CN1331601C - Method of Chiral alkamine ligand used as catalyst of asymmetric addition process for terminal alkyne to fluoroalkylaryl ketone - Google Patents

Method of Chiral alkamine ligand used as catalyst of asymmetric addition process for terminal alkyne to fluoroalkylaryl ketone Download PDF

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CN1331601C
CN1331601C CNB031170269A CN03117026A CN1331601C CN 1331601 C CN1331601 C CN 1331601C CN B031170269 A CNB031170269 A CN B031170269A CN 03117026 A CN03117026 A CN 03117026A CN 1331601 C CN1331601 C CN 1331601C
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alkyl
substituted
group
benzyl
chiral
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CN1449865A (en
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姜标
司玉贵
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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Priority to PCT/CN2003/000462 priority patent/WO2004087628A1/en
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Abstract

The present invention provides a method of using chiral ligand (1R, 2R)-2-N, N-substituted amino-1-(4-substituted phenyl)-1-ethanol or enantiomorph thereof as a catalyst for asymmetric addition of acetylene copper or acetylene zinc to trifluoromethylarylketone. The catalyst has the structure general formula, wherein R<1> and R<2> are amino protecting groups; R<3> is alkyl, or alkoxyl or silica group substituted alkyl, or an ester group, or carboxyl, or methylol, or a naphthenic base, or aryl or CH2OR<4>; R<4> is an oxygen protecting group; Z is H, or an electron-withdrawing group or an electron donating group. The catalyst can efficiently build a chiral quaternary carbon center in a high-activity inhibitor Efavirenz(Sustiva <TM>) of HIV transferase in the mode of high enantio selectivity especially by a catalystprecursor applied to asymmetric Efavirenz(Sustiva <TM>) synthesis by the technical method of asymmetric addition with chiral ligand participation of acetylene copper or acetylene zinc to trifluoromethylarylketone, thereby, efficiently synthesizing the Efavirenz(Sustiva <TM>).

Description

Chiral amino alcohol ligand is applied to the method for Terminal Acetylenes to the asymmetric addition of fluorine-containing alkylaryl ketone
Technical field
The present invention relates to a kind of chiral ligand and be used for the method for Terminal Acetylenes the asymmetric addition of fluorine-containing alkylaryl ketone.
Background technology
Human immune system's defective virus (HIV, Human immunodeficiency virus) is easily undergone mutation, and this can cause chemical sproof generation.As everyone knows, there have been some inhibitors medicines to be found and to be used for the treatment of HIV and similar disease, such as azidothymidine or AZT.Efavirenz (Sustiva TM), DPC961 and DPC 083 are second generation HIV non-nucleoside inhibitors (NNRTIs, non-nucleoside reverse transcriptase inhibitors), wherein Efavirenz (Sustiva TM) go on the market.DPC-961 and DPC 083 carrying out at present clinical research test (Journal of MedicinalChemistry vol.43, NO.10,2000,2019-2030).
Some method is used to Efavirenz (Sustiva TM) synthetic (Angew.Chem.Int.Ed.no.5,1999,711-713; Journal of Organic Chemistry vol.63, no.23,1998,8536-8543).These have reported synthetic Efavirenz (Sustiva TM) method in need to use excessive greatly chiral ligand and excessive greatly highly basic (lithium alkyl and LHMDS), and reaction needs spend subzero 50 and carry out, the condition harshness is difficult for industrialization.The present invention relates to a kind of new chiral ligand and be used for the purposes of Terminal Acetylenes the asymmetric addition of fluorine-containing alkylaryl ketone.This technology is used to make up Efavirenz (Sustiva TM) the quaternary carbon chiral centre, the high optical activity of product and as mild as a dove reaction condition make this technology have good industrial prospect.
Summary of the invention
The problem to be solved in the present invention provides chiral amino alcohol ligand and is used for the method for Terminal Acetylenes to the asymmetric addition of fluorine-containing alkylaryl ketone, and the high optical activity of product and reaction condition as mild as a dove make this technology have good industrial prospect.Efavirenz (Sustiva in particular for direct synthesis of optically active TM) the application of technology of precursor, promptly alkynes copper that participates in by the chiral ligand amino alcohol or alkynes zinc generate the product tertiary alcohol to the asymmetric addition of trifluoromethyl aryl ketones intermediate, and this compound promptly generates product HIV through easy conversion and moves enzyme inhibitor medicine Efavirenz (Sustiva TM).
The application that the invention provides a class chiral amino alcohol ligand is used for the method for Terminal Acetylenes to the asymmetric addition of fluorine-containing alkylaryl ketone.Specifically, relate to the chiral amino alcohol ligand of following structure, (1R, 2R)-2-N, N-substituted-amino-1-substituted-phenyl-1-ethanol or its enantiomer (1S, 2S)-2-N, N-substituted-amino-1-substituted-phenyl-1-ethanol is used for the method for Terminal Acetylenes to the asymmetric addition of fluorine-containing alkylaryl ketone:
Or
Figure C0311702600052
R wherein 1, R 2Be amino protecting group,
R 3Be alkyl, alkyl, ester group, carboxyl, methylol, cycloalkyl, aryl or CH that the alkyl that alkoxyl replaces, siloxy replace 2OR 4Described alkyl, alkyl, ester group, carboxyl that the alkyl that alkoxyl replaces, siloxy replace are recommended as C 1～C 20, further be recommended as C 1～C 4; Cycloalkyl is recommended as C 3～C 20, further be recommended as cyclopropane.Recommend R 3Be CH 2OR 4, R wherein 4Be the oxygen protecting group.Described aryl is recommended as phenyl.
That Z represents on the phenyl ring is adjacent, or contraposition single replaces or two replace, Z is H, electron withdraw group or electron donating group, described electron withdraw group is recommended as halo, NO 2, CF 3, CH 3SO 2, CH 3CH 2SO 2Perhaps AcO, described electron donating group is recommended as especially C of alkoxyl 1～C 20Alkoxyl (C for example 1～C 4Alkoxyl), OH, Me 2NCH 2CH 2O, Et 2NCH 2CH 2O, PhCH 2OCO, NH 2, alkyl C especially 1～C 20Alkyl (for example methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group), further recommending Z is H, F, Cl, Br, I, CH 3SO 2OH, PhCH 2O, AcO, MeO, EtO, Me 2NCH 2CH 2O, Et 2NCH 2CH 2O, PhCH 2OCO, t-Bu, i-Pr, NH2, or NO 2Especially recommending Z is H, Cl, Br, CH 3SO 2Perhaps NO 2
Recommend R 1, R 2=Me.; Z=NO 2, further recommend R 1=R 2=Me; Z=NO 2R 3=tert-butoxy methyl is especially recommended R 1, R 2=Me; Z=NO 2R 3=tertiary butyl dimethyl Si methyl or triphenyl methoxy.
Above-mentioned chiral amino alcohol ligand is used as the catalyst that asymmetric syntheses has following structural compounds, obtains corresponding
Figure C0311702600061
Or
Figure C0311702600062
In the formula Y represent on the phenyl ring adjacent, or contraposition single replaces or two replace, Y is H, electron withdraw group or electron donating group, described electron withdraw group is recommended as halo, NO 2, CF 3, CH 3SO 2, CH 3CH 2SO 2Perhaps AcO, described electron donating group is recommended as especially C of alkoxyl 1～C 20Alkoxyl (C for example 1～C 4Alkoxyl), OH, Me 2NCH 2CH 2O, Et 2NCH 2CH 2O, PhCH 2OCO, NH 2, alkyl C especially 1～C 20Alkyl (for example methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group), further recommending Y is H, Cl, Br, CH 3SO 2, CH 3CH 2SO 2, NO 2Perhaps F, especially recommending Y is Cl or F.
P is H or amino protecting group,
Rf is fluorine-containing alkyl, is recommended as C 1-C 20Contain fluoroalkyl, further be recommended as C 1-C 4Contain fluoroalkyl,
R is a trialkyl silyl, and aryl, alkyl or cycloalkyl are recommended as C 1-C 20Alkyl or cycloalkyl, further be recommended as C 1-C 4Alkyl or cyclopropane, the heteroaryl that described aryl is recommended as phenyl, naphthyl, substituted-phenyl, contain N, S or O is pyridine radicals, furyl, thienyl, pyrrole radicals, pyranose etc. for example;
Reaction equation is for example following:
Figure C0311702600071
Comprise the steps:
(a) with chiral ligand (1R, 2R)-2-N, N-substituted-amino-1-substituted-phenyl-1-ethanol or (1S, 2S)-2-N, N-substituted-amino-1-substituted-phenyl-1-ethanol has following structure
Figure C0311702600072
Or
Figure C0311702600073
R wherein 1, R 2, R 3, Z as previously mentioned;
Be mixed in the organic solvent with a kind of Terminal Acetylenes and slaine, add organic base again, described Terminal Acetylenes is
Figure C0311702600074
R as previously mentioned;
(b) substrate reactions of the following structure of adding obtains aforementioned product
Figure C0311702600075
Y, P, Rf are as previously mentioned in the formula;
Reaction recommends to add proton source cancellation reaction, separates obtaining product then.Described proton source is recommended saturated aqueous ammonium chloride, water, rare or concentrated hydrochloric acid, perhaps aqueous citric acid solution.
The reaction mole proportioning of part and the fluorine-containing alkylaryl ketone of substrate is recommended as 0.1-3 in the said method: 1, further be recommended as 0.5-3: and 1, especially be recommended as 1.2-1.5: 1.
The reaction mole proportioning of slaine and the fluorine-containing alkylaryl ketone of substrate is recommended as 0.1-3 in the said method: 1, further be recommended as 0.5-3: and 1, especially be recommended as 1.2-1.5: 1.
The mol ratio of part and Terminal Acetylenes is recommended as 0.1-3 in the said method: 1, further be recommended as 0.5-3: and 1, especially be recommended as 1.2-1.5: 1.
The mol ratio of Terminal Acetylenes and the fluorine-containing alkylaryl ketone of substrate is recommended as 0.1-3 in the said method: 1, further be recommended as 0.5-3: and 1, especially be recommended as 1.2-1.5: 1.
Described slaine is recommended as zinc salt or mantoquita, further is recommended as Zn (II) or Cu salt, further is recommended as ZnCl 2, ZnBr 2, ZnF 2, ZnI 2, Zn (OTf) 2, Zn (SO 3CF 2H) 2, CuCl 2, CuBr 2, Cu (OTf) 2CuCl, CuBr, CuI, CuOTf especially is recommended as Zn (OTf) 2Perhaps Zn (SO 3CF 2H) 2.
Organic base is recommended as the amine that contains lone pair electrons on the nitrogen-atoms, further recommends MeNiPr 2, HNEt 2, NiPr 3, pyridine, piperidinyl piperidine, EtNiPr 2, NBu 3, NEt 3, especially be recommended as NEt 3
The reaction mole proportioning 1-4 of organic base and the fluorine-containing alkylaryl ketone of substrate: 1, be recommended as 3: 1
Organic solvent is recommended as non-protonic solvent or ether in the said method, further is recommended as oxolane, dioxane, and ether, benzene, dimethyl ether, toluene, n-hexane, cyclohexane, perhaps their mixture, especially the solvent of Tui Jianing is a toluene.
Reaction temperature is between 0 ℃ and 100 ℃ in the said method, is recommended as 0 ℃ and 50 ℃, and especially the recommendation response temperature is 20～40 ℃.
The chiral ligand of recommending in the said method is the compound of following structure:
Figure C0311702600081
Or
R wherein 4Be the oxygen protecting group, R 1, R 2, Z as previously mentioned.
Further the chiral ligand of recommending is the compound of following structure:
Figure C0311702600083
Or
Figure C0311702600084
R wherein 1, R 2, R 4As previously mentioned, further recommend R 1=R 2=Me.
Especially the chiral ligand of Tui Jianing is compound or its enantiomer of following structure
Figure C0311702600085
Above-mentioned chiral ligand Or its enantiomer synthetic with
Figure C0311702600087
Or its enantiomer to be raw material through conventional last protecting group method protect obtains
Figure C0311702600088
Or corresponding enantiomer.The method of last protecting group is with reference to T.W.Greene et al., Protective groups in OrganicSynthesis 3rd Ed.John Wiley 1999.For example
Figure C0311702600089
In 2 bit aminos can be in organic solvent realize the protection of amino earlier again with the reducing agent reduction with corresponding fatty aldehyde or aromatic aldehyde condensation, for example formic acid, NaBH of reducing agent wherein 4, KBH 4LiAlH 4Or Pd/C etc.; Perhaps use R 1X or R 2X carries out amido protecting under the effect of organic solvent neutralization bases, wherein X is a halogen; Under acid catalysis, realize the tert-butyl group protection of terminal hydroxy group with isobutene, perhaps use R 4Cl realizes the R of terminal hydroxy group 4Protection obtains above-mentioned part; Above-mentioned reaction condition is conventional reaction condition, and described alkali is inorganic base or organic base, for example K 2CO 3, Na 2CO 3, NaOH, KOH, NEt 3Deng.Described organic solvent is for example: alcohol, halogenated alkane, ether etc.Concrete example as, reflux with formaldehyde and formic acid and can realize amino two methyl protection, use NaBH again with the benzaldehyde condensation 4Reduction can realize amino benzyl protection.
Other part can or be bought from the market with the conventional method preparation and obtain.
The recommendering folder invention is used for the technology that asymmetric syntheses has following structural compounds with part:
Reaction equation is as follows:
Figure C0311702600092
P in the formula, Rf are as previously mentioned;
Further recommend part of the present invention to be used for the technology of the following structural compounds of asymmetric syntheses, reaction equation is as follows:
Especially recommend part of the present invention to be applied to the technology of synthetic following structural compounds
Comprise the steps:
When (a) being recommended in 20～40 ℃, (1R, 2R)-2-N, the amino replacement-1-(4-substituted-phenyl) of N--1-ethanol has following structure with chiral ligand
Figure C0311702600095
R wherein 1, R 2Be amino protecting group, R 3As previously mentioned; R 1, R 2Be recommended as methyl, R 3Be recommended as uncle's fourth oxygen methyl, Z is recommended as H, Cl, Br, CH 3SO 2Perhaps NO 2
Be mixed in the organic solvent with Terminal Acetylenes and Zn (II) salt or Cu salt, recommendation is dissolved in non-protonic solvent, add a kind of organic base again, wherein Terminal Acetylenes as previously mentioned, be recommended as cyclopropyl acethlene, mantoquita or divalent zinc salt are recommended as TFMS zinc, and protonic solvent is recommended as toluene, organic base is recommended as triethylamine
(b) add the substrate that following structure is arranged, recommendation response 10 hours,
(c) add proton source cancellation reaction;
(d) separation obtains product.
Unless otherwise indicated, the alkyl of the present invention hydrocarbon functional group of saturated fat that refers to side chain or straight chain; Recommending alkyl is 1 to 20 carbon number, further is recommended as the hydrocarbon functional group of saturated fat of the side chain or the straight chain of 1 to 4 carbon number, for example methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group etc.Halogen is fluorine, chlorine, bromine or iodine.
Among the present invention, R 1And R 2Be that any suitable amino protecting group includes but not limited to alkyl, substituted alkyl, benzyl, substituted benzyl or N-trialkyl silyl protecting group etc.Above-mentioned amino protecting group is recommended as C 1-C 20Alkyl, substituted alkyl, benzyl, substituted benzyl or N-trialkyl silyl protecting group etc.Substituting group on described alkyl or the benzyl is recommended phenyl, naphthyl, halo, nitro, C 1～C 3Hydroxyl, C 1～C 3Hydroxyalkyl, C 1～C 3Alkoxyl, CN etc.P, R 1And R 2C for example 1-C 4Alkyl, C is arranged 1-C 4Alkyl replace or do not have the benzyl of replacement; To methoxy-benzyl; To nitrobenzyl; P-chlorobenzyl; 2,4 dichloro benzyls; 2, the 4-dimethoxy-benzyl; Or the trimethyl silicon based protecting group of N-; other amino protecting group is with reference to T.W.Greene et al.; Protective groups in Organic Synthesis 3rd Ed.John Wiley 1999, the amino protecting group that pp.494-653. recommends is to methoxy-benzyl.
Among the present invention, P is H or any suitable amino protecting group, and amino protecting group as mentioned above.
Among the present invention, R 4In the oxygen protecting group be that any suitable oxygen protecting group includes but not limited to alkyl, substituted alkyl, benzyl, substituted benzyl or O-trialkyl silyl protecting group etc.Above-mentioned oxygen protecting group is recommended as C 1-C 20Alkyl, substituted alkyl, benzyl, substituted benzyl or O-trialkyl silyl protecting group.Substituting group on described alkyl or the benzyl is recommended phenyl, naphthyl, halo, nitro, C 1～C 3Hydroxyl, C 1～C 3Hydroxyalkyl, C 1～C 3Alkoxyl, CN etc.R 4C1-C for example 4Alkyl, benzhydryl, tert-butyl group dimethyl be silica-based, C is arranged 1-C 4Alkyl replace or do not have the benzyl of replacement, to methoxy-benzyl, to nitrobenzyl, p-chlorobenzyl, 2,4 dichloro benzyls, 2, the 4-dimethoxy-benzyl is to methoxy-benzyl; To nitrobenzyl; P-chlorobenzyl; 2,4 dichloro benzyls; 2, the 4-dimethoxy-benzyl; Or the silica-based protecting group of tert-butyl group dimethyl.Other oxygen protecting group is with reference to T.W.Greene et al., Protective groups in Organic Synthesis 3rd Ed.John Wiley 1999, and the oxygen protecting group that pp.17-245. recommends is the tert-butyl group.
Part provided by the invention can further be applied to the synthetic of Sustiva, and synthetic method is:
Figure C0311702600111
The invention provides alkynes copper that the amino alcohol part participates in or alkynes zinc method to the asymmetric addition of fluorine-containing alkylaryl ketone intermediate, obtain the product propargyl alcohol, the ee value is up to 99%, chiral ligand in the high optical activity of product and reaction condition as mild as a dove and the reaction can easily reclaim repeated use, and these advantages make this technology have good industrial prospect.When substrate was the trifluoromethyl aryl ketones, addition compound product promptly generated product HIV through easy conversion and moves enzyme inhibitor medicine Sustiva.
Following examples help to understand this patent but are not limited thereto scope.
Embodiment 1
(1R, 2R)-2-N, N-dimethylamino-3-is to nitre phenyl-1, the preparation of ammediol:
Reference literature Jiang, B.; Chen, Z.L.; Tang, X.X.Org.Lett.2002,4,3451. is synthetic
Embodiment 2
(1R, 2R)-3-tert-butoxy-2-N, N dimethylamino-1-is to the preparation of nitre phenyl-1-propyl alcohol: under 0-5 ℃, concentrated sulfuric acid 0.8g is added dropwise to that (1R, 2R)-2-N, N-dimethylamino-3-is to nitre phenyl-1, ammediol (1.8g, CH 7.5mmol) 2Cl 2(20mL) in the solution.Keep 0-5 ℃ to feed isobutene gas one hour down.Be added dropwise to concentrated sulfuric acid 0.2g again, mixture is got back to room temperature vigorous stirring reaction 5-7h and is fed isobutene gas continuously.Mixture is as cold as 0-5 ℃ and adds saturated K 2CO 3Solution.Organic facies drying (Na 2SO 4) concentrate the back recrystallization purifying and get 100.0-101.3 ℃ of ligand 1 .44g (65%) .mp; [α] D 20=+23.5 (c, 1.00, CHCl 3); FTIR (KBr) 3333,2972,1606,1523,1357,1197,861cm -1 1HNMR (300MHz, CDCl 3) δ 8.19 (d, J=8.8Hz, 2H), 7.60 (d, J=8.4Hz, 2H), 4.59 (d, J=9.9Hz, 1H), 3.34 (dd, J=3.0Hz, and 9.9Hz, 1H), 3.21 (dd, J=6.5Hz, and 10Hz, 1H), 2.56 (m, 1H), 2.47 (s, 6H), 1.06 (s, 9H); 13CNMR (75MHz, CDCl 3) δ 150.6,147.6,128.46,123.49,73.3,70.3,69.8,56.0,41.8,27.4; MS (EI) m/e 223 (M+-73,3), 209 (21), 144 (68), 88 (100), 71 (10), 57 (31); Anal.calcd. for C 15H 24N 2O 4: C, 60.81; H, 8.11; N, 9.46.Found:C, 60.72; H, 8.26; N, 914.
Embodiment 3
(1R, 2R)-3-tertiary butyl dimethyl Si base-2-N, N dimethylamino-1-is to the preparation of nitre phenyl-1-propyl alcohol: (1R, 2R)-2-N, N-dimethylamino-3-is to nitre phenyl-1, and (1.946g 8.1mmol) is dissolved in CH to ammediol 2Cl 2(30mL), 0 ℃ add down TBDMSCl (1.28g, 5.3mmol) and imidazoles (1.4g, 20.6mmol) the mixture stirring post processing of spending the night gets product 2.72g.FTIR (KBr) 3344,2954,1606,1525,1349cm -1 1HNMR (300MHz, CDCl 3) δ 8.25-8.20 (d, J=8.5Hz, 2H), 7.6-7.55 (d, J=8.5Hz, 2H), 4.65 (d, J=9.7Hz, 1H), 3.77-3.6 (dd, J=11.3Hz, 2.7Hz 1H), 3.5-3.45 (dd, J=11.3Hz, 6.0Hz 1H), 2.50 (m, 7H), 0.90 (s, 9H), 0.01 (s, 6H); 13CNMR (75MHz, CDCl 3) δ 150.2,147.4,128.0,123.3,69.0,57.1,41.6,25.7,17.9 ,-5.9; MS (EI) m/e297 (M+-57,0.3), 209 (8.2), 202 (100) .Anal.calcd.for C 17H 30N 2O 4Si:C, 57.60; H, 8.53; N, 7.90.Found:C, 57.82; H, 8.18; N, 7.77.
Embodiment 4
(1R, 2R)-3-three benzyloxies-2-N, N dimethylamino-1-is to the preparation of nitre phenyl-1-propyl alcohol: (1R, 2R)-2-N, N-dimethylamino-3-is to nitre phenyl-1, and (1.946g 8.1mmol) is dissolved in CH to ammediol 2Cl 2(50mL), 0 ℃ add down triphenylchloromethane (3.34g, 12mmol) and triithylamine (2mL) the mixture stirring post processing of spending the night get product 4.8g.FTIR (KBr) 3344,2954,1606,1525,1349cm -1 1HNMR (300MHz, CDCl 3) δ 8.09-8.06 (d, J=8.4Hz, 2H), 7.36-7.33 (d, J=8.6Hz, 2H), 7.25-7.17 (m, 5H), 4.27 (d, J=10.0Hz, 1H), 3..28 (dd, J=10.2Hz, 6.4Hz 1H), 3.01 (dd, J=10.7Hz, 3.9Hz 1H), 2.71 (m, 1H), 2.45 (s, 6H), 0.1 (s, 6H); 13CNMR (75MHz, CDCl 3) δ 150.1,147.6,143.6,128.9,128.8,128.7,128.6,128.4,128.1,127.9,127.8,127.3,123.7,87.7,70.9,70.6,58.6,41.6
Embodiment 5
(1R, 2R)-2-N-benzyl-N-methylamino-3-is to nitre phenyl-1, the preparation of ammediol:
(1R, 2R)-2-amino-3-is to nitre phenyl-1, ammediol (2.12g, 10mmol) and benzaldehyde (1.2g 10.5mmol) adds in the methyl alcohol (10mL), adds CuSO again 4(0.2g).Mixture back flow reaction 7hr, cool to room temperature filters, and adds THF (10mL) in the filtrate. add NaBH then in batches 4(0.4g).Cool off behind the mixture back flow reaction 2hr. add the 5%HCl souring soln.Concentrating with extracted with diethyl ether. residue and HCHO (10mL) and HCOOH (10mL) back flow reaction 8hr. cooling neutralize with NaOH.CH 2Cl 2Extraction, NaSO 4Drying gets the direct the next step of 1.2g product behind the recrystallization purifying again.
Embodiment 6
(1R, 2R)-3-tertiary butyl dimethyl Si base-2-N-benzyl-N-methylamino-1-(to the nitre phenyl)-1-propyl alcohol:
(1R, 2R)-2-N-benzyl-N-methylamino-3-is to nitre phenyl-1, and ammediol (632mg) is dissolved in CH 2Cl 2(15mL), be chilled to add again under 0 ℃ tert-butyl chloro-silicane (300mg, 2mmol) and phonetic azoles (136mg, 2mmol).Mixture reacts the post processing of spending the night and gets product 600mg.FTIR(KBr)3344，2972，1606，1525，1348cm -1； 1HNMR(300MHz，CDCl 3)δ8.17(d，J＝8.8Hz，2H)，7.50(d，J＝8.4Hz，2H)，7.38-7.31(m，5H)，4.70(d，J＝9.6Hz，1H)，4.04(d，J＝13.0Hz，1H)，3.77-3.55(m，3H)，2.70(m，1H)，2.43(s，3H)，0.90(s，9H)，0.01(s，6H)； 13CNMR(75MHz，CDCl 3)δ150.6，147.6，138.46，129.2，128.8，128.4，127.7，123.69，70.3，69.8，60.1，58.0，37.5，26.0，18.3，-5.4；MS(EI)m/e?415(M+-15，0.9)，278(100)，91(73)；
Embodiment 7
(1R, 2R)-3-(triphenyl methoxyl group)-2-N-benzyl-N-methylamino-1-(to the nitre phenyl)-1-propyl alcohol: (1R, 2R)-2-N-benzyl-N-methylamino-3-is to nitre phenyl-1, and (380mg 1.2mmol) is dissolved in CH to ammediol 2Cl 2(15mL), 0 ℃ add down triphenylchloromethane (334mg, 1.2mmol) and Et 3N (0.2mL).Separate after stirring is spent the night product 500mg.mp58.0-59.3℃；FTIR(KBr)3314，2926，1602，1521，1346cm -1； 1HNMR(300MHz，CDCl 3)δ8.07(d，J＝8.8Hz，2H)，7.40-7.19(m，22H)，4.30(d，J＝9.6Hz，1H)，3.94(d，J＝13.0Hz，1H)，3.73(d，J＝6.8Hz，1H)，3.36(m，1H)，3.06(m，1H)2.89(m，1H)，2.33(s，3H)； 13CNMR(75MHz，CDCl 3)δ150.6，147.6，143.46，138.2，129.3，128.8，128.7，128.6，128.4，128.0，127.7?127.4，123.7，87.8，70.5，69.8，60.1，58.0，37.0；MS(EI)m/e?406(M+-152，24.9)，243(100)；Anal.calcd.for?C 15H 24N 2O 4：C，77.42；H，6.09；N，5.02.Found：C，77.26；H，6.06；N，4.65..
Embodiment 8
(1R, 2R)-3-(triphenyl methoxyl group)-2-N, N-dimethylamino-1-(phenyl)-1-propyl alcohol synthetic (1R, 2R)-2-N, N-dimethylamino-1-(phenyl)-1, (1.95g 10mmol) is dissolved in CH to ammediol 2Cl 2(50mL), 0 ℃ add down triphenylchloromethane (3.33g, 12mmol) and the post processing of triithylamine (2mL) stirred overnight at room temperature get product 4.0g.FTIR (KBr) 3344,2954,1609,1525,1349 cm -1 1HNMR (300MHz, CDCl 3) δ 7.26-7.06 (m, 20H), 4.87 (d, J=10.0Hz, 1H), and 3.76 (dd, J=10.2Hz, 6.4Hz 1H), 3.51 (dd, J=10.7Hz, 3.9Hz 2H), 2.80 (m, 1H), 2.38 (s, 6H); 13CNMR (75MHz, CDCl 3) δ 143.6,138.9,128-129 (16C), 125.7-126.6 (4C), 84.9,72.9,68.6,69.6,49.6,39.6.
Embodiment 9
(1R, 2R)-3-(triphenyl methoxyl group)-2-N, N-dimethylamino-1-(to the mesyl phenyl)-1-propyl alcohol synthetic
(1R, 2R)-2-N, N-dimethylamino-1-(to the mesyl phenyl)-1, (5.46g 20mmol) is dissolved in CH to ammediol 2Cl 2(80mL), 0 ℃ add down triphenylchloromethane (6.8g, 25mmol) and the post processing of triithylamine (4mL) stirred overnight at room temperature get product 9.10g.FTIR(KBr)3344，2954，1609，1525，1349cm -1； 1HNMR(300MHz，CDCl 3)δ7.48-7.40(d，J＝8.4Hz，2H)，7.27-7.19(d，J＝8.6Hz，2H)，7.12-7.04(m，15H)，4.86(d，J＝10.0Hz，1H)，3.72(dd，J＝10.2Hz，6.4Hz?1H)，3.56(dd，J＝10.2Hz，6.4Hz?2H)，2.94(s，3H)，2.81(m，1H)，2.38(s，6H)； 13CNMR(75MHz，CDCl 3)δ143.8，143.0，138.6，135.0，129-126(16C)，84.9，72.9，69.6，68.0，49.6，41.0，39.6.
Embodiment 10
The addition of cyclopropyl acethlene p-trifluoromethyl phenyl ketone
Under 25 ℃, the amino alcohol part (1R, 2R)-3-tert-butoxy-2-N, N-dimethylamino-1-to nitre phenyl-1-propyl alcohol (2.96g, 10mmol) and Zn (OTf) 2(3.6g 10mmol) is dissolved in the toluene (10mL).Add NEt again 3(2.1mL, 15mmol).Add after one hour cyclopropyl acethlene (1.2mL, 12mmol) and trifluoromethyl ketone (1.74g, 10mmol).Mixture reacts 10hr down for 25 ℃.Saturated citric acid cancellation reaction.Ethyl acetate extraction.Organic facies merge dry back concentrate product (75% productive rate, 99.3%ee), water reclaims part with in the NaOH and back.
Embodiment 11
Cyclopropyl acethlene is to the addition of 2-amino-5-chlorphenyl trifluoromethyl ketone
Under 25 ℃, the amino alcohol part (1R, 2R)-3-tertiary butyl dimethyl Si base-2-N, N-dimethylamino-1-to nitre phenyl-1-propyl alcohol (3.54g, 10mmol) and Zn (OTf) 2(3.6g 10mmol) is dissolved in the toluene (10mL).Add NEt again 3(2.1mL, 15mmol).Add after one hour cyclopropyl acethlene (1.2mL, 12mmol), add after two hours 2-amino-5-chlorphenyl trifluoromethyl ketone (2.23g, 10mmol).Mixture reacts 10hr down for 25 ℃.Saturated citric acid cancellation reaction.Ethyl acetate extraction.Organic facies merge dry back concentrate product (60% productive rate, 90.1%ee).
Embodiment 13 cyclopropyl acethlenes are to the addition of 2-amino-5-chlorphenyl trifluoromethyl ketone
Under 25 ℃, the amino alcohol part (1R, 2R)-3-tert-butoxy-2-N, N-dimethylamino-1-to nitre phenyl-1-propyl alcohol (2.96g, 10mmol) and Zn (OTf) 2(3.6g 10mmol) is dissolved in the toluene (10mL).Add NEt again 3(2.1mL, 15mmol).Add after one hour cyclopropyl acethlene (1.2mL, 12mmol), add after two hours 2-amino-5-chlorphenyl trifluoromethyl ketone (2.23g, 10mmol).Mixture reacts 10hr down for 25 ℃.Saturated citric acid cancellation reaction.Ethyl acetate extraction.Organic facies merge dry back concentrate product (60% productive rate, 99.1%ee).
Embodiment 14
Tert-butyl group acetylene is to 2-amino-4, the addition of 5-difluorophenyl trifluoromethyl ketone
Under 25 ℃, the amino alcohol part (1R, 2R)-3-tertiary butyl dimethyl Si base-2-N, N dimethylamino-1-to nitre phenyl-1-propyl alcohol (354mg, 1mmol) and Zn (OTf) 2(0.36g 1mmol) is dissolved in the toluene (2mL).Add NEt again 3(0.21mL, 1.5mmol).Adding tert-butyl group acetylene after one hour (1.3mL, 12mmol) with 2-amino-4,5-difluorophenyl trifluoromethyl ketone (2.3g, 10mmol).Mixture reacts 10hr down for 25 ℃.Watery hydrochloric acid cancellation reaction.Ethyl acetate extraction.Organic facies merge dry back concentrate product.(85% productive rate, 94.1%ee).
Embodiment 15
Phenylacetylene is to 2-amino-4, the addition of 5-difluorophenyl trifluoromethyl ketone
Under 25 ℃, the amino alcohol part (1R, 2R)-3-triphenyl methoxyl group-2-N-benzyl-N-methylamino-1-to nitre phenyl-1-propyl alcohol (558mg, 1mmol) and Cu (OTf) 2(0.36g 1mmol) is dissolved in the toluene (10mL).Add NEt again 3(0.21mL, 1.5mmol).Add after one hour phenylacetylene (1.1mL, 12mmol) and 2-amino-4,5-difluorophenyl trifluoromethyl ketone (2.3g, 10mmol).Mixture reacts 10hr down for 25 ℃.Saturated citric acid cancellation reaction.Ethyl acetate extraction.Organic facies merge dry back concentrate product (67%yield, 55%ee).
Embodiment 16
Cyclopropyl acethlene is to the addition of 2-amino-5-chlorphenyl trifluoromethyl ketone
Under 25 ℃, and the amino alcohol part (1R, 2R)-2-methyl-2-N-methyl-N-benzyl-1-phenyl-1-ethanol (2.55g, 10mmol) and Zn (OTf) 2(3.6g 10mmol) is dissolved in the toluene (10mL).Add NEt again 3(2.1mL, 15mmol).Add after one hour cyclopropyl acethlene (1.2mL, 12mmol), add after two hours 2-amino-5-chlorphenyl trifluoromethyl ketone (2.23g, 10mmol).Mixture reacts 10hr down for 25 ℃.Saturated aqueous ammonium chloride cancellation reaction.Ethyl acetate extraction.Organic facies merge dry back concentrate product (51% productive rate, 96.1%ee).

Claims (7)

1. the application of chiral amino alcohol ligand in asymmetric syntheses is characterized in that in organic solvent and under 25 ℃, in the presence of the organic base, described chiral amino alcohol ligand catalytic substrate, a kind of molecular formula are
Figure C031170260002C1
Terminal Acetylenes and slaine carry out the product that asymmetric catalysis synthesis obtains to have following structural formula:
Figure C031170260002C2
Or
Figure C031170260002C3
Described substrate structure formula is as follows:
Figure C031170260002C4
The reaction mole proportioning of described slaine, organic base, part, Terminal Acetylenes and substrate is 0.1～3: 1-4: 0.1-3: 0.1-3: 1; Described slaine is Zn (II) salt or Cu salt;
Described organic base is the amine that contains lone pair electrons on the nitrogen-atoms;
Described organic solvent is non-protonic solvent or ether;
Described chiral amino alcohol ligand be have following structural formula (1R, 2R)-2-N, N-substituted-amino-2-replaces R 3-1-substituted-phenyl-1-ethanol or its enantiomer (1S, 2S)-2-N, N-substituted-amino-2-replaces R 3-1-substituted-phenyl-1-ethanol.
Figure C031170260002C5
Or
Wherein, P is H or amino protecting group; Rf contains fluoroalkyl; R is trialkyl silyl, alkyl, cycloalkyl or aryl; That Y represents on H or the phenyl ring is adjacent, or the single of contraposition replace or dibasic electron withdraw group or electron donating group; R 1, R 2Be C 1-C 4Alkyl, C 1-C 4The amino protecting group of substituted alkyl, benzyl, substituted benzyl or N-trialkyl silyl; R 3Be the alkyl of alkyl, alkoxyl replacement or alkyl, ester group, carboxyl, methylol, cycloalkyl, aryl or the CH that siloxy replaces 2OR 4, R wherein 4Oxygen protecting group for alkyl, substituted alkyl, benzyl, substituted benzyl or O-trialkyl silyl; That Z represents on H or the phenyl ring is adjacent, or the single of contraposition replace or dibasic electron withdraw group or electron donating group.
2. the application of chiral amino alcohol ligand in asymmetric syntheses according to claim 1 is characterized in that the amino protecting group among the described P is C 1-C 20Alkyl, C 1-C 20Substituted alkyl, benzyl, substituted benzyl or N-trialkyl silyl protecting group;
Described electron withdraw group is halogen, NO 2, CF 3, CH 3SO 2, CH 3CH 2SO 2Perhaps AcO;
Described electron donating group is C 1-C 20Alkoxyl, OH, Me 2NCH 2CH 2O, Et 2NCH 2CH 2O, PhCH 2OCO, NH 2Or C 1-C 20Alkyl.
R 3Be C 1-C 20Alkyl, C 1-C 20Alkyl, C that alkyl that alkoxyl replaces or siloxy replace 1-C 20Ester group, C 1-C 20Carboxyl, methylol, C 3-C 20Cycloalkyl, aryl or CH 2OR 4
R 4Be C 1-C 20Alkyl, C 1-C 20Substituted alkyl, benzyl, substituted benzyl or O-trialkyl silyl protecting group;
Rf is C 1-C 20Contain fluoroalkyl;
Substituting group on described alkyl or the benzyl is phenyl, naphthyl, halogen generation, nitro, C 1～C 3Hydroxyl, C 1～C 3Hydroxyalkyl, C 1～C 3Alkoxyl or CN;
R is trialkyl silyl, C 1-C 20Alkyl, C 1-C 20Cycloalkyl or aryl.
3 application of chiral amino alcohol ligand in asymmetric syntheses as claimed in claim 1 or 2 is characterized in that described electron donating group is C 1-C 4Alkoxyl, OH, Me 2NCH 2CH 2O, Et 2NCH 2CH 2O, PhCH 2OCO, NH 2, C 1-C 4Alkyl.
R 3Be C 1-C 4Alkyl, C 1-C 4Alkyl, C that alkyl that alkoxyl replaces or siloxy replace 1-C 4Ester group, C 1-C 4Carboxyl, methylol, C 1-C 4Cycloalkyl, aryl or CH 2OR 4
R 4Be C 1-C 4Alkyl, C 1-C 4Substituted alkyl, benzyl, substituted benzyl or O-trialkyl silyl protecting group;
Rf is C 1-C 4Contain fluoroalkyl.
4. the application of the described chiral amino alcohol ligand of claim 1 in asymmetric syntheses is characterized in that reacting the back and adds proton source cancellation reaction, separates obtaining product, chiral ligand by in the alkali and water extract again and reclaim use.
5. the application of chiral amino alcohol ligand in asymmetric syntheses according to claim 1 is characterized in that being used for synthetic following structure chipal compounds:
Figure C031170260003C1
Comprise the steps:
(a) (1R, 2R)-2-N, N-substituted-amino-1-(4-Z substituted-phenyl)-2-replaces CH will to have the chiral ligand of following structure 2OR 4-1-ethanol:
Figure C031170260003C2
Be mixed in the organic solvent with Terminal Acetylenes and Zn (II) salt or Cu salt, wherein R 1, R 2Be amino protecting group, R 4Be the oxygen protecting group, described R 1, R 2Or R 4According to claim 1; Z is H, Cl, Br, CH 3SO 2Perhaps NO 2Described Terminal Acetylenes is
Figure C031170260003C3
R adds organic base according to claim 1 again;
(b) add the substrate that following structure is arranged:
Add proton source cancellation reaction;
(c) separate and to obtain product, in the water alkali and reclaim part.
6. the application of chiral amino alcohol ligand in asymmetric syntheses according to claim 1 is characterized in that described slaine is for comprising ZnCl 2, ZnBr 2, ZnF 2, ZnI 2, Zn (OTf) 2, Zn (SO 3CF 2H) 2, CuCl 2, CuBr 2, Cu (OTf) 2, CuCl, CuBr, Cu (OTf) or CuI.
7. the application of chiral amino alcohol ligand in asymmetric syntheses according to claim 1 is characterized in that described described organic base is MeNiPr 2, HNEt 2, NiPr 3, pyridine, piperidines, EtNiPr 2, NBu 3Or NEt 3
CNB031170269A 2003-04-04 2003-05-16 Method of Chiral alkamine ligand used as catalyst of asymmetric addition process for terminal alkyne to fluoroalkylaryl ketone Expired - Fee Related CN1331601C (en)

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