CN102304007A - Asymmetric catalytic hydrogenation reaction method of intra-annular N-alkylimine - Google Patents
Asymmetric catalytic hydrogenation reaction method of intra-annular N-alkylimine Download PDFInfo
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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
Technical field
The method of asymmetric synthesis of Chiral Amine particularly relates to a kind of method with the asymmetric hydrogenation of N-alkyl imines in the catalytic ring of chiral diamine metal catalyst in the present invention relates to encircle.
Background technology
Asymmetric efficient the synthesizing of high enantioselectivity chipal compounds; In chemical industry, agricultural, herding and each field of medicine, receive common concern day by day; 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 efficient production chipal compounds.The asymmetric catalytic hydrogenation reaction is meant 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 the effect, hydrogen generates chiral product to the addition reaction of unsaturated link(age) in the unsaturated prochirality compound (being called substrate).Unsaturated prochirality compound generally comprises prochiral olefin (C=C), ketone (C=O), imines compounds such as (C=N).The asymmetric catalytic hydrogenation reaction is because of using hydrogen cheap and easy to get, and little to the pollution of environment, chiral product has high enantioselectivity again, so receive the generally attention of industry member.As far back as the seventies in last century; Suitability for industrialized production (the H.-U.Blaser that U.S. Monsanto Company just utilizes the asymmetric catalytic hydrogenation technology successfully to develop to treat Parkinsonian L-DOPA; 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 among the formula I; B.Breit; A.Mann; " Hydroformylation of Homoallylic Azides:A Rapid Approach toward Alkaloids ", Org.Lett.2009,11; 261) have analgesic activity, and can be used for treating the 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 treat cardiovascular disorder.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) can be used for treating the central nervous system vegetative nervous system disease of unifying as a kind of tachykinin receptor.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).The imines asymmetric catalytic hydrogenation has been successfully applied to large-scale industrial production; Wherein, The most successful industrialization instance 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 present known largest asymmetric catalytic hydrogenation process with 10,000 tons/year output.In addition, Japanese Daiichi company and DOW Chemical (Dowpharma) have also successfully realized the broad-spectrum antibacterials levofloxacins (suitability for industrialized production of (S)-levonoxacin) and treatment Alzheimer's disease medicine (S)-18986 through the asymmetric catalytic hydrogenation gordian technique of imines respectively.
(formula I)
Summary of the invention
The purpose of this invention is to provide the method that N-alkyl imines carries out the asymmetric catalytic hydrogenation reaction in a kind of the ring.
The method of asymmetric catalytic hydrogenation reaction provided by the invention comprises the steps: under the condition that chiral catalyst shown in the formula II exists, and with hydrogen N-alkyl imines in the ring shown in the formula III is carried out addition reaction, obtains the Chiral Amine product;
(formula II)
In the said formula II general structure, M is metal Ru Ru, rhodium Rh or iridium Ir;
Said 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; R ' in the said chiral diamine ligands for the total number of carbon atoms be 1-10 alkyl, trifluoromethyl, phenyl, naphthyl, contain substituent phenyl or contain substituent naphthyl; Saidly contain substituent phenyl and contain in the substituent naphthyl, said substituting group is selected from least a in alkyl, methoxyl group, fluorine, chlorine, bromine, nitro and the trifluoromethyl that the total number of carbon atoms is 1-10;
Said R " is selected from least a in the alkyl that H, benzyl and the total number of carbon atoms are 1-10;
Said L
2Be η
6-benzene dentate, η
5-luxuriant dentate, contain substituent η
6-benzene dentate or contain substituent η
5-luxuriant dentate saidly contains substituent η
6-benzene dentate with contain substituent η
5In-luxuriant the dentate, said substituting group is selected from least a in the alkyl that the total number of carbon atoms is 1-10, and said substituting group is selected from least a in the alkyl that the total number of carbon atoms is 1-10;
Said 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 dibenzyl diphenol deutero-phosphoric acid negative ion;
(formula III)
In the said formula III general structure; R is alkyl, cycloalkyl, aryl, fragrant benzyl, contains substituent alkyl, contains substituent cycloalkyl or contain substituent aryl; Wherein, Saidly contain substituent cycloalkyl and contain in the substituent aryl, said substituting group all is selected from least a in fluorine, chlorine, bromine, nitro, methyl, methoxyl group, trifluoromethyl, hydroxyl and the kharophen;
N is 1,2 or 3.
In the aforesaid method, in the said formula II general structure, the said substituent chiral diamine L of single sulphonyl that contains
1Be preferably (R; R)-the single sulphonyl-1 of N-; 2-diaryl quadrol (shown in IVa); (S; S)-the single sulphonyl-1 of N-; 2-diaryl quadrol (shown in IVb); (R, R)-the single sulphonyl-1 of N-, 2-cyclohexanediamine (shown in Va); (S; S)-the single sulphonyl-1 of N-; 2-cyclohexanediamine (shown in Vb); (R, R)-the single sulphonyl of N--1-substituted azole-3,4-diamines (shown in VIa); (S; S)-the single sulphonyl of N--1-substituted azole-3; 4-diamines (shown in VIb); (R)-and the single sulphonyl-2 of N-, 2 '-diaminostilbene, 1 '-dinaphthalene (shown in VIIa) or (the S)-single sulphonyl-2 of N-; 2 '-diaminostilbene, 1 '-dinaphthalene (shown in VIIb);
(formula IVa) (formula Va) (formula VIa) (formula VIIa)
(formula IVb) (formula Vb) (formula VIb) (formula VIIb)
Said L
2Be preferably η
6-benzene dentate, η
6-1,4-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 the said four aryl boron anions, said aryl is preferably phenyl or 3,5-two (trifluoromethyl) phenyl;
In the said formula III general structure; Said alkyl is preferably the alkyl that the total number of carbon atoms is 1-5; Said cycloalkyl is preferably cyclopentyl, cyclohexyl, suberyl or ring octyl group; Said aryl is preferably phenyl, naphthyl, thienyl, furyl or pyridyl, and said fragrant benzyl is preferably benzyl or naphthalene benzyl.
Chiral catalyst shown in the said formula II is preferably shown in the formula IXa by (R; R)-title complex of the single sulphonyl of N--diaryl quadrol and transition metal iridium, ruthenium or rhodium formation or formula IXb shown in by (S; S)-title complex of the single sulphonyl of N--diaryl quadrol and transition metal iridium, ruthenium or rhodium formation
(formula IXa) (formula IXb)
In said formula IXa and the IXb general structure, M is metal Ru Ru, rhodium Rh or iridium Ir;
Ar is phenyl, to the substituted phenyl of methoxyl group 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
6-1,4-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 dibenzyl diphenol deutero-phosphoric acid negative ion; In the said four aryl boron anions, said aryl is phenyl or 3,5-two (trifluoromethyl) phenyl; Said dibenzyl diphenol deutero-phosphoric acid negative ion 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).
(formula XIa) (formula XIb) (formula XIc) (formula XId) (formula XIe)
Said addition reaction can add additive in reaction system before the reaction beginning, realization is caught reaction product amine, reduces its poisoning effect to catalyzer, to improve the efficient and the enantioselectivity of hydrogenation; Be the method for said asymmetric catalytic hydrogenation reaction, also comprise the steps: before said addition reaction is carried out, in reaction system, to add additive.Said additive is selected from Ue-5908 and tert-Butyl dicarbonate ((Boc)
2O) a kind of in, preferred tert-Butyl dicarbonate.The molar ratio of N-alkyl imines is 0: 1～5: 1 in said additive and the said ring; 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; Preferred 1: 1～2: 1, the mole dosage that feeds intake of said additive was not 0.
Said addition reaction is under the condition that organic solvent exists, to carry out.Said organic solvent is single organic solvent or mixed organic solvents; Wherein, said single organic solvent is a methylene dichloride, 1, and 2-ethylene dichloride, chloroform, ethyl acetate, tetrahydrofuran (THF), benzene,toluene,xylene, chlorinated benzene, ether, dioxane, acetone or the total number of carbon atoms are any one in the monohydroxy-alcohol of 1-10; Said mixed organic solvents is at least a composition the in the monohydroxy-alcohol of 1-10 by alkyl chloride based solvent and the total number of carbon atoms, and wherein, said alkyl chloride based solvent is selected from methylene dichloride, 1, at least a in 2-ethylene dichloride and the chloroform.
N-alkyl imines is 10-2000 with the molar ratio (S/C) of said chiral catalyst in the said ring: 1, specifically can be 100-1000: 1,100-500: 1 or 500-1000: and 1, preferred 50-1000: 1.
In the said 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, preferred 6-24 hour.
The invention provides the method for asymmetric synthesis of Chiral Amine in a kind of the ring.This method is the asymmetric catalytic hydrogenation with N-alkyl imines in the chiral diamine metal catalyst catalysis ring, has realized the efficient asymmetric synthesis of Chiral Amine in the 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 the material preparation process, thereby present method has important industrial application value.
Embodiment
Below in conjunction with specific embodiment the present invention is described further, but the present invention is not limited to following examples.
The gordian technique that is used to prepare Chiral Amine in the ring provided by the invention---the universal method of the asymmetric catalytic hydrogenation reaction of N-alkyl imines is following in the ring:
In autoclave, add N-alkyl imines, additive, solvent etc. in catalyzer, the reaction substrate ring successively., charge into hydrogen to certain pressure and stir several times behind the gas with nitrogen replacement, react the specific time.Stop to stir, behind the careful emptying hydrogen, reaction solution is removed metal catalyst through silica gel column chromatography.Evaluation to above-mentioned reaction is an efficient of weighing reaction through the mensuration of reaction conversion ratio, and the mensuration of the enantiomeric excess (ee) through reaction product is weighed the enantioselectivity of reaction.
The transformation efficiency (conv.) of reaction, expression has the reaction raw materials of how many ratios to be converted into product, representes with percentage ratio that usually its calculation formula is: the reactant that conv.=[transforms]/[initial reactant] x100%.In the ring according to the invention the transformation efficiency of the asymmetric catalytic hydrogenation of N-alkyl imines reaction be with the reaction mixture before the purifying directly pass through proton nmr spectra (
1H NMR) peak area of the interior N-alkyl imines raw material of remaining unreacted ring calculates with the peak area that has converted the characteristic peak of product in.
The enantiomeric excess of product (ee), excessive to another enantiomorph of enantiomorph in the expression reaction product, represent with percentage ratio that usually its calculation formula is: ee=([S]-[R)/([S]+[R]) x100%.The enantioselectivity of the asymmetric catalytic hydrogenation reaction of cyclic n nitroso compound according to the invention-alkyl imines; Be the enantiomeric excess (being the ee value) of product, be behind the purifying product through (S)-configuration product among the chirality high pressure liquid chromatography figure (chirality OJ-H post or chirality AD-H post) with (R)-peak area of configuration product calculates.
The general preparation method of single sulfonylation chiral diamine ligands that the asymmetric catalytic hydrogenation reaction of the interior N-alkyl imines of ring provided by the invention is used is following:
Will (R, R)-chiral diamine (see formula XII, as: a (R, R)-cyclohexanediamine, b (R; R)-1, and 2-phenylbenzene-quadrol, c (R, R)-1; 2-two (4-methoxyl group-phenyl)-quadrol) 20mmol places flask, and with the methylene dichloride dissolving, reaction flask is placed in the ice bath.Different SULPHURYL CHLORIDE (is seen formula XIII; As: d Methanesulfonyl chloride, e trifluoromethyl SULPHURYL CHLORIDE, f phenyl SULPHURYL CHLORIDE, g right-aminomethyl phenyl SULPHURYL CHLORIDE, h be right-trifluoromethyl SULPHURYL CHLORIDE, i 2; 4; 6-triisopropyl phenyl SULPHURYL CHLORIDE, j 1-naphthyl SULPHURYL CHLORIDE) 20mmol dissolves with methylene dichloride; Slowly be added drop-wise in the chiral diamine solution with dropping funnel, stirring reaction spends the night then.Reaction solution under reduced pressure revolves dried, and column chromatography (elutriant is a methylene chloride-methanol, and volume ratio is 10: 1) purifying obtains the substituted chiral diamine ligands of various single alkylsulfonyls, and yield is 25-95%.
(formula XII)
With as above method; Adopt (S; S)-chiral diamine reacts with different SULPHURYL CHLORIDE; Can also prepare various (S, S)-single 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 the reaction formula of the single sulphonyl chiral diamine of preparation and used various (R, R)-particular chemical of chiral diamine and SULPHURYL CHLORIDE is suc as formula shown in the XII.
The general preparation method of the chiral metal catalyst that the asymmetric catalytic hydrogenation reaction of the interior N-alkyl imines of ring provided by the invention is used is following:
N-alkyl imines carries out in the method for asymmetric hydrogenation in the ring provided by the invention, and the chiral metal catalyst that is adopted generally prepares according to following two kinds of methods through single sulphonyl chiral diamine ligands and metal precursor (reaction formula of Preparation of Catalyst and used various metal precursor are suc as formula shown in the XIII):
Preparation method is added in (method one) acid: single sulphonyl chiral diamine ligands, metal precursor and KOH stirred 5 minutes in methylene dichloride earlier, added entry again, and the extraction separatory is neutral up to water, and organic phase is through CaH
2After the drying, decompression (for example: (R, R)-1) obtains a solid after revolving and desolventizing.With this solid and 2,2 '-dibenzyl phosphatase reaction obtains catalyzer after the 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).
(formula XIII)
(method two) metal-salt exchange process: single sulphonyl chiral diamine ligands and metal precursor are dissolved in the methylene dichloride; With the triethylamine is alkali; Reaction is 0.5 hour under the room temperature; Decompression (for example: (R obtains a solid after revolving and desolventizing; R)-2); 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 through 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)-the shaped metal catalyzer can use (S, S)-single sulphonyl-chiral diamine ligands and metal precursor be by as above two kinds of methods preparations.
The representative catalyzer of synthetic of the present invention (numbering respectively be (R, R)-1～(R, R)-15) structure is as follows:
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).Used four aryl boric acid potassium KBArF among the following embodiment
4In the structural formula that contains BArF, Ar is 3,5-two (trifluoromethyl) benzene.
In the reaction of the asymmetric catalytic hydrogenation of N-alkyl imines, the general preparation method of N-alkyl imines is shown in XIV in the various rings of reactant in the ring provided by the invention, and concrete experimental implementation is following:
Method 1: under nitrogen atmosphere, cyclic lactam (50.0mmol) is dissolved in toluene (100mL), adds trimethylchlorosilane (55.0mmol) and triethylamine (60.0mmol) then, 50 degree reacted 6 hours down.Be chilled to room temperature then, add sherwood oil (100mL), with the diatomite filtration under diminished pressure filtrating is revolved dried, underpressure distillation get final product the cyclic lactam protected of N-trimethylchlorosilane.Afterwards it is dissolved in 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, the dichloromethane extraction separatory, organic phase is revolved after with anhydrous sodium sulfate drying dried.Crude product is through underpressure distillation or column chromatography purification; Obtain N-alkyl imines in the 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, behind the terminal amino group ketone (50.0mmol) and formic acid (500mmol) mixing with the Boc protection, stirred 12 hours under the room temperature.After residue formic acid is removed in decompression; Crude product is through underpressure distillation or column chromatography purification; Obtain N-alkyl imines in the 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).
(formula XIV)
The asymmetric catalytic hydrogenation reaction method of N-alkyl imines in the ring provided by the invention is used for Chiral Amine in the synthetic ring as gordian technique, can be got by the reaction of one kettle way shown in the method for fractional steps shown in the formula XV or the formula XVI.
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; Again under the condition that chiral catalyst exists, carry out addition reaction with N-alkyl imines in the ring of hydrogen after to separation and purification, obtain the Chiral Amine product;
(formula XV)
Pot method comprises the following steps: according to the literature method (GDWilliams, RAPike, CEWade, M.Wills, "A? One-Pot? Process? For? The? Enantioselective? Synthesis? Of? Amines? Via? Reductive? Amination? under? Transfer? Hydrogenation? Conditions ", Org.Lett.2003, 5,4227) synthesis of various N-alkyl imide ring substrate, the reaction product was used without purification directly to the next step asymmetric hydrogenation reaction, the reaction system was added directly chiral catalysts and additives, with hydrogen on the ring N-alkyl crude imine addition reaction product obtained chiral amines;
(formula XVII) (formula XVI)
In the one kettle way, in the said formula XVII general structure, R is alkyl, cycloalkyl, aryl, contains substituent alkyl, contains substituent cycloalkyl or contain substituent aryl shown in the above-mentioned formula XVI; Among the said R, said substituting group all is selected from least a in fluorine, chlorine, bromine, nitro, methyl, methoxyl group, trifluoromethyl, hydroxyl and the kharophen; Said alkyl is preferably the alkyl that carbonatoms is 1-5; Said cycloalkyl is preferably cyclopentyl, cyclohexyl, suberyl or ring octyl group; Said aryl is preferably phenyl, naphthyl, thienyl, furyl or pyridyl, and said fragrant benzyl is preferably benzyl or naphthalene benzyl; In the one kettle way, n is 1,2 or 3 shown in the method for fractional steps shown in the formula XV or the formula XVI.
The screening of embodiment 1-9, additive and the optimization of additive amount
Asymmetric catalytic hydrogenation with 2-phenylpyrrole quinoline is a model reaction; Catalyzer (R, R)-3a with (R, R)-catalysis of 4f under; Carried out the screening of asymmetric catalysis additive and the optimization of additive amount, experimental design and the result of specific embodiment 1-9 see table 1.
The concrete operations of asymmetric catalytic hydrogenation reaction are following: the hydrogenation experiment is all carried out in autoclave.With mole dosage is that catalyzer, the reaction substrate 2-phenylpyrrole quinoline of 0.2mmol, the certain quantity of additive of reaction substrate 2-phenylpyrrole quinoline 1% is dissolved in the 1mL solvent, behind nitrogen replacement gas, charges into 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 the table 1.
After reaction is accomplished, stop to stir, reaction solution is removed used metal catalyst through silica gel column chromatography (elutriant is for by volume ratio being the mixed solution that 5: 95 triethylamines and sherwood oil are formed).The mensuration of reaction conversion ratio is directly to pass through nucleus magnetic resonance with the reaction solution before the purifying
1H NMR characterizes, and the enantiomeric excess of product (be the ee value, the absolute configuration of product is R) is that the product behind the purifying is measured through high pressure liquid chromatography (chirality AD-H post), and the result is as shown in table 1.
(formula XVIII)
The optimization of the screening of table 1, additive and addition consumption
Can find out through above experimental result: in as above reaction system,, can poisoning effect be arranged, make the transformation efficiency and the enantioselectivity of reaction all decrease catalyzer if there is benzylamine in the reactant; The reaction of the asymmetric catalytic hydrogenation that in dichloromethane solvent, carries out, (can reduce its poisoning effect) during the doping tert-Butyl dicarbonate outside with the benzylamine reaction, the transformation efficiency and the enantioselectivity of reaction all are 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 is near 100%, and the enantioselectivity of product reaches maximum, is 95%ee.
Embodiment 10-27, screening of catalyst
Asymmetric catalytic hydrogenation with 2-phenylpyrrole quinoline is a model reaction, has carried out screening of catalyst, catalyst system therefor be respectively (R, R)-3～(R, R)-15, experimental design and the result of specific embodiment 10-27 see table 2.
The concrete operations of asymmetric catalytic hydrogenation reaction are following: the hydrogenation experiment is all carried out in autoclave.With mole dosage is that catalyzer, 0.2mmol reaction substrate 2-phenylpyrrole quinoline and the 0.22mmol tert-Butyl dicarbonate of reaction substrate 2-phenylpyrrole quinoline 1% is dissolved in the 1mL methylene dichloride; Behind nitrogen replacement gas; Charge into 50atm hydrogen, 40 ℃ were reacted 10 hours.Stop to stir, reaction solution is removed metal catalyst through silica gel column chromatography (elutriant is for by volume ratio being the mixed solution that 5: 95 triethylamines and sherwood oil are formed).The mensuration of reaction conversion ratio is directly to pass through nucleus magnetic resonance with the reaction solution before the purifying
1H NMR characterizes, and the enantiomeric excess of product (be the ee value, the absolute configuration of product is R) is that the product behind the purifying is measured through high pressure liquid chromatography (chirality AD-H post), and the result is as shown in table 2.
(formula XIX)
Table 2, screening of catalyst
Can find out from above experimental result: the asymmetric catalytic hydrogenation model reaction with 2-phenylpyrrole quinoline, under listed catalyzer condition, the skeleton of catalyzer has very big influence to reactive activity and enantioselectivity; In all catalyzer, (R, R)-enantioselectivity of 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
Asymmetric catalytic hydrogenation with 2-phenylpyrrole quinoline is a model reaction, has carried out catalyst levels, hydrogen pressure, the optimization of temperature of reaction and the further optimization of reaction solvent, and experimental design and the result of specific embodiment 28-40 see table 3.
The concrete operations of asymmetric catalytic hydrogenation reaction are following: the hydrogenation experiment is all carried out in autoclave.With mole dosage is 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 the 1mL solvent; With nitrogen replacement several times behind the gas; Charge into the hydrogen of certain pressure, react certain hour at a certain temperature.
In this reaction, the kind of solvent for use, the pressure of hydrogen, temperature of reaction and reaction times all list in the table 3.
Stop to stir, reaction solution is removed metal catalyst through silica gel column chromatography (elutriant is for by volume ratio being the mixed solution that 5: 95 triethylamines and sherwood oil are formed).The mensuration of reaction conversion ratio is directly to pass through nucleus magnetic resonance with the reaction solution before the purifying
1H NMR characterizes, and the enantiomeric excess of product (be the ee value, the absolute configuration of product is R) is that the product behind the purifying is measured through high pressure liquid chromatography (chirality AD-H post), and the result is as shown in table 3.
(formula XX)
The optimization of table 3, catalyst levels, hydrogen pressure, temperature of reaction
Can find out from above experimental result: asymmetric catalytic hydrogenation model reaction with 2-phenylpyrrole quinoline; Optimal catalyst (the R that filters out with embodiment 10-27; R)-4f; Optimum additive tert-Butyl dicarbonate and optimum solvent (ethylene dichloride) are under the 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; Catalytic effect was best when temperature of reaction was 40 ℃; When S/C is 100 or 500; The transformation efficiency of 10 hours internal reactions is near 100%, and 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, the ring
With N-alkyl imines in the different rings is substrate, under optimized reaction conditions, carries out the asymmetric catalytic hydrogenation reaction, and the experimental design of specific embodiment 41-57 is following:
The hydrogenation experiment is all carried out in autoclave.With mole dosage is the catalyzer (R of N-alkyl imines 1mol% in the reaction substrate ring; R)-4f, 0.2mmol reaction substrate ring in the tert-Butyl dicarbonate of N-alkyl imines and 0.22mmol be dissolved in the ethylene dichloride of 1mL; Behind nitrogen replacement gas; Charge into 50atm hydrogen, 40 ℃ were reacted 10 hours.
In this reaction, N-alkyl imines is followed successively by 19a-p suc as formula shown in the XIX in the used reaction substrate ring, and corresponding embodiment 41-57 is specifically as shown in table 4 respectively.
Stop to stir, reaction solution is removed metal catalyst through silica gel column chromatography (elutriant is for by volume ratio being the mixed solution that 5: 95 triethylamines and sherwood oil are formed).The mensuration of reaction conversion ratio is directly to pass through nucleus magnetic resonance with the reaction solution before the purifying
1H NMR characterizes, and the enantiomeric excess of product (be the ee value, the absolute configuration of product is R) is that the product behind the purifying is measured through high pressure liquid chromatography (chirality OJ-H post or chirality AD-H post), and the result is as shown in table 4.
(formula XXI)
The applied research of N-alkyl imines asymmetric catalytic hydrogenation reaction substrate in table 4, the ring
Can find out from above experimental result: the asymmetric catalytic hydrogenation of N-alkyl imines reacts in ring; The catalytic condition of optimum (in ethylene dichloride, with (R, R)-4f is a catalyzer; Tert-Butyl dicarbonate is an additive; Hydrogen pressure is 50 normal atmosphere, and temperature of reaction is 40 ℃) under, in 10 hours; N-alkyl imines hydrogenation smoothly in the listed various ring; Productive rate reaches 90%-96%, and the enantiomeric excess of product (removes 20k:67%ee, 20o:53%) reaches 92-98%.
Chiral Amine in embodiment 58-74, the asymmetric reduction amination one kettle way preparation ring
In this reaction, used reaction substrate terminal amino group ketone is followed successively by 21a-p suc as formula shown in the XXII, and corresponding embodiment 58-73 is specifically as shown in table 5 respectively.
Under the effect of formic acid; Different terminal amino group ketone directly removes Boc protection base and dehydrating condensation generates N-alkyl imines (G.D.Williams in the 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), revolve unnecessary formic acid then; Crude product at the catalytic condition of optimum (in ethylene dichloride; With (R, R)-4f is a catalyzer, tert-Butyl dicarbonate is an additive; Hydrogen pressure is 50 normal atmosphere; Temperature of reaction is 40 ℃) under, carry out the asymmetric catalytic hydrogenation reaction, concrete operations are following:
The hydrogenation experiment is all carried out in autoclave.With mole dosage is the catalyzer (R of N-alkyl imines 1mol% in the reaction substrate ring; R)-4f, 0.2mmol reaction substrate ring in the tert-Butyl dicarbonate of N-alkyl imines and 0.22mmol be dissolved in the ethylene dichloride of 1mL; Behind nitrogen replacement gas; Charge into 50atm hydrogen, 40 ℃ were reacted 10 hours.
Stop to stir, reaction solution is removed metal catalyst through silica gel column chromatography (elutriant is for by volume ratio being the mixed solution that 5: 95 triethylamines and sherwood oil are formed).The mensuration of reaction conversion ratio is directly to pass through nucleus magnetic resonance with the reaction solution before the purifying
1H NMR characterizes, and the enantiomeric excess of product (be the ee value, the absolute configuration of product is R) is that the product behind the purifying is measured through high pressure liquid chromatography (chirality OJ-H post or chirality AD-H post), and the result is as shown in table 5.
(formula XXII)
The applied research of table 5, one kettle way asymmetric reduction amination reaction substrate
Can find out from above experimental result: the asymmetric reduction amination reaction; Under the effect of formic acid, directly remove earlier Boc protection base and 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); Revolve unnecessary formic acid then, at the catalytic condition of optimum (in ethylene dichloride, with (R; R)-4f is a catalyzer; Tert-Butyl dicarbonate is an additive, and hydrogen pressure is 50 normal atmosphere, and 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 who obtains under the enantiomeric excess fundamental sum hydrogenation conditions of product is consistent, and having only has decline individually slightly.
The foregoing description prepare Chiral Amine product 20a-q in the 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:
[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).
[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).
[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).
[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).
[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).
[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).
[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).
[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).
[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).
[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).
[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).
[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).
[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).
[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).
[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 catalyzer that uses in the above embodiment of the present invention (R, R)-the concrete preparation process of 4g-i is following:
(R，R)-4e：
Under nitrogen atmosphere, (R, R)-single 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) stirs in methylene dichloride after 5 minutes, adds and adds entry again after 5 minutes, and the extraction separatory is neutrality up to water, and organic phase is through CaH
2The decompression of dry back is revolved dried, obtains solid (512mg).(292mg 0.5mmol) processes methylene dichloride (30mL) solution, under the nitrogen protection, with HNTf with this solid
2(140mg, methylene dichloride 0.5mmol) (10mL) solution slowly is added drop-wise in this solution.After adding, continue to stir 30 minutes, reaction solution is revolved dried, obtain the red solid catalyzer (R, R)-4e (406mg, yield 94%).
(R，R)-4g：
According to (R, R)-preparation method of 4e, wherein with 2, (124mg 0.5mmol) replaces HNTf to 2 '-biphenyl phosphoric acid
2, with reaction solution revolve dried obtain the red solid catalyzer (R, R)-4g (437mg, yield 95%).
(R，R)-4h：
According to (R, R)-preparation method of 4e, wherein with (R)-2, (174mg 0.2mmol) replaces HNTf to 2 '-biphenyl phosphoric acid
2, with reaction solution revolve dried obtain the red solid catalyzer (R, R)-4h (452mg, yield 95%).
(R，R)-4i：
According to (R, R)-preparation method of 4e, wherein with (S)-2, (174mg 0.2mmol) replaces HNTf to 2 '-biphenyl phosphoric acid
2, with reaction solution revolve dried obtain the red solid catalyzer (R, R)-4i (457mg, yield 96%).
According to the general preparation method two of aforementioned catalyzer, the catalyzer that uses in the above embodiment of the present invention (R, R)-3a, (R, R)-4a-f, (R, R)-7-15a, (R, R)-5, (R, concrete preparation process R)-6 is following:
(R，R)-3a：
Under nitrogen atmosphere, in the two-mouth bottle of 25ml, add [RuCl successively
2(p-cymene)]
2(172mg, 0.25mmol), (R; R)-single tolysulfonyl-1,2-diphenyl ethylene diamine part (R, R)-TsDPEN (184mg; 0.5mmol); Methylene dichloride (20mL), triethylamine TEA (1mL) stirred 1 hour under the room temperature; Washing; Anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains red solid 313mg with normal hexane and chloroform recrystallization.This red solid 139mg (0.2mmol) is dissolved in the methylene dichloride (20mL), adds silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), stirred 0.5 hour under the room temperature; Remove by filter deposition 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 [RuCl successively
2(p-cymene)]
2(172mg, 0.25mmol), (R, R)-MsDPEN (145mg; 0.5mmol), methylene dichloride (20mL), triethylamine TEA (1mL) stirred 1 hour under the room temperature; Washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains red solid 275mg with normal hexane and chloroform recrystallization.This red solid 124mg (0.2mmol) is dissolved in the methylene dichloride (20mL), adds silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), stirred 0.5 hour under the room temperature; Remove by filter deposition and obtain yellow solid; Be catalyzer (R, R)-4a (145mg, yield 99%).
(R，R)-4b：
According to (R, R)-preparation method of 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 (R, R)-preparation method of 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 (R, R)-preparation method of 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 (R, R)-preparation method of 4a, wherein with four aryl boric acid potassium KBArF
4(181mg, 0.2mmol, said KBArF
4In, Ar is 3,5-two (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 [RuCl successively
2(benzene)]
2(144mg, 0.25mmol), (R, R)-TsDPEN (184mg; 0.5mmol), methylene dichloride (20mL), triethylamine TEA (1mL) stirred 1 hour under the room temperature; Washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains red solid 289mg with normal hexane and chloroform recrystallization.This red solid 128mg (0.2mmol) is dissolved in the methylene dichloride (20mL), adds silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), stirred 0.5 hour under the room temperature; Remove by filter deposition 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 [RuCl successively
2(hexamethylbenzene)]
2(186mg, 0.25mmol), (R, R)-TsDPEN (184mg; 0.5mmol), methylene dichloride (20mL), triethylamine TEA (1mL) stirred 1 hour under the room temperature; Washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains red solid 323mg with normal hexane and chloroform recrystallization.This red solid 145mg (0.2mmol) is dissolved in the methylene dichloride (20mL), adds silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), stirred 0.5 hour under the room temperature; Remove by filter deposition 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 [RuCl successively
2(p-cymene)]
2(172mg, 0.25mmol), (R; R)-single benzene sulfonyl-1; 2-diphenyl ethylene diamine part (177mg, 0.5mmol), methylene dichloride (20mL); Triethylamine TEA (1mL); Stirred 1 hour washing, anhydrous sodium sulfate drying under the room temperature; Removal of solvent under reduced pressure obtains red solid 307mg with normal hexane and chloroform recrystallization.This red solid 136mg (0.2mmol) is dissolved in the methylene dichloride (20mL), adds silver trifluoromethanesulfonate AgOTf 52mg (0.2mm0l), stirred 0.5 hour under the room temperature; Remove by filter deposition 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 [RuCl successively
2(p-cymene)]
2(172mg; 0.25mmol), (R, R)-single tolysulfonyl-cyclohexanediamine part (134mg; 0.5mmol); Methylene dichloride (20mL), triethylamine TEA (1mL) stirred 1 hour under the room temperature; Washing; Anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains red solid 251mg with normal hexane and chloroform recrystallization.This red solid 112mg (0.2mmol) is dissolved in the methylene dichloride (20mL), adds silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), stirred 0.5 hour under the room temperature; Remove by filter deposition 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 [RuCl successively
2(p-cymene)]
2(172mg, 0.25mmol), (R, R)-single methylsulfonyl-cyclohexanediamine part (196mg; 0.5mmol), methylene dichloride (20mL), triethylamine TEA (1mL) stirred 1 hour under the room temperature; Washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains red solid 236mg with normal hexane and chloroform recrystallization.This red solid 104mg (0.2mmol) is dissolved in the methylene dichloride (20mL), adds silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), stirred 0.5 hour under the room temperature; Remove by filter deposition 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 [RuCl successively
2(p-cymene)]
2(172mg, 0.25mmol), (R; R)-single fluoroform sulphonyl-1; 2-diphenyl ethylene diamine part (172mg, 0.5mmol), methylene dichloride (20mL); Triethylamine TEA (1mL); Stirred 1 hour washing, anhydrous sodium sulfate drying under the room temperature; Removal of solvent under reduced pressure obtains red solid 301mg with normal hexane and chloroform recrystallization.This red solid 135mg (0.2mmol) is dissolved in the methylene dichloride (20mL), adds silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), stirred 0.5 hour under the room temperature; Remove by filter deposition 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 [RuCl successively
2(p-cymene)]
2(172mg, 0.25mmol), (R; R)-and list-2,4,6-tri isopropyl benzenesulfonyl-1; 2-diphenyl ethylene diamine part (240mg, 0.5mmol), methylene dichloride (20mL); Triethylamine TEA (1mL); Stirred 1 hour washing, anhydrous sodium sulfate drying under the room temperature; Removal of solvent under reduced pressure obtains red solid 365mg with normal hexane and chloroform recrystallization.This red solid 162mg (0.2mmol) is dissolved in the methylene dichloride (20mL), adds silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), stirred 0.5 hour under the room temperature; Remove by filter deposition 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 [RuCl successively
2(p-cymene)]
2(172mg, 0.25mmol), (R; R)-single to trifluoromethyl benzene sulfonyl-1; 2-diphenyl ethylene diamine part (210mg, 0.5mmol), methylene dichloride (20mL); Triethylamine TEA (1mL); Stirred 1 hour washing, anhydrous sodium sulfate drying under the room temperature; Removal of solvent under reduced pressure obtains red solid 336mg with normal hexane and chloroform recrystallization.This red solid 150mg (0.2mmol) is dissolved in the methylene dichloride (20mL), adds silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), stirred 0.5 hour under the room temperature; Remove by filter deposition 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 [RuCl successively
2(p-cymene)]
2(172mg, 0.25mmol), (R; R)-list-1-naphthalene sulfonyl-1; 2-diphenyl ethylene diamine part (202mg, 0.5mmol), methylene dichloride (20mL); Triethylamine TEA (1mL); Stirred 1 hour washing, anhydrous sodium sulfate drying under the room temperature; Removal of solvent under reduced pressure obtains red solid 330mg with normal hexane and chloroform recrystallization.This red solid 146mg (0.2mmol) is dissolved in the methylene dichloride (20mL), adds silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), stirred 0.5 hour under the room temperature; Remove by filter deposition 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 [IrCl successively
2Cp*]
2(211mg, 0.25mmol), (R, R)-TsDPEN (184mg; 0.5mmol), methylene dichloride (20mL), triethylamine TEA (1mL) stirred 1 hour under the room temperature; Washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains red solid 350mg with normal hexane and chloroform recrystallization.This red solid 155mg (0.2mmol) is dissolved in the methylene dichloride (20mL), adds silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), stirred 0.5 hour under the room temperature; Remove by filter deposition 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 [RhCl successively
2Cp*]
2(166mg, 0.25mmol), (R, R)-TsDPEN (184mg; 0.5mmol), methylene dichloride (20mL), triethylamine TEA (1mL) stirred 1 hour under the room temperature; Washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains red solid 308mg with normal hexane and chloroform recrystallization.This red solid 137mg (0.2mmol) is dissolved in the methylene dichloride (20mL), adds silver trifluoromethanesulfonate AgOTf 52mg (0.2mmol), stirred 0.5 hour under the room temperature; Remove by filter deposition and obtain yellow solid; Be catalyzer (R, R)-6a (153mg, yield 96%).
Claims (10)
1. the method for an asymmetric catalytic hydrogenation reaction comprises the steps: under the condition that chiral catalyst shown in the formula II exists, and with hydrogen N-alkyl imines in the ring shown in the formula III is carried out addition reaction, obtains the Chiral Amine product;
(formula II)
In the said formula II general structure, M is metal Ru Ru, rhodium Rh or iridium Ir;
Said L
1* for containing the substituent chiral diamine L of single sulphonyl
1With the reacted chiral diamine ligands of metal precursor; R ' in the said chiral diamine ligands for the total number of carbon atoms be 1-10 alkyl, trifluoromethyl, phenyl, naphthyl, contain substituent phenyl or contain substituent naphthyl; Saidly contain substituent phenyl and contain in the substituent naphthyl, said substituting group is selected from least a in alkyl, methoxyl group, fluorine, chlorine, bromine, nitro and the trifluoromethyl that the total number of carbon atoms is 1-10;
Said R " is selected from least a in the alkyl that H, benzyl and the total number of carbon atoms are 1-10;
Said L
2Be η
6-benzene dentate, η
5-luxuriant dentate, contain substituent η
6-benzene dentate or contain substituent η
5-luxuriant dentate saidly contains substituent η
6-benzene dentate with contain substituent η
5In-luxuriant the dentate, said substituting group is selected from least a in the alkyl that the total number of carbon atoms is 1-10;
Said X is C1
-, Br
-, I
-, OAc
-, NO
3 -, HSO
4 -, H
2PO
4 -, [OTf]
-, [BF
4]
-, [SbF
6]
-, [PF
6]
-, [NTf
2]
-, four aryl boron anions or dibenzyl diphenol deutero-phosphoric acid negative ion;
(formula III)
In the said formula III general structure; R is alkyl, cycloalkyl, aryl, fragrant benzyl, contains substituent alkyl, contains substituent cycloalkyl or contain substituent aryl; Wherein, Saidly contain substituent cycloalkyl and contain in the substituent aryl, said substituting group all is selected from least a in fluorine, chlorine, bromine, nitro, methyl, methoxyl group, trifluoromethyl, hydroxyl and the kharophen;
N is 1,2 or 3.
2. method according to claim 1; It is characterized in that: in the said formula II general structure; Said contain the substituent chiral diamine L1 of single sulphonyl for (R, R)-the single sulphonyl-1 of N-, 2-diaryl quadrol; (S; S)-the single sulphonyl-1 of N-; 2-diaryl quadrol; (R, R)-the single sulphonyl-1 of N-, the 2-cyclohexanediamine; (S; S)-the single sulphonyl-1 of N-; The 2-cyclohexanediamine; (R, R)-the single sulphonyl of N--1-substituted azole-3, the 4-diamines; (S; S)-the single sulphonyl of N--1-substituted azole-3; The 4-diamines; (R)-and the single sulphonyl-2 of N-, 2 '-diaminostilbene, 1 '-dinaphthalene or (the S)-single sulphonyl-2 of N-; 2 '-diaminostilbene, 1 '-dinaphthalene;
Said L
2Be η
6-benzene dentate, η
6-1,4-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 or η
5-luxuriant dentate or η
5The luxuriant dentate of-pentamethyl-;
In the said four aryl boron anions, said aryl is phenyl or 3,5-two (trifluoromethyl) phenyl;
In the said formula III general structure; Said alkyl is that the total number of carbon atoms is the alkyl of 1-5; Said cycloalkyl is cyclopentyl, cyclohexyl, suberyl or ring octyl group, and said aryl is phenyl, naphthyl, thienyl, furyl or pyridyl, and said fragrant benzyl is benzyl or naphthalene benzyl.
3. method according to claim 1 and 2; It is characterized in that: chiral catalyst shown in the said formula II is by (R shown in the formula IXa; R)-title complex of the single sulphonyl of N--diaryl quadrol and transition metal iridium, ruthenium or rhodium formation or formula IXb shown in by (S; S)-title complex of the single sulphonyl of N--diaryl quadrol and transition metal iridium, ruthenium or rhodium formation
(formula IXa) (formula IXb)
In said formula IXa and the IXb general structure, M is metal Ru Ru, rhodium Rh or iridium Ir;
Ar is phenyl, to the substituted phenyl of methoxyl group 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
6-1,4-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]
-, [BF
4]
-, [SbF
6]
-, [PF
6]
-, [NTf
2]
-, four aryl boron anions or dibenzyl diphenol deutero-phosphoric acid negative ion; In the said four aryl boron anions, said aryl is phenyl or 3,5-two (trifluoromethyl) phenyl; Said dibenzyl diphenol deutero-phosphoric acid negative ion is 2; 2 '-biphenyl phosphoric acid negative ion, (R)-2,2 '-naphthyl naphthalene phosphoric acid negative ion, (S)-2,2 '-naphthyl naphthalene phosphoric acid negative ion, (R)-8H-2; 2 '-naphthyl naphthalene phosphoric acid negative ion or (S)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion.
4. according to the arbitrary described method of claim 1-3, it is characterized in that: the method for said asymmetric catalytic hydrogenation reaction also comprises the steps: before said addition reaction is carried out, in reaction system, to add additive.
5. method according to claim 4 is characterized in that: said additive is selected from a kind of in Ue-5908 and the tert-Butyl dicarbonate, preferred tert-Butyl dicarbonate.
6. according to claim 4 or 5 described methods, it is characterized in that: the molar ratio of N-alkyl imines is 0: 1～5: 1 in said additive and the said ring, and preferred 1: 1～2: 1, the mole dosage that feeds intake of said additive was not 0.
7. according to the arbitrary described method of claim 1-6, it is characterized in that: said addition reaction is under the condition that organic solvent exists, to carry out.
8. method according to claim 7 is characterized in that: said organic solvent is single organic solvent or mixed organic solvents; Wherein, said single organic solvent is a methylene dichloride, 1, and 2-ethylene dichloride, chloroform, ethyl acetate, tetrahydrofuran (THF), benzene,toluene,xylene, chlorinated benzene, ether, dioxane, acetone or the total number of carbon atoms are any one in the monohydroxy-alcohol of 1-10; Said mixed organic solvents is at least a composition the in the monohydroxy-alcohol of 1-10 by alkyl chloride based solvent and the total number of carbon atoms, and wherein, said alkyl chloride based solvent is selected from methylene dichloride, 1, at least a in 2-ethylene dichloride and the chloroform.
9. according to the arbitrary described method of claim 1-8, it is characterized in that: the molar ratio of N-alkyl imines and said chiral catalyst is 10-2000 in the said ring: 1, and preferred 50-1000: 1.
10. according to the arbitrary described method of claim 1-9, it is characterized in that: in the said addition reaction step, temperature is-10-100 ℃, preferred 0-60 ℃, pressure is 1-100atm, preferred 5-60atm, the time is 1-72 hour, preferred 6-24 hour.
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| CN111233829A (en) * | 2019-12-27 | 2020-06-05 | 深圳黑尔格科技有限公司 | Preparation method of nicotine with optical activity |
| CN111825508A (en) * | 2019-04-15 | 2020-10-27 | 中国科学院化学研究所 | Preparation method of dihydro 9-phenanthrene amine compound and chiral product prepared by same |
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| CN111825508A (en) * | 2019-04-15 | 2020-10-27 | 中国科学院化学研究所 | Preparation method of dihydro 9-phenanthrene amine compound and chiral product prepared by same |
| CN111825508B (en) * | 2019-04-15 | 2021-11-16 | 中国科学院化学研究所 | Preparation method of dihydro 9-phenanthrene amine compound and chiral product prepared by same |
| CN111233829A (en) * | 2019-12-27 | 2020-06-05 | 深圳黑尔格科技有限公司 | Preparation method of nicotine with optical activity |
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