CN102050688A - Asymmetric catalytic hydrogenation method for ketone-derived N-alkylimine - Google Patents

Asymmetric catalytic hydrogenation method for ketone-derived N-alkylimine Download PDF

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CN102050688A
CN102050688A CN2010105773012A CN201010577301A CN102050688A CN 102050688 A CN102050688 A CN 102050688A CN 2010105773012 A CN2010105773012 A CN 2010105773012A CN 201010577301 A CN201010577301 A CN 201010577301A CN 102050688 A CN102050688 A CN 102050688A
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phosphoric acid
naphthyl
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范青华
陈飞
何艳梅
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Abstract

The invention discloses a method for performing the asymmetric catalytic hydrogenation of ketone-derived N-alkylimine. In the method disclosed by the invention, the catalytic hydrogenation of the ketone-derived N-alkylimine is performed in the presence of a chiral catalyst formed by a chiral diamine ligand and a transitional metal to obtain a chiral amine product with high yield and high enantioselectivity. The enantiomeric excess of a chiral amine product formed by the hydrogenation of an acyclic N-alkylimine substrate may reach 98 percent ee; and the enantiomeric excess of a chiral amine product formed by the hydrogenation of an exocyclic N-alkylimine substrate may reach over 99 percent ee. The method disclosed by the invention realizes the asymmetric catalytic hydrogenation of ketone-derived N-alkylimine with high enantioselectivity, and the obtained chiral amine product is an important medicinal and material intermediate and has a bright actual application prospect.

Description

A kind of asymmetric catalytic hydrogenation method of ketone deutero-N-alkyl imines
Technical field
The present invention relates to the method for the asymmetric catalytic hydrogenation reaction of imine compound, particularly relate to a kind of asymmetric catalytic hydrogenation method of ketone deutero-N-alkyl imines.
Background technology
Asymmetric efficient the synthesizing of high enantioselectivity chipal compounds, in chemical industry, agricultural, herding and each field of medicine, be subjected to 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, " Chiralchemistry ", 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 ChiralPhosphorus 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 be subjected to 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).
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).All contain the Chiral Amine primitive in the skeleton structure of many bioactive compoundss and chiral drug, for example: among the formula I (1S, 4S)-sertraline (W.M.Welch, A.R.Kraska, R.Sarges, B.K.Koe, " Nontricyclic antidepressant agents dedrivedfrom cis-and trans-1-amino-4-aryltetralins ", J.Med.Chem.1984,27,1508) be a kind of effective antidepressant drug, Compound C inacalcet (O.R.Thiel, C.Bernard, W.Tormos, A.Brewin, S.Hirotani, K.Murakami, K.Saito, R.D.Larsen, M.J.Martinelli, P.J.Reider, " Practical synthesis of the calcimimetic agent, cinacalcet ", Tetrahedron Lett.2008,49,13) and NPS-586 (A.Kessler, H.Faure, C.Petrel, D.Rognan, M.C é sario, M.Ruat, P.Dauban, R.H.Dodd, " N 1-Benzoyl-N 2-[1-(1-naphthyl) ethyl]-trans-1,2-diaminocyclohexanes:Development of4-Chlorophenylcarboxamide (Calhex 231) as a New Calcium Sensing Receptor Ligand Demonstrating PotentCalcilytic Activity "; J.Med.Chem.2006; 49; 5119) all can regulate the content of blood calcium, be used for the treatment of osteoporosis.Though the reaction of the asymmetric catalytic hydrogenation of imines has obtained extensive, deep research, and be acknowledged as the best approach of synthesizing optical homochiral aminated compounds, but compare with the asymmetric catalytic hydrogenation of prochiral olefin and ketone compounds, imine compound because of the existence of its cis-trans-isomer, relatively poor chemical stability and amine impurity and product to possible the poisoning effect that catalyzer exists, make the asymmetric catalytic hydrogenation of this type of prochirality compound react and also lack systematic research.In the report of the asymmetric catalytic hydrogenation reaction of existing imines class substrate, the asymmetric hydrogenation of ketone deutero-N-alkyl imines especially has only the chiral metal catalyst of a few transition metals and chiral ligand formation can this type of reaction of catalysis.Wherein employed chiral ligand is most of for containing the phosphine chiral ligand, and the enantioselectivity and the also relatively low (C.N.Thomas of catalytic efficiency of the reaction of imines asymmetric catalytic hydrogenation, E.-S.Mohamed, " Chiral Amine Synthesis-Recent Developments and Trends for Enamide Reduction; ReductiveAmination, and Imine Reduction ", Adv.Synth.Catal.2010,352,753).Recently, Chinese Academy of Sciences Shanghai organic fourth Kui Ling group with iridium metals chirality P-N title complex as catalyzer, realized the asymmetric catalytic hydrogenation of the high enantioselectivity of a series of ketone deutero-N-alkyl imines, the enantiomeric excess of 13 kinds of N-alkyl hydrogenation of imines products is all between 89%-98%, be the highest (Z.Han in the bibliographical information so far, Z.Wang, X.Zhang, K.Ding, " Spiro[4,4]-1; 6-nonadiene-Based Phosphine-Oxazoline Ligands for Iridium-CatalyzedEnantioselective Hydrogenation of Ketimines ", Angew.Chem.Int.Ed.2009,48,5345).The imines asymmetric catalytic hydrogenation has been successfully applied to large-scale industrial production, wherein, the most successful industrialization example is suitability for industrialized production (the H-U Blaser of chirality weedicide (S)-metolachlor of successfully developing of Syngenta company, " The Chiral Switch of (S)-Metolachlor:A Personal Account of anIndustrial 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)-levofloxacin) and treatment Alzheimer's disease medicine (S)-18986 by the asymmetric catalytic hydrogenation gordian technique of imines respectively.
In the research of asymmetric catalytic hydrogenation, except that chiral phosphine ligand, non-phosphine chiral ligand (as: chirality amine part and chiral beta-alkamine part) also is the crucial part of a class, and than chiral phosphine ligand stability high, synthetic simple, price is relatively cheap.At present; the Chiral Amine part; especially chiral diamine ligands has been widely used in the multiple asymmetric reaction, such as protonated, the conjugate addition reaction of the acidylate of: transfer hydrogenation, Mukaiyama aldol reaction, Michael addition reaction, the reaction of Sharpless bishydroxy, alcohol, enol negative ion,
Epoxidation Reaction of Alkenes etc. (J-C Kizirian, " Chiral Tertiary Diamines in Asymmetric Synthesis ", Chem.Rev.2008,108,140).Though chiral diamine ligands and transition metal (such as: ruthenium, rhodium and iridium) catalyzer that forms has been widely used in the transfer hydrogenation of ketone and imine compound (transfer hydrogenation has been the reduction reaction that adopts the hydrogen source beyond the hydrogen to carry out, hydrogen source comprises: Virahol, formic acid-triethylamine azeotrope, sodium formiate etc.), and become one of high efficiency method (the S.Gladiali and E.Alberico of synthesis of chiral secondary alcohol and Chiral Amine, " Asymmetric transfer hydrogenation:chiral ligands and applications ", Chem.Soc.Rev.2006,35,226), but the application in asymmetric catalytic hydrogenation of chiral diamine ligands and chiral metal catalyst thereof only has several example reports, comprising quinoline substrate (H.Zhou, Z.Li, Z.Wang, T.Wang, L.Xu, Y.He, Q-H Fan, J.Pan, L.Gu, A.S.C.Chan, " Hydrogenation of quinolines usinga recyclable phosphine-free chiral cationic ruthenium catalyst:Enhancement of catalyst stability and selectivity inan ionic liquid ", Angew.Chem.Int.Ed.2008,47,8464; Z-W Li, T-L Wang, Y-M He, Z-J Wang, Q-H Fan, J.Pan, L-J Xu, " Air-Stable and Phosphine-Free Iridium Catalysts for Highly Enantioselective Hydrogenation ofQuinoline Derivatives ", Org.Lett.2008,10,5265; Z-J Wang, H-F Zhou, T-L Wang, Y-M He, Q-H Fan, " Highlyenantioselective hydrogenation of quinolines under solvent-free or highly concentrated conditions ", Green Chem.2009,11,767), imines (C.Li, J.Xiao in the ring, " Asymmetric Hydrogenation of Cyclic Imines with an Ionic Cp*Rh (III) Catalyst ", J.Am.Chem.Soc.2008,130,13208), acyclic N-aryl imine (C.Li, C.Wang, B.Villa-Marcos, J.Xiao, " Chiral Counteranion-Aided Asymmetric Hydrogenation of Acyclic Imines ", J.Am.Chem.Soc.2008,130,14450) asymmetric catalytic hydrogenation, and the asymmetric hydrogenation of the catalytic ketone deutero-of chiral diamine metal complexes acyclic N-alkyl imines and the outer N-alkyl imines of ring also rarely has report.
Ikariya groups in 2009 have reported the asymmetric catalytic hydrogenation reaction (S.Shirai of the catalytic aryl ketones deutero-of unique one routine chiral diamine metal complexes acyclic N-alkyl imines, H.Nara, Y.Kayaki, T.Ikariya, " Remarkable Positive Effect of Silver Salts onAsymmetric Hydrogenation of Acyclic Imines with Cp*Ir Complexes Bearing Chiral N-Sulfonylated DiamineLigands ", Organometallics 2009,28,802).In this piece article, the asymmetric catalytic hydrogenation reaction of aromatic ketone deutero-acyclic N-alkyl imines only has been discussed, do not comprise alkyl ketone deutero-acyclic N-alkyl imines class substrate; And the enantioselectivity of the asymmetric catalytic hydrogenation of aromatic ketone deutero-acyclic N-alkyl imines reaction is lower, and the enantiomeric excess of product only is 35%-72%, does not reach industrialization demands far away.
Summary of the invention
The purpose of this invention is to provide the method that a kind of ketone deutero-N-alkyl imines carries out asymmetric hydrogenation.
Ketone deutero-N-alkyl imines provided by the invention carries out the method for asymmetric catalytic hydrogenation reaction, comprises the steps: with hydrogen ketone deutero-N-alkyl imines to be carried out addition reaction under the condition that chiral catalyst exists, and obtains the Chiral Amine product; It is characterized in that: described chiral catalyst is a compound shown in the formula III general structure;
Figure BSA00000376525600031
In the described formula III general structure, M is metal Ru Ru, rhodium Rh or iridium Ir;
Described L 1 *(amido that alkylsulfonyl replaces sloughs hydrogen and metal forms chemical bond in order to contain the reaction of substituent chiral diamine L1 of single sulphonyl and metal precursor, another amido and metal form coordinate bond) after the chiral diamine ligands structure, R ' in described single sulphonyl substituting group is the alkyl of 1-10 for carbonatoms, trifluoromethyl, phenyl, naphthyl, contain substituent phenyl or contain substituent naphthyl, the described substituent phenyl and containing in the substituent naphthyl of containing, described substituting group is selected from the alkyl that carbonatoms is 1-10, methoxyl group, fluorine, chlorine, bromine, at least a in nitro and the trifluoromethyl;
Described R " is selected from least a in the alkyl that H, benzyl and carbonatoms are 1-10;
Described L 2Be η 6-benzene dentate, η 5-luxuriant dentate, contain substituent η 6-benzene dentate or contain substituent η 5-luxuriant dentate describedly contains substituent η 6-benzene dentate and contain substituent η 5In-luxuriant the dentate, described substituting group all is selected from least a in the alkyl that carbonatoms 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 formula IX shown in 2,2 '-dibenzyl phosphoric acid negative ion;
Figure BSA00000376525600032
Among the described formula IX, L is 2,2 '-xenyl, contain substituent 2,2 '-xenyl, 2,2 '-di-naphthyl, contain substituent 2,2 '-di-naphthyl, 8H-2,2 '-di-naphthyl or contain substituent 8H-2,2 '-di-naphthyl; Describedly contain substituent 2,2 '-xenyl, contain substituent 2,2 '-di-naphthyl and contain substituent 8H-2, in 2 '-di-naphthyl, described substituting group all is selected from the alkyl that carbonatoms is 1-10, carbonatoms is the alkoxyl group of 1-10, aryl, contain substituent carbonatoms and be the alkyl of 1-10 and contain at least a in the substituent aryl, described contain substituent carbonatoms be 1-10 alkyl and contain in the substituent aryl, described substituting group all is selected from methyl, sec.-propyl, the tertiary butyl, fluorine, chlorine, methoxyl group, trifluoromethyl, at least a in hydroxyl and the kharophen.
Figure BSA00000376525600041
Among the above-mentioned preparation method, the described 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);
Described 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-;
Chiral catalyst shown in the described formula III is preferably shown in the formula VIIIa by (R, R)-title complex that the single sulphonyl of N--diaryl quadrol and transition metal iridium, ruthenium or rhodium form or formula VIIIb shown in by (S, S)-title complex of the single sulphonyl of N--diaryl quadrol and transition metal iridium, ruthenium or rhodium formation;
In described formula VIIIa and the VIIIb general structure, M is metal Ru Ru, rhodium Rh or iridium Ir;
The phenyl that Ar is phenyl, replace 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] -Shown in (two (fluoroform sulphonyl) imines negative ion), four aryl boron anions or the formula IX 2,2 '-dibenzyl phosphoric acid negative ion; In the described four aryl boron anions, described aryl is phenyl or 3,5-two (trifluoromethyl) phenyl;
Shown in the described formula IX 2,2 '-dibenzyl phosphoric acid negative ion is preferably (R)-2,2 '-naphthyl naphthalene phosphoric acid negative ion (formula IXc), (S)-2,2 '-naphthyl naphthalene phosphoric acid negative ion (formula IXd), raceme (±)-2,2 '-naphthyl naphthalene phosphoric acid negative ion, contain substituent (R)-2,2 '-naphthyl naphthalene phosphoric acid negative ion (formula IXe), contain substituent (S)-2,2 '-naphthyl naphthalene phosphoric acid negative ion (formula IXf), contain substituent raceme (±)-2,2 '-naphthyl naphthalene phosphoric acid negative ion, (R)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion (formula IXg), (S)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion (formula IXh), raceme (±)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion, contain substituent (R)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion (formula IXi), contain substituent (S)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion (formula IXj), contain substituent raceme (±)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion, 2,2 '-biphenyl phosphoric acid negative ion (formula IXa) or contain substituent 2,2 '-biphenyl phosphoric acid negative ion (formula IXb), described substituting group is selected from methyl, sec.-propyl, the tertiary butyl, methoxyl group, trifluoromethyl, phenyl and contain substituent phenyl, naphthyl and contain at least a in the substituent naphthyl, the described substituting group that contains substituent phenyl and contain in the substituent naphthyl all is selected from methyl, sec.-propyl, the tertiary butyl, fluorine, chlorine, methoxyl group, trifluoromethyl, hydroxyl, kharophen, phenyl, 3,5-two (trifluoromethyl) phenyl and 3, at least a in 5-two (sec.-propyl) phenyl.
Figure BSA00000376525600051
Wherein, described 2,2 '-dibenzyl phosphoric acid negative ion most preferably is 2,2 '-biphenyl phosphoric acid negative ion (formula IXa) or 3,3 '-position contains substituent 2,2 '-biphenyl phosphoric acid negative ion (formula IXb), (R)-2,2 '-naphthyl naphthalene phosphoric acid negative ion (formula IXc), (S)-2,2 '-naphthyl naphthalene phosphoric acid negative ion (formula IXd), 3, substituent (R)-2 are contained in 3 '-position, 2 '-naphthyl naphthalene phosphoric acid negative ion (formula IXe), 3, substituent (S)-2 are contained in 3 '-position, 2 '-naphthyl naphthalene phosphoric acid negative ion (formula IXf), (R)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion (formula IXg), (S)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion (formula IXh), 3, substituent (R)-8H-2 is contained in 3 '-position, 2 '-naphthyl naphthalene phosphoric acid negative ion (formula IXi), 3, substituent (S)-8H-2 is contained in 3 '-position, 2 '-naphthyl naphthalene phosphoric acid negative ion (formula IXj), described substituting group is selected from phenyl, naphthyl, the phenyl that alkyl replaces, the naphthyl that alkyl replaces, at least a in the naphthyl that phenyl that methoxyl group replaces and methoxyl group replace, described alkyl substituent most preferably is methyl, the sec.-propyl or the tertiary butyl.
Described ketone deutero-N-alkyl imines is the outer N-alkyl imines of ring shown in alkyl imines of acyclic N-shown in the formula X or the formula XI;
Figure BSA00000376525600052
In the described formula X general structure, R 1For alkyl, cycloalkyl, aryl, contain substituent alkyl, contain substituent cycloalkyl or contain substituent aryl, R 2For alkyl, cycloalkyl, fragrant benzyl, contain substituent alkyl, contain substituent cycloalkyl or contain substituent fragrant benzyl, R 3For alkyl or contain substituent alkyl; Described R 1, R 2And R 3In, described substituting group all is selected from least a in fluorine, chlorine, bromine, nitro, methyl, methoxyl group, trifluoromethyl, hydroxyl and the kharophen; Described alkyl is preferably the alkyl that carbonatoms is 1-5, and described cycloalkyl is preferably cyclopentyl, cyclohexyl, suberyl or ring octyl group, and described aryl is preferably phenyl, naphthyl, thienyl or furyl, and described fragrant benzyl is preferably benzyl or naphthalene benzyl;
Figure BSA00000376525600053
In the described formula XI general structure, R is alkyl, cycloalkyl, fragrant benzyl, contains substituent alkyl, contains substituent cycloalkyl or contain substituent fragrant benzyl, and described substituting group all is selected from least a in fluorine, chlorine, bromine, nitro, methyl, methoxyl group, trifluoromethyl, hydroxyl and the kharophen; The preferred carbonatoms of described alkyl is the alkyl of 1-5, and described cycloalkyl is preferably cyclopentyl, cyclohexyl, suberyl or ring octyl group, preferred benzyl of described fragrant benzyl or naphthalene benzyl; N is the integer of 1-4, preferred 1 or 2; X is selected from CH 2, at least a among O, S and the NH, preferred CH 2, at least a among O and the S.
Described addition reaction can be carried out under without any the condition of additive; Also can add additive in reaction system before the reaction beginning, realization is caught trace unhindered amina in the reactant, reduces its poisoning effect to catalyzer, to improve the efficient and the enantioselectivity of hydrogenation; Be the method that described ketone deutero-N-alkyl imines carries out the 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 ((EtOCO) 2O) and tert-Butyl dicarbonate ((Boc) 2O) a kind of in, preferred tert-Butyl dicarbonate ((Boc) 2O); The mol ratio of described additive and described ketone deutero-N-alkyl imines is 0: 1～5: 1, be specially 0.05-5.0: 1,0.05-1.1: 1,0.05-0.5: 1,0.05-0.2: 1,0.2-5.0: 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 0: 1～2: 1, the mole dosage of described additive was not 0.
Described addition reaction can be carried out under condition of no solvent; Also can carry out under the condition that organic solvent exists, described organic solvent is single organic solvent or mixed organic solvents; Described 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 carbonatoms are the monohydroxy-alcohol of 1-10; Described mixed organic solvents is that the monohydroxy-alcohol of 1-10 is formed by alkyl chloride based solvent and carbonatoms, and wherein, described alkyl chloride based solvent is selected from methylene dichloride, 1, at least a in 2-ethylene dichloride and the chloroform.
In the described addition reaction, the mol ratio (S/C) of described ketone deutero-N-alkyl imines and described chiral catalyst is 10-5000: 1, specifically can be 50-500: 1,100-500: 1,100-2000: 1 or 500-2000: and 1, preferred 50-2000: 1.
In the described addition reaction, temperature is-10-100 ℃,-10-90 ℃,-10-25 ℃,-10-40 ℃,-10-60 ℃,-10-90 ℃, 25-90 ℃, 25-60 ℃, 25-40 ℃, 40-90 ℃, 40-60 ℃ or 60-90 ℃, preferred 0-60 ℃, the pressure of hydrogen (i.e. Fan Ying pressure) is 1-100atm, specifically can be 10-100atm, 10-30atm, 10-50atm, 10-80atm, 30-100atm, 30-80atm, 30-50atm, 50-100atm, 50-80atm or 80-100atm, preferred 5-60atm, reaction times is 1-72 hour, specifically can be 10-48 hour, 15-48 hour or 10-15 hour, preferred 6-24 hour.
The invention provides the method that a kind of ketone deutero-N-alkyl imines carries out asymmetric hydrogenation.This method adopts the chiral diamine transition metal complex as catalyzer, in solvent-free, single organic solvent or mixed organic solvents, realize the efficient asymmetric hydrogenation of ketone deutero-N-alkyl imines, obtained present acyclic and the outer N-alkyl imines class substrate asymmetric catalytic hydrogenation of ring reacts best enantioselectivity (up to 99%ee).Utilizing the resulting various Chiral Amine products 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.
Description of drawings
Fig. 1 for embodiment 146-160 prepare gained (1S, 4S)-19f 1H NMR collection of illustrative plates.
Fig. 2 for embodiment 146-160 prepare gained (1S, 4S)-19f 13C NMR collection of illustrative plates.
Fig. 3 be embodiment 160 preparation gained (1S, 4S)-sertraline 1H NMR collection of illustrative plates.
Fig. 4 be embodiment 160 preparation gained (1S, 4S)-sertraline 13C NMR collection of illustrative plates.
Fig. 5 is the HPLC spectrogram of four possibility isomer of 19f among the embodiment 146-160.
Fig. 6 for embodiment 146-160 prepare gained (1S, 4S)-the HPLC spectrogram of 19f.
Embodiment
The invention will be further described below in conjunction with specific embodiment, but the present invention is not limited to following examples.
The universal method of the asymmetric catalytic hydrogenation reaction of ketone deutero-N-alkyl imines provided by the invention is as follows:
In autoclave, add catalyzer, reaction substrate N-alkyl imines, additive, solvent etc. 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 by the mensuration of reaction conversion ratio, and the mensuration of the enantiomeric excess (ee) by 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, represents with percentage ratio that usually its calculation formula is: the reactant that conv.=[transforms]/[initial reactant] x 100%.The transformation efficiency of the asymmetric catalytic hydrogenation of ketone deutero-N-alkyl imines of the present invention reaction be with the reaction solution before the purifying directly by proton nmr spectra ( 1H NMR) peak area of the characteristic peak of surplus stock and product calculates in.
The enantiomeric excess of product (ee), excessive to another enantiomorph of enantiomorph represents with percentage ratio that usually its calculation formula is: ee=([S]-[R])/([S]+[R]) x 100% in the expression reaction product.The enantioselectivity of the asymmetric catalytic hydrogenation reaction of ketone deutero-N-alkyl imines of the present invention, be the enantiomeric excess (being the ee value) of product, be behind the purifying product by (S)-configuration product among the chirality high pressure liquid chromatography figure (chirality OD-H post or chirality AD-H post) with (R)-peak area of configuration product calculates.With chiral drug (1S, 4S)-sertraline synthetic intermediate (R)-19f is an example, concrete method of calculation are as follows: can learn from accompanying drawing 5, accompanying drawing 6, (1S, 4S)-retention time of 19f is 9.83 minutes, its enantiomorph (1R, 4R)-retention time of 19f is 8.27 minutes; With reference to the accompanying drawings 7, shown in the accompanying drawing 8, retention time is 9.83 minutes principal product (1S, 4S)-the peak area per-cent of 19f is 99.128, retention time is 8.27 minutes product (1R, 4R)-and the peak of 19f is invisible, and promptly peak area per-cent is 0, so the absolute configuration of product is (1S, 4S), enantiomeric excess is: (99.128-0) ÷ (99.128+0) * 100%=100%.Consider the intrinsic instrumental error of HPLC, so its enantiomeric excess note is done:＞99%.
The general preparation method of single sulfonylation chiral diamine ligands that the asymmetric catalytic hydrogenation reaction of ketone deutero-N-alkyl imines provided by the invention is used is as follows:
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 XII, as: d Methanesulfonyl chloride, e trifluoromethyl SULPHURYL CHLORIDE, f phenyl SULPHURYL CHLORIDE, g right-aminomethyl phenyl SULPHURYL CHLORIDE, h be right-difluoromethyl phenyl 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 is spin-dried for, and column chromatography (elutriant is a 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%.
Figure BSA00000376525600071
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 (T.Oda, R.Irie, T.Katsuki, H.Okawa, " Catalytic Epoxidation Using Binuclear Nickel Complexes asCatalysts ", Synlett 1992,641).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 ketone deutero-N-alkyl imines provided by the invention is used is as follows:
Ketone deutero-N-alkyl imines provided by the invention carries out in the method for asymmetric hydrogenation, and the chiral metal catalyst that is adopted generally prepares according to following two kinds of methods by 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):
Figure BSA00000376525600081
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, extracted organic phase, 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)-3f～(R, R)-4f, (R, R)-7f～(R, R)-15f.(R.Noyori, " TheHydrogenation/Transfer Hydrogenation Network:Asymmetric Hydrogenation of Ketones with Chiraln6-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).
(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 by ion-exchange, as: (R, R)-3a-e～(R, R)-4a-e, (R, R)-7a-e～(R, R)-15a-e, (R, R)-5, (R, R)-6.(D.C.Baker，“A?Chiral?RhodiumComplex?for?Rapid?Asymmetric?Transfer?Hydrogenation?of?Imines?with?High?Enantioselectivity”，Org.Lett?1999，1，841)。
(S, S)-the shaped metal catalyzer can with (S, S)-single sulphonyl-chiral diamine ligands and metal precursor prepare by as above two kinds of methods.
The representative catalyzer of synthetic of the present invention (numbering respectively be (R, R)-1～(R, R)-15) structure is as follows:
Figure BSA00000376525600091
Wherein: X=OTf (a), BF 4(b), PF 6(c), SbF 6(d), BArF 4(e), 2,2 '-biphenyl phosphoric acid (f).
The general preparation method of the middle reactant N-alkyl imines of the asymmetric catalytic hydrogenation reaction of ketone deutero-N-alkyl imines provided by the invention is as follows:
Under nitrogen atmosphere, with alkylamine (or fragrant benzylamine, 50.0mmol) and ketone (50.0mmol) be dissolved in the 50mL anhydrous methylene chloride, add
Figure BSA00000376525600101
Molecular sieve.After at room temperature stirring 3-5 days, use the diatomite filtration under diminished pressure, revolve and desolventize, crude product is by underpressure distillation or recrystallization purifying, obtain required N-alkyl imines, productive rate 30-80% (C.Wang, X.Wu, L.Zhou, J.Sun, " A Highly EnantioselectiveOrganocatalytic Method for Reduction of Aromatic N-Alkyl Ketimines ", Chem.Eur.J.2008,14,8789).N-alkyl imines synthetic chemical equation is suc as formula (particular chemical of various acyclics and the outer N-alkyl imines of ring is seen formula XIX, formula XX among embodiment 5 and the embodiment 6) shown in the XIV:
Figure BSA00000376525600102
The screening of embodiment 1-9, additive and the optimization of additive amount
The asymmetric catalytic hydrogenation that reacts the N-benzyl-phenyl methyl imines that generates with methyl phenyl ketone and benzylamine is a model reaction, at catalyzer (R, R)-3a and (R, R)-catalysis of 4e under, 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: the hydrogenation experiment is all carried out in autoclave.With mole dosage is that catalyzer, reaction substrate N-benzyl-phenyl methyl imines of 0.2mmol, the certain quantity of additive of reaction substrate N-benzyl-phenyl methyl imines 2% is dissolved in the 1mL solvent, behind nitrogen replacement gas, charge 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 finished, 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 1: 1 methylene dichloride 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 (that is: ee value, the absolute configuration of product is R) is that product behind the purifying is through high pressure liquid chromatography (chirality OD-H
The optimization of the screening of table 1, additive and addition consumption
Figure BSA00000376525600104
Figure BSA00000376525600111
By above experimental result as can be seen: in as above reaction system,, can poisoning effect be arranged, make the transformation efficiency and the enantioselectivity of reaction all decrease to 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
The asymmetric catalytic hydrogenation that reacts the N-benzyl-phenyl methyl imines that generates with methyl phenyl ketone and benzylamine is a model reaction, carried out screening of catalyst, catalyst system therefor be 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: the hydrogenation experiment is all carried out in autoclave.With mole dosage is that catalyzer, 0.2mmol reaction substrate N-benzyl-phenyl methyl imines and the 0.22mmol tert-Butyl dicarbonate of reaction substrate N-benzyl-phenyl methyl imines 2% is dissolved in the 1mL methylene dichloride, behind nitrogen replacement gas, charge into 50atm hydrogen, 40 ℃ were reacted 10 hours.The kind of this reaction catalyst system therefor is as shown in table 2.
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 1: 1 methylene dichloride 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 (that is: 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.
Table 2, screening of catalyst
Figure BSA00000376525600113
Figure BSA00000376525600121
From above experimental result as can be seen: the asymmetric catalytic hydrogenation model reaction of the N-benzyl-phenyl methyl imines that generates with methyl phenyl ketone and benzylamine reaction, under listed catalyzer condition, the transformation efficiency that is responded is all near 100%; The enantioselectivity that most of catalyzer is obtained all between 60-94%, have only (R, R)-6a, (R, R)-8a only obtains 27% and 25%ee; In all catalyzer, (R, R)-4e and (R, R)-enantioselectivity of 11e catalyzed reaction is the highest, reaches 95% and 94% enantiomeric excess.
The screening of embodiment 28-40, asymmetric catalytic hydrogenation reaction solvent
The asymmetric catalytic hydrogenation of the N-benzyl-phenyl methyl imines that generates with the reaction of methyl phenyl ketone and benzylamine is a model reaction, has carried out the screening 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: the hydrogenation experiment is all carried out in autoclave.With mole dosage is the catalyzer (R of reaction substrate N-benzyl-phenyl methyl imines 2%, R)-tert-Butyl dicarbonate of 4e, 0.2mmol reaction substrate N-benzyl-phenyl methyl imines and 0.22mmol is dissolved in the 1mL reaction solvent, behind nitrogen replacement gas, charge into 50atm hydrogen, 40 ℃ were reacted 10 hours.
Wherein, being numbered 38 experiment in the table 3 is the asymmetric catalytic hydrogenation reaction of carrying out under condition of no solvent.
Be numbered 39 and 40 experiment in the table 3 and be the asymmetric catalytic hydrogenation reaction of under the mixed solvent condition, carrying out, wherein, CH 2Cl 2-MeOH (1: 1) represents CH 2Cl 2With the mixed solvent that MeOH gets with 1: 1 mixing of volume ratio, CH 2Cl 2-MeOH (4: 1) represents CH 2Cl 2With MeOH with 4: 1 mixings of volume ratio mixed solvent.
In the above-mentioned reaction, solvent types is all listed in the table 3.
Stop to stir, reaction solution is removed metal catalyst through silica gel column chromatography (elutriant is methylene dichloride-sherwood oil, and volume ratio is 1: 1).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 (that is: 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.
The screening of table 3, solvent
Figure BSA00000376525600123
Figure BSA00000376525600131
* annotate: among the embodiment 39 and 40 catalyst system therefor be (R, R)-4f.
From above experimental result as can be seen: the asymmetric catalytic hydrogenation model reaction of the N-benzyl-phenyl methyl imines that generates with methyl phenyl ketone and benzylamine reaction, optimal catalyst (the R that filters out with previous embodiment 1-9 and 10-27, R)-4e, (R, R)-4f and optimum additive tert-Butyl dicarbonate are under the reaction conditions, when the asymmetric catalytic hydrogenation under different single organic solvent, mixed solvent system and the condition of no solvent is screened, for the listed transformation efficiency that is responded all near 100%; The enantiomeric excess of product reaches 59%-96%; With methylene dichloride, 1,2-ethylene dichloride, when toluene is reaction solvent, the enantioselectivity of reaction reaches 95%-96%ee; The ee value that condition of no solvent is following and the methylene chloride-methanol mixed solvent system is obtained is also up to 93%-94%.
The optimization of the consumption of embodiment 41-54, asymmetric catalytic hydrogenation catalysts, hydrogen pressure, temperature of reaction
The asymmetric catalytic hydrogenation that reacts the N-benzyl-phenyl methyl imines that generates with methyl phenyl ketone and benzylamine is a model reaction, 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 41-54 with the results are shown in Table 4.
The concrete operations of asymmetric catalytic hydrogenation reaction are as follows: the hydrogenation experiment is all carried out in autoclave.With mole dosage is the catalyzer (R of reaction substrate N-benzyl-phenyl methyl imines 2%, R)-tert-Butyl dicarbonate of 4e, 0.2mmol reaction substrate N-benzyl-phenyl methyl imines 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 4.
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 1: 1 methylene dichloride 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 (that is: 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 4.
Figure BSA00000376525600132
The optimization of table 4, catalyst levels, hydrogen pressure, temperature of reaction
Figure BSA00000376525600133
Figure BSA00000376525600141
From above experimental result as can be seen: the asymmetric catalytic hydrogenation model reaction of the N-benzyl-phenyl methyl imines that generates with methyl phenyl ketone and benzylamine reaction, with embodiment 1-9, optimal catalyst (the R that embodiment 10-27 and embodiment 28-40 filter out, R)-4e, optimum additive tert-Butyl dicarbonate and optimum solvent (1, the 2-ethylene dichloride, toluene) be under the reaction conditions, to catalyst levels, hydrogen pressure, when the carrying out of temperature of reaction and reaction solvent further screened, with 1, in the 2-ethylene dichloride, hydrogen pressure is 50 normal atmosphere, catalytic effect was best when temperature of reaction was 40 ℃, when S/C is 50 or 100, the transformation efficiency of 10 hours internal reactions is near 100%, and the enantiomeric excess of product reaches 95% and 96%.
The further screening of embodiment 55-66, catalyzer---difference 2, the screening of 2 '-dibenzyl phosphoric acid tetraethylammonium difluoride
The asymmetric catalytic hydrogenation that reacts the N-benzyl-phenyl methyl imines that generates with methyl phenyl ketone and benzylamine is a model reaction, carried out the further screening of catalyzer, catalyst system therefor is (R, R)-4 the chiral metal catalyst of the different phosphoric acid negative ions of skeleton structure, the experimental design of specific embodiment 55-66 with the results are shown in Table 5.
The concrete operations of asymmetric catalytic hydrogenation reaction are as follows: the hydrogenation experiment is all carried out in autoclave.With mole dosage be reaction substrate N-benzyl-phenyl methyl imines 2mol% catalyzer, 0.2mmol reaction substrate N-benzyl-phenyl methyl imines and 5mol% 2,2 '-dibenzyl phosphoric acid (in order to guarantee negative ion concentration certain in the reaction system), be dissolved in the mixed solvent of 1mL (this mixed solvent is the mixed solution that 4: 1 methylene dichloride and methyl alcohol are formed by volume ratio), 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 methylene dichloride-sherwood oil, and volume ratio is 1: 1).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 enantiomeric excess of product (that is: ee value) and absolute configuration are 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 5.
Figure BSA00000376525600142
The further screening of table 5, catalyzer---difference 2, the screening of 2 '-dibenzyl phosphoric acid tetraethylammonium difluoride
Figure BSA00000376525600143
From above experimental result as can be seen: the asymmetric catalytic hydrogenation model reaction of the N-benzyl-phenyl methyl imines that generates with methyl phenyl ketone and benzylamine reaction, under listed catalyzer condition, have only 2,2 '-biphenyl phosphoric acid negative ion and (S)-2, the metal chiral catalyst that 2 '-naphthyl naphthalene phosphoric acid negative ion constitutes (R, catalytic activity R)-4 is very high, and the transformation efficiency of reaction is near 100%, and the enantiomeric excess of product is higher, reaches 90%ee; Other 2, the activity of 2 '-dibenzyl phosphoric acid tetraethylammonium difluoride is lower, the enantioselectivity of catalyzed reaction is also lower.
The applied research of embodiment 67-90, acyclic N-alkyl imines asymmetric catalytic hydrogenation reaction substrate
With different acyclic N-alkyl imines is substrate, under optimized reaction conditions, carries out the asymmetric catalytic hydrogenation reaction, and the experimental design of specific embodiment 67-90 is as follows:
The hydrogenation experiment is all carried out in autoclave.With mole dosage is the catalyzer (R of reaction substrate acyclic N-alkyl imines 2mol%, R)-tert-Butyl dicarbonate of 4e, 0.2mmol reaction substrate acyclic N-alkyl imines and 0.22mmol is dissolved in 1 of 1mL, in the 2-ethylene dichloride, behind nitrogen replacement gas, charge into 50atm hydrogen, 40 ℃ were reacted 10 hours.
In this reaction, used reaction substrate acyclic N-alkyl imines is followed successively by 16a-x suc as formula shown in the XIX, and corresponding embodiment 67-90 is specifically as shown in table 5 respectively.
Stop to stir, reaction solution is removed metal catalyst through silica gel column chromatography (elutriant is methylene dichloride-sherwood oil, and volume ratio is 1: 1).The mensuration of reaction conversion ratio is directly to pass through nucleus magnetic resonance with the reaction solution before the purifying 1H NMR characterizes, the enantiomeric excess of product (that is: ee value, the absolute configuration of product is R) be that product behind the purifying is measured through high pressure liquid chromatography (chirality OD-H post or chirality AD-H post), shown in result such as the table 5 (data in the bracket are that catalyst levels is 1mol%, i.e. the result who obtains during S/C=100).
Figure BSA00000376525600152
The applied research of table 5, acyclic N-alkyl imines asymmetric catalytic hydrogenation reaction substrate
Figure BSA00000376525600153
From above experimental result as can be seen: the asymmetric catalytic hydrogenation reaction of the acyclic N-alkyl imines that generates with ketone and alkylamine (comprising fragrant benzyl amine) reaction, at the catalytic condition of optimum (1, in the 2-ethylene dichloride, with (R, R)-4e is a catalyzer, tert-Butyl dicarbonate is an additive, hydrogen pressure is 50 normal atmosphere, temperature of reaction is 40 ℃) under, in 10 hours, the hydrogenation smoothly of listed various acyclic N-alkyl imines, productive rate reaches 90%-96%, the enantiomeric excess of product (when removing dialkyl group imines 16v:S/C=50,42%ee; During S/C=100,40%ee) reach 61-98% (S/C=50) and 60-97% (S/C=100).
Embodiment 91-114
With different acyclic N-alkyl imines is substrate, under optimized reaction conditions, carries out the asymmetric catalytic hydrogenation reaction, and the experimental design of specific embodiment 91-114 is as follows:
The hydrogenation experiment is all carried out in autoclave.With mole dosage is the catalyzer (R of reaction substrate 2mol%, R)-4f, 0.2mmol reaction substrate and mole dosage are 2 of reaction substrate 5mol%, 2 '-biphenyl phosphoric acid (in order to guarantee negative ion concentration certain in the reaction system), be dissolved in the mixed solvent of 1mL (this mixed solvent is the mixed solution that 4: 1 methylene dichloride and methyl alcohol are formed by volume ratio), with nitrogen replacement several times behind the gas, charge into 50atm hydrogen, 40 ℃ were reacted 10 hours.
In this reaction, used reaction substrate acyclic N-alkyl imines is followed successively by 16a-x shown in embodiment 67-90 Chinese style XIX, and corresponding embodiment 91-114 is specifically as shown in table 6 respectively.
Stop to stir, reaction solution is removed metal catalyst through silica gel column chromatography (elutriant is a methylene chloride-methanol, and volume ratio is 10: 1).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 (that is: ee value, the absolute configuration of product is R) is that the product behind the purifying is measured through high pressure liquid chromatography (chirality OD-H post or chirality AD-H post), and the result is as shown in table 6.
Figure BSA00000376525600162
Figure BSA00000376525600171
From above experimental result as can be seen: the asymmetric catalytic hydrogenation reaction of the acyclic N-alkyl imines that generates with ketone and alkylamine (comprising fragrant benzyl amine) reaction, at mixed solvent (methylene chloride-methanol, volume ratio is 4: 1) under the condition, with (R, R)-4f is a catalyzer, hydrogen pressure is 50 normal atmosphere, temperature of reaction is 40 ℃, need not outer doping, in 10 hours, listed various acyclic N-alkyl imines hydrogenation smoothly, productive rate reaches 82%-94%, and the enantiomeric excess of product (removing dialkyl group imines 16x:35%ee) all reaches 55-93%.
Embodiment 115-138
With different acyclic N-alkyl imines is substrate, under optimized reaction conditions, carries out the asymmetric catalytic hydrogenation reaction, and the experimental design of specific embodiment 115-138 is as follows:
The hydrogenation experiment is all carried out in autoclave.With mole dosage is the catalyzer (R of reaction substrate acyclic N-alkyl imines 0.2mol%, R)-tert-Butyl dicarbonate of 4e, 2.5mmol reaction substrate acyclic N-alkyl imines and 2.75mmol, behind nitrogen replacement gas, charge into 50atm hydrogen, 40 ℃ were reacted 10 hours.
In this reaction, used reaction substrate acyclic N-alkyl imines is followed successively by 16a-x shown in embodiment 67-90 Chinese style XIX, and corresponding embodiment 115-138 is specifically as shown in table 7 respectively.
Stop to stir, reaction solution is removed metal catalyst through silica gel column chromatography (elutriant is methylene dichloride-sherwood oil, and volume ratio is 1: 1).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 (that is: ee value, the absolute configuration of product is R) is that the product behind the purifying is measured through high pressure liquid chromatography (chirality OD-H post or chirality AD-H post), and the result is as shown in table 7.
Figure BSA00000376525600181
The applied research of acyclic N-alkyl imines asymmetric catalytic hydrogenation reaction substrate under table 7, the condition of no solvent
From above experimental result as can be seen: the asymmetric catalytic hydrogenation reaction of the acyclic N-alkyl imines that generates with ketone and alkylamine (comprising fragrant benzyl amine) reaction, catalytic condition (solvent-free reaction system at optimum, with (R, R)-4e is a catalyzer, tert-Butyl dicarbonate is an additive, hydrogen pressure is 50 normal atmosphere, temperature of reaction is 40 ℃) under, in 10 hours, the hydrogenation smoothly of listed various acyclic N-alkyl imines, productive rate reaches 90%-99%, and the enantiomeric excess of product (removing dialkyl group imines 16x:41%ee) reaches 55-95%.
The foregoing description prepare products therefrom 17a-x optically-active, NMR (Nuclear Magnetic Resonance) spectrum ( 1H, 13C NMR), high resolution mass spectrum and high pressure liquid chromatography data are as follows:
Figure BSA00000376525600183
Figure BSA00000376525600184
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.34-7.12(m，10H)，5.55(b，1H)，4.43(b，1H)，4.02(d，J＝14.4Hz，1H)，1.44(d，J＝7.2Hz，3H)，1.38(s，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)156.2，142.0，140.1，128.4，128.2，127.2，127.0，126.6，80.0，54.1，47.5，28.4，17.9；
High resolution mass spectrum (P-SI HRMS mass): C 20H 26NO 2 +([M+H] +) molecular ion peak calculated value: m/z 312.1964, measured value: m/z312.1959;
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=7.2min (principal product), t R2=8.1min (inferior product).
Figure BSA00000376525600191
Figure BSA00000376525600192
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.34-7.22(m，6H)，7.04(b，2H)，6.79(d，J＝8.7Hz，2H)，5.52(b，1H)，4.40(b，1H)，4.00(b，1H)，3.78(s，3H)，1.43(d，J＝7.2Hz，3H)，1.40(s，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)158.3，156.0，141.9，132.0，128.2，127.0，113.5，79.7，55.1，53.8，47.0，28.3，17.8；
High resolution mass spectrum (P-SI HRMS mass): C 21H 28NO 3 +([M+H] +) molecular ion peak calculated value: m/z 342.2069, measured value: m/z342.2061;
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=10.4min (principal product), t R2=14.2min (inferior product).
Figure BSA00000376525600193
Figure BSA00000376525600194
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.32(s，5H)，7.10(s，2H)，6.98-6.92(m，2H)，5.54(b，1H)，4.39(b，1H)，4.05(d，J＝14.4Hz，1H)，1.50-1.44(m，12H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)163.3，160.1，156.1，141.7，135.8，128.4，127.3，115.1，114.8，80.1，54.1，46.7，28.4，17.8；
High resolution mass spectrum (P-SI HRMS mass): C 20H 25FNO 2 +([M+H] +) molecular ion peak calculated value: m/z 330.1869, measured value: m/z330.1866;
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=6.6min (principal product), t R2=7.5min (inferior product).
Figure BSA00000376525600195
Figure BSA00000376525600196
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.29-7.06(m，10H)，5.26(b，1H)，4.31(b，1H)，4.06(d，J＝15.9Hz，1H)，1.92-1.83(m，2H)，1.40(s，9H)，0.86(t，J＝7.2Hz，3H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)156.3，140.6，139.9，128.3，128.1，128.0，127.3，126.5，79.8，60.7，47.2，28.4，24.5，11.4；
High resolution mass spectrum (P-SI HRMS mass): C 21H 28NO 2 +([M+H] +) molecular ion peak calculated value: m/z 326.2120, measured value: m/z326.2118;
Chirality HPLC analysis (analysis condition: product is measured after removing the Boc-protecting group, chirality OD-H post, and eluent: normal hexane: Virahol=99: 1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t R1=5.6min (principal product), t R2=6.1min (inferior product).
Figure BSA00000376525600197
Figure BSA00000376525600198
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.25-7.09(m，9H)，5.52(b，1H)，4.41(b，1H)，3.98(d，J＝16.2Hz，1H)，2.31(s，3H)，1.41(d，J＝7.5Hz，3H)，1.38(s，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)156.2，140.2，138.8，136.7，129.0，128.1，127.1，126.9，126.5，79.8，53.6，47.2，28.4，21.0，17.9；
High resolution mass spectrum (P-SI HRMS mass): C 21H 28NO 2 +([M+H] +) molecular ion peak calculated value: m/z 326.2120, measured value: m/z326.2117;
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=7.3min (principal product), t R2=10.3min (inferior product).
Figure BSA00000376525600202
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.26-7.10(m，7H)，6.84(d，J＝8.7Hz，2H)，5.51(b，1H)，4.38(b，1H)，3.98(d，J＝17.7Hz，1H)，3.78(s，3H)，1.41(d，J＝7.5Hz，3H)，1.39(s，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)158.8，156.2，140.3，133.9，128.5，128.2，126.9，126.9，126.5，113.7，79.9，55.3，53.5，47.1，28.5，18.0；
High resolution mass spectrum (P-SI HRMS mass): C 21H 28NO 3 +([M+H] +) molecular ion peak calculated value: m/z 342.2069, measured value: m/z342.2059;
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=11.3min (principal product), t R2=14.3min (inferior product).
Figure BSA00000376525600203
Figure BSA00000376525600204
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.25-7.13(m，7H)，6.95(t，J＝8.4Hz，2H)，5.48(b，1H)，4.39(b，1H)，4.05(d，J＝15.0Hz，1H)，1.42(d，J＝7.2Hz，3H)，1.39(s，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)163.5，160.3，156.0，139.9，137.7，128.8，128.7，128.2，126.9，126.6，115.2，114.9，80.0，55.3，47.3，28.3，17.9；
High resolution mass spectrum (P-SI HRMS mass): C 20H 25FNO 2 +([M+H] +) molecular ion peak calculated value: m/z 330.1869, measured value: m/z330.1867;
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=7.1min (principal product), t R2=8.1min (inferior product).
Figure BSA00000376525600205
Figure BSA00000376525600206
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.26-7.11(m，9H)，5.46(b，1H)，4.41(b，1H)，4.03(d，J＝13.8Hz，1H)，1.42(d，J＝6.9Hz，3H)，1.38(s，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)156.0，140.6，139.8，132.9，128.5，128.4，128.3，126.9，126.7，80.1，53.5，47.5，28.4，17.9；
High resolution mass spectrum (P-SI HRMS mass): C 20H 25ClNO 2 +([M+H] +) molecular ion peak calculated value: m/z 346.1574, measured value: m/z346.1573;
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=8.8min (inferior product).
Figure BSA00000376525600207
Figure BSA00000376525600208
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.42-7.39(m，2H)，7.28-7.11(m，7H)，5.39(b，1H)，4.43(d，J＝13.2Hz，1H)，4.05(d，J＝15.3Hz，1H)，1.42(d，J＝6.9Hz，3H)，1.38(s，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)156.1，141.2，139.8，131.5，128.9，128.3，127.0，126.8，121.1，80.2，53.6，47.7，28.4，17.9；
High resolution mass spectrum (P-SI HRMS mass): C 20H 25BrNO 2 +([M+H] +) molecular ion peak calculated value: m/z 390.1069, measured value: m/z390.1064;
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=9.5min (inferior product).
Figure BSA00000376525600211
Figure BSA00000376525600212
1H?NMR(300MHz，CDCl 3)：δ(ppm)8.13-8.11(m，2H)，7.39(d，J＝8.1Hz，2H)，7.30-7.16(m，5H)，5.36(b，1H)，5.52(d，J＝13.5Hz，1H)，4.18(d，J＝15.3Hz，1H)，1.52(d，J＝6.9Hz，3H)，1.38(s，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)155.8，150.0，147.0，139.3，128.5，128.2，127.8，127.1，123.5，80.7，54.1，48.4，28.4，17.8；
High resolution mass spectrum (P-SI HRMS mass): C 20H 25N 2O 4 +([M+H] +) molecular ion peak calculated value: m/z 357.1814, measured value: m/z357.1810;
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=18.7min (inferior product).
Figure BSA00000376525600213
Figure BSA00000376525600214
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.26-7.03(m，9H)，5.52(b，1H)，4.43(b，1H)，4.05(d，J＝15.0Hz，1H)，2.31(s，3H)，1.44(d，J＝7.2Hz，3H)，1.41(s，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)156.1，141.7，140.1，137.7，128.2，128.0，127.8，126.8，126.5，124.1，79.8，53.7，47.3，28.3，21.5，17.9；
High resolution mass spectrum (P-SI HRMS mass): C 21H 28NO 2 +([M+H] +) molecular ion peak calculated value: m/z 326.2120, measured value: m/z326.2112;
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=6.6min (principal product), t R2=7.3min (inferior product).
Figure BSA00000376525600215
Figure BSA00000376525600216
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.26-7.15(m，6H)，6.89-6.76(m，3H)，5.46(b，1H)，4.43(b，1H)，4.02(d，J＝15.9Hz，1H)，3.74(s，3H)，1.43(d，J＝7.2Hz，3H)，1.38(s，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)159.8，156.2，143.7，140.2，129.4，128.2，127.0，126.6，119.5，113.2，112.6，80.0，55.3，54.0，47.5，28.5，17.9；
High resolution mass spectrum (P-SI HRMS mass): C 21H 28NO 3 +([M+H] +) molecular ion peak calculated value: m/z 342.2069, measured value: m/z342.2062;
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=10.8min (principal product), t R2=12.8min (inferior product).
Figure BSA00000376525600217
Figure BSA00000376525600218
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.26-7.14(m，9H)，5.44(b，1H)，4.43(b，1H)，4.09(b，1H)，2.74(s，3H)，1.41(d，J＝6.9Hz，3H)，1.37(s，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)156.0，144.3，139.7，134.3，129.6，128.3，127.3，127.2，127.0，126.8，125.3，80.2，53.7，47.7，28.4，17.8；
High resolution mass spectrum (P-SI HRMS mass): C 20H 25ClNO 2 +([M+H] +) molecular ion peak calculated value: m/z 346.1574, measured value: m/z346.1570;
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=7.1min (principal product), t R2=7.8min (inferior product).
Figure BSA00000376525600221
Figure BSA00000376525600222
1H?NMR(300MHz，CDCl 3)；δ(ppm)7.28-7.25(m，1H)，7.19-7.08(m，6H)，6.95-6.93(m，2H)，5.59(b，1H)，4.24(d，J＝14.4Hz，1H)，3.94(d，J＝15.3Hz，1H)，2.23(s，3H)，1.43(m，12H)；
13C?NMR(75MHz，CDCl 3)；δ(ppm)155.7，140.0，138.8，137.8，130.6，127.9，127.6，127.2，126.7，126.4，125.8，79.8，51.4，46.2，28.4，19.1，17.9；
High resolution mass spectrum (P-SI HRMS mass): C 21H 28NO 2 +([M+H] +) molecular ion peak calculated value: m/z 326.2120, measured value: m/z326.2114;
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=5.5min (inferior product), t R2=5.9min (principal product).
Figure BSA00000376525600223
Figure BSA00000376525600224
1H?NMR(300MHz，CDCl 3)；δ(ppm)7.34-7.06(m，9H)，5.61(b，1H)，4.40(b，1H)，4.18(b，1H)，1.43(d，J＝7.2Hz，3H)，1.41(s，9H)；
13C?NMR(75MHz，CDCl 3)；δ(ppm)155.6，139.7，139.3，134.4，129.7，128.5，128.0，126.8，126.6，126.4，79.7，52.3，47.0，28.3，17.9；
High resolution mass spectrum (P-SI HRMS mass): C 20H 25ClNO 2 +([M+H] +) molecular ion peak calculated value: m/z 346.1574, measured value: m/z346.1568;
Chirality HPLC analysis (analysis condition: product is measured after removing the Boc-protecting group, chirality OD-H post, and 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=8.4min (inferior product).
Figure BSA00000376525600225
Figure BSA00000376525600226
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.26-7.11(m，5H)，6.85-6.78(m，3H)，5.46(b，1H)，4.37(b，1H)，1.41(d，J＝15.9Hz，1H)，3.86(s，3H)，3.79(s，3H)，1.44(d，J＝7.2Hz，3H)，1.40(s，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)155.6，148.5，147.9，139.7，134.0，127.7，126.6，126.1，118.5，110.8，110.4，79.3，55.4，55.3，53.2，46.8，27.9，17.3；
High resolution mass spectrum (P-SI HRMS mass): C 22H 29NO 4Na +([M+Na] +) molecular ion peak calculated value: m/z 394.19888, measured value: m/z394.19863;
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=9.7min (inferior product), t R2=11.2min (principal product).
Figure BSA00000376525600227
Figure BSA00000376525600228
1H?NMR(300MHz，CDCl 3)；δ(ppm)8.23(b，1H)，7.86-7.78(m，2H)，7.59-7.42(m，4H)，7.09-7.07(m，3H)，6.89-6.87(m，2H)，6.35(b，1H)，4.22(b，1H)，3.88(d，J＝16.2Hz，1H)，1.61(d，J＝6.6Hz，3H)，1.47(s，9H)；
13C?NMR(75MHz，CDCl 3)；δ(ppm)155.7，139.9，136.6，133.8，132.2，128.7，127.8，126.8，126.5，126.2，125.8，124.8，124.7，124.1，80.0，50.4，46.2，28.4，18.0；
High resolution mass spectrum (P-SI HRMS mass): C 24H 28NO 2 +([M+H] +) molecular ion peak calculated value: m/z 362.2120, measured value: m/z362.2119;
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=7.0min (principal product), t R2=8.3min (inferior product).
Figure BSA00000376525600231
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.81-7.76(m，3H)，7.70(s，1H)，7.48-7.42(m，3H)，7.26-7.14(m，5H)，5.75(b，1H)，4.47(b，1H)，4.04(d，J＝12.3Hz，1H)，1.56(d，J＝7.2Hz，3H)，1.42(s，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)156.3，140.1，139.4，133.2，132.7，128.2，128.1，128.0，127.6，126.9，126.6，126.1，125.9，125.3，80.0，54.0，47.4，28.4，17.9；
High resolution mass spectrum (P-SI HRMS mass): C 24H 28NO 2 +([M+H] +) molecular ion peak calculated value: m/z 362.2120, measured value: m/z362.2110;
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=10.5min (principal product), t R2=12.9min (inferior product).
Figure BSA00000376525600233
Figure BSA00000376525600234
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.29-7.18(m，6H)，6.95-6.92(m，2H)，5.62(d，J＝99.3Hz，1H)，4.50(b，1H)，4.07(d，J＝16.5Hz，1H)，1.48(d，J＝6.9Hz，3H)，1.42(s，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)155.6，146.3，139.9，128.1，126.7，126.5，126.4，124.5，80.0，50.2，47.0，28.3，19.3；
High resolution mass spectrum (P-SI HRMS mass): C 18H 24NO 2S +([M+H] +) molecular ion peak calculated value: m/z 318.1528, measured value: m/z318.1522;
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=7.0min (principal product), t R2=7.9min (inferior product).
Figure BSA00000376525600235
Figure BSA00000376525600236
1H?NMR(300MHz，CDCl 3)；δ(ppm)7.35-7.14(m，5H)，6.27-6.25(m，1H)，6.17(b，1H)，5.42(d，J＝131.7Hz，1H)，4.41(b，1H)，4.11(b，1H)，1.41-1.39(m，12H)；
13C?NMR(75MHz，CDCl 3)；δ(ppm)155.8，154.9，141.8，140.0，128.1，126.5，110.0，107.3，80.0，49.7，48.5，46.8，28.3，17.0；
High resolution mass spectrum (P-SI HRMS mass): C 18H 24NO 3 +([M+H] +) molecular ion peak calculated value: m/z 302.1756, measured value: m/z302.1752;
Chirality HPLC analysis (analysis condition: product is measured after removing the Boc-protecting group, chirality OD-H post, and eluent: normal hexane: Virahol=99: 1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t R1=18.8min (inferior product), t R2=20.6min (principal product).
Figure BSA00000376525600237
Figure BSA00000376525600238
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.31-7.18(m，5H)，4.39-4.3(m，2H)，3.92(b，0.6H)，3.41(b，0.4H)，1.74-1.64(m，5H)，1.49-1.32(m，10H)，1.26-0.86(m，8H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)156.4，155.9，140.3，139.7，128.1，127.6，126.7，126.4，79.2，58.3，56.7，48.9，47.442.0，41.6，30.7，30.4，30.2，29.9，28.3，26.3，26.2，26.1，17.5，16.8；
High resolution mass spectrum (HRMS-ESI mass): C 20H 31NO 2Na +([M+Na] +) molecular ion peak calculated value: m/z 340.22470, measured value: m/z340.22412;
Chirality HPLC analysis (analysis condition: product is measured after removing the Boc-protecting group, chirality OD-H post, and eluent: normal hexane: Virahol=99: 1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t R1=7.2min (inferior product), t R2=8.1min (principal product).
Figure BSA00000376525600242
1H?NMR(300MHz，CDCl 3)：δ(ppm)2.48(s，3H)，2.42-2.30(m，1H)，1.81-1.62(m，5H)，1.50(bs，1H)，1.76-1.65(m，5H)，1.49-1.30(m，9H)，0.92(d，3H，J＝6.3Hz)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)156.2，80.1，57.6，41.5，34.0，29.6，28.3，27.8，26.6，26.6，26.5，15.9；
High resolution mass spectrum (HRMS-ESI mass): C 14H 27NO 2Na +([M+Na] +) molecular ion peak calculated value: m/z 264.19395, measured value: m/z264.19373;
Chirality HPLC analysis (analysis condition: product is measured after removing the Boc-protecting group, chirality OD-H post, and eluent: normal hexane: Virahol=99: 1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t R1=6.7min (inferior product), t R2=7.9min (principal product).
Figure BSA00000376525600243
Figure BSA00000376525600244
1H?NMR(300MHz，CDCl 3)：δ(ppm)2.62-2.42(m，3H)，1.78-1.68(m，5H)，1.54-1.41(m，2H)，1.48-1.12(m，12H)，1.03-0.82(m，11H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)156.0，79.8，57.4，49.2，29.9，28.3，27.8，26.8，26.7，26.7，23.6，16.8，11.5；
High resolution mass spectrum (HRMS-ESI mass): C 17H 33NO 2Na +([M+Na] +) molecular ion peak calculated value: m/z 306.24090, measured value: m/z306.24065;
Chirality HPLC analysis (analysis condition: product is measured after removing the Boc-protecting group, chirality OD-H post, and eluent: normal hexane: Virahol=99: 1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t R1=5.6min (inferior product), t R2=7.2min (principal product).
Figure BSA00000376525600245
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.30-7.16(m，5H)，4.42-4.14(m，2H)，3.85(b，0.6H)，3.36(b，0.4H)，1.81(b，1H)，1.49-1.33(m，9H)，1.07(b，3H)，0.88(b，6H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)156.0，140.4，139.8，128.2，127.6，126.8，126.6，79.4，59.7，58.0，48.9，47.4，32.4，28.4，20.1，17.8，17.1；
High resolution mass spectrum (HRMS-ESI mass): C 17H 27NO 2Na +([M+Na] +) molecular ion peak calculated value: m/z 300.19340, measured value: m/z300.19306;
Chirality HPLC analysis (analysis condition: product is measured after removing the Boc-protecting group, chirality OD-H post, and eluent: normal hexane: Virahol=99: 1, flow velocity: 1.0mL/min, temperature: 20 ℃, ultraviolet detection wavelength: λ=220nm): appearance time: t R1=4.7min (inferior product), t R2=5.1min (principal product).
The applied research of embodiment 139-145, the outer N-alkyl imines asymmetric catalytic hydrogenation reaction substrate of ring
With the outer N-alkyl imines of different rings is substrate, under optimized reaction conditions, carries out the asymmetric catalytic hydrogenation reaction, and the experimental design of specific embodiment 139-145 is as follows:
The hydrogenation experiment is all carried out in autoclave.With mole dosage is the catalyzer (R of the outer N-alkyl imines 2mol% of reaction substrate ring, R)-tert-Butyl dicarbonate of the outer N-alkyl imines of 4e, 0.2mmol reaction substrate ring and 0.22mmol is dissolved in 1 of 1mL, in the 2-ethylene dichloride, behind nitrogen replacement gas, charge into 50atm hydrogen, 40 ℃ were reacted 10 hours.Wherein, among the embodiment 145 catalyst system therefor replace with (S, S)-4e.
In this reaction, the outer N-alkyl imines of used reaction substrate ring is 18a-f shown in the formula XX, corresponds respectively to embodiment 139-145, and is specifically as shown in table 8.
Stop to stir, reaction solution is removed metal catalyst through silica gel column chromatography (elutriant is methylene dichloride-sherwood oil, and volume ratio is 1: 1).The mensuration of reaction conversion ratio is directly to pass through nucleus magnetic resonance with the reaction solution before the purifying 1H NMR characterizes, the enantiomeric excess of product (that is: ee value, the absolute configuration of product is R) be that product behind the purifying is measured through high pressure liquid chromatography (chirality OD-H post or chirality AD-H post), shown in result such as the table 8 (data in the bracket are that catalyst levels is 1mol%, the result who obtains during S/C=100).
Figure BSA00000376525600251
The applied research of table 8, the outer N-alkyl imines asymmetric catalytic hydrogenation reaction substrate of ring
Figure BSA00000376525600252
*Annotate: among the embodiment 145 catalyst system therefor be (S, S)-4e.
From above experimental result as can be seen: the asymmetric catalytic hydrogenation of N-alkyl imines reacts outside the ring that generates with α-benzo cyclic ketones and alkylamine (comprising fragrant benzyl amine) reaction, at the catalytic condition of optimum (1, in the 2-ethylene dichloride, with (R, R)-4e is a catalyzer, tert-Butyl dicarbonate (1.1 equivalent) is an additive, hydrogen pressure is 50 normal atmosphere, temperature of reaction is 40 ℃) under, in 10 hours, the outer N-alkyl imines hydrogenation smoothly of listed various rings, productive rate reaches 95%-98%, and the enantiomeric excess of product reaches 92-＞99% (S/C=50) and 87-96% (S/C=100).
Embodiment 146-152
With the outer N-alkyl imines of different rings is substrate, under optimized reaction conditions, carries out the asymmetric catalytic hydrogenation reaction, and the experimental design of specific embodiment 146-152 is as follows:
The hydrogenation experiment is all carried out in autoclave.With mole dosage is the catalyzer (R of reaction substrate 2mol%, R)-4f, 0.2mmol reaction substrate acyclic N-alkyl imines 18a-f and reaction substrate mole dosage 5% 2,2 '-biphenyl phosphoric acid (in order to guarantee negative ion concentration certain in the reaction system), be dissolved in the mixed solvent of 1mL (this mixed solvent is that 4: 1 methylene dichloride and methyl alcohol is formed by volume ratio), with nitrogen replacement several times behind the gas, charge into 50atm hydrogen, 40 ℃ were reacted 10 hours.Wherein, among the embodiment 152 catalyst system therefor replace with (S, S)-4f.
In this reaction, the outer N-alkyl imines of used reaction substrate ring is 18a-f shown in the formula XX, corresponds respectively to embodiment 146-152, and is specifically as shown in table 9.
Stop to stir, reaction solution is removed metal catalyst through silica gel column chromatography (elutriant is a methylene chloride-methanol, and volume ratio is 10: 1).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 (that is: ee value, the absolute configuration of product is R) is that the product behind the purifying is measured through high pressure liquid chromatography (chirality OD-H post or chirality AD-H post), and the result is as shown in table 9.
Figure BSA00000376525600261
The applied research of the outer N-alkyl imines asymmetric catalytic hydrogenation reaction substrate of ring in table 9, the mixed organic solvents system
Figure BSA00000376525600262
*Annotate: among the embodiment 152 catalyst system therefor be (S, S)-4f.
From above experimental result as can be seen: the asymmetric catalytic hydrogenation of N-alkyl imines reacts outside the ring that generates with α-benzo cyclic ketones and alkylamine (comprising fragrant benzyl amine) reaction, at mixed solvent (methylene chloride-methanol, volume ratio is 4: 1) under the condition, with (R, R)-4f is a catalyzer, hydrogen pressure is 50 normal atmosphere, temperature of reaction is 40 ℃, need not outer doping, in 10 hours, the outer N-alkyl imines hydrogenation smoothly of listed various rings, productive rate reaches 91%-95%, and the enantiomeric excess of product reaches 82-95%
Embodiment 153-159
With the outer N-alkyl imines of different rings is substrate, under optimized reaction conditions, carries out the asymmetric catalytic hydrogenation reaction, and the experimental design of specific embodiment 153-159 is as follows:
The hydrogenation experiment is all carried out in autoclave.With mole dosage is the catalyzer (R of the outer N-alkyl imines 0.2mol% of reaction substrate ring, R)-tert-Butyl dicarbonate of 4e, 2.5mmol reaction substrate acyclic N-alkyl imines and 2.75mmol, behind nitrogen replacement gas, charge into 50atm hydrogen, 40 ℃ were reacted 10 hours.Wherein, embodiment 159 catalyst system therefors replace with (S, S)-4e.
In this reaction, the outer N-alkyl imines of used ring is followed successively by 18a-f, and is specifically as shown in table 10.
Stop to stir, reaction solution is removed metal catalyst through silica gel column chromatography (elutriant is that volume ratio is 1: 1 the mixed solution of being made up of methylene dichloride and sherwood oil).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 (that is: ee value, the absolute configuration of product is R) is that the product behind the purifying is measured through high pressure liquid chromatography (chirality OD-H post or chirality AD-H post), and the result is as shown in table 10.
Table 10, condition of no solvent be the applied research of the outer N-alkyl imines asymmetric catalytic hydrogenation reaction substrate of ring down
Figure BSA00000376525600271
*Annotate: embodiment 159 catalyst system therefors be (S, S)-4e.
From above experimental result as can be seen: the asymmetric catalytic hydrogenation of N-alkyl imines reacts outside the ring that generates with α-benzo cyclic ketones and alkylamine (comprising fragrant benzyl amine) reaction, catalytic condition (solvent-free reaction system at optimum, with (R, R)-4e is a catalyzer, tert-Butyl dicarbonate is an additive, hydrogen pressure is 50 normal atmosphere, temperature of reaction is 40 ℃) under, in 10 hours, the outer N-alkyl imines hydrogenation smoothly of listed various ring, productive rate reaches 89%-94%, and the enantiomeric excess of product reaches 89-96% (S/C=100).
The optically-active of method for preparing products therefrom 19a-f, NMR (Nuclear Magnetic Resonance) spectrum ( 1H, 13C NMR), high resolution mass spectrum and high pressure liquid chromatography data are as follows:
Figure BSA00000376525600272
Figure BSA00000376525600273
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.29-7.19(m，9H)，5.95(b，0.5H)，5.37(s，0.5H)，4.67-4.42(m，1H)，4.11-4.38(m，1H)，2.89-2.71(m，2H)，2.32(d，J＝18.6Hz，1H)，1.90(b，1H)，1.37(s，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)156.1，143.4，142.7，141.9，140.2，139.6，128.1，127.5，127.2，126.3，126.1，124.7，124.1，123.6，79.7，62.7，61.2，49.1，47.1，30.4，30.1，28.2；
High resolution mass spectrum (P-SI HRMS mass): C 21H 26NO 2 +([M+H] +) molecular ion peak calculated value: m/z 324.1964, measured value: m/z324.1951;
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=10.0min (inferior product).
Figure BSA00000376525600275
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.27-7.08(m，9H)，5.62-5.57(m，0.5H)，4.92(b，0.5H)，4.68(d，J＝15.3Hz，0.5H)，4.46(d，J＝16.5Hz，0.5H)，4.14(d，J＝15.6Hz，0.5H)，3.80(d，J＝16.5Hz，0.5H)，2.79-2.69(m，2H)，2.10-1.57(m，4H)，1.36(s，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)156.7，156.3，140.4，139.5，138.6，137.8，137.6，136.3，129.3，129.0，128.4，128.1，127.6，127.1，126.9，126.8，126.4，126.3，126.2，79.9，57.4，55.4，50.0，48.1，29.6，29.3，28.3，22.6，22.3；
High resolution mass spectrum (P-SI HRMS mass): C 22H 28NO 2 +([M+H] +) molecular ion peak calculated value: m/z 338.2120, measured value: m/z338.2116;
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=6.6min (principal product), t R2=9.3min (inferior product).
Figure BSA00000376525600276
Figure BSA00000376525600277
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.13-7.06(m，4H)，5.27(b，0.5H)，4.56(b，0.5H)，3.13-2.56(m，4H)，2.07-1.75(m，5H)，1.55-1.19(m，4H)，1.51-1.19(m，9H)，0.97-0.86(s，6H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)156.7，156.0，138.5，137.9，137.1，136.9，129.0，128.8，126.3，126.1，125.9，125.8，79.3，79.0，58.6，56.3，55.9，52.9，29.7，29.2，28.7，28.3，28.1，27.4，22.8，20.6，20.2；
High resolution mass spectrum (P-SI HRMS mass): C 19H 30NO 2 +([M+H] +) molecular ion peak calculated value: m/z 304.2277, measured value: m/z304.2270;
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=4.3min (principal product), t R2=4.9min (inferior product).
Figure BSA00000376525600282
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.15-7.09(m，4H)，5.25-5.47(m，0.5H)，5.25-5.19(m，0.5H)，2.76-2.71(m，2H)，2.60(d，J＝23.4Hz，3H)，2.02-1.98(m，2H)，1.88-1.71(m，2H)，1.51(d，J＝19.5Hz，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)156.6，156.3，138.3，138.0，136.1，135.7，129.1，127.0，126.8，126.6，126.5，126.1，126.0，79.5，79.3，55.7，54.2，29.9，29.7，29.5，28.5，28.4，27.9，27.5，22.2，22.0；
High resolution mass spectrum (P-SI HRMS mass): C 16H 24NO 2 +([M+H] +) molecular ion peak calculated value: m/z 262.1807, measured value: m/z262.1803;
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=5.5min (principal product), t R2=7.7min (inferior product).
Figure BSA00000376525600283
Figure BSA00000376525600284
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.31-7.11(m，6H)，7.04(b，1H)，6.88(b，1H)，6.79(d，J＝8.1Hz，1H)，5.72(b，0.5H)，5.06(b，0.5H)，4.69-4.48(m，1H)，4.23-4.08(m，2.5H)，3.82(d，J＝16.5Hz，0.5H)，2.16-1.88(m，2H)，1.39(s，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)156.1，139.8，139.2，128.1，127.3，126.9，126.4，126.0，123.1，121.8，120.4，116.8，80.0，65.1，52.5，50.7，49.4，47.3，28.1，27.8；
High resolution mass spectrum (P-SI HRMS mass): C 21H 26NO 3 +([M+H] +) molecular ion peak calculated value: m/z 340.1913, measured value: m/z340.1908;
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=13.8min (principal product), t R2=24.8min (inferior product).
Figure BSA00000376525600285
Figure BSA00000376525600286
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.32(d，J＝8.1Hz，1H)，7.26-7.17(m，3H)，7.09(m，1H)，6.94(d，J＝7.5Hz，1H)，6.81(s，1H)，5.40(d，J＝50.4Hz，1H)，4.18(s，1H)，2.63(s，3H)，2.34-2.22(m，1H)，2.00(d，J＝12.6Hz，1H)，1.74(d，J＝6.6Hz，1H)，1.53(s，9H)；
13C?NMR(75MHz，CDCl 3)：δ(ppm)156.7，156.4，147.3，138.2，136.9，132.4，130.8，130.2，128.2，127.5，79.8，55.3，54.2，43.3，30.3，29.9，29.4，28.6，22.3，21.9；
High resolution mass spectrum (P-SI HRMS mass): C 22H 26NO 2Cl 2 +([M+H] +) molecular ion peak calculated value: m/z 406.1341, measured value: m/z406.1336;
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=8.2min[(1R, 4R)-21], t R2=8.9min[(1R, 4S)-21], t R3=9.8min[(1S, 4S)-21], t R4=14.4min[(1S, 4R)-21].
Embodiment 160, chiral drug (1S, 4S)-((1S's, 4S)-4-(3, the 4-dichlorophenyl)-1,2,3, the 4-tetrahydrochysene closes naphthalene-1-amine hydrochlorate) is synthetic for sertraline
Figure BSA00000376525600291
With chiral drug (1S; 4S)-during sertraline is synthetic key intermediate---the chirality ring is outer, and imines (S)-18f is a raw material; at first under optimized reaction conditions; carry out the asymmetric catalytic hydrogenation reaction; reaction product is after column chromatography removes metal catalyst; the hydrochloric acid that adds 4N, remove the Boc protecting group and generate Chiral Amine hydrochloride product (1S, 4S)-sertraline.
Concrete operations are as follows: the hydrogenation experiment is carried out in autoclave.With catalyzer (S, S)-4e (24mg, 0.0172mmol), the tert-Butyl dicarbonate of 0.5g (1.72mmol) reactant (S)-18f and 410mg (18.9mmol) is dissolved in 1 of 0.2mL, in the 2-ethylene dichloride, behind nitrogen replacement gas, charge into 50atm hydrogen, 40 ℃ were reacted 10 hours.Stop to stir, reaction solution is removed metal catalyst and is carried out purifying through silica gel column chromatography, obtain 650mg hydrogenated products (1S, 4S)-19f (productive rate 99%,＞99%ee, the ratio cis/trans of cis-product and trans product＞99%).Product is to measure the enantiomeric excess (that is: ee value) of product and the absolute configuration of product by high pressure liquid chromatography (chirality AD-H post).
Saturated solution (4N in the ethyl acetate of hydrogenchloride, 650mg (the 1S that adds preparation 10mL), 4S)-19f, after the stirring at room 6 hours, decompression is revolved and is desolventized, and crude product is behind recrystallization purifying, obtain final product (1S, 4S)-and sertraline (500mg, two step overall yields 90%, the enantiomeric excess of product＞99%ee).
The NMR (Nuclear Magnetic Resonance) spectrum of chiral diamine catalyzer ( 1H NMR), mass spectrum and ultimate analysis data are as follows:
RuBArF (p-cymene) (S, S)-MsDPEN (catalyzer (S, S)-4e):
1H?NMR(300MHz，CDCl 3)：δ(ppm)7.68(s，8H)，7.50-7.42(d，J＝24.0Hz，4H)，7.25-6.71(m，10H)，5.81-5.69(m，3H)，5.15(s，1H)，3.81-3.63(m，2H)，2.72-2.69(m，1H)，2.46-2.08(m，6H)，1.27-1.11(m，6H)；
High resolution mass spectrum (HRMS-ESI mass): C 25H 31N 2O 2RuS +([M-BArF] +) molecular ion peak calculated value: m/z 525.11497, measured value: m/z 525.11444; Negative ion [BArF] -Calculated value: m/z 863.06488, measured value: m/z 863.07040;
C 57H 44BF 24N 2O 2The results of elemental analyses of RuS, calculated value: C, 49.29; H, 3.19; N, 2.02; Measured value: C, 49.47; H, 3.28; N, 2.00.
Figure BSA00000376525600292
(1S，4S)-setraline
Figure BSA00000376525600293
1H?NMR(300MHz，MeOD)：δ(ppm)7.57(d，J＝7.2Hz，1H)，7.50-7.45(m，2H)，7.39-7.29(m，2H)，7.22(dd，J＝8.4Hz，1.8Hz，1H)，6.91(d，J＝7.2Hz，1H)，4.52-4.49(m，1H)，4.21-4.16(m，1H)，2.85(s，3H)，2.35-2.17(m，3H)，2.09-1.96(m，1H)；
13C?NMR(75MHz，MeOD)：δ(ppm)147.6，141.3，133.5，132.0，132.0，131.7，131.6，131.0，130.2，128.6，58.1，46.1，31.7，28.6，24.4。
Fig. 1 and Fig. 2 be respectively embodiment 146-160 prepare gained (1S, 4S)-19f 1The HNMR collection of illustrative plates and 13C NMR collection of illustrative plates.Fig. 3 and Fig. 4 be respectively embodiment 160 preparation gained (1S, 4S)-sertraline 1H NMR collection of illustrative plates and 13C NMR collection of illustrative plates.As seen from the figure, the above-claimed cpd structure is correct, is target compound.
Four isomer HPLC peak area data of table 11,19f
Figure BSA00000376525600301
By Fig. 5 and table 11 as can be known, and required chiral drug intermediate (1S, 4S)-retention time of 19f is 9.83 minutes, its enantiomorph (1R, 4R)-retention time of 19f is 8.27 minutes.Another to enantiomorph (1R, 4S)-retention time of 19f is 8.91 minutes, (1S, 4R)-retention time of 19f is 14.44 minutes.
Fig. 6 is the HPLC spectrogram of the hydrogenated products 19f of compound 18f among the embodiment 146-160, and corresponding peak area data are as shown in table 12.
Table 12, (1S, 4S)-the HPLC peak area of 19f
Figure BSA00000376525600302
By Fig. 6 and table 12 as can be known, according to the method for hydrogenation of the described imines 18f of embodiment, products therefrom be mainly (1S, 4S)-19f, its enantiomorph (1R, 4R)-19f is invisible in the drawings.The enantiomeric excess that calculates product thus is＞99%.
According to the general preparation method one of aforementioned catalyzer, the catalyzer that uses in the above embodiment of the present invention (R, R)-3f～(R, R)-4f, (R, R)-7f～(R, R)-the concrete preparation process of 15f is as follows:
(R，R)-3f：
Under nitrogen atmosphere, (R, R)-single tolysulfonyl-1,2-diphenyl ethylene diamine part (R, R)-TsDPEN (367mg, 1.0mmol), metal precursor [RuCl 2(p-cymene)] 2(344mg, 0.5mmol) and KOH (400mg, 7.1mmol) stirring at room after 5 minutes in methylene dichloride (7mL), add 7mL water after, use dichloromethane extraction, organic phase is through CaH 2The decompression of dry back is spin-dried for, and obtains solid (R, R)-1 (561mg).With (R, R)-1 (330mg 0.5mmol) makes methylene dichloride (30mL) solution, and under the nitrogen protection, with 2, (124mg, methylene dichloride 0.5mmol) (10mL) solution slowly is added drop-wise in this solution 2 '-biphenyl phosphoric acid.After adding, continue to stir 30 minutes, reaction solution be spin-dried for, obtain the red solid catalyzer (R, R)-3f (295mg, yield 65%).
(R，R)-4f：
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, add 7mL water after, use dichloromethane extraction, organic phase is through CaH 2The decompression of dry back is spin-dried for, and obtains solid (512mg).With this solid (292mg 0.5mmol) makes methylene dichloride (30mL) solution,, under the nitrogen protection, with 2, (124mg, methylene dichloride 0.5mmol) (10mL) solution slowly is added drop-wise in this solution 2 '-biphenyl phosphoric acid.After adding, continue to stir 30 minutes, reaction solution be spin-dried for, obtain the red solid catalyzer (R, R)-4f (332mg, yield 80%).
(R，R)-7f：
Under nitrogen atmosphere, (R, R)-single tolysulfonyl-1,2-diphenyl ethylene diamine part (R, R)-(366mg is 1.0mmol) with metal precursor [RuCl for TsDPEN 2(benzene)] 2(288mg, 0.5mmol) and KOH (400mg 7.1mmol) stirs in methylene dichloride after 5 minutes, add 7mL water after, use dichloromethane extraction, organic phase is through CaH 2The decompression of dry back is spin-dried for, and obtains solid 423mg.With this solid (302mg 0.5mmol) makes methylene dichloride (30mL) solution,, under the nitrogen protection, with 2, (124mg, methylene dichloride 0.5mmol) (10mL) solution slowly is added drop-wise in this solution 2 '-biphenyl phosphoric acid.After adding, continue to stir 30 minutes, reaction solution be spin-dried for, obtain the red solid catalyzer (R, R)-7f (302mg, yield 71%).
(R，R)-8f：
Under nitrogen atmosphere, (R, R)-single tolysulfonyl-1,2-diphenyl ethylene diamine part (R, R)-(366mg is 1.0mmol) with metal precursor [RuCl for TsDPEN 2(hexamethylbenzene)] 2(373mg, 0.5mmol) and KOH (400mg 7.1mmol) stirs in methylene dichloride after 5 minutes, uses dichloromethane extraction, and organic phase is through CaH 2The decompression of dry back is spin-dried for, and obtains solid 462mg.(344mg 0.5mmol) makes methylene dichloride (30mL) solution, and under the nitrogen protection, with 2, (124mg, methylene dichloride 0.5mmol) (10mL) solution slowly is added drop-wise in this solution 2 '-biphenyl phosphoric acid with this solid.After adding, continue to stir 30 minutes, reaction solution be spin-dried for, obtain the red solid catalyzer (R, R)-8f (318mg, yield 68%).
(R，R)-9f：
Under nitrogen atmosphere, (R, R)-single benzene sulfonyl-1, (352mg is 1.0mmol) with metal precursor [RuCl for 2-diphenyl ethylene diamine part 2(cymene)] 2(344mg, 0.5mmol) and KOH (400mg 7.1mmol) stirs in methylene dichloride after 5 minutes, add 7mL water after, use dichloromethane extraction, organic phase is through CaH 2The decompression of dry back is spin-dried for, and obtains solid 489mg.(323mg 0.5mmol) makes methylene dichloride (30mL) solution, and under the nitrogen protection, with 2, (124mg, methylene dichloride 0.5mmol) (10mL) solution slowly is added drop-wise in this solution 2 '-biphenyl phosphoric acid with this solid.After adding, continue to stir 30 minutes, reaction solution be spin-dried for, obtain the red solid catalyzer (R, R)-9f (277mg, yield 62%).
(R，R)-10f：
Under nitrogen atmosphere, (R, R)-(268mg is 1.0mmol) with metal precursor [RuCl for single tolysulfonyl-cyclohexanediamine part 2(cymene)] 2(344mg, 0.5mmol) and KOH (400mg 7.1mmol) stirs in methylene dichloride after 5 minutes, add 7mL water after, use dichloromethane extraction, organic phase is through CaH 2The decompression of dry back is spin-dried for, and obtains solid 368mg.(281mg 0.5mmol) makes methylene dichloride (30mL) solution, and under the nitrogen protection, with 2, (124mg, methylene dichloride 0.5mmol) (10mL) solution slowly is added drop-wise in this solution 2 '-biphenyl phosphoric acid with this solid.After adding, continue to stir 30 minutes, reaction solution be spin-dried for, obtain the red solid catalyzer (R, R)-10f (271mg, yield 67%).
(R，R)-11f：
Under nitrogen atmosphere, (R, R)-(192mg is 1.0mmol) with metal precursor [RuCl for single methylsulfonyl-cyclohexanediamine part 2(cymene)] 2(344mg, 0.5mmol) and KOH (400mg 7.1mmol) stirs in methylene dichloride after 5 minutes, add 7mL water after, use dichloromethane extraction, organic phase is through CaH 2The decompression of dry back is spin-dried for, and obtains solid 366mg.(243mg 0.5mmol) makes methylene dichloride (30mL) solution, and under the nitrogen protection, with 2, (124mg, methylene dichloride 0.5mmol) (10mL) solution slowly is added drop-wise in this solution 2 '-biphenyl phosphoric acid with this solid.After adding, continue to stir 30 minutes, reaction solution be spin-dried for, obtain the red solid catalyzer (R, R)-11f (275mg, yield 75%).
(R，R)-12f：
Under nitrogen atmosphere, (R, R)-single fluoroform sulphonyl-1, (344mg is 1.0mmol) with metal precursor [RuCl for 2-diphenyl ethylene diamine part 2(cymene)] 2(344mg, 0.5mmol) and KOH (400mg 7.1mmol) stirs in methylene dichloride after 5 minutes, add 7mL water after, use dichloromethane extraction, organic phase is through CaH 2The decompression of dry back is spin-dried for, and obtains solid 428mg.(319mg 0.5mmol) makes methylene dichloride (30mL) solution, and under the nitrogen protection, with 2, (124mg, methylene dichloride 0.50mmol) (10mL) solution slowly is added drop-wise in this solution 2 '-biphenyl phosphoric acid with this solid.After adding, continue to stir 30 minutes, reaction solution be spin-dried for, obtain the red solid catalyzer (R, R)-12f (345mg, yield 78%).
(R，R)-13f：
Under nitrogen atmosphere, (R, R)-list-2,4,6-tri isopropyl benzenesulfonyl-1, (479mg is 1.0mmol) with metal precursor [RuCl for 2-diphenyl ethylene diamine part 2(cymene)] 2(344mg, 0.5mmol) and KOH (400mg 7.1mmol) stirs in methylene dichloride after 5 minutes, add 7mL water after, use dichloromethane extraction, organic phase is through CaH 2The decompression of dry back is spin-dried for, and obtains solid 507mg.With this solid 386mg, 0.5mmol) make methylene dichloride (30mL) solution, under the nitrogen protection, 2, (124mg, methylene dichloride 0.5mmol) (10mL) solution slowly is added drop-wise in this solution 2 '-biphenyl phosphoric acid.After adding, continue to stir 30 minutes, reaction solution be spin-dried for, obtain the red solid catalyzer (R, R)-13f (357mg, yield 70%).
(R，R)-14f：
Under nitrogen atmosphere, (R, R)-single to trifluoromethyl benzene sulfonyl-1, (421mg is 1.0mmol) with metal precursor [RuCl for 2-diphenyl ethylene diamine part 2(cymene)] 2(344mg, 0.5mmol) and KOH (400mg 7.1mmol) stirs in methylene dichloride after 5 minutes, add 7mL water after, use dichloromethane extraction, organic phase is through CaH 2The decompression of dry back is spin-dried for, and obtains solid 603mg.(357mg 0.5mmol) makes methylene dichloride (30mL) solution, and under the nitrogen protection, with 2, (124mg, methylene dichloride 0.5mmol) (10mL) solution slowly is added drop-wise in this solution 2 '-biphenyl phosphoric acid with this solid.After adding, continue to stir 30 minutes, reaction solution be spin-dried for, obtain the red solid catalyzer (R, R)-14f (279mg, yield 58%).
(R，R)-15f：
Under nitrogen atmosphere, (R, R)-list-1-naphthalene sulfonyl-1, (403mg is 1.0mmol) with metal precursor [RuCl for 2-diphenyl ethylene diamine part 2(cymene)] 2(344mg, 0.5mmol) and KOH (400mg 7.1mmol) stirs in methylene dichloride after 5 minutes, add 7mL water after, use dichloromethane extraction, organic phase is through CaH 2The decompression of dry back is spin-dried for, and obtains solid 492mg.(348mg 0.5mmol) makes methylene dichloride (30mL) solution, and under the nitrogen protection, with 2, (124mg, methylene dichloride 0.5mmol) (10mL) solution slowly is added drop-wise in this solution 2 '-biphenyl phosphoric acid with this solid.After adding, continue to stir 30 minutes, reaction solution be spin-dried for, obtain the red solid catalyzer (R, R)-15f (321mg, yield 68%).
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-e～(R, R)-4a-e, (R, R)-7a-e～(R, R)-15a-e, (R, R)-5, (R, concrete preparation process R)-6 is as follows:
(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 precipitation and obtain yellow solid, be catalyzer (R, R)-3a (160mg, yield 99%).
(R，R)-3b：
According to (R, R)-preparation method of 3a, wherein with silver tetrafluoroborate AgBF 4(39mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-3b 147mg, yield 98%.
(R，R)-3c：
According to (R, R)-preparation method of 3a, wherein with phosphofluoric acid silver AgPF 6(51mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-3c 155mg, yield 96%.
(R，R)-3d：
According to (R, R)-preparation method of 3a, wherein with hexafluoro telluric acid silver AgSbF 6(69mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-3d 176mg, yield 98%.
(R，R)-3e：
According to (R, R)-preparation method of 3a, wherein with four aryl boric acid potassium KBArF 4(181mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-3e 299mg, yield 98%.
(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 precipitation 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)-4e：
According to (R, R)-preparation method of 4a, wherein with four aryl boric acid potassium KBArF 4(181mg 0.2mmol) replaces 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 precipitation and obtain yellow solid, be catalyzer (R, R)-7a (148mg, yield 98%).
(R，R)-7b：
According to (R, R)-preparation method of 7a, wherein with silver tetrafluoroborate AgBF 4(39mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-7b 137mg, yield 99%.
(R，R)-7c：
According to (R, R)-preparation method of 7a, wherein with phosphofluoric acid silver AgPF 6(51mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-7c 147mg, yield 98%.
(R，R)-7d：
According to (R, R)-preparation method of 7a, wherein with hexafluoro telluric acid silver AgSbF 6(69mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-7d 163mg, yield 97%.
(R，R)-7e：
According to (R, R)-preparation method of 7a, wherein with four aryl boric acid potassium KBArF 4(181mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-7e 291mg, yield 99%.
(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 precipitation and obtain yellow solid, be catalyzer (R, R)-8a (164mg, yield 98%).
(R，R)-8b：
According to (R, R)-preparation method of 8a, wherein with silver tetrafluoroborate AgBF 4(39mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-8b 152mg, yield 98%.
(R，R)-8c：
According to (R, R)-preparation method of 8a, wherein with phosphofluoric acid silver AgPF 6(51mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-8c 162mg, yield 97%.
(R，R)-8d：
According to (R, R)-preparation method of 8a, wherein with hexafluoro telluric acid silver AgSbF 6(69mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-8d 183mg, yield 99%.
(R，R)-8e：
According to (R, R)-preparation method of 8a, wherein with four aryl boric acid potassium KBArF 4(181mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-8e 298mg, yield 96%.
(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 (0.2mmol), stirred 0.5 hour under the room temperature, remove by filter precipitation and obtain yellow solid, be catalyzer (R, R)-9a (156mg, yield 98%).
(R，R)-9b：
According to (R, R)-preparation method of 9a, wherein with silver tetrafluoroborate AgBF 4(39mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-9b 144mg, yield 98%.
(R，R)-9c：
According to (R, R)-preparation method of 9a, wherein with phosphofluoric acid silver AgPF 6(51mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-9c 157mg, yield 99%.
(R，R)-9d：
According to (R, R)-preparation method of 9a, wherein with hexafluoro telluric acid silver AgSbF 6(69mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-9d 171mg, yield 97%.
(R，R)-9e：
According to (R, R)-preparation method of 9a, wherein with four aryl boric acid potassium KBArF 4(181mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-9e 298mg, yield 99%.
(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 precipitation and obtain yellow solid, be catalyzer (R, R)-10a (141mg, yield 99%).
(R，R)-10b：
According to (R, R)-preparation method of 10a, wherein with silver tetrafluoroborate AgBF 4(39mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-10b 126mg, yield 97%.
(R，R)-10c：
According to (R, R)-preparation method of 10a, wherein with phosphofluoric acid silver AgPF 6(51mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-10c 137mg, yield 97%.
(R，R)-10d：
According to (R, R)-preparation method of 10a, wherein with hexafluoro telluric acid silver AgSbF 6(69mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-10d 156mg, yield 98%.
(R，R)-10e：
According to (R, R)-preparation method of 10a, wherein with four aryl boric acid potassium KBArF 4(181mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-10e 274mg, yield 96%.
(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 precipitation and obtain yellow solid, be catalyzer (R, R)-11a (123mg, yield 97%).
(R，R)-11b：
According to (R, R)-preparation method of 11a, wherein with silver tetrafluoroborate AgBF 4(39mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-11b 111mg, yield 97%.
(R，R)-11c：
According to (R, R)-preparation method of 11a, wherein with phosphofluoric acid silver AgPF 6(51mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-11c 124mg, yield 98%.
(R，R)-11d：
According to (R, R)-preparation method of 11a, wherein with hexafluoro telluric acid silver AgSbF 6(69mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-11d 139mg, yield 96%.
(R，R)-11e：
According to (R, R)-preparation method of 11a, wherein with four aryl boric acid potassium KBArF 4(181mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-11e 259mg, yield 96%.
(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 precipitation and obtain yellow solid, be catalyzer (R, R)-12a (153mg, yield 97%).
(R，R)-12b：
According to (R, R)-preparation method of 12a, wherein with silver tetrafluoroborate AgBF 4(39mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-12b 144mg, yield 99%.
(R，R)-12c：
According to (R, R)-preparation method of 12a, wherein with phosphofluoric acid silver AgPF 6(51mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-12c 152mg, yield 97%.
(R，R)-12d：
According to (R, R)-preparation method of 12a, wherein with hexafluoro telluric acid silver AgSbF 6(69mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-12d 170mg, yield 97%.
(R，R)-12e：
According to (R, R)-preparation method of 12a, wherein (181mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf with four aryl boric acid potassium KBArF4.Obtain catalyzer (R, R)-12e 282mg, yield 94%.
(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 precipitation and obtain yellow solid, be catalyzer (R, R)-13a (182mg, yield 99%).
(R，R)-13b：
According to (R, R)-preparation method of 13a, wherein with silver tetrafluoroborate AgBF 4(39mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-13b 170mg, yield 99%.
(R，R)-13c：
According to (R, R)-preparation method of 13a, wherein with phosphofluoric acid silver AgPF 6(51mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-13c 180mg, yield 98%.
(R，R)-13d：
According to (R, R)-preparation method of 13a, wherein with hexafluoro telluric acid silver AgSbF 6(69mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-13d 200mg, yield 99%.
(R，R)-13e：
According to (R, R)-preparation method of 13a, wherein with four aryl boric acid potassium KBArF 4(181mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-13e 317mg, yield 97%.
(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 precipitation and obtain yellow solid, be catalyzer (R, R)-14a (168mg, yield 97%).
(R，R)-14b：
According to (R, R)-preparation method of 14a, wherein with silver tetrafluoroborate AgBF 4(39mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-14b 159mg, yield 99%.
(R，R)-14c：
According to (R, R)-preparation method of 14a, wherein with phosphofluoric acid silver AgPF 6(51mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-14c 170mg, yield 99%.
(R，R)-14d：
According to (R, R)-preparation method of 14a, wherein with hexafluoro telluric acid silver AgSbF 6(69mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-14d 184mg, yield 97%.
(R，R)-14e：
According to (R, R)-preparation method of 14a, wherein with four aryl boric acid potassium KBArF 4(181mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-14e 306mg, 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 precipitation and obtain yellow solid, be catalyzer (R, R)-15a (166mg, yield 98%).
(R，R)-15b：
According to (R, R)-preparation method of 15a, wherein with silver tetrafluoroborate AgBF 4(39mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-15b 154mg, yield 98%.
(R，R)-15c：
According to (R, R)-preparation method of 15a, wherein with phosphofluoric acid silver AgPF 6(51mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-15c 165mg, yield 98%.
(R，R)-15d：
According to (R, R)-preparation method of 15a, wherein with hexafluoro telluric acid silver AgSbF 6(69mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-15d 185mg, yield 99%.
(R，R)-15e：
According to (R, R)-preparation method of 15a, wherein with four aryl boric acid potassium KBArF 4(181mg 0.2mmol) replaces silver trifluoromethanesulfonate AgOTf.Obtain catalyzer (R, R)-15e 302mg, yield 97%.
(R，R)-5：
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 precipitation and obtain yellow solid, be catalyzer (R, R)-5 (172mg, yield 97%).
(R，R)-6：
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 precipitation and obtain yellow solid, be catalyzer (R, R)-6 (153mg, yield 96%).

Claims (10)

1. the method that ketone deutero-N-alkyl imines carries out the asymmetric catalytic hydrogenation reaction comprises the steps: with hydrogen ketone deutero-N-alkyl imines to be carried out addition reaction under the condition that chiral catalyst exists, and obtains the Chiral Amine product; It is characterized in that: described chiral catalyst is a compound shown in the formula III general structure;
Figure FSA00000376525500011
In the described formula III general structure, M is Ru, Rh or Ir;
Described L 1 *For containing single sulphonyl substituting group-SO 2The chiral diamine L1 of R ' and the reacted chiral diamine ligands of metal precursor, described R ' for carbonatoms be 1-10 alkyl, trifluoromethyl, phenyl, naphthyl, contain substituent phenyl or contain substituent naphthyl, the described substituent phenyl and containing in the substituent naphthyl of containing, described substituting group all are selected from least a in alkyl, methoxyl group, fluorine, chlorine, bromine, nitro and the trifluoromethyl that carbonatoms is 1-10;
Described R " is selected from least a in the alkyl that H, benzyl and carbonatoms are 1-10;
Described L 2Be η 6-benzene dentate, η 5-luxuriant dentate, contain substituent η 6-benzene dentate or contain substituent η 5-luxuriant dentate describedly contains substituent η 6-benzene dentate and contain substituent η 5In-luxuriant the dentate, described substituting group all is selected from least a in the alkyl that carbonatoms is 1-10;
Described X is Cl -, Br -, I -, OAc -, NO 3 -, HSO 4 -, H 2PO 4 -, [OTf] -, [BF 4] -, [SbF 6] -, [PF 6] -, [NTf 2] -, shown in four aryl boron anions or the formula IX 2,2 '-dibenzyl phosphoric acid negative ion;
Figure FSA00000376525500012
Among the described formula IX, L is 2,2 '-xenyl, contain substituent 2,2 '-xenyl, 2,2 '-di-naphthyl, contain substituent 2,2 '-di-naphthyl, 8H-2,2 '-di-naphthyl or contain substituent 8H-2,2 '-di-naphthyl; Describedly contain substituent 2,2 '-xenyl, contain substituent 2,2 '-di-naphthyl and contain substituent 8H-2, in 2 '-di-naphthyl, described substituting group all is selected from the alkyl that carbonatoms is 1-10, carbonatoms is the alkoxyl group of 1-10, aryl, contain substituent carbonatoms and be the alkyl of 1-10 and contain at least a in the substituent aryl, described contain substituent carbonatoms be 1-10 alkyl and contain in the substituent aryl, described substituting group all is selected from methyl, sec.-propyl, the tertiary butyl, fluorine, chlorine, methoxyl group, trifluoromethyl, at least a in hydroxyl and the kharophen.
2. method according to claim 1, it is characterized in that: in the described formula III general structure, described 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;
Described 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 described four aryl boron anions, described aryl is phenyl or 3,5-two (trifluoromethyl) phenyl.
3. method according to claim 2, it is characterized in that: chiral catalyst shown in the described formula III is by (R shown in the formula VIIIa, R)-title complex of the single sulphonyl of N--diaryl quadrol and transition metal iridium, ruthenium or rhodium formation or formula VIIIb shown in by (S, S)-title complex of the single sulphonyl of N--diaryl quadrol and transition metal iridium, ruthenium or rhodium formation
Figure FSA00000376525500021
In described formula VIIIa and the VIIIb general structure, M is Ru, Rh or Ir;
The phenyl that Ar is phenyl, replace 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] -, shown in four aryl boron anions or the formula IX 2,2 '-dibenzyl phosphoric acid negative ion.
4. according to the arbitrary described method of claim 1-3, it is characterized in that: shown in the described formula IX 2,2 '-dibenzyl phosphoric acid negative ion is (R)-2,2 '-naphthyl naphthalene phosphoric acid negative ion, (S)-2,2 '-naphthyl naphthalene phosphoric acid negative ion, raceme (±)-2,2 '-naphthyl naphthalene phosphoric acid negative ion, contain substituent (R)-2,2 '-naphthyl naphthalene phosphoric acid negative ion, contain substituent (S)-2,2 '-naphthyl naphthalene phosphoric acid negative ion, contain substituent raceme (±)-2,2 '-naphthyl naphthalene phosphoric acid negative ion, (R)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion, (S)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion, raceme (±)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion, contain substituent (R)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion, contain substituent (S)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion, contain substituent raceme (±)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion, 2,2 '-biphenyl phosphoric acid negative ion or contain substituent 2,2 '-biphenyl phosphoric acid negative ion; Describedly contain substituent (R)-2,2 '-naphthyl naphthalene phosphoric acid negative ion, contain substituent (S)-2,2 '-naphthyl naphthalene phosphoric acid negative ion, contain substituent raceme (±)-2,2 '-naphthyl naphthalene phosphoric acid negative ion, contain substituent (R)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion, contain substituent (S)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion, contain substituent raceme (±)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion and contain substituent 2, in 2 '-biphenyl phosphoric acid negative ion, described substituting group all is selected from methyl, sec.-propyl, the tertiary butyl, methoxyl group, trifluoromethyl, phenyl, contain substituent phenyl, naphthyl and contain at least a in the substituent naphthyl, the described substituting group that contains substituent phenyl and contain in the substituent naphthyl all is selected from methyl, sec.-propyl, the tertiary butyl, fluorine, chlorine, methoxyl group, trifluoromethyl, hydroxyl, kharophen, phenyl, 3,5-two (trifluoromethyl) phenyl and 3, at least a in 5-two (sec.-propyl) phenyl.
5. according to the arbitrary described method of claim 1-4, it is characterized in that: shown in the described formula IX 2,2 '-dibenzyl phosphoric acid negative ion is 2,2 '-biphenyl phosphoric acid negative ion, 3,3 '-position contains substituent 2,2 '-biphenyl phosphoric acid negative ion, 3, substituent (R)-2 are contained in 3 '-position, 2 '-naphthyl naphthalene phosphoric acid negative ion, substituent (S)-2,2 '-naphthyl naphthalene phosphoric acid negative ion are contained in 3,3 '-position, 3, substituent (R)-8H-2 is contained in 3 '-position, 2 '-naphthyl naphthalene phosphoric acid negative ion or 3, substituent (S)-8H-2,2 '-naphthyl naphthalene phosphoric acid negative ion are contained in 3 '-position; Described 3,3 '-position contains substituent 2,2 '-biphenyl phosphoric acid negative ion, 3, substituent (R)-2 are contained in 3 '-position, 2 '-naphthyl naphthalene phosphoric acid negative ion, 3, substituent (S)-2 are contained in 3 '-position, 2 '-naphthyl naphthalene phosphoric acid negative ion, 3, substituent (R)-8H-2 is contained in 3 '-position, 2 '-naphthyl naphthalene phosphoric acid negative ion and 3, substituent (S)-8H-2 is contained in 3 '-position, in 2 '-naphthyl naphthalene phosphoric acid negative ion, described substituting group all is selected from phenyl, naphthyl, the phenyl that alkyl replaces, the naphthyl that alkyl replaces, at least a in the naphthyl that phenyl that methoxyl group replaces and methoxyl group replace, in the naphthyl that phenyl that described alkyl replaces and alkyl replace, described alkyl is methyl, the sec.-propyl or the tertiary butyl.
6. according to the arbitrary described method of claim 1-5, it is characterized in that: described ketone deutero-N-alkyl imines is the outer N-alkyl imines of ring shown in alkyl imines of acyclic N-shown in the formula X or the formula XI;
Figure FSA00000376525500031
In the described formula X general structure, R 1For alkyl, cycloalkyl, aryl, contain substituent alkyl, contain substituent cycloalkyl or contain substituent aryl, R 2For alkyl, cycloalkyl, fragrant benzyl, contain substituent alkyl, contain substituent cycloalkyl or contain substituent fragrant benzyl, R 3For alkyl or contain substituent alkyl; Described R 1, R 2And R 3In, described substituting group all is selected from least a in fluorine, chlorine, bromine, nitro, methyl, methoxyl group, trifluoromethyl, hydroxyl and the kharophen, described alkyl is that carbonatoms is the alkyl of 1-5, described cycloalkyl is cyclopentyl, cyclohexyl, suberyl or ring octyl group, described aryl is phenyl, naphthyl, thienyl or furyl, and described fragrant benzyl is benzyl or naphthalene benzyl;
Figure FSA00000376525500032
In the described formula XI general structure, R is alkyl, cycloalkyl, fragrant benzyl, contains substituent alkyl, contains substituent cycloalkyl or contain substituent fragrant benzyl, and described substituting group all is selected from least a in fluorine, chlorine, bromine, nitro, methyl, methoxyl group, trifluoromethyl, hydroxyl and the kharophen; Described alkyl is that carbonatoms is the alkyl of 1-5, and described cycloalkyl is cyclopentyl, cyclohexyl, suberyl or ring octyl group, and described fragrant benzyl is benzyl or naphthalene benzyl; N is the integer of 1-4, preferred 1 or 2; X is selected from CH 2, at least a among O, S and the NH, preferred CH 2, at least a among O and the S.
7. according to the arbitrary described method of claim 1-6, it is characterized in that: described ketone deutero-N-alkyl imines carries out the method for asymmetric catalytic hydrogenation reaction, also comprises the steps: to add additive in reaction system before described addition reaction is carried out; Described additive is selected from a kind of in Ue-5908 and the tert-Butyl dicarbonate, preferred tert-Butyl dicarbonate; The mol ratio of described additive and described ketone deutero-N-alkyl imines is 0: 1～5: 1, and preferred 0: 1～2: 1, the mole dosage of described additive was not 0.
8. according to the arbitrary described method of claim 1-7, it is characterized in that: described addition reaction is to carry out under the condition that organic solvent exists; Described organic solvent is single organic solvent or mixed organic solvents; Described 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 carbonatoms are the monohydroxy-alcohol of 1-10; Described mixed organic solvents is that the monohydroxy-alcohol of 1-10 is formed by alkyl chloride based solvent and carbonatoms, and wherein, described 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 mol ratio of described ketone deutero-N-alkyl imines and described chiral catalyst is 10-5000: 1, and preferred 50-2000: 1.
10. according to the arbitrary described method of claim 1-9, it is characterized in that: in the described 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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