benzene dentate, η 6-1,2,3,4,5-pentamethylbenzene dentate, η 6-1,2,3,4,5,6-hexamethyl-benzene dentate, η 5-luxuriant dentate or η 5the luxuriant dentate of-pentamethyl-;
In described four aryl boron anions, described aryl is preferably phenyl or 3,5-bis-(trifluoromethyl) phenyl;
In described formula III general structure, described alkyl is preferably the alkyl that the total number of carbon atoms is 1-5, described cycloalkyl is preferably cyclopentyl, cyclohexyl, suberyl or ring octyl group, described aryl is preferably phenyl, naphthyl, thienyl, furyl or pyridyl, and described fragrant benzyl is preferably benzyl or naphthalene benzyl.
Shown in described formula II, chiral catalyst is preferably shown in formula IXa by (R, R) shown in the title complex that-N-mono-sulphonyl-diaryl quadrol and transition metal iridium, ruthenium or rhodium form or formula IXb by (S, S) title complex that-N-mono-sulphonyl-diaryl quadrol and transition metal iridium, ruthenium or rhodium form
Figure BDA0000076035040000033
(formula IXa) (formula IXb)
In described formula IXa and IXb general structure, M is metal Ru Ru, rhodium Rh or iridium Ir;
Ar is phenyl, to the phenyl of methoxy substitution or to methyl substituted phenyl;
R ' is methyl, trifluoromethyl, phenyl, 4-aminomethyl phenyl, 4-trifluoromethyl, 4-isopropyl phenyl, 3,5-3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2,4,6-triisopropyl phenyl, pentamethyl-phenyl or naphthyl;
L 2be η 6-benzene dentate, η 6-Isosorbide-5-Nitrae-dimethyl benzene dentate, η 6-1-methyl-4-isopropyl benzene dentate, η 6-1,3,5 ,-Three methyl Benzene dentate, η 6-1,2,3,4,5-pentamethylbenzene dentate, η 6-1,2,3,4,5,6-hexamethyl-benzene dentate, η 5-luxuriant dentate or η 5the luxuriant dentate of-pentamethyl-;
X is [OTf] -(trifluoro formic acid negative ion), [BF 4] -(tetrafluoride boron anion), [SbF 6] -(antimony hexafluoride negative ion), [PF 6] -(phosphorus hexafluoride negative ion), [NTf 2] -(two (fluoroform sulphonyl) imines negative ion), four aryl boron anions or the derivative phosphoric acid negative ion of dibenzyl diphenol; In described four aryl boron anions, described aryl is phenyl or 3,5-bis-(trifluoromethyl) phenyl; The derivative phosphoric acid negative ion of described dibenzyl diphenol is 2,2 '-biphenyl phosphoric acid negative ion (formula XIa), (R)-2,2 '-naphthyl naphthalene phosphoric acid negative ion (formula XIb), (S)-2,2 '-naphthyl naphthalene phosphoric acid negative ion (formula XIc), (R)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion (formula XId) or (S)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion (formula XIe).
Figure BDA0000076035040000041
(formula XIa) (formula XIb) (formula XIc) (formula XId) (formula XIe)
Described addition reaction can add additive before reaction starts in reaction system, and realization is caught reaction product amine, reduces its poisoning effect to catalyzer, to improve efficiency and the enantioselectivity of hydrogenation; Be the method for described asymmetric catalytic hydrogenation reaction, also comprise the steps:, before described addition reaction is carried out, in reaction system, to add additive.Described additive is selected from Ue-5908 and tert-Butyl dicarbonate ((Boc) 2o) a kind of in, preferably tert-Butyl dicarbonate.In described additive and described ring, the molar ratio of N-alkyl imines is 0: 1～5: 1, specifically can be 0.2-5.0: 1,0.2-1.1: 1,0.2-0.5: 1,0.5-5.0: 1,0.5-1.1: 1 or 1.1-5.0: 1, preferably 1: 1～2: 1, the mole dosage that feeds intake of described additive was not 0.
Described addition reaction is to carry out under the condition existing at organic solvent.Described organic solvent is single organic solvent or mixed organic solvents; Wherein, described single organic solvent is methylene dichloride, 1, any one in the monohydroxy-alcohol that 2-ethylene dichloride, chloroform, ethyl acetate, tetrahydrofuran (THF), benzene,toluene,xylene, chlorinated benzene, ether, dioxane, acetone or the total number of carbon atoms are 1-10; At least one in the monohydroxy-alcohol that described mixed organic solvents is 1-10 by alkyl chloride based solvent and the total number of carbon atoms forms, and wherein, described alkyl chloride based solvent is selected from methylene dichloride, 1, at least one in 2-ethylene dichloride and chloroform.
N-alkyl imines is 10-2000 with the molar ratio (S/C) of described chiral catalyst in described ring: 1, specifically can be 100-1000: 1,100-500: 1 or 500-1000: and 1, preferred 50-1000: 1.
In described addition reaction step, temperature is-10-100 ℃, specifically can be-10 to 90 ℃ ,-10 to 60 ℃ ,-10 to 40 ℃ ,-10 to 25 ℃, 25-90 ℃, 25-60 ℃, 25-40 ℃, 40-90 ℃, 40-60 ℃ or 60-90 ℃, preferred 0-60 ℃, pressure is 1-100atm, specifically can be 10-100atm, 30-100atm, 50-100atm, 80-100atm, 30-80atm, 30-50atm or 50-80atm, preferred 5-60atm, time is 1-72 hour, specifically can be 10 hours, preferably 6-24 hour.
The invention provides a kind of method of asymmetric synthesis that encircles interior Chiral Amine.The method is the asymmetric catalytic hydrogenation with N-alkyl imines in chiral diamine metal catalyst catalysis ring, has realized the efficient asymmetric synthesis of Chiral Amine in ring, and enantioselectivity is up to 98%.Utilizing Chiral Amine product in the resulting various rings of method provided by the invention, be the important chiral intermediate in medicine and material preparation process, thereby present method has important industrial application value.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described, but the present invention is not limited to following examples.
Gordian technique for the preparation of Chiral Amine in ring provided by the invention---in ring, the universal method of the asymmetric catalytic hydrogenation reaction of N-alkyl imines is as follows:
In autoclave, add successively N-alkyl imines, additive, solvent etc. in catalyzer, reaction substrate ring.With nitrogen replacement, several times after gas, be filled with hydrogen to certain pressure and stir, react the specific time.Stop stirring, after careful emptying hydrogen, reaction solution, through silica gel column chromatography, is removed metal catalyst.To the evaluation of above-mentioned reaction, be by the mensuration of reaction conversion ratio, to weigh the efficiency of reaction, the mensuration of the enantiomeric excess (ee) by reaction product is weighed the enantioselectivity of reaction.
The transformation efficiency (conv.) of reaction, indicates that the reaction raw materials of how many ratios is converted into product, conventionally with percentage ratio, represents, its calculation formula is: the reactant that conv.=[transforms]/[initial reactant] x100%.In ring of the present invention the transformation efficiency of the asymmetric catalytic hydrogenation of N-alkyl imines reaction be with the reaction mixture before purifying directly by proton nmr spectra ( 1h NMR) in, in remaining unreacted ring, the peak area of N-alkyl imines raw material calculates with the peak area that is converted to the characteristic peak of product.
The enantiomeric excess of product (ee), represents in reaction product excessive to another enantiomorph of an enantiomorph, conventionally with percentage ratio, represents, its calculation formula is: ee=([S]-[and R)/([S]+[R]) x100%.The enantioselectivity of the asymmetric catalytic hydrogenation reaction of cyclic n nitroso compound-alkyl imines of the present invention, being the enantiomeric excess (being ee value) of product, is that the product after purifying calculates by (S)-configuration product in chirality high pressure liquid chromatography figure (chirality OJ-H post or chirality AD-H post) and the peak area of (R)-configuration product.
To react the general preparation method of single sulfonylation chiral diamine ligands used as follows for the asymmetric catalytic hydrogenation of N-alkyl imines in ring provided by the invention:
By (R, R)-chiral diamine (is shown in formula XII, as: a (R, R)-cyclohexanediamine, b (R, R)-1,2-phenylbenzene-quadrol, c (R, R)-1,2-bis-(4-methoxyl group-phenyl)-quadrol) 20mmol is placed in flask, with methylene dichloride, dissolves, and reaction flask is placed in ice bath.Different SULPHURYL CHLORIDE (is shown in formula XIII, as: d Methanesulfonyl chloride, e trimethyl fluoride sulfonyl chlorine, f phenyl SULPHURYL CHLORIDE, the p-aminomethyl phenyl SULPHURYL CHLORIDE of g, the p-trifluoromethyl SULPHURYL CHLORIDE of h, i 2,4,6-triisopropyl phenyl SULPHURYL CHLORIDE, j 1-naphthyl SULPHURYL CHLORIDE) 20mmol dissolves with methylene dichloride, with dropping funnel, be slowly added drop-wise in chiral diamine solution, then stirring reaction spends the night.Reaction solution is under reduced pressure spin-dried for, and column chromatography (elutriant is methylene chloride-methanol, and volume ratio is 10: 1) purifying obtains the chiral diamine ligands that various single alkylsulfonyls replace, and yield is 25-95%.
(formula XII)
With as above method, adopt (S, S)-chiral diamine reacts from different SULPHURYL CHLORIDE, can also prepare various (S, S)-mono-sulphonyl chiral diamine ligands (J.E.D.Matins, M.Wills, " Ir (III) complexes of diamine ligands for asymmetric ketone hydrogenation ", Tetrahedron 2009,65, and 5782).More than prepare the reaction formula of single sulphonyl chiral diamine and the particular chemical of various (R, R)-chiral diamine used and SULPHURYL CHLORIDE suc as formula shown in XII.
To react the general preparation method of chiral metal catalyst used as follows for the asymmetric catalytic hydrogenation of N-alkyl imines in ring provided by the invention:
In ring provided by the invention, N-alkyl imines carries out in the method for asymmetric hydrogenation, and the chiral metal catalyst adopting is generally prepared according to following two kinds of methods by single sulphonyl chiral diamine ligands and metal precursor (reaction formula prepared by catalyzer and various metal precursor used are suc as formula shown in XIII):
Preparation method is added in (method one) acid: single sulphonyl chiral diamine ligands, metal precursor and KOH first stir 5 minutes in methylene dichloride, then add water, and extraction separatory is until water is neutral, and organic phase is through CaH 2after dry, decompression (for example: (R, R)-1) obtains a solid after revolving and desolventizing.By this solid and 2,2 '-dibenzyl phosphatase reaction, obtains catalyzer after processing, as: (R, R)-4e, (R, R)-4g-i.(R.Noyori, " The Hydrogenation/Transfer Hydrogenation Network:Asymmetric Hydrogenation of Ketones with Chiral η 6-Arene/N-Tosylethylene diamine-Ruthenium (II) Catal ysts ", J.Am.Chem.Soc.2006,128,8724); Ir catalyzer: T.Ohkuma, " Asymmetric Hydrogenation of α-Hydroxy Ketones Catalyzed by MsDPEN-Cp*Ir (III) Complex ", Org.Lett.2007,9,2565).
Figure BDA0000076035040000061
(formula XIII)
(method two) metal-salt exchange process: single sulphonyl chiral diamine ligands and metal precursor are dissolved in methylene dichloride, take triethylamine as alkali, under room temperature, react 0.5 hour, decompression (for example: (R obtains a solid after revolving and desolventizing, R)-2), the negative ion silver salt such as this solid and silver trifluoromethanesulfonate (exception: what four aryl boron salt catalysts adopted is four aryl boron potassium or sodium salts) obtain the metal chiral catalyst of corresponding different negative ions by ion-exchange, as: (R, R)-3a, (R, R)-4a-f, (R, R)-7-15a, (R, R)-5, (R, R)-6.(D.C.Baker，“A?Chiral?Rhodium?Complex?for?Rapid?Asymmetric?Transfer?Hydrogenation?of?Imines?with?High?Enantioselectivity”，Org.Lett.1999，1，841)。
(S, S)-shaped metal catalyzer can use (S, S)-mono-sulphonyl-chiral diamine ligands and metal precursor by as above two kinds of method preparations.
The structure of the representative catalyzer that the present invention synthesizes (numbering respectively is (R, R)-1～(R, R)-15) is as follows:
Figure BDA0000076035040000071
Wherein: X=OTf (a), BF 4(b), PF 6(c), SbF 6(d), NTf 2(e), BArF (f), 2,2 '-biphenyl phosphoric acid negative ion (g), (R)-2,2 '-naphthyl naphthalene phosphoric acid negative ion (h), (S)-2,2 '-naphthyl naphthalene phosphoric acid negative ion (i).Four aryl boric acid potassium KBArF used in following embodiment 4in the structural formula that contains BArF, Ar is 3,5-bis-(trifluoromethyl) benzene.
In ring provided by the invention, in the reaction of the asymmetric catalytic hydrogenation of N-alkyl imines, in the various rings of reactant, the general preparation method of N-alkyl imines is as shown in XIV, and specific experiment operation is as follows:
Method 1: under nitrogen atmosphere, cyclic lactam (50.0mmol) is dissolved in to toluene (100mL), then adds trimethylchlorosilane (55.0mmol) and triethylamine (60.0mmol), the lower reaction of 50 degree 6 hours.Then be chilled to room temperature, add sherwood oil (100mL), with diatomite filtration under diminished pressure, filtrate is spin-dried for, underpressure distillation gets final product to obtain the cyclic lactam of N-trimethylchlorosilane protection.Be dissolved in afterwards anhydrous tetrahydro furan (50mL), added corresponding grignard reagent (60.0mmol) reflux 3 hours.Reaction solution is chilled to room temperature, ammonium chloride saturated solution cancellation reaction, dichloromethane extraction separatory, organic phase is with being spin-dried for after anhydrous sodium sulfate drying.Crude product is by underpressure distillation or column chromatography purification, obtain N-alkyl imines in required ring, productive rate 25-55% (M.Chang, W.Li, X.Zhang, " Iridium-Catalyzed Enantioselective Hydrogenation of Cyclic Imines " Adv.Synth.Catal.2010,352,3121).
Method 2: under nitrogen atmosphere, by after the terminal amino group ketone (50.0mmol) of Boc protection and formic acid (500mmol) mixing, stir under room temperature 12 hours.Decompression is removed after residue formic acid, crude product is by underpressure distillation or column chromatography purification, obtain N-alkyl imines in required ring, productive rate 25-95% (G. D.Williams, R.A.Pike, C.E.Wade, M.Wills, " A One-Pot Process for the Enantioselective Synthesis of Amines via Reductive Amination under Transfer Hydrogenation Conditions ", Org.Lett.2003,5,4227).
Figure BDA0000076035040000081
(formula XIV)
The asymmetric catalytic hydrogenation reaction method of N-alkyl imines in ring provided by the invention,, can be obtained by one pot reaction shown in the method for fractional steps shown in formula XV or formula XVI for the synthesis of Chiral Amine in ring as gordian technique.
Wherein, the method of fractional steps (formula XV) comprises the steps: according to N-alkyl imines substrate in the synthetic various rings of bibliographical information method, under the condition existing at chiral catalyst again, in the ring with hydrogen after to separation and purification, N-alkyl imines carries out addition reaction, obtains Chiral Amine product;
Figure BDA0000076035040000082
(formula XV)
One kettle way comprises the steps: according to bibliographical information method (G.D.Williams, R.A.Pike, C.E.Wade, M.Wills, " A One-Pot Process for the Enantioselective Synthesis of Amines via Reductive Amination under Transfer Hydrogenation Conditions ", Org.Lett.2003, 5, 4227) N-alkyl imines substrate in synthetic various rings, reaction product is without separation and purification, be directly used in next step asymmetric catalytic hydrogenation reaction, in reaction system, directly add chiral catalyst and additive, with hydrogen, to encircling interior N-alkyl imines crude product, carry out addition reaction, obtain Chiral Amine product,
Figure BDA0000076035040000083
(formula XVII) (formula XVI)
Shown in above-mentioned formula XVI, in one kettle way, in described formula XVII general structure, R is alkyl, cycloalkyl, aryl, contains substituent alkyl, contains substituent cycloalkyl or contain substituent aryl; In described R, described substituting group is all selected from least one in fluorine, chlorine, bromine, nitro, methyl, methoxyl group, trifluoromethyl, hydroxyl and kharophen; Described alkyl is preferably the alkyl that carbonatoms is 1-5, described cycloalkyl is preferably cyclopentyl, cyclohexyl, suberyl or ring octyl group, described aryl is preferably phenyl, naphthyl, thienyl, furyl or pyridyl, and described fragrant benzyl is preferably benzyl or naphthalene benzyl; Shown in the method for fractional steps shown in formula XV or formula XVI, in one kettle way, n is 1,2 or 3.
The screening of embodiment 1-9, additive and the optimization of additive amount
The asymmetric catalytic hydrogenation of 2-phenylpyrrole quinoline of take is model reaction, under the catalysis of catalyzer (R, R)-3a and (R, R)-4f, carried out the screening of asymmetric catalysis additive and the optimization of additive amount, the experimental design of specific embodiment 1-9 with the results are shown in Table 1.
The concrete operations of asymmetric catalytic hydrogenation reaction are as follows: hydrogenation experiment is all carried out in autoclave.By mole dosage, be that the catalyzer of reaction substrate 2-phenylpyrrole quinoline 1%, the reaction substrate 2-phenylpyrrole quinoline of 0.2mmol, a certain amount of additive are dissolved in 1mL solvent, with after nitrogen replacement gas, be filled with 50atm hydrogen, 40 ℃ of reaction regular hours.In this reaction, the kind of catalyzer, the kind of additive and consumption, reaction times all list in table 1.
After having reacted, stop stirring, reaction solution, through silica gel column chromatography (elutriant is for by volume ratio being the mixed solution that 5: 95 triethylamines and sherwood oil form), is removed metal catalyst used.The mensuration of reaction conversion ratio is directly to pass through nucleus magnetic resonance with the reaction solution before purifying 1h NMR characterizes, and the enantiomeric excess of product (be ee value, the absolute configuration of product is R) is that the product after purifying is measured through high pressure liquid chromatography (chirality AD-H post), and result is as shown in table 1.
Figure BDA0000076035040000091
(formula XVIII)
The optimization of the screening of table 1, additive and addition consumption
Figure BDA0000076035040000092
By above experimental result, can find out: in as above reaction system, if there is benzylamine in reactant, can have poisoning effect to catalyzer, transformation efficiency and the enantioselectivity of reaction are all decreased; The asymmetric catalytic hydrogenation reaction of carrying out in dichloromethane solvent, (can react with benzylamine its poisoning effect of reduction) during doping tert-Butyl dicarbonate outside, transformation efficiency and the enantioselectivity of reaction are all greatly improved; When the mole dosage of tert-Butyl dicarbonate and reaction substrate reaches 1.1 when above, obtain best catalytic result, the transformation efficiency of reaction approaches 100%, and the enantioselectivity of product reaches maximum, is 95%ee.
Embodiment 10-27, screening of catalyst
The asymmetric catalytic hydrogenation of 2-phenylpyrrole quinoline of take is model reaction, has carried out screening of catalyst, and used catalyst is respectively (R, R)-3～(R, R)-15, the experimental design of specific embodiment 10-27 with the results are shown in Table 2.
The concrete operations of asymmetric catalytic hydrogenation reaction are as follows: hydrogenation experiment is all carried out in autoclave.The catalyzer, 0.2mmol reaction substrate 2-phenylpyrrole quinoline and the 0.22mmol tert-Butyl dicarbonate that by mole dosage, are reaction substrate 2-phenylpyrrole quinoline 1% are dissolved in 1mL methylene dichloride, with after nitrogen replacement gas, be filled with 50atm hydrogen, 40 ℃ are reacted 10 hours.Stop stirring, reaction solution, through silica gel column chromatography (elutriant is for by volume ratio being the mixed solution that 5: 95 triethylamines and sherwood oil form), is removed metal catalyst.The mensuration of reaction conversion ratio is directly to pass through nucleus magnetic resonance with the reaction solution before purifying 1h NMR characterizes, and the enantiomeric excess of product (be ee value, the absolute configuration of product is R) is that the product after purifying is measured through high pressure liquid chromatography (chirality AD-H post), and result is as shown in table 2.
Figure BDA0000076035040000101
(formula XIX)
Table 2, screening of catalyst
From above experimental result, can find out: the asymmetric catalytic hydrogenation model reaction with 2-phenylpyrrole quinoline, under listed catalyzer condition, the skeleton of catalyzer has a great impact activity and the enantioselectivity of reaction; In all catalyzer, the enantioselectivity of (R, R)-4f catalyzed reaction is the highest, reaches 97% enantiomeric excess.
The optimization of the consumption of embodiment 28-40, asymmetric catalytic hydrogenation catalysts, hydrogen pressure, temperature of reaction and solvent
The asymmetric catalytic hydrogenation of 2-phenylpyrrole quinoline of take is model reaction, has carried out catalyst levels, hydrogen pressure, the optimization of temperature of reaction and the further optimization of reaction solvent, the experimental design of specific embodiment 28-40 with the results are shown in Table 3.
The concrete operations of asymmetric catalytic hydrogenation reaction are as follows: hydrogenation experiment is all carried out in autoclave.By mole dosage, be the catalyzer (R of reaction substrate 2-phenylpyrrole quinoline 1%, R) tert-Butyl dicarbonate of-4f, 0.2mmol reaction substrate 2-phenylpyrrole quinoline and 0.22mmol is dissolved in 1mL solvent, with nitrogen replacement several times after gas, be filled with the hydrogen of certain pressure, react at a certain temperature certain hour.
In this reaction, the kind of solvent for use, the pressure of hydrogen, temperature of reaction and reaction times all list in table 3.
Stop stirring, reaction solution, through silica gel column chromatography (elutriant is for by volume ratio being the mixed solution that 5: 95 triethylamines and sherwood oil form), is removed metal catalyst.The mensuration of reaction conversion ratio is directly to pass through nucleus magnetic resonance with the reaction solution before purifying 1h NMR characterizes, and the enantiomeric excess of product (be ee value, the absolute configuration of product is R) is that the product after purifying is measured through high pressure liquid chromatography (chirality AD-H post), and result is as shown in table 3.
(formula XX)
The optimization of table 3, catalyst levels, hydrogen pressure, temperature of reaction
Figure BDA0000076035040000112
From above experimental result, can find out: the asymmetric catalytic hydrogenation model reaction with 2-phenylpyrrole quinoline, optimal catalyst (the R filtering out with embodiment 10-27, R)-4f, optimum additive tert-Butyl dicarbonate and optimum solvent (ethylene dichloride) are under reaction conditions, to catalyst levels, hydrogen pressure, when the carrying out of temperature of reaction and reaction solvent further screened, with in ethylene dichloride, hydrogen pressure is 50 normal atmosphere, when temperature of reaction is 40 ℃, the effect of catalysis is best, when S/C is 100 or 500, in 10 hours, the transformation efficiency of reaction approaches 100%, the enantiomeric excess of product reaches 97% and 93%.
The applied research of N-alkyl imines asymmetric catalytic hydrogenation reaction substrate in embodiment 41-57, ring
The N-alkyl imines in different rings of take is substrate, under the reaction conditions of optimizing, carries out asymmetric catalytic hydrogenation reaction, and the experimental design of specific embodiment 41-57 is as follows:
Hydrogenation experiment is all carried out in autoclave.By mole dosage, be the catalyzer (R of N-alkyl imines 1mol% in reaction substrate ring, R) in-4f, 0.2mmol reaction substrate ring, the tert-Butyl dicarbonate of N-alkyl imines and 0.22mmol is dissolved in the ethylene dichloride of 1mL, with after nitrogen replacement gas, be filled with 50atm hydrogen, 40 ℃ are reacted 10 hours.
In this reaction, in reaction substrate ring used, N-alkyl imines is followed successively by 19a-p suc as formula shown in XIX, and corresponding embodiment 41-57, specifically as shown in table 4 respectively.
Stop stirring, reaction solution, through silica gel column chromatography (elutriant is for by volume ratio being the mixed solution that 5: 95 triethylamines and sherwood oil form), is removed metal catalyst.The mensuration of reaction conversion ratio is directly to pass through nucleus magnetic resonance with the reaction solution before purifying 1h NMR characterizes, and the enantiomeric excess of product (be ee value, the absolute configuration of product is R) is that the product after purifying is measured through high pressure liquid chromatography (chirality OJ-H post or chirality AD-H post), and result is as shown in table 4.
Figure BDA0000076035040000121
(formula XXI)
The applied research of N-alkyl imines asymmetric catalytic hydrogenation reaction substrate in table 4, ring
Figure BDA0000076035040000122
From above experimental result, can find out: in ring, the asymmetric catalytic hydrogenation of N-alkyl imines reacts, at optimum catalytic condition (in ethylene dichloride, with (R, R)-4f is catalyzer, tert-Butyl dicarbonate is additive, hydrogen pressure is 50 normal atmosphere, temperature of reaction is 40 ℃) under, in 10 hours, N-alkyl imines hydrogenation smoothly in listed various ring, productive rate reaches 90%-96%, and the enantiomeric excess of product (except 20k:67%ee, 20o:53%) reaches 92-98%.
Chiral Amine in embodiment 58-74, asymmetric reduction amination one kettle way preparation ring
In this reaction, reaction substrate terminal amino group ketone used is followed successively by 21a-p suc as formula shown in XXII, and corresponding embodiment 58-73, specifically as shown in table 5 respectively.
Under the effect of formic acid, different terminal amino group ketone directly removes Boc protecting group and dehydrating condensation generates N-alkyl imines (G.D.Williams in ring, R.A.Pike, C.E.Wade, M.Wills, " A One-Pot Process for the Enantioselective Synthesis of Amines via Reductive Amination under Transfer Hydrogenation Conditions ", Org.Lett.2003, 5, 4227), then revolve unnecessary formic acid, crude product at optimum catalytic condition (in ethylene dichloride, with (R, R)-4f is catalyzer, tert-Butyl dicarbonate is additive, hydrogen pressure is 50 normal atmosphere, temperature of reaction is 40 ℃) under, carry out asymmetric catalytic hydrogenation reaction, concrete operations are as follows:
Hydrogenation experiment is all carried out in autoclave.By mole dosage, be the catalyzer (R of N-alkyl imines 1mol% in reaction substrate ring, R) in-4f, 0.2mmol reaction substrate ring, the tert-Butyl dicarbonate of N-alkyl imines and 0.22mmol is dissolved in the ethylene dichloride of 1mL, with after nitrogen replacement gas, be filled with 50atm hydrogen, 40 ℃ are reacted 10 hours.
Stop stirring, reaction solution, through silica gel column chromatography (elutriant is for by volume ratio being the mixed solution that 5: 95 triethylamines and sherwood oil form), is removed metal catalyst.The mensuration of reaction conversion ratio is directly to pass through nucleus magnetic resonance with the reaction solution before purifying 1h NMR characterizes, and the enantiomeric excess of product (be ee value, the absolute configuration of product is R) is that the product after purifying is measured through high pressure liquid chromatography (chirality OJ-H post or chirality AD-H post), and result is as shown in table 5.
Figure BDA0000076035040000131
(formula XXII)
The applied research of table 5, one kettle way asymmetric reduction amination reaction substrate
Figure BDA0000076035040000132
From above experimental result, can find out: asymmetric reduction amination reaction, first under the effect of formic acid, directly remove Boc protecting group dehydrating condensation and generate imines (G. D.Williams, R.A.Pike, C.E.Wade, M.Wills, " A One-Pot Process forthe Enantioselective Synthesis of Amines via Reductive Amination under Transfer Hydrogenation Conditions ", Org.Lett.2003, 5, 4227), then revolve unnecessary formic acid, at optimum catalytic condition (in ethylene dichloride, with (R, R)-4f is catalyzer, tert-Butyl dicarbonate is additive, hydrogen pressure is 50 normal atmosphere, temperature of reaction is 40 ℃) under, in 10 hours, N-alkyl imines crude product hydrogenation smoothly in the ring of listed various generations, the result obtaining under the enantiomeric excess fundamental sum hydrogenation conditions of product is consistent, only have individually and slightly decline.
Above-described embodiment prepare Chiral Amine product 20a-q in gained ring optically-active, NMR (Nuclear Magnetic Resonance) spectrum ( 1h, 13c NMR), high resolution mass spectrum and high pressure liquid chromatography data are as follows:
Figure BDA0000076035040000141
[α] d 20=+86.8 ° (c=1.0, acetone);
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.30-7.14(m，5H)，4.95-4.75(br，m，1H)，3.62(br，s，2H)，2.30(br，s，1H)，1.93-1.79(m，3H)，1.45-1.18(br，m，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)154.6，145.2，128.2，126.5，125.5，79.2，61.4，60.8，47.2，36.1，34.8，28.2，23.3.
Chirality HPLC analysis (analysis condition: chirality AD-H post, eluent: normal hexane/Virahol=99/1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t r1=9.4min (principal product), t r2=10.2min (inferior product).
Figure BDA0000076035040000142
[α] d 20=+93.6 ° (c=1.0, acetone);
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.07(m，4H)，4.77(br，s，1H)，3.60-3.58(br，m，2H)，2.32-2.24(m，4H)，1.97-1.75(m，3H)，1.40-1.22(br，m，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)154.6，142.0，135.9，128.9，125.4，79.1，61.0，47.1，35.9，28.3，23.3，21.1.
Chirality HPLC analysis (analysis condition: chirality AD-H post, eluent: normal hexane/Virahol=99/1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t r1=7.5min (principal product), t r2=8.7min (inferior product).
[α] d 20=+69.8 ° (c=1.0, acetone);
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.05(d，J＝8.7Hz，2H)，6.80(d，J＝8.4Hz，2H)，4.72(br，s，1H)，3.74(s，3H)，3.55(br，s，2H)，2.22-2.20(br，m，1H)，1.91-1.71(m，3H)，1.37-1.19(br，m，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)158.2，154.5，137.1，126.5，113.5，79.0，60.5，55.1，47.0，35.9，28.2，23.2.
Chirality HPLC analysis (analysis condition: chirality AD-H post, eluent: normal hexane/Virahol=99/1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t r1=13.6min (principal product), t r2=15.8min (inferior product).
Figure BDA0000076035040000144
[α] d 20=+77.0 ° (c=1.0, acetone);
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.10-7.05(m，2H)，6.95-6.87(m，2H)，4.86-4.69(br，m，1H)，3.55(br，s，2H)，2.23(br，s，1H)，1.91-1.67(m，3H)，1.39-1.14(br，m，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)163.1，159.9，154.4，140.9，139.8，126.9，126.8，115.0，114.7，79.2，60.6，60.1，47.0，36.0，34.8，28.1，23.1.
Chirality HPLC analysis (analysis condition: chirality AD-H post, eluent: normal hexane/Virahol=99/1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t r1=8.9min (principal product), t r2=10.1min (inferior product).
Figure BDA0000076035040000145
[α] d 20=+91.8 ° (c=1.0, acetone);
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.26(d，J＝8.4Hz，2H)，7.10(d，J＝8.1Hz，2H)，4.90-4.74(br，m，1H)，3.61-3.59(br，m，2H)，2.30-2.28(br，m，1H)，1.89-1.74(m，3H)，1.45-1.20(br，m，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)154.5，143.8，142.7，132.1，128.3，126.9，79.4，60.8，60.2，47.3，47.1，36.0，34.8，28.5，28.2，23.5，23.2.
Chirality HPLC analysis (analysis condition: chirality AD-H post, eluent: normal hexane/Virahol=99/1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t r1=8.9min (principal product), t r2=11.4min (inferior product).
Figure BDA0000076035040000146
[α] d 20=+83.6 ° (c=1.0, acetone);
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.41-7.03(m，4H)，4.76(br，s，1H)，3.60(br，s，2H)，2.28(br，s，1H)，1.90-1.75(m，3H)，1.43-1.20(br，m，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)154.4，154.3，145.1，144.1，131.2，128.1，127.2，126.4，125.4，120.1，79.3，79.0，61.2，60.7，47.1，35.9，34.8，28.2，23.2.
Chirality HPLC analysis (analysis condition: chirality AD-H post, eluent: normal hexane/Virahol=99/1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t r1=8.7min (principal product), t r2=11.6min (inferior product).
Figure BDA0000076035040000151
[α] d 20=+82.1 ° (c=1.0, acetone);
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.20-7.14(m，1H)，7.02-6.94(m，3H)，4.91-4.72(br，m，1H)，3.62-3.60(br，m，2H)，2.32-2.27(m，4H)，1.98-1.80(m，3H)，1.46-1.18(br，m，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)154.7，145.1，144.1，137.6，128.1，127.2，126.2，122.7，122.4，79.2，61.3，60.7，47.1，36.0，34.9，28.6，28.2，23.3，21.5.
Chirality HPLC analysis (analysis condition: chirality OJ-H post, eluent: normal hexane/Virahol=99/1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t r1=6.7min (principal product), t r2=7.4min (inferior product).
Figure BDA0000076035040000152
[α] d 20=+78.6 ° (c=1.0, acetone);
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.18-7.13(m，1H)，6.72-6.67(m，3H)，4.88-4.69(br，m，1H)，3.72(s，3H)，3.57(br，s，2H)，2.24(br，s，1H)，1.88-1.78(m，3H)，1.42-1.16(br，m，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)159.5，154.4，146.8，145.8，129.1，117.8，111.6，111.1，79.0，61.2，60.5，55.0，47.0，35.8，34.6，28.4，28.1，23.1.
Chirality HPLC analysis (analysis condition: chirality AD-H post, eluent: normal hexane/Virahol=99/1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t r1=15.8min (principal product), t r2=19.9min (inferior product).
Figure BDA0000076035040000153
[α] d 20=+78.5 ° (c=1.0, acetone);
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.27-7.22(m，1H)，6.96-6.85(m，3H)，4.93-4.74(br，m，1H)，3.62-3.60(br，m，2H)，2.32-2.30(br，m，1H)，1.91-1.78(m，3H)，1.46-1.20(br，m，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)164.7，161.4，154.6，148.2，129.8，121.2，121.2，113.6，113.3，112.7，112.4，79.5，61.0，60.4，47.2，36.0，34.8，28.6，28.3，23.3.
High resolution mass spectrum (P-SI HRMS mass): C 15h 20fNO 2na +([M+Na] +) molecular ion peak calculated value: m/z 288.13703, measured value: m/z 288.13696;
Chirality HPLC analysis (analysis condition: chirality AD-H post, eluent: normal hexane/Virahol=99/1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t r1=8.9min (principal product), t r2=10.1min (inferior product).
Figure BDA0000076035040000154
[α] d 20=+86.5 ° (c=1.0, acetone);
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.23-7.13(m，3H)，7.03(d，J＝7.2Hz，1H)，4.88-4.69(br，m，1H)，3.59-3.57(br，m，2H)，2.29-2.28(br，m，1H)，1.88-1.81(m，3H)，1.44-1.18(br，m，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)154.5，147.4，146.4，134.1，129.5，126.7，125.8，123.8，79.5，61.0，60.4，47.4，47.1，35.9，34.8，28.5，28.2，23.5，23.3.
High resolution mass spectrum (P-SI HRMS mass): C 15h 20clNO 2na +([M+Na] +) molecular ion peak calculated value: m/z 304.10748, measured value: m/z 304.10736:
Chirality HPLC analysis (analysis condition: chirality AD-H post, eluent: normal hexane/Virahol=99/1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t r1=8.6min (principal product), t r2=9.5min (inferior product).
Figure BDA0000076035040000155
[α] d 20=+70.6 ° (c=1.0, acetone);
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.20-7.15(m，1H)，7.05-6.99(m，1H)，6.90-6.82(m，2H)，5.25-5.08(br，m，1H)，3.81(s，3H)，3.61-3.48(br，m，2H)，2.27-2.21(br，m，1H)，1.80(br，s，3H)，1.45(br，s，3H)，1.18(br，s，6H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)156.2，154.6，133.0，127.4，126.0，125.3，120.2，110.2，78.9，56.1，55.4，47.3，46.9，33.9，32.9，28.6，28.2，23.2.
Chirality HPLC analysis (analysis condition: chirality AD-H post, eluent: normal hexane/Virahol=99/1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t r1=9.8min (inferior product), t r2=12.0min (principal product).
Figure BDA0000076035040000161
[α] d 20=+81.5 ° (c=1.0, acetone);
1H?NMR(300MHz，CDCl 3)：δ(ppm)6.66-6.63(m，1H)，6.56-6.54(m，2H)，4.74-4.58(br，m，1H)，3.69-3.68(m，6H)，3.45(br，s，2H)，2.11(br，s，1H)，1.79-1.60(m，3H)，1.30-1.06(br，m，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)154.2，148.5，147.3，137.5，136.5，117.2，110.7，108.6，78.7，60.6，60.0，55.5，55.4，46.7，35.7，34.4，27.9，22.8.
High resolution mass spectrum (P-SI HRMS mass): C 17h 25nO 4na +([M+Na] +) molecular ion peak calculated value: m/z 330.16758, measured value: m/z330.16769;
Chirality HPLC analysis (analysis condition: chirality OJ-H post, eluent: normal hexane/Virahol=90/10, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t r1=7.1min (principal product), t r2=8.8min (inferior product).
Figure BDA0000076035040000162
[α] d 20=+115.3 ° (c=1.0, acetone);
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.83-7.80(m，3H)，7.62(s，1H)，7.46(br，s，2H)，7.35-7.32(m，1H)，5.14-4.96(m，1H)，3.74-3.72(br，m，2H)，2.38-2.36(br，m，1H)，2.00-1.83(m，3H)，1.51-1.18(br，m，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)154.7，142.4，141.6，133.3，132.5，128.1，127.7，126.1，125.4，124.5，124.2，123.9，122.8，79.3，61.4，60.9，47.2，35.9，34.8，28.6，28.2，23.6，23.2.
Chirality HPLC analysis (analysis condition: chirality AD-H post, eluent/normal hexane: Virahol=99/1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t r1=10.6min (principal product), t r2=12.6min (inferior product).
Figure BDA0000076035040000163
[α] d 20=+92.3 ° (c=1.0, acetone);
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.09-7.08(m，1H)，6.88-6.82(m，2H)，5.06(br，m，1H)，3.52-3.45(br，m，2H)，2.22(br，s，1H)，2.04-1.85(m，3H)，1.40-1.30(br，m，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)154.3，148.8，126.3，123.3，123.0，79.4，56.7，46.2，35.4，34.5，28.3，23.7，23.2.
Chirality HPLC analysis (analysis condition: chirality AD-H post, eluent: normal hexane/Virahol=99/1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t r1=8.7min (principal product), t r2=9.6min (inferior product).
Figure BDA0000076035040000164
[α] d 20=+35.9 ° (c=1.0, acetone);
1H?NMR(300MHz，CDCl 3)：δ(ppm)3.66(br，s，1H)，3.24(br，s，2H)，1.81-1.58(m，5H)，1.40(s，9H)，1.25-1.20(br，m，5H)，0.85-0.81(m，3H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)154.7，78.8，57.3，46.1，34.3，33.9，30.6，29.9，28.6，23.8，23.1，22.7，14.1.
Chirality GC analyzes (analysis condition: Chiralcel CP7502, column temperature: 120 ℃): appearance time: t r1=30.3min (principal product), t r2=34.1min (inferior product).
[α] d 20=+114.8 ° (c=1.0, acetone);
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.34-7.29(m，2H)，7.22-7.16(m，3H)，5.43-5.42(br，m，1H)，4.08-4.03(br，m，1H)，2.80-2.71(m，1H)，2.31-2.27(br，m，1H)，1.92-1.80(m，1H)，1.54-1.40(m，13H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)155.5，140.2，128.4，126.3，126.2，79.3，53.1，39.9，28.3，28.0，25.3，19.2.
Chirality HPLC analysis (analysis condition: chirality AD-H post, eluent: normal hexane/Virahol=99/1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t r1=8.6min (inferior product), t r2=9.7min (principal product).
Figure BDA0000076035040000166
[α] d 20=+71.6 ° (c=1.0, acetone);
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.31-7.16(m，5H)，5.24-5.18(m，0.5H)，4.95-4.89(m，0.5H)，4.15-4.11(br，m，0.5H)，3.89-3.84(br，m，0.5H)，3.03-2.84(m，1H)，2.44-2.21(m，1H)，1.92-1.26(m，16H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)156.2，156.0，144.9，143.8，128.5，128.3，126.6，126.5，125.8，125.6，79.4，79.3，60.5，58.3，43.4，43.2，36.4，35.6，29.9，29.7，29.7，29.5，28.6，28.4，26.5，25.6.
Chirality HPLC analysis (analysis condition: chirality AD-H post, eluent: normal hexane/Virahol=99/1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t r1=7.9min (principal product), t r2=8.6min (inferior product).
According to the general preparation method one of aforementioned catalyzer, the concrete preparation process of catalyzer (R, the R)-4g-i using in the above embodiment of the present invention is as follows:
(R，R)-4e：
Under nitrogen atmosphere, (R, R)-mono-methylsulfonyl-1,2-diphenyl ethylene diamine part (R, R)-MsDPEN (291mg, 1.0mmol), metal precursor [RuCl 2(p-cymene)] 2(344mg, 0.5mmol) and KOH (400mg, 7.1mmol) stirred after 5 minutes in methylene dichloride, added after 5 minutes and added water again, and extraction separatory is until water is neutral, and organic phase is through CaH 2after dry, decompression is spin-dried for, and obtains solid (512mg).This solid (292mg, 0.5mmol) is made to methylene dichloride (30mL) solution, under nitrogen protection, by HNTf 2the methylene dichloride of (140mg, 0.5mmol) (10mL) solution is slowly added drop-wise in this solution.After adding, continue to stir 30 minutes, reaction solution is spin-dried for, obtain red solid catalyzer (R, R)-4e (406mg, yield 94%).
(R，R)-4g：
According to the preparation method of (R, R)-4e, wherein with 2,2 '-biphenyl phosphoric acid (124mg, 0.5mmol) replaces HNTf 2, reaction solution is spin-dried for and obtains red solid catalyzer (R, R)-4g (437mg, yield 95%).
(R，R)-4h：
According to the preparation method of (R, R)-4e, wherein with (R)-2,2 '-biphenyl phosphoric acid (174mg, 0.2mmol) replaces HNTf 2, reaction solution is spin-dried for and obtains red solid catalyzer (R, R)-4h (452mg, yield 95%).
(R，R)-4i：
According to the preparation method of (R, R)-4e, wherein with (S)-2,2 '-biphenyl phosphoric acid (174mg, 0.2mmol) replaces HNTf 2, reaction solution is spin-dried for and obtains red solid catalyzer (R, R)-4i (457mg, yield 96%).
According to the general preparation method two of aforementioned catalyzer, the concrete preparation process of catalyzer (R, the R)-3a using in the above embodiment of the present invention, (R, R)-4a-f, (R, R)-7-15a, (R, R)-5, (R, R)-6 is as follows:
(R，R)-3a：
Under nitrogen atmosphere, in the two-mouth bottle of 25ml, add successively [RuCl 2(p-cymene)] 2(172mg, 0.25mmol), (R, R)-mono-tolysulfonyl-1,2-diphenyl ethylene diamine part (R, R)-TsDPEN (184mg, 0.5mmol), methylene dichloride (20mL), triethylamine TEA (1mL), stirs under room temperature 1 hour, washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, obtains red solid 313mg with normal hexane and Gossypol recrystallized from chloroform.This red solid 139mg (0.2mmol) is dissolved in methylene dichloride (20mL), add silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), under room temperature, stir 0.5 hour, remove by filter precipitation and obtain yellow solid, be catalyzer (R, R)-3a (160mg, yield 99%).
(R，R)-4a：
Under nitrogen atmosphere, in the two-mouth bottle of 25ml, add successively [RuCl 2(p-cymene)] 2(172mg, 0.25mmol), (R, R)-MsDPEN (145mg, 0.5mmol), methylene dichloride (20mL), triethylamine TEA (1mL), stirs under room temperature 1 hour, washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, obtains red solid 275mg with normal hexane and Gossypol recrystallized from chloroform.This red solid 124mg (0.2mmol) is dissolved in methylene dichloride (20mL), add silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), under room temperature, stir 0.5 hour, remove by filter precipitation and obtain yellow solid, be catalyzer (R, R)-4a (145mg, yield 99%).
(R，R)-4b：
According to the preparation method of (R, R)-4a, wherein with silver tetrafluoroborate AgBF 4(39mg, 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-4b 130mg, yield 97%.
(R，R)-4c：
According to the preparation method of (R, R)-4a, wherein with phosphofluoric acid silver AgPF 6(51mg, 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-4c 140mg, yield 96%.
(R，R)-4d：
According to the preparation method of (R, R)-4a, wherein with hexafluoro telluric acid silver AgSbF 6(69mg, 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-4d 161mg, yield 98%.
(R，R)-4f：
According to the preparation method of (R, R)-4a, wherein with four aryl boric acid potassium KBArF 4(181mg, 0.2mmol, described KBArF 4in, Ar is 3,5-bis-(trifluoromethyl) benzene) replacement silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-4e 287mg, yield 99%.
(R，R)-7a：
Under nitrogen atmosphere, in the two-mouth bottle of 25ml, add successively [RuCl 2(benzene)] 2(144mg, 0.25mmol), (R, R)-TsDPEN (184mg, 0.5mmol), methylene dichloride (20mL), triethylamine TEA (1mL), stirs under room temperature 1 hour, washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, obtains red solid 289mg with normal hexane and Gossypol recrystallized from chloroform.This red solid 128mg (0.2mmol) is dissolved in methylene dichloride (20mL), add silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), under room temperature, stir 0.5 hour, remove by filter precipitation and obtain yellow solid, be catalyzer (R, R)-7a (148mg, yield 98%).
(R，R)-8a：
Under nitrogen atmosphere, in the two-mouth bottle of 25ml, add successively [RuCl 2(hexamethylbenzene)] 2(186mg, 0.25mmol), (R, R)-TsDPEN (184mg, 0.5mmol), methylene dichloride (20mL), triethylamine TEA (1mL), stirs under room temperature 1 hour, washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, obtains red solid 323mg with normal hexane and Gossypol recrystallized from chloroform.This red solid 145mg (0.2mmol) is dissolved in methylene dichloride (20mL), add silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), under room temperature, stir 0.5 hour, remove by filter precipitation and obtain yellow solid, be catalyzer (R, R)-8a (164mg, yield 98%).
(R，R)-9a：
Under nitrogen atmosphere, in the two-mouth bottle of 25ml, add successively [RuCl 2(p-cymene)] 2(172mg, 0.25mmol), (R, R)-mono-benzene sulfonyl-1,2-diphenyl ethylene diamine part (177mg, 0.5mmol), methylene dichloride (20mL), triethylamine TEA (1mL), under room temperature, stir washing, anhydrous sodium sulfate drying 1 hour, removal of solvent under reduced pressure, obtains red solid 307mg with normal hexane and Gossypol recrystallized from chloroform.This red solid 136mg (0.2mmol) is dissolved in methylene dichloride (20mL), add silver trifluoromethanesulfonate AgOTf 52mg (0.2mm0l), under room temperature, stir 0.5 hour, remove by filter precipitation and obtain yellow solid, be catalyzer (R, R)-9a (156mg, yield 98%).
(R，R)-10a：
Under nitrogen atmosphere, in the two-mouth bottle of 25ml, add successively [RuCl 2(p-cymene)] 2(172mg, 0.25mmol), (R, R)-mono-tolysulfonyl-cyclohexanediamine part (134mg, 0.5mmol), methylene dichloride (20mL), triethylamine TEA (1mL), stirs under room temperature 1 hour, washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, obtains red solid 251mg with normal hexane and Gossypol recrystallized from chloroform.This red solid 112mg (0.2mmol) is dissolved in methylene dichloride (20mL), add silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), under room temperature, stir 0.5 hour, remove by filter precipitation and obtain yellow solid, be catalyzer (R, R)-10a (141mg, yield 99%).
(R，R)-11a：
Under nitrogen atmosphere, in the two-mouth bottle of 25ml, add successively [RuCl 2(p-cymene)] 2(172mg, 0.25mmol), (R, R)-mono-methylsulfonyl-cyclohexanediamine part (196mg, 0.5mmol), methylene dichloride (20mL), triethylamine TEA (1mL), stirs under room temperature 1 hour, washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, obtains red solid 236mg with normal hexane and Gossypol recrystallized from chloroform.This red solid 104mg (0.2mmol) is dissolved in methylene dichloride (20mL), add silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), under room temperature, stir 0.5 hour, remove by filter precipitation and obtain yellow solid, be catalyzer (R, R)-11a (123mg, yield 97%).
(R，R)-12a：
Under nitrogen atmosphere, in the two-mouth bottle of 25ml, add successively [RuCl 2(p-cymene)] 2(172mg, 0.25mmol), (R, R)-mono-fluoroform sulphonyl-1,2-diphenyl ethylene diamine part (172mg, 0.5mmol), methylene dichloride (20mL), triethylamine TEA (1mL), under room temperature, stir washing, anhydrous sodium sulfate drying 1 hour, removal of solvent under reduced pressure, obtains red solid 301mg with normal hexane and Gossypol recrystallized from chloroform.This red solid 135mg (0.2mmol) is dissolved in methylene dichloride (20mL), add silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), under room temperature, stir 0.5 hour, remove by filter precipitation and obtain yellow solid, be catalyzer (R, R)-12a (153mg, yield 97%).
(R，R)-13a：
Under nitrogen atmosphere, in the two-mouth bottle of 25ml, add successively [RuCl 2(p-cymene)] 2(172mg, 0.25mmol), (R, R)-mono--2,4,6-tri isopropyl benzenesulfonyl-1,2-diphenyl ethylene diamine part (240mg, 0.5mmol), methylene dichloride (20mL), triethylamine TEA (1mL), under room temperature, stir washing, anhydrous sodium sulfate drying 1 hour, removal of solvent under reduced pressure, obtains red solid 365mg with normal hexane and Gossypol recrystallized from chloroform.This red solid 162mg (0.2mmol) is dissolved in methylene dichloride (20mL), add silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), under room temperature, stir 0.5 hour, remove by filter precipitation and obtain yellow solid, be catalyzer (R, R)-13a (182mg, yield 99%).
(R，R)-14a：
Under nitrogen atmosphere, in the two-mouth bottle of 25ml, add successively [RuCl 2(p-cymene)] 2(172mg, 0.25mmol), (R, R)-mono-to trifluoromethyl benzene sulfonyl-1,2-diphenyl ethylene diamine part (210mg, 0.5mmol), methylene dichloride (20mL), triethylamine TEA (1mL), under room temperature, stir washing, anhydrous sodium sulfate drying 1 hour, removal of solvent under reduced pressure, obtains red solid 336mg with normal hexane and Gossypol recrystallized from chloroform.This red solid 150mg (0.2mmol) is dissolved in methylene dichloride (20mL), add silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), under room temperature, stir 0.5 hour, remove by filter precipitation and obtain yellow solid, be catalyzer (R, R)-14a (168mg, yield 97%).
(R，R)-15a：
Under nitrogen atmosphere, in the two-mouth bottle of 25ml, add successively [RuCl 2(p-cymene)] 2(172mg, 0.25mmol), (R, R)-mono--1-naphthalene sulfonyl-1,2-diphenyl ethylene diamine part (202mg, 0.5mmol), methylene dichloride (20mL), triethylamine TEA (1mL), under room temperature, stir washing, anhydrous sodium sulfate drying 1 hour, removal of solvent under reduced pressure, obtains red solid 330mg with normal hexane and Gossypol recrystallized from chloroform.This red solid 146mg (0.2mmol) is dissolved in methylene dichloride (20mL), add silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), under room temperature, stir 0.5 hour, remove by filter precipitation and obtain yellow solid, be catalyzer (R, R)-15a (166mg, yield 98%).
(R，R)-5a：
Under nitrogen atmosphere, in the two-mouth bottle of 25ml, add successively [IrCl 2cp*] 2(211mg, 0.25mmol), (R, R)-TsDPEN (184mg, 0.5mmol), methylene dichloride (20mL), triethylamine TEA (1mL), stirs under room temperature 1 hour, washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, obtains red solid 350mg with normal hexane and Gossypol recrystallized from chloroform.This red solid 155mg (0.2mmol) is dissolved in methylene dichloride (20mL), add silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), under room temperature, stir 0.5 hour, remove by filter precipitation and obtain yellow solid, be catalyzer (R, R)-5a (172mg, yield 97%).
(R，R)-6a：
Under nitrogen atmosphere, in the two-mouth bottle of 25ml, add successively [RhCl 2cp*] 2(166mg, 0.25mmol), (R, R)-TsDPEN (184mg, 0.5mmol), methylene dichloride (20mL), triethylamine TEA (1mL), stirs under room temperature 1 hour, washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, obtains red solid 308mg with normal hexane and Gossypol recrystallized from chloroform.This red solid 137mg (0.2mmol) is dissolved in methylene dichloride (20mL), add silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), under room temperature, stir 0.5 hour, remove by filter precipitation and obtain yellow solid, be catalyzer (R, R)-6a (153mg, yield 96%).

Claims (5)

1. the method for asymmetric catalytic hydrogenation reaction, comprise the steps: at formula (R, R)-3, formula (R, R)-4 or formula (R, R) under the condition that chiral catalyst shown in-14 exists, with hydrogen, N-alkyl imines in ring shown in formula III is carried out to addition reaction, obtain Chiral Amine product;
Figure FDA0000379188910000011
Wherein: the X in formula (R, R)-3 and formula (R, R)-14 is OTf,
X in formula (R, R)-4 be selected from following any one: OTf, BF 4, SbF 6, PF 6, NTf 2or BArF;
In described formula III general structure, R is alkyl, aryl, fragrant benzyl or contains substituent aryl, wherein, described in contain in substituent aryl, described substituting group is all selected from least one in fluorine, chlorine, bromine, nitro, methyl, methoxyl group, trifluoromethyl and hydroxyl;
Described alkyl is that the total number of carbon atoms is the alkyl of 1-5, and described aryl is phenyl, naphthyl, thienyl, furyl or pyridyl, and described fragrant benzyl is benzyl or naphthalene benzyl;
The method of described asymmetric catalytic hydrogenation reaction, also comprises the steps:, before described addition reaction is carried out, in reaction system, to add additive; Described additive is selected from a kind of in Ue-5908 and tert-Butyl dicarbonate;
In described additive and described ring, the molar ratio of N-alkyl imines is 1:1～2:1;
Described addition reaction is to carry out under the condition existing at organic solvent, and described organic solvent is single organic solvent, and described single organic solvent is toluene, dimethylbenzene, methylene dichloride, 1, any one in 2-ethylene dichloride and chloroform.
2. method according to claim 1, is characterized in that: in described ring, the molar ratio of N-alkyl imines and described chiral catalyst is 10-2000:1.
3. method according to claim 2, is characterized in that: in described ring, the molar ratio of N-alkyl imines and described chiral catalyst is 50-1000:1.
4. method according to claim 1, is characterized in that: in described addition reaction step, temperature is-10-100 ℃, and pressure is 1-100atm, and the time is 1-72 hour.
5. method according to claim 4, is characterized in that: in described addition reaction step, temperature is 0-60 ℃, and pressure is 5-60atm, and the time is 6-24 hour.
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