CN103664816B - The one kettle way asymmetric synthesis technique of hiv reverse transcriptase inhibitor Sustiva compounds - Google Patents

The one kettle way asymmetric synthesis technique of hiv reverse transcriptase inhibitor Sustiva compounds Download PDF

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CN103664816B
CN103664816B CN201310438807.9A CN201310438807A CN103664816B CN 103664816 B CN103664816 B CN 103664816B CN 201310438807 A CN201310438807 A CN 201310438807A CN 103664816 B CN103664816 B CN 103664816B
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姜标
李金华
张琛
李晓贤
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The present invention relates to (S)-6-chloro-4-cyclopropyl acethlene base-4-Trifluoromethyl-1,4-dihydro-2H-1, the divisional application that the new one kettle way asymmetric synthesis technique of 3-benzoxazine-2-ketone (Sustiva Efavirenz) compounds is application number is 201110001621.8, the applying date is on 01 06th, 2011, denomination of invention is " the one kettle way asymmetric synthesis technique of hiv reverse transcriptase inhibitor Sustiva compounds ".Described compound can be used as the reverse transcriptase inhibitors of human immunodeficiency virus (HIV).The invention still further relates to the new amino alcohol ligands for this technique.

Description

The one kettle way asymmetric synthesis technique of hiv reverse transcriptase inhibitor Sustiva compounds
The divisional application that the present patent application is application number is 201110001621.8, the applying date is on 01 06th, 2011, denomination of invention is " the one kettle way asymmetric synthesis technique of hiv reverse transcriptase inhibitor Sustiva compounds ".
Technical field:
The present invention relates to (S)-6-chloro-4-cyclopropyl acethlene base-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone (Sustiva Efavirenz, formula I) new one kettle way asymmetric synthesis technique, namely Terminal Acetylenes generates the propargyl tertiary alcohol to the enantioselectivity addition of trifluorumethylketone, this adduct is synthesis AntiHIV1 RT activity reverse transcriptase inhibitors Efavirenz(DMP266) key intermediate, it is without separation and purification, adopts the mode of continuous one pot reaction to close ring by a step under alkali promotes and obtains Efavirenz.The invention still further relates to the new amino alcohol ligands for this technique.
Background technology:
Reverse transcription is specific to retrovirus copies.Virus replication requires that the reversed transcriptive enzyme of encoding viral produces the DNA copy of virus sequence by the reverse transcription of viral RNA genes group.Because the suppression of the reversed transcriptive enzyme to encoding viral can interrupt virus replication, therefore, for the chemotherapy of retroviral infection, reversed transcriptive enzyme is a clinical related target.
Chemical compound lot is effective in treatment HIV (human immunodeficiency virus) (HIV), and this virus can cause human immune system's Progressive symmetric erythrokeratodermia to destroy and the retrovirus causing AIDS to fall ill.To the inhibitor based on nucleosides, such as Zidovodine and the inhibitor based on non-nucleosides, by being known effective methods for the treatment of for the inhibitor of hiv reverse transcriptase, have been found that benzoxazine ketone is the useful hiv reverse transcriptase inhibitor based on non-nucleosides at present.In addition, HIV (human immunodeficiency virus) (HIV) is easily suddenlyd change, this can cause resistance, Efavirenz, DPC961 and DPC083 of being researched and developed by E.I.Du Pont Company have the efficient HIV non-nucleoside reverse transcriptase inhibitor (NNRTIs) of the more highly active s-generation, and wherein Efavirenz has been used for the treatment of the choice drug of HIV by U.S. FDA approval.Consider important medical value and the social effect of reverse transcriptase inhibitors compounds, be badly in need of developing for the preparation of the economy of Efavirenz efficient asymmetric synthesis technique.
Thompson etc. are at tetrahedron magazine (TetrahedronLetters, 1995,36, a kind of method of asymmetric synthesis benzoxazinone is described 937-940), be shown below, it is the synthesis of the acetylide by having height enantioselectivity, then adopts condensing agent cyclisation, finally completes the synthesis of benzoxazinone.
The phosgene of severe toxicity wherein not only will be used as condensing agent, and also to use a large amount of jeopardously highly basic (alkyl lithium reagents) and expensive part in the step of asymmetric addition, the reaction conditions simultaneously required is very harsh (low temperature and anhydrous and oxygen-free) also, totally unfavorable to industrial mass production.In addition, be carry out Benzylation obtaining by p-methoxybenzyl chloride and aniline nitrogen-atoms to methoxy-benzyl aniline raw material, owing to employing ceric ammonium nitrate in debenzylation step, thus above-mentioned total method will produce a large amount of waste liquid containing heavy metal waste.
The three-step approach of synthesis benzoxazinone is described in European patent 582455A1:
This universal method is: (1) adopts the pivalyl amine of n-Butyl Lithium and p-Chlorobenzoic acid amide to carry out metal replacement, then carries out nucleophilic substitution with ester and forms trifluoroacetyl group ketone; (2) by carrying out Ge Liya addition to ketone, the synthesis tertiary alcohol; (3) tertiary alcohol reacts with excessive condensing agent again.The method not only will use poisonous condensing agent, and next needs to use optical activity resolving agent such as (-)-dextrocamphoric acid to carry out purifying optical isomer, finally also will obtain optically pure benzoxazinone by hydrolysis dextrocamphoric acid, operate cumbersome.
Young etc. describe in pct international patent application WO9520389A1 for suppress hiv reverse transcriptase, prevention or treatment HIV benzoxazin ketone compound.Also the synthetic method corresponding to above-mentioned EP582455A1 is disclosed in WO9520389A1.In addition, Young etc. are also at biocide and chemotherapy impurity (AntimicrobialAgentsandChemotherapy, 1995, 39, benzoxazinone is discussed as the clinical effectiveness of hiv reverse transcriptase inhibitor in treatment HIV 2602-2605), external activity and his kinetic activity, and disclose the method for the simplification synthesis benzoxazinone corresponding to EP582455A1, the cyclization precursor tertiary alcohol is wherein obtained by corresponding amine and the addition of cyclopropyl acethlene base lithium reagent, not only still there is above-mentioned defect, and combined coefficient is still very low.
United States Patent (USP) 5922864 describes a kind of cyclization by relating to alkyl chloroformate and chloroformic acid aryl ester to prepare the method for benzoxazin ketone compound, wherein relate to and first methoxy-benzyl being protected, again through asymmetric addition, remove benzyl protection afterwards next again with alkyl chloroformate or the protection of chloroformic acid aryl ester, the product of separation and purification closes ring in the basic conditions and obtains benzoxazinone, severe toxicity is used and the analogue of the phosgene not easily stored and operate and phosgene although avoid, but there is protection in multistep and go protection and corresponding separation and purification work, complicated operation, add industrial difficulty and cost.
In sum, the method of more than synthesizing benzoxazinone compound all employs the ligand stock of severe toxicity or reluctant reagent and costliness, the inconvenience of synthesis technique complex operation, in addition inefficient chromatographic purification step or (S)-6-chloro-4-cyclopropyl acethlene base-4-Trifluoromethyl-1 of low yield, 4-dihydro-2H-3, 1-benzoxazine-2-ketone (Sustiva Efavirenz, formula 1) total synthetic route, therefore, be badly in need of seeking the new synthesis technique that can adapt to the benzoxazinone compound of large-scale industrialized production, above-mentioned restricted condition be avoided or be improved to such synthesis technique can not only, and required benzoxazinone compound can also be provided efficiently.
For this reason, the invention provides a kind of new asymmetric synthesis (S)-6-chloro-4-cyclopropyl acethlene base-4-Trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazine-2-ketone (Sustiva Efavirenz, formula I) one kettle way technique, this benzoxazinone compound can be used as the reversed transcriptive enzyme of human immunodeficiency virus (HIV); Invention also provides a kind of new chiral amino alcohol ligand, it can be used for the synthesis technique of above-mentioned asymmetric ethynylation ketone.
One section is not had to describe the method for the present invention in order to the benzoxazin ketone compound of asymmetric synthesis as hiv reverse transcriptase inhibitor in above citing document.
Summary of the invention
The invention provides a kind of Efavirenz(Sustiva) the efficient asymmetric synthesis technique of new one kettle way of compounds, the invention still further relates to a series of new amino alcohol ligands for this technique simultaneously.
The present invention establishes Terminal Acetylenes that a kind of chiral amino alcohol ligand participates in generates chirality tertiary alcohol method to the enantioselectivity addition of trifluorumethylketone intermediate, and this chirality tertiary alcohol is synthesis Efavirenz(Sustiva) key intermediate of compounds.The inventive method can be used for direct construction Efanvirenz(Sustiva) chirality quaternary carbon center in compounds molecule, the alkynes copper participated in by chiral amino alcohol or alkynes zinc generate the chirality propargyl tertiary alcohol to the enantioselectivity addition of trifluorumethylketone intermediate, and product ee value is up to 99% and this tertiary alcohol just can generate Efavirenz(Sustiva without the direct step cyclisation in the basic conditions of separation enantioselectivity) compounds.This processing condition are gentle, effectively avoid using the reagent such as the phosgene class condensing agent of severe toxicity and heavy metal ceric ammonium nitrate, easy and simple to handle and step is few, and part is cheap and can recycle very easily in addition, is extremely easy to heavy industrialization.The invention provides and can obtain enantiomer-pure product Efavirenz(Sustiva) the effectively non-chromatogram purification of compounds and the method for chemical resolution, also provide the chiral amino alcohol ligand that some are new simultaneously.
In the present invention, provide a kind of novel process, a kind of amino alcohol ligands be used for the compound that the asymmetric synthesis of continuous print one pot reaction has following general structure:
In formula, Y is hydrogen, monosubstituted or polysubstitutedly draws electronics or electron-donating group; Recommendation Y is hydrogen, monosubstituted or two replace draw electronics or electron-donating group, Y can be positioned at phenyl ring neighbour, or contraposition; Further recommendation Y is H, F, Cl, Br, I, CN, CF 3, CHF 2, CF 3o, CHF 2o, CH 3sO 2, CH 3cH 2sO 2, CH 3sO 2o, PhCH 2o, AcO, MeO, EtO, Me 2nCH 2cH 2o, Et 2nCH 2cH 2o, PhCH 2oCO, t-Bu, i-Pr, NH 2or NO 2; Especially Y is recommended to be F, Cl, Br, CN, CF 3, CHF 2, CF 3o, CHF 2o, CH 3sO 2, CH 3cH 2sO 2or NO 2;
Rf is perfluoroalkyl, is recommended as C 1-C 20perfluoroalkyl; Further recommendation C 1-C 4perfluoroalkyl;
R is silica-based, the R that alkyl or phenyl replaces 6the alkyl, the R that replace 6the alkoxyl group, the R that replace 6the thio alkoxy, the R that replace 6the cycloalkyl, the R that replace 6the aryl replaced or R 6the benzyl replaced; R is recommended to be three (C 1-C 20) alkyl silyl, tert-butyl diphenyl are silica-based, R 6the C replaced 1-C 20alkyl, R 6the C replaced 3-C 7cycloalkyl, R 6the C replaced 1-C 20alkoxyl group, R 6the C replaced 1-C 20thio alkoxy, R 6the phenyl, the R that replace 6the benzyl, the R that replace 6the naphthyl, the R that replace 6the furans, the R that replace 6the thiophene, the R that replace 6the pyrroles replaced, R 6the thiazole, the R that replace 6the pyrazoles, the R that replace 6the imidazoles, the R that replace 6the pyridine, the R that replace 6the pyrimidine, the R that replace 6the triazole, the R that replace 6the tetrazole, the R that replace 6the cumarone, the R that replace 6the thionaphthene replaced or R 6the benzopyrrole replaced; Described aryl and R 6shown in being defined as follows;
Substituent R of the present invention 6hydrogen, halogen, nitro, hydroxyl, methyl, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy, CN, CF 3, CHF 2, CHF 2o, CF 3o, CH 3sO 2or CH 3cH 2sO 2; Replacement mode is monosubstituted, and two replace or three replacements; Substituent position at the ortho position of aryl, the optional position in contraposition and a position;
Aryl of the present invention is phenyl, naphthyl, heteroaryl or benzo heteroaryl; Wherein said heteroaryl refers to that five yuan or hexa-atomic containing heteroatomic cyclic aromatic compound, and wherein heteroatoms is O, S or N;
Described amino alcohol ligands is compound or its whole mapping or the diastereomer of following structure:
Wherein R 1, R 2it is identical or different group; R 1and R 2be any suitable amino protecting group, include but not limited to alkyl, R 6the alkyl, the R that replace 6it is silica-based that the benzyl replaced, alkyl or phenyl replace; Or R 1, R 2can Cheng Huanwei-(CH 2) nx (CH 2) m-, wherein X can be CH 2, O, S or NH; N, m are the integers of 1 to 6; Recommend R 1, R 2for containing R 6c 1-C 20alkyl, containing R 6benzyl, three (C 1-C 20) alkyl silyl or tert-butyl diphenyl silica-based; Or R 1, R 2can be-(CH 2) nx (CH 2) m-; Wherein X is CH 2, O, S or NH; N, m are the integer of 1 to 6; Described R 6definition as previously shown;
R 3for hydrogen, R 6the alkyl, the R that replace 6the cycloalkyl, the R that replace 6the alkoxyl group, the R that replace 6the thio alkoxy, the R that replace 6the carboxyl, the R that replace 6the carbalkoxy, the R that replace 6the sulfo-carbalkoxy, the R that replace 6the aryl, the R that replace 6the benzyl replaced or CH 2oR 4; Wherein R 4for hydrogen or oxygen protecting group, described oxygen protecting group is any suitable oxygen base protecting group, includes but not limited to alkyl, R 6the alkyl replaced, R 6the cycloalkyl, the R that replace 6the benzyl replaced, R 6the aryl, the R that replace 6it is silica-based that the trityl replaced, alkyl or phenyl replace; Recommend R 3hydrogen, R 6the C replaced 1-C 20alkyl, R 6the C replaced 3-C 7cycloalkyl, R 6the C replaced 1-C 20alkoxyl group, R 6the C replaced 1-C 20thio alkoxy, R 6the C replaced 1-C 20carboxyl, containing R 6c 1-C 20carbalkoxy, containing R 6c 1-C 20sulfo-carbalkoxy, containing R 6phenyl, R 6the benzyl, the R that replace 6the furans, the R that replace 6the thiophene, the R that replace 6the pyrroles replaced, R 6the pyridine, the R that replace 6the pyrimidine, the R that replace 6the thiazole, the R that replace 6the pyrazoles, the R that replace 6the imidazoles, the R that replace 6the triazole, the R that replace 6the tetrazole, the R that replace 6the cumarone, the R that replace 6the thionaphthene, the R that replace 6the benzopyrrole replaced or CH 2oR 4; Wherein R 4for hydrogen, R 6the C replaced 1-C 20alkyl, R 6the C replaced 3-C 7cycloalkyl, three (C 1-C 20) alkyl silyl, tert-butyl diphenyl are silica-based, R 6the benzyl, the R that replace 6the trityl, the R that replace 6the phenyl, the R that replace 6the naphthyl, the R that replace 6the pyrimidyl, the R that replace 6the pyridyl replaced or R 6the thiazolyl replaced; Described aryl and R 6definition as previously shown;
Z is hydrogen, monosubstituted or polysubstitutedly draws electronics or electron-donating group, Z can be positioned at phenyl ring neighbour, or contraposition; Described drawing electron group is halogen, OH, NO 2, CN, CF 3, CHF 2, CF 3o, CHF 2o, CH 3sO 2, CH 3cH 2sO 2, PhCH 2oCO, PhCH 2o or AcO; Described electron-donating group is C 1-C 3alkoxyl group, OH, Me 2nCH 2cH 2o, Et 2nCH 2cH 2o, NH 2, C 1-C 4alkyl; Z is recommended to be H, F, Cl, Br, I, CN, CF 3, CHF 2, CF 3o, CHF 2o, OH, CH 3sO 2, PhCH 2o, AcO, MeO, EtO, Me 2nCH 2cH 2o, Et 2nCH 2cH 2o, PhCH 2oCO, t-Bu, i-Pr, NH 2, CH 3cH 2sO 2or NO 2;
W is-(CH 2) q-,-(CH 2) qo-,-(CH 2) qs-or-(CH 2) qnH-, wherein q can be the integer of 0 to 3;
This technique comprises the steps:
A protection that () is amino: by formula (II) compound or hydrochloride,
In the presence of a base, in the mixed solvent of organic solvent and water, temperature 0 DEG C at 60 DEG C, with ClCOOR 5reaction 1-72 hour, fully extracts after reacting completely and concentrating under reduced pressure evaporate to dryness can obtain formula (III) compound;
Wherein R 5r 6the C replaced 1-C 20alkyl, R 6the C replaced 3-C 7cycloalkyl, R 6the phenyl replaced or R 6the naphthyl replaced; Wherein Y, Rf are as previously mentioned;
Alkali described in above-mentioned steps a is mineral alkali or organic bases; Wherein mineral alkali is selected from alkali-metal oxyhydroxide, alkali-metal carbonate, alkali-metal supercarbonate, alkali alcoholate, alkali-metal phosphoric acid salt or alkali-metal hydrophosphate; Wherein organic bases is selected from MeN (i-Pr) 2, HNEt 2, N (i-Pr) 3, pyridine, NEt 3, piperidines, EtN (i-Pr) 2or Bu 3n;
In above-mentioned steps a, the reaction mol ratio of organic solvent and water is recommended as (20-1): 1;
Described formula II compound or hydrochloride: alkali: ClCOOR 5mol ratio be 1:(1-20): (1-20);
(b) 1. Terminal Acetylenes to the asymmetric reduction reaction of the trifluorumethylketone that chloro-formic ester is protected:
0 DEG C at 60 DEG C, by chiral amino alcohol ligand, its general structure is compound or its whole mapping or the diastereomer of following structure:
Wherein R 1, R 2, R 3, the description of Z and W as previously mentioned;
With Terminal Acetylenes and Zn(Ι Ι) salt, Cu(Ι Ι) salt or Cu(Ι) salt and organic bases be mixed in organic solvent, and wherein Terminal Acetylenes is , R as previously mentioned;
Then, the compound of formula (III) is added in the mixture 1. walked at (b);
The organic bases of described step b is selected from amine atom N having lone-pair electron, as MeN(i-Pr) 2, diethylamide, triisopropylamine, pyridine, NEt 3, piperidines, NBu 3or EtN (i-Pr) 2;
Zinc salt or the mantoquita of described step b are selected from ZnCl 2, ZnBr 2, ZnF 2, ZnI 2, CuCl 2, CuBr 2, CuI 2, CuCl, CuBr, CuI, Cu (OTf) 2, Cu (OTf), Cu(PhSO 3), Cu(PhSO 3) 2, Cu(OTs) 2, Cu(OTs), Cu (OMs) 2, Cu (OMs), Zn (OTf) 2, Zn (ODf) 2, Zn (OMs) 2, Zn(OTs) 2or Zn(PhSO 3) 2;
Described in step a or b, organic solvent is selected from acetonitrile, tetrahydrofuran (THF), methyltetrahydrofuran, dioxane, Et 2o, dme, methyl tertiary butyl ether, ethyl acetate, n-butyl acetate, isopropyl acetate, benzene,toluene,xylene, normal hexane, normal heptane, octane, hexanaphthene, CH 2cl 2, 1,2-ethylene dichloride, DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, acetone, methyl alcohol, ethanol, Virahol or their mixture;
Described formula III compound: the amino alcohol ligands of chirality: Terminal Acetylenes: Zn salt or Cu salt: the mol ratio of organic bases is (0.1-3): (0.1-3): (0.1-3): (0.1-4);
2. continuous print one kettle way cyclization:
Recommendation high performance liquid phase is followed the tracks of and detection reaction, 1. walks material content when being less than 5% in (b), at 200 DEG C, recommends the reflux temperature of solvent, then reacts 5-48 hour, until the product that (b) 1. walks generation is all converted into cyclisation product for 60 DEG C.Recommendation adds proton source cancellation reaction, by extracting and separating organic phase and aqueous phase.Organic phase is directly concentrated obtains cyclisation product, and yield is greater than 95%, ee value and is greater than 99%; Aqueous phase is through alkali cleaning and extraction Recovery Design, and the rate of recovery is greater than 90%, ee value for being greater than 99%.
Wherein proton source can be saturated aqueous ammonium chloride, water, dilute hydrochloric acid, dilute sulphuric acid, acetic acid, formic acid or aqueous citric acid solution;
The amino alcohol ligands structure of recommending is compound or its whole mapping or the diastereomer of following structure:
Wherein R 1, R 2, R 3, the description of Z and W as previously mentioned;
Further recommendation chiral amino alcohol ligand is compound or the enantiomorph of following structure:
Wherein R 1, R 2, R 4with Z as previously mentioned;
Especially recommendation chiral amino alcohol ligand is compound or its enantiomorph of following structure:
Wherein R 1, R 2, R 4with Z as previously mentioned;
Recommend technique of the present invention for the synthesis of the compound of following structure or its enantiomorph:
Specifically comprise the steps:
A chloro-formic ester protection that () is amino:
By formula (IV) compound or hydrochloride,
In the presence of a base, in the mixed solvent of organic solvent and water, temperature 0 DEG C at 30 DEG C, with the C of chloroformic acid 1-C 10alkyl ester, C 3-C 5cycloalkyl ester, phenylester or the reaction of naphthyl ester, about 1 to 48 hours reaction times, fully extraction concentrating under reduced pressure evaporate to dryness can obtain formula V compound after reacting completely, further recrystallization obtains the sterling compound of formula V;
In aforesaid method, R 5be recommended as C 1-C 7alkyl, C 3-C 5cycloalkyl, phenyl, benzyl or naphthyl;
In aforesaid method, as previously shown, wherein basic metal is recommended as Na, K or Li in the definition of alkali;
In aforesaid method, recrystallization solvent is recommended as sherwood oil, normal hexane, normal heptane, hexanaphthene or methylcyclohexane;
In aforesaid method, the reaction mol ratio of organic solvent and water is recommended as (10-1) further: 1;
Described compound IV or hydrochloride: alkali: ClCOOR 5mol ratio be 1:(1-10): (1-10);
(b) 1. Terminal Acetylenes to the asymmetric reduction reaction of the trifluorumethylketone that chloro-formic ester is protected:
The amino alcohol ligands of chirality, its general structure is compound or its whole mapping or the diastereomer of following structure:
Wherein R 1, R 2, R 3, the description of Z and W as previously mentioned;
With Terminal Acetylenes, Zn(II), Cu(I) or Cu(II) salt and organic bases be mixed in organic solvent, wherein Terminal Acetylenes is;
1. the reactant adding the following structure of formula V in mixed solution is walked at (b):
Wherein R 5as previously mentioned;
Recommendation response temperature is 0-30 DEG C, is especially recommended as room temperature, recommendation response time 1-48 hour;
Organic solvent in described step a or b is selected from the arbitrary combination solvent of tetrahydrofuran (THF), 2-methyltetrahydrofuran, ethyl acetate, n-butyl acetate, isopropyl acetate, ether, methyl tertiary butyl ether, Isosorbide-5-Nitrae-dioxane, normal hexane, normal heptane, hexanaphthene, benzene,toluene,xylene, acetonitrile or above-mentioned solvent;
Formula V compound described in step b: the amino alcohol ligands of chirality: Terminal Acetylenes: Zn salt or Cu salt: the mol ratio of organic bases is 1:(0.5-3): (0.5-3): (0.5-3): (2-3.5);
2. continuous print one kettle way cyclization:
Recommendation high performance liquid phase is followed the tracks of and detection reaction, in (b), 1. walk material content when being less than 5%, at 150 DEG C, recommend solvent reflux temperature for 30 DEG C, reaction 5-48 hour, until the product that (b) 1. walks generation is all converted into Efavirenz(Sustiva).Recommendation adds proton source cancellation reaction, by extracting and separating organic phase and aqueous phase.Organic phase is directly concentrated obtains product E favirenz(Sustiva, formula I), crystal formation is 1 type, and yield is greater than 95%, ee value and is greater than 99%; Aqueous phase is through alkali cleaning and extraction Recovery Design, and the rate of recovery is greater than 90%, ee value for being greater than 99%.
Proton source described in aforesaid method is recommended as saturated aqueous ammonium chloride, water, dilute hydrochloric acid, dilute sulphuric acid, acetic acid, formic acid or aqueous citric acid solution;
Further recommendation chiral ligand is compound or its enantiomorph of following structure:
Wherein R 1, R 2, R 4as previously mentioned;
In aforesaid method, the reaction mol ratio of part and substrate ketone is recommended as (0.1-3): 1, is recommended as further (0.5-3): 1, is especially recommended as (1.2-1.5): 1;
In aforesaid method, the reaction mol ratio of Terminal Acetylenes and substrate ketone is recommended as (0.1-3): 1, is recommended as further (0.5-3): 1, is especially recommended as (1.2-1.5): 1;
In aforesaid method, zinc salt or mantoquita are recommended as ZnCl 2, ZnBr 2, ZnF 2, CuCl 2, CuBr 2, CuCl, CuBr, Cu (OTf) 2, Cu(PhSO 3) 2, Cu(OTs) 2, Cu (OMs) 2, Zn (OTf) 2, Zn (ODf) 2, Zn (OMs) 2, Zn(OTs) 2or Zn(PhSO 3) 2; Especially Zinc(II is recommended) be Zn(OTf) 2;
In aforesaid method, the reaction mol ratio of metal-salt and substrate ketone is recommended as (0.1-3): 1, is recommended as further (0.5-3): 1, is especially recommended as (1.2-1.5): 1;
In aforesaid method, the reaction mol ratio of organic bases and substrate ketone is recommended as (1-4): 1, is recommended as further (2.0-3.5): 1;
The organic bases recommended is diethylamide, triisopropylamine, pyridine, NEt 3or piperidines; The organic bases of further recommendation is NEt 3;
Recommend asymmetric reduction reaction temperature 0 DEG C to 60 DEG C; Further recommendation response temperature is 0 DEG C to 30 DEG C; Especially recommendation response temperature is room temperature;
Ring-closure reaction temperature is recommended to be 30 DEG C to 200 DEG C; Further recommendation response temperature is 30 DEG C to 150 DEG C;
Further recommendation R 1, R 2for containing R 6c 1-C 4alkyl, t-Butyldimethylsilyl, tert-butyl diphenyl are silica-based, benzyl, C 1-C 4alkyl replace benzyl, halogen substiuted benzyl, to methoxy-benzyl, to nitrobenzyl, 2,4-dimethoxy-benzyls; Or R 1, R 2cheng Huanwei-(CH 2) 2o (CH 2) 2-,-(CH 2) 2n (CH 2) 2-,-(CH 2) 4-,-(CH 2) 5-or-(CH 2) 6-;
Further recommendation R 5for methyl esters, ethyl ester, ring propyl ester, p-nitrophenyl, to nitrobenzyl, rubigan, p-chlorobenzyl, 2,4 dichloro benzene base or 2,4-dichloro benzyl;
Further recommendation R is R 6the C replaced 1-C 4alkyl, three (C 1-C 4) alkyl silyl, tert-butyl diphenyl are silica-based, R 6the C replaced 3-C 7cycloalkyl, R 6the C replaced 1-C 4alkoxyl group, R 6the C replaced 1-C 4thio alkoxy, R 6the phenyl, the R that replace 6the benzyl replaced, furans, thiophene, pyrroles, pyridine, pyrimidine, thiazole, pyrazoles, imidazoles; Described R 6definition as previously mentioned;
Further recommendation R 3for hydrogen, containing R 6c 1-C 4alkyl, containing R 6c 3-C 7cycloalkyl, containing R 6benzyl or CH 2oR 4; Further recommendation R 4for hydrogen, R 6the C replaced 1-C 4alkyl, R 6the C replaced 3-C 7cycloalkyl, three (C 1-C 4) alkyl silyl, tert-butyl diphenyl are silica-based, trityl or R 6the benzyl replaced; Wherein R 6definition as previously shown;
Further recommendation Z is H, F, Cl, Br, CN, CF 3, CHF 2, CHF 2o, CF 3o, CH 3sO 2or NO 2;
Further recommendation W is-CH 2-,-CH 2cH 2-,-(CH 2) qo-or-(CH 2) qnH-; Wherein q can be 0 or 1;
Further recommendation Y is H, Cl, F, Br, I, CN, CF 3, CHF 2, CF 3o, CHF 2o, CH 3sO 2, CH 3cH 2sO 2, CH 3sO 2o, PhCH 2o, AcO, MeO, EtO, Me 2nCH 2cH 2o, Et 2nCH 2cH 2o, PhCH 2oCO, t-Bu, i-Pr, NH 2or NO 2; Especially Y is recommended to be F, Cl, Br, CN, CF 3, CHF 2, CF 3o, CHF 2o, CH 3sO 2, CH 3cH 2sO 2or NO 2; More Y is recommended to be F, Cl, Br.
The invention provides a kind of new chiral ligand, compound or its whole mapping or diastereomer for following structure:
Wherein R 1, R 2, R 3, R 4, Z and W definition as previously shown.
The synthesis of new part:
Four parts as implied above and isomer thereof can be transformed by following compounds and isomer thereof,
Wherein amino protection can refer to T.W.Greeneetal., ProtectivegroupsinOrganicSynthesis3rdEd.JohnWiley1999, pp.17-245.
Such as its 1 bit amino can restore with suitable aldehyde condensation and protect, and reductive agent is as formic acid, NaBH 4, KBH 4, LiAlH 4or Pd/C.1 bit amino also can use R under alkali effect 1x or R 2x reacts protection in organic solvent, and wherein X is halogen.In addition, 1 bit amino can also in acetic acid, and Zn powder is protected with suitable aldehyde reaction under promoting.Above-mentioned reaction is popular response, and described alkali can be inorganic or organic bases, such as K 2cO 3, Na 2cO 3, NaOH or NEt 3.Described organic solvent can be alcohol, DMF, N,N-dimethylacetamide, halogenated alkane or ethers.The two methyl of detailed enforcement as under reflux conditions realized 1 bit amino with formaldehyde and formic acid are protected, or prior to benzaldehyde NaBH again 4reduction realizes benzyl protection, wherein adds mantoquita (CuSO during condensation 4) as catalyzer or add dewatering agent.
Such as part again or the synthesis of its enantiomorph can by compound through reacting with formaldehyde selectivity aldol, restore amination, the method for concrete amination also can refer to above, and namely substrate ketone and suitable amine are reacted by condensating reductive and realizes amination.
Unless otherwise indicated, alkyl of the present invention refers to the hydrocarbon functional group of the saturated fatty of side chain or straight chain; Recommend alkyl to be 1 to 20 carbon numbers, be recommended as the side chain of 1 to 4 carbon numbers or the hydrocarbon functional group of saturated fatty of straight chain further, such as methyl, ethyl, n-propyl, normal-butyl, isobutyl-or the tertiary butyl etc.
Described halogen is fluorine, chlorine or bromine;
Described cycloalkyl refers to 3 to 7 carbon atoms.
The alkyl of described alkoxyl group or thio alkoxy refers to the hydrocarbon functional group of the saturated fatty of side chain or straight chain; Recommend alkyl to be 1 to 20 carbon numbers, be recommended as the side chain of 1 to 4 carbon numbers or the hydrocarbon functional group of saturated fatty of straight chain further;
Described carbalkoxy or sulfo-carbalkoxy are recommended as the carbon number of 1 to 20, recommend 1 to 4 carbon numbers further;
Described Aryl means phenyl, naphthyl, heteroaryl or benzo heteroaryl, wherein heteroaryl refer to five yuan or hexa-atomic containing heteroatomic cyclic aromatic compound, heteroatoms refers to O, S or N; Recommend phenyl, naphthyl, furans, thiophene, pyrroles, thiazole, pyrazoles, imidazoles, pyridine, pyrimidine, triazole, tetrazole, cumarone, thionaphthene, benzopyrrole; Further recommendation phenyl, naphthyl, pyridine, pyrimidine, furans, thiophene, pyrroles or thiazole;
Described substituent R 6refer to hydrogen, halogen, nitro, hydroxyl, methyl, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy, CN, CF 3, CHF 2, CF 3o, CHF 2o, CH 3sO 2or CH 3cH 2sO 2; Replacement mode is monosubstituted, and two replace or three replacements; Substituent position at the ortho position of aryl, the optional position in contraposition and a position;
-described drawing electron group includes but not limited to halogen, nitro, CN, CF 3, CHF 2, CF 3o, CHF 2o, CH 3sO 2, CH 3cH 2sO 2, PhCH 2oCO or AcO; Described electron-donating group includes but not limited to that alkoxyl group (recommends C 1-C 20alkoxyl group), OH, PhCH 2o, Me 2nCH 2cH 2o, Et 2nCH 2cH 2o, NH 2or alkyl (recommends C 1-C 20alkyl);
Described amino protecting group refers to any suitable amino protecting group, includes but not limited to C 1-C 20alkyl, containing substituent C 1-C 20alkyl, benzyl, containing substituent benzyl, three (C 1-C 20) alkyl silyl or tert-butyl diphenyl silica-based; Be recommended as C 1-C 4alkyl, containing substituent C 1-C 4alkyl, benzyl, containing substituent benzyl, three (C 1-C 4) alkyl silyl or tert-butyl diphenyl silica-based; Described substituent definition as previously shown; Concrete amino protecting group can refer to T.W.Greeneetal., ProtectivegroupsinOrganicSynthesis3 rded.JohnWiley1999, pp.494-653.
Described hydroxyl protecting group is the protecting group of any suitable hydroxyl, includes but not limited to C 1-C 20alkyl, C 3-C 7cycloalkyl, containing substituent C 1-C 20alkyl, benzyl, containing substituent benzyl, three (C 1-C 20) alkyl silyl or tert-butyl diphenyl silica-based; Be recommended as C 1-C 4alkyl, C 3-C 7cycloalkyl, C 1-C 4alkoxyl group, C 1-C 4thio alkoxy, three (C 1-C 4) alkyl silyl, the silica-based hydroxyl of tert-butyl diphenyl, C 1-C 4carboxyl, C 1-C 4carbalkoxy, C 1-C 4sulfo-carbalkoxy, aryl or CH 2oR 4; Wherein R 4be recommended as hydrogen, C 1-C 4alkyl, C 3-C 7cycloalkyl, containing substituent C 1-C 4alkyl, benzyl, containing substituent benzyl, three (C 1-C 4) alkyl silyl or tert-butyl diphenyl silica-based; Described aryl and substituent definition are as previously shown; Concrete hydroxyl protecting group can refer to T.W.Greeneetal., ProtectivegroupsinOrganicSynthesis3 rded.JohnWiley1999, pp.494-653.
Apply method of the present invention, Efavirenz can synthesize with such as following route:
The invention provides the chiral amino alcohol ligand that some are new, also provide the method for such part for asymmetric reduction reaction simultaneously, specifically provide the novel process that it is applied to the continuous one pot reaction of asymmetric synthesis hiv reverse transcriptase inhibitor Efavirenz, the ee value of its product is greater than 99%, and chemical yield is greater than 90%.These processing condition are gentle, easy and simple to handle, environmental protection; Part is cheap and easy to get and industrially can all to reclaim, recycle, economical and efficient.
Compared with existing method of synthesizing Efavirenz, present invention process relate to chiral amino alcohol ligand participate in. asymmetric reduction reaction, this reaction conditions is gentle, part used is cheap and easy to get, and can be recycled by simple post-processing operation, especially it is worth mentioning that asymmetric reduction reaction and ensuing cyclization merge by this technique, the continuous one pot reaction without separation and purification is adopted directly to obtain the finished product Efavirenz, the ee value of its product is greater than 99%, chemical yield is greater than 90%, reclaim part by simple extracting operation simultaneously, the production stage greatly simplified, cheap and easy to get and the part of reusable edible also reduces production cost, in addition, avoid and use high toxicity and the phosgene and the analogue thereof that not easily store use, dangerous highly basic alkyl lithium reagents and eliminate the metal reagent ceric ammonium nitrate removed needed for benzyloxy protection, whole production technique is easy and simple to handle, an environmental protection and efficient! be of value to the extensive industrialization carrying out Efavirenz.
Embodiment
Following examples contribute to understanding this patent but are not limited thereto scope.
Embodiment 1
(1R, 2R)-2-N, N-dimethylamino-3-is to the preparation of nitre phenyl-1,3-PD:
Reference Jiang, B; Chen, Z.L.; Tang, X.X.Org.Lett., 2002,4,3451.
Synthesis
Embodiment 2
(1R, 2R)-3-tert.-butoxy-2-N, N-dimethylamino-1-is to the preparation of nitre phenyl-1-propanol:
At 0-5 DEG C, vitriol oil 0.8g is added dropwise to (1R, 2R)-2-N, N-dimethylamino-3-is to the CH of nitre phenyl-1,3-PD (1.8g, 7.5mmol) 2cl 2(20mL) in solution.Isobutene gas is passed at keeping 0-5 DEG C.Be added dropwise to vitriol oil 0.2g again, mixture is got back to room temperature vigorous stirring reaction 5-7h and is passed into isobutene gas continuously.Mixture is as cold as 0-5 DEG C and adds saturated K 2cO 3solution.Organic phase drying (Na 2sO 4) concentrated after recrystallization purifying obtain ligand 1 .44g, yield is 65%.Mp100.0 – 101.3 DEG C; [α] d 20=+23.5 (c, 1.00, CHCl 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=3.0,9.9Hz; 1H), 3.21 (dd, J=6.5,10Hz; 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/e223 (M +-73,3), 209 (21), 144 (68), 88 (100), 71 (10), 57 (31); Ultimate analysis calculated value (Anal.calcd.For) C 15h 24n 2o 4; C, 60.81; H, 8.11; N, 9.46. measured value (Found): C, 60.72; H, 8.26; N, 9.14.
Embodiment 3
(1R, 2R)-3-tertiary butyl dimethyl Si base-2-N, N-dimethylamino-1-is to the preparation of nitre phenyl-1-propanol:
(1R, 2R)-2-N, N-dimethylamino-3-is dissolved in CH to nitre phenyl-1,3-PD (1.95g, 8.1mmol) 2cl 2(30mL), add the product 2.72g that TBDMSCl (1.28g, 5.3mmol) and imidazoles (1.4g, 20.6mmol) mixture stir aftertreatment of spending the night at 0 DEG C, yield is 94%.FTIR(KBr)3344，2954，1606，1525，1349cm -1； 1HNMR(300MHz,CDCl 3)δ8.25-8.20(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=11.3,2.7Hz1H),3.5-3.45(dd,J=11.3,6.0Hz1H),2.50(m,7H),1.85(s,8H),0.1(s,6H); 13CNMR(75MHz,CDCl 3)δ150.2,147.4,128.0,123.3,69.0,57.1,41.6,25.7,17.9,-5.9;MS(EI)m/e297(M +-57,0.3),209(8.2),202(100).Anal.calcd.ForC 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
The preparation of (1R, 2R)-3-trityloxy-2-N, N-dimethylamino-1-p-nitrophenyl-1-propyl alcohol:
(1R, 2R)-2-N, N-dimethylamino-3-is dissolved in CH to nitre phenyl-1,3-PD (1.95g, 8.1mmol) 2cl 2(50mL), add triphenylmethyl chloride (3.34g, 12mmol) and triethylamine (2mL) mixture at 0 DEG C and stir aftertreatment of spending the night and obtain product 3.4g, yield is 87.2.FTJR（KBr）3344，2954，1606，1525，1349cm -1； 1HNMR(300MHz,CDCl 3)δ8.09-8.06（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=10.2，6.4Hz1H）,3.01（dd,J=10.7，3.9Hz1H）,2.71(m,1H),2.45(s,6H),0.1(s,6H); 13CNMR(75MHz,CDCl 3)δ150.1,147.6,128.9,128.8,128.7,128.6,128.4,128.1,127.9,127.8,127.3,123.7,87.7,70.9,70.6,58.6,41.6
Embodiment 5
(1R, 2R)-2-N-benzyl-N-methylamino--3-is to the preparation of nitre phenyl-1,3-PD:
(1R, 2R)-2-amino-3-adds in methyl alcohol (10mL) nitre phenyl-1,3-PD (2.12g, 10mmol) and phenyl aldehyde (1.2g10.5mmol), then adds CuSO 4(0.2g).Mixture back flow reaction 7hr, cool to room temperature, filters, adds THF(10mL in filtrate).Then add NaBH in batches 4(0.4g).Cool after mixture back flow reaction 2hr.Add 5%HCL souring soln.Concentrate by extracted with diethyl ether, resistates and HCHO(10mL) and HCOOH(10mL) back flow reaction 8hr.Cooling, neutralizes with NaOH.CH 2cl 2extraction, NaSO 4dry.The direct the next step of 1.2g product is obtained again after recrystallization purifying.
Embodiment 6
(1R, 2R)-3-tertiary butyl dimethyl Si base-2-N-benzyl-N-methylamino--1-is to nitre phenyl-1-propanol:
With reference to the method for example 3, productive rate is 85.8%.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,2H),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)，0.10(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/e415(M +-15,0.9),278(100),91(73);
Embodiment 7
(1R, 2R)-3-triphenylmethoxy-2-N-benzyl-N-methylamino--1-is to nitre phenyl-1-propanol;
With reference to the method for example 4, productive rate is 85.3%.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/e406(M +-152,24.9),243(100),Anal.calcd.ForC 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
The synthesis of (1R, 2R)-3-triphenylmethoxy-2-N, N-dimethylamino-1-phenyl-1-propanol
With reference to the method for example 4, productive rate is 86.2%.FTIR(KBr)3344，2954，1609，1525，1349cm -1； 1HNMR(300MHz,CDCl 3)δ7.26-7.06（m,20H）,4.87(d，J=10.0Hz，1H),3.76(dd,J=10.2Hz,6.4Hz1H),3.51(dd,J=10.7,3.9Hz2H),2.80（m，1H）,2.38(s,6H), 13CNMR(75MHz,CDCl 3)δ143.6，138.9，128-129，125.7-126.6，84.9，72.9，68.6，69.6，49.6，39.6。
Embodiment 9
(1R, 2R)-3-trityloxy-2-N, N-dimethylamino-1-is to the synthesis of methanesulfonylphenYl-1-propyl alcohol
With reference to the method for example 4, productive rate is 84.6%.FTIR(KBr)3344，2954，1609，1525，1349cm -1； 1HNMR(300MHz,CDCl 3)δ7.48-7.40（d,J=834Hz，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=10.2，6.4Hz，1H）,3.56(dd，J=10.2，6.4Hz，2H)，2.94（s，3H）,2.81（m，1H），2.38（s，6H）； 13CNMR(75MHz,CDCl 3)δ143.8，143.0，138.6，135.0，129-126，84.9，72.9，69.6，68.0，49.6，41.0，39.6。
Embodiment 10
(1R, 2R)-2-N-pyrrolidyl-3-p-nitrophenyl-1,3-PD:
(1R, 2R)-2-amino-3-p-nitrophenyl-1,3-PD (2.12g, 10mmol) is dissolved in (10mL) in DMF, adds anhydrous K at 0-5 DEG C 2cO 3(3.15g, 22mmol), drip Isosorbide-5-Nitrae-dibromobutane (2.4g, 11mmol), mixture returns to stirring at room temperature 35 hours.Filtrate washing after filtering, EtOAc extracts.Purifying obtains product 2.2g(83%) be yellow oil.FTIR(neat)3393，2969，1605，1521，1348cm -1； 1HNMR(300MHz,CDCl 3)δ8.10（d，J=8.9Hz，2H），7.53（d，J=8.7Hz，2H）,4.63(d,J=8.1Hz,1H),3.80(br,2H),3.56(m,2H),2.81-2.70(m,5H),1.79-1.68(m,4H);MS(ESI)m/e267(M ++1).
Embodiment 11
(1R, 2R)-3-tertiary butyl dimethyl Si base-2-N-pyrrolidyl-1-p-nitrophenyl-1-propyl alcohol:
With reference to the method for example 3, productive rate is 83.6%.FTIR(neat)3346，2937，2924，2858,1604，1525，1347cm -1； 1HNMR(300MHz,CDCl 3)δ8.18（d，J=8.5Hz，2H），7.59（d，J=8.9Hz，2H）,4.70(d,J=8.5Hz,1H),3.65(dd,J=4.0，11.0Hz,1H),3.52(dd,J=5.3,10.8Hz,1H),2.82-2.71(m,5H),1.83-1.73(m,4H),0.85(s,9H),-0.08(s,6H); 13CNMR(75MHz,CDCl 3)δ150.8,147.2,127.7,123.2,69.8,67.4,58.2,49.2,25.7,23.4,17.9,-5.8;MS(ESI)m/e381(M ++1).
Embodiment 12
(1R, 2R)-3-acetoxyl group-2-N, N-dimethylamino-1-is to the preparation of nitre phenyl-1-propanol:
(1R, 2R)-2-N, N-dimethylamino-3-is dissolved in CH to nitre phenyl-1,3-PD (2.12g, 10mmol) 2cl 2(50mL), add triethylamine (2mL, 14mmol) at 0 DEG C, be progressively added dropwise to Ac 2o(1.2mL, 11mmol), react 15 to 20 minutes.With dchloromethane after reacting completely, saturated sodium bicarbonate washs, and saturated brine washs, and anhydrous sodium sulfate drying filtering and concentrating drains to obtain yellow oil, crude yield 96.11%. 1HNMR(300MHz,CDCl 3)δ8.15-8.13(d,J=8.1Hz,2H),7.50-7.47(d,J=10.8Hz,2H),5.77-5.75(d,J=6.9Hz,1H),3.10-3.07(d,J=7.5Hz,2H),2.78-2.74(d,J=11.1Hz,1H),2.47（s，6H），2.00(s,3H).
Embodiment 13
(1R, 2R)-3-benzoyloxy-2-N, N-dimethylamino-1-is to the preparation of nitre phenyl-1-propanol:
With reference to the method for example 12, use Benzoyl chloride and triethylamine, productive rate is 83.6%. 1HNMR(300MHz,CDCl 3),δ8.15-8.13(d,J=8.1Hz,2H),7.50-7.47(d,J=10.8Hz,2H),5.77-5.75(d,J=6.9Hz,1H),3.10-3.07(d,J=7.5Hz,2H),2.78-2.74(d,J=11.1Hz,1H)，2.47（s，6H），2.00(s,3H).
Embodiment 14
(1R, 2R)-3-pivaloyl oxygen base-2-N, N-dimethylamino-1-is to the preparation of nitre phenyl-1-propanol:
With reference to the method for example 12, use pivaloyl chloride and triethylamine, productive rate is 88.2%. 1HNMR(300MHz,CDCl 3)δ8.16-8.13(d,J=8.4Hz,2H),7.41-7.38(d,J=8.7Hz,2H),5.74-5.71(d,J=8.1Hz,1H),3.11-3.09(m,2H),2.81-2.78(d,J=7.8Hz,1H)，2.47（s，6H），1.14(s,9H).
Embodiment 15
The preparation of (1S, 2R)-1-dimethylamino-2-indanol:
Under room temperature, in 20mL water, add 2.5mL acetic acid, then add 5mL formaldehyde solution, 1.490g(1S, 2R)-1-amino-2-indanol, 2.600g zinc powder.After stirred at ambient temperature reaction 3h, with the cancellation of 15mL ammoniacal liquor, dichloromethane extraction, anhydrous sodium sulfate drying, rapid column chromatography (EA:PE=1:2,210mL; Methyl alcohol: DCM=1:10,330mL), productive rate is 78.2%. 1HNMR(400MHz,CDCl 3)δ7.25(ddd,J=24.5,16.2,7.4Hz,4H),4.59(dd,J=22.0,13.4Hz,1H),4.44(q,J=7.9Hz,1H),4.07(d,J=7.9Hz,1H),3.26(dd,J=16.3,8.2Hz,1H),2.80(dd,J=16.3,7.6Hz,1H).
Embodiment 16
(S) preparation of-2-dimethylamino-1-phenylethyl alcohol:
Under room temperature, in 20mL water, add 2.5mL acetic acid, then add 5mL formaldehyde solution, 1.372g(S)-2-amino-1-phenylethyl alcohol, 2.600g zinc powder.After stirred at ambient temperature reaction 3h, with the cancellation of 15mL ammoniacal liquor, dichloromethane extraction, anhydrous sodium sulfate drying, rapid column chromatography (EA: normal hexane=1:2,210mL; Methyl alcohol: DCM=1:5,240mL), productive rate is 83.1%. 1HNMR(400MHz,CDCl 3)δ7.36(dt,J=14.9,7.4Hz,4H),7.30–7.24(m,1H),4.69(dd,J=10.6,3.3Hz,1H),2.51–2.44(m,1H),2.39(d,J=3.5Hz,1H),2.35(s,6H).
Embodiment 17
The preparation of (1R, 2R)-3-benzyloxy-2-N, N-dimethylamino-1-Alpha-Naphthyl-1-propyl alcohol
(1R, 2R)-2-N, N-dimethylamino-1--naphthyl-1,3-PD (980mg, 4.0mmol) is dissolved in CH 2cl 2(25mL), benzyl chlorine (567mg, 4.5mmol) and NaH(144mg, 6mmol at 0 DEG C, is added) mixture stirs aftertreatment of spending the night and obtains product, and yield is 70.0%. 1HNMR(300MHz,CDCl 3)δ8.02–7.91(m,2H),7.77(dt,J=7.5,1.4Hz,1H),7.57(td,J=7.5,1.4Hz,1H),7.48–7.37(m,2H),7.37–7.18(m,5H),7.11(dd,J=7.5,1.4Hz,1H),4.67(s,2H),4.47(s,1H),3.80(dd,J=12.4,5.0Hz,1H),3.32(dd,J=12.5,5.1Hz,1H),3.21(t,J=5.0Hz,1H),2.33(s,6H),2.27(s,1H).;MS(EI)m/e335.19(100),336.19(24.5),337.20(2.8).
Embodiment 18
The preparation of (1R, 2R)-1-N, N-dimethylamino-1-betanaphthyl-3-triphen methoxy-2-propyl alcohol
(1R, 2R)-1-N, N-dimethylamino-1-betanaphthyl-1,3-PD (980mg, 4.0mmol) is dissolved in CH 2cl 2(25mL), triphenylmethyl chloride (1.8g, 6mmol) and NaH(144mg, 6mmol at 0 DEG C, is added) mixture stirs aftertreatment of spending the night and obtains product, and yield is 67.0%. 1HNMR(300MHz,CDCl 3)δ7.84–7.79(m,3H),7.79–7.63(m,3H),7.53(t,J=1.4Hz,2H),7.48–7.40(m,4H),7.38(dd,J=7.5,1.4Hz,2H),7.35–7.27(m,11H),7.27–7.16(m,16H),4.12(dt,J=9.7,1.7Hz,2H),3.76(dd,J=46.2,5.7Hz,3H),3.69(d,J=1.6Hz,1H),3.47(dd,J=12.4,1.7Hz,2H),2.36(s,11H),2.22(s,2H);MS(EI)m/e487.25(M +100),488.25(37.1),489.26(7.1).
Embodiment 19
The preparation of (2S, 3R)-3-N, N-dimethylamino-4-methyl-7-oxo-dicyclo [2.2.1] heptane-2-alcohol
(2S, 3R)-3-amino-4-methyl-7-oxo-dicyclo [2.2.1] heptane-2-alcohol (572mg, 4.0mmol) is dissolved in tetrahydrofuran (THF) (25mL), adds methyl iodide (1.28g, 9mmol) and K at 0 DEG C 2cO 3(1.38g, 10mmol) mixture stirs aftertreatment of spending the night and obtains product, and yield is 87.6%. 1HNMR(300MHz,CDCl 3)δ3.69(dd,J=6.8,1.4Hz,1H),3.30(td,J=4.5,1.4Hz,1H),2.67(d,J=6.6Hz,1H),2.35(s,8H),2.15(s,1H),1.93(dd,J=8.0,3.9Hz,1H),1.78–1.74(m,1H),1.68(dd,J=8.0,4.0Hz,1H),1.53–1.49(m,1H),1.27(s,4H);MS(EI)m/e143.09(100),144.10(7.8).
Embodiment 20
(S) preparation of-2-N, N-dimethylamino-2-phenylethyl alcohol
Method with reference to embodiment 16 is synthesized, and yield is 85.3%. 1HNMR(300MHz,CDCl 3)δ7.32(ddd,J=16.9,11.0,4.6Hz,4H),7.27–7.23(m,1H),4.17(t,J=5.1Hz,1H),4.03(dd,J=12.4,5.0Hz,1H),3.74(dd,J=12.5,5.1Hz,1H),2.35(s,6H),0.63(s,1H);MS(EI)m/e165.12(100),166.12(11).
Embodiment 21
The preparation of (1R, 2R)-2-N, N-dimethylamino-1,2,3,4-tetralyl-1-alcohol
Get amino-1,2,3,4-tetralyl-1-alcohol (652mg, 4.0mmol) of (1R, 2R)-2-, add CH 3cHO(10mL) and HCOOH(10mL), back flow reaction 12hr.Cooling, neutralizes with NaOH.CH 2cl 2extraction, NaSO 4drying, yield is 78.3%. 1HNMR(300MHz,CDCl 3)δ7.00(dd,J=19.0,3.8Hz,5H),4.90(s,1H),3.08–2.95(m,3H),2.80–2.65(m,7H),2.23(s,1H),1.94(s,1H),1.65(s,1H),1.14–1.10(m,8H);MS(EI)m/e219.16(M +100),220.17(15.4),221.17(1.3).
Embodiment 22
The preparation of (1R, 2R)-3-trityloxy-2-N, N-dimethylamino-1-m-chloro phenyl-1-propanol:
(1R, 2R)-2-N, N-dimethylamino-3-rubigan-1,3-PD (1.9g, 4.0mmol) is dissolved in CH 2cl 2(25mL), add triphenylmethyl chloride (1.8g, 6mmol) and triethylamine (1mL) mixture at 0 DEG C and stir aftertreatment of spending the night and obtain product, yield is 87.2%.
Embodiment 23
(1R, 2R)-3-benzyloxy-2-N, N-diethylin-1-is to the preparation of fluorophenyl-1-propyl alcohol:
(1R, 2R)-2-N, N-diethylin-3-is dissolved in CH to fluorophenyl-1,3-PD (1.3g, 4.0mmol) 2cl 2(25mL), benzyl chlorine (567mg, 4.5mmol) and NaH(144mg, 6mmol at 0 DEG C, is added) mixture stirs aftertreatment of spending the night and obtains product, and yield is 67.0%.
Embodiment 24
(1R, 2R)-3-(2 '-pyridyloxy) preparation of-2-N, N-dimethylamino-1-p-trifluoromethyl phenyl-1-propyl alcohol:
(1R, 2R)-2-N, N-dimethylamino-3-p-trifluoromethyl phenyl-1, ammediol (1.4g, 4.0mmol) be dissolved in DMF (20mL), at 0 DEG C, add 2-chloropyridine (678mg, 6mmol) and NaH(144mg, mmol) mixture stirs aftertreatment of spending the night and obtains product, and yield is 63.2%.
Embodiment 25
(1R, 2R)-3-trimethylsiloxy group-2-N, N-dimethylamino-1-is to the preparation of cyano-phenyl-1-propyl alcohol:
(1R, 2R)-2-N, N-dimethylamino-3-is dissolved in CH to cyano-phenyl-1,3-PD (1.2g, 4.0mmol) 2cl 2(25mL), add trimethylchlorosilane (648mg, 6mmol) and pyridine (1mL) mixture at 0 DEG C and stir aftertreatment of spending the night and obtain product, yield is 85.2.
Embodiment 26
The preparation of the methyl-formiate of the chloro-2-trifluoroacetyl aniline of 4-:
10mL acetonitrile is added in 50mL reaction flask, under stirring, add the hydrochloride of 1.5g2-amino-5 chloro-phenyl-trifluorumethylketone, be cooled to 5 DEG C, drip 10% aqueous sodium hydroxide solution 2.3g, be then added dropwise to 1.88g methyl-chloroformate and 2.3g (10%) NaOH aqueous solution 2.3g respectively simultaneously, drip and about need 4.5-5 hours, temperature control 5 DEG C, continues stirring 3 hours.Aftertreatment: separate aqueous phase, organic phase salt is washed, and after anhydrous sodium sulfate drying is concentrated, recrystallization obtains yellow solid product, and productive rate is 91.8%.
Embodiment 27
The preparation of the ethyl formate of 3-methoxyl group-2-trifluoroacetyl aniline:
With reference to the method for embodiment 21, react with Vinyl chloroformate, recrystallization obtains yellow solid product, and productive rate is 92.3%.
Embodiment 28
The preparation of the n-propyl formate of the chloro-2-trifluoroacetyl aniline of 3-:
With reference to the method for embodiment 21, react with n-propyl chloroformate, recrystallization obtains yellow solid product, and productive rate is 92.8%.
Embodiment 29
The preparation of the isopropyl formate of the fluoro-2-trifluoroacetyl aniline of 4-:
With reference to the method for embodiment 21, react with isopropyl chlorocarbonate, recrystallization obtains yellow solid product, and productive rate is 95.8%.
Embodiment 30
The preparation of the n-buty formate of 4-cyano group-2-trifluoroacetyl aniline:
With reference to the method for embodiment 21, react with butyl chloroformate, recrystallization obtains yellow solid product, and productive rate is 98.3%.
Embodiment 31
The preparation of the tetryl formate of 4-trifluoromethyl-2-trifluoroacetyl aniline:
At 0-30 DEG C, add 10mL tetrahydrofuran (THF) in 50mL reaction flask, under stirring, add the mesylate of 1.5g2-amino-5 chloro-phenyl-trifluorumethylketone, add 10%KOH aqueous solution 1.2g, be then added dropwise to 1.1g isobutyl chlorocarbonate, drip and about need 0.5-5 hours, continue stirring 5 hours.Aftertreatment: separate aqueous phase, organic phase salt is washed, and after anhydrous sodium sulfate drying is concentrated, recrystallization obtains yellow solid product, and productive rate is 87.8%.
Embodiment 32
The preparation of the formic acid n-pentyl ester of 4-difluoromethyl-2-trifluoroacetyl aniline:
With reference to the method for embodiment 21, react with n-amyl chlorocarbonate, recrystallization obtains yellow solid product, and productive rate is 90.8%.
Embodiment 33
The preparation of the formic acid ring pentyl ester of 4-methoxyl group-2-trifluoroacetyl aniline:
With reference to the method for embodiment 21, react with chloroformate cyclopentyl ester, recrystallization obtains yellow solid product, and productive rate is 70.2%.
Embodiment 34
The preparation of the positive heptyl ester of formic acid of 4-chloro-2-trifluoroacetyl aniline:
With reference to the method for embodiment 21, react with the positive heptyl ester of chloroformic acid, recrystallization obtains yellow solid product, and productive rate is 98.5%.
Embodiment 35
The preparation of the formic acid p-nitrophenyl ester of the chloro-2-trifluoroacetyl aniline of 4-:
With reference to the method for embodiment 21, react with p-nitrophenyl chloroformate ester, recrystallization obtains yellow solid product, and productive rate is 98.5%.
Embodiment 36
The preparation of the formic acid ring propyl ester of the chloro-2-trifluoroacetyl aniline of 4-:
Add 10mL methyltetrahydrofuran in 50mL reaction flask, under stirring, add the mesylate (319mg of 2-amino-5-chloro-phenyl-trifluorumethylketone, 1mmol), be cooled to 5 DEG C, drip 10% wet chemical (1.38g, 10mmol), then be added dropwise to chloroformic acid ring propyl ester (1.2g respectively simultaneously, 10mmol) He 10% wet chemical (1.38g, 10mmol), drips and about needs 4.5-5 hours, temperature control 60 DEG C, continues stirring 48 hours.Aftertreatment: separate aqueous phase, organic phase salt is washed, and after anhydrous sodium sulfate drying is concentrated, recrystallization obtains yellow solid product, and productive rate is 90.5%.
Embodiment 37
The preparation of the formic acid ring pentyl ester of the fluoro-2-trifluoroacetyl aniline of 4-:
Add 10mL acetonitrile in 50mL reaction flask, under stirring, add the hydrochloride (243mg of 2-amino-5-fluorine phenyl trifluoromethyl ketone, 1mmol), be cooled to 5 DEG C, drip 10% potassium hydroxide aqueous solution (230mg, 5mmol), then be added dropwise to chloroformate cyclopentyl ester (1.5g respectively simultaneously, 10mmol) with the 10%KOH aqueous solution (560mg, 10mmol), drip and about need 4.5-5 hours, temperature control 50 DEG C, continues stirring 36 hours.Aftertreatment: separate aqueous phase, organic phase salt is washed, and after anhydrous sodium sulfate drying is concentrated, recrystallization obtains yellow solid product, and productive rate is 90.8%.
Embodiment 38
The preparation of the formic acid ring heptyl ester of the chloro-2-trifluoroacetyl aniline of 4-:
Add 10mL tetrahydrofuran (THF) in 50mL reaction flask, under stirring, add the mesylate (319mg of 2-amino-5-chloro-phenyl-trifluorumethylketone, 1mmol), be cooled to 5 DEG C, add sodium methylate (540mg, 10mmol), then be added dropwise to chloroformic acid ring heptyl ester (2.6g respectively simultaneously, 15mmol) with sodium methylate (540mg, 10mmol), drip and about need 4.5-5 hours, temperature control 5 DEG C, continues stirring 24 hours.Aftertreatment: separate aqueous phase, organic phase salt is washed, and after anhydrous sodium sulfate drying is concentrated, recrystallization obtains yellow solid product, and productive rate is 93.5%.
Embodiment 39
The preparation of formic acid 20 ester of 4-trifluoromethoxy-2-trifluoroacetyl aniline:
Add 10mL1 in 50mL reaction flask, 2-ethylene dichloride, under stirring, add the hydrochloride (293mg, 1mmol) of 2-amino-5-Trifluoromethoxyphen-l trifluorumethylketone, be cooled to 5 DEG C, add sodium bicarbonate (420mg, 5mmol), be then added dropwise to chloroformic acid 20 ester (3.6g, 10mmol) and sodium bicarbonate (840mg respectively simultaneously, 10mmol), drip and about need 4.5-5 hours, temperature control 40 DEG C, continue stirring 72 hours.Aftertreatment: separate aqueous phase, organic phase salt is washed, and after anhydrous sodium sulfate drying is concentrated, recrystallization obtains yellow solid product, and productive rate is 91.1%.
Embodiment 40
The preparation of the formic acid certain herbaceous plants with big flowers base ester of the fluoro-2-trifluoroacetyl aniline of 3,4-bis-:
Add 10mL t-butyl methyl ether in 50mL reaction flask, under stirring, add 2-amino-4, the hydrochloride (261mg, 1mmol) of 5-difluorophenyl trifluorumethylketone, is cooled to 5 DEG C, add disodium-hydrogen (2.3g, 16mmol), be then added dropwise to chloroformic acid certain herbaceous plants with big flowers base ester (1.8g, 8mmol) and disodium-hydrogen (1.2g respectively simultaneously, 8mmol), drip and about need 4.5-5 hours, temperature control 30 DEG C, continue stirring 56 hours.Aftertreatment: separate aqueous phase, organic phase salt is washed, and after anhydrous sodium sulfate drying is concentrated, recrystallization obtains yellow solid product, and productive rate is 90.1%.
Embodiment 41
The preparation of the formic acid naphthyl ester of 3-methoxyl group-2-trifluoroacetyl aniline:
Add 10mL acetonitrile in 50mL reaction flask, under stirring, add the hydrochloride (255mg of 2-amino-4-methoxyl phenyl trifluoromethyl ketone, 1mmol), be cooled to 5 DEG C, add potassium tert.-butoxide (1.1g, 10mmol), then be added dropwise to chloroformic acid naphthyl ester (4.1g respectively simultaneously, 20mmol) with potassium tert.-butoxide (1.1g, 10mmol), drip and about need 4.5-5 hours, temperature control 30 DEG C, continues stirring 12 hours.Aftertreatment: separate aqueous phase, organic phase salt is washed, and after anhydrous sodium sulfate drying is concentrated, recrystallization obtains yellow solid product, and productive rate is 90.1%.
Embodiment 42
The preparation of 4-cyclopropyl-1,1,1-tri-fluoro-2-phenyl butyl-3-alkynes-2-alcohol:
At 25 DEG C, amino alcohol ligands (1R, 2R)-3-tert.-butoxy-2-N, N-dimethylamino-1-are to nitre phenyl-1-propanol (2.96g, 10mmol) and Zn(OTf) 2(3.6g, 10mmol) is dissolved in toluene (10mL), then adds NEt3(2.1mL, 15mmol).Cyclopropyl acethlene (1.2mL, 12mmol) and trifluoromethyl ketone (1.74g, 10mmol) is added after one hour.10hr is reacted at 25 DEG C, mixture.Saturated citric acid cancellation reaction.Extraction into ethyl acetate.Organic phase merges dry rear concentrating and to obtain product (90% productive rate, 99.3%ee), with rear recovery part in aqueous phase sodium hydroxide.
Embodiment 43
(S)-6,7-bis-chloro-4-phenylacetylene base-4-Trifluoromethyl-1s, 4-dihydro-2H-1, at 3-benzoxazine-2-ketone 25 DEG C, amino alcohol ligands (1R, 2S)-3-acetoxyl group-2-N, N-dimethylamino-1-p-nitrophenyl-1-propyl alcohol (2.82g, 10mmol) and Cu(OTf) 2(3.6g, 10mmol) is dissolved in tetrahydrofuran (THF) (10mL), then adds diethylamine (3.29g, 45mmol).Add formic acid ring propyl ester (3.42g, 10mmol) of phenylacetylene (1.2g, 12mmol) and the chloro-2-trifluoroacetyl group-aniline of 4,5-bis-afterwards again.18hr is reacted at 25 DEG C, mixture.After raw material aniline reacts completely, direct raised temperature backflow, about 12 to 36 hours all can generate cyclisation product, with dilute hydrochloric acid cancellation reaction after reacting completely, extraction into ethyl acetate, organic phase merges dry rear concentrating and to obtain product (95% productive rate, 99.1%ee), with rear recovery part in aqueous phase sodium hydroxide.
Embodiment 44
(S) the positive pentynyl of-6,7-bis-fluoro-4--4-Trifluoromethyl-1,4-dihydro-2H-1, at 3-benzoxazine-2-ketone 25 DEG C, amino alcohol ligands (1R, 2S)-3-benzoyloxy-2-N, N-dimethylamino-1-p-nitrophenyl-1-propyl alcohol (3.44g, 10mmol) and Cu(OTs) 2(4.06g, 10mmol) is dissolved in dimethylbenzene (10mL), then adds diisopropyl ethyl amine (5.81g, 45mmol).Add the positive heptyl ester (3.37g, 10mmol) of formic acid of positive pentyne (0.82g, 12mmol) and 4,5-bis-fluoro-2-trifluoroacetyl group-aniline afterwards again.18hr is reacted at 25 DEG C, mixture.After raw material aniline reacts completely, direct raised temperature backflow, about 12 to 32 hours all can generate cyclisation product, with dilute hydrochloric acid cancellation reaction after reacting completely, extraction into ethyl acetate, organic phase merges dry rear concentrating and to obtain product (95% productive rate, 99.1%ee), with rear recovery part in aqueous phase sodium hydroxide.
Embodiment 45
(S)-6,7-bis-chloro-4-phenylacetylene base-4-Trifluoromethyl-1s, at 4-dihydro-2H-1,3-benzoxazine-2-ketone 25 DEG C, amino alcohol ligands (1S, 2R)-1-dimethylamino-2-indanol (1.77g, 10mmol) and ZnI 2(3.19g, 10mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (10mL), then adds pyridine (3.56g, 45mmol).Add formic acid ring heptyl ester (3.98g, 10mmol) of phenylacetylene (1.2g, 12mmol) and the chloro-2-trifluoroacetyl group-aniline of 4,5-bis-afterwards again.18hr is reacted at 25 DEG C, mixture.After raw material aniline reacts completely, direct raised temperature backflow, about 12 to 32 hours all can generate cyclisation product, with dilute hydrochloric acid cancellation reaction after reacting completely, extraction into ethyl acetate, organic phase merges dry rear concentrating and to obtain product (95% productive rate, 99.1%ee), with rear recovery part in aqueous phase sodium hydroxide.
Embodiment 46
(S)-6-nitro-4-naphthalene ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, at 3-benzoxazine-2-ketone 25 DEG C, amino alcohol ligands (1R, 2R)-3-benzyloxy-2-N, N-diethylin-1-are to fluorophenyl-1-propyl alcohol (4.55g, 15mmol) and Cu(OTf) (2.12g, 10mmol) be dissolved in dimethylbenzene (10mL), then add tri-isopropyl amine (6.44g, 45mmol).Add formic acid certain herbaceous plants with big flowers base ester (4.18g, 10mmol) of naphthalene acetylene (2.28g, 15mmol) and 4-nitro-2-trifluoroacetyl group-aniline afterwards again.18hr is reacted at 25 DEG C, mixture.After raw material aniline reacts completely, direct raised temperature backflow, about 12 to 32 hours all can generate cyclisation product, with dilute hydrochloric acid cancellation reaction after reacting completely, extraction into ethyl acetate, organic phase merges dry rear concentrating and to obtain product (95% productive rate, 99.1%ee), with rear recovery part in aqueous phase sodium hydroxide.
Embodiment 47
(S)-5-chloro-4-tert-butyl acetylene base-4-Trifluoromethyl-1, at 4-dihydro-2H-1,3-benzoxazine-2-ketone 25 DEG C, amino alcohol ligands (1R, 2S)-3-ring propoxy--2-N, N-dimethylamino-1-p-nitrophenyl-1-propyl alcohol (8.4g, 30mmol) and CuBr 2(4.4g, 20mmol) is dissolved in benzene (20mL), then adds tri-isopropyl amine (12.8g, 90mmol).Add the formic acid 20 ester (10.9g, 20mmol) of tert-butyl acetylene (2.5g, 30mmol) and 3-Cl-2-trifluoroacetyl group-aniline afterwards again.18hr is reacted at 25 DEG C, mixture.After raw material aniline reacts completely, direct raised temperature backflow, about 12 to 32 hours all can generate cyclisation product, with dilute hydrochloric acid cancellation reaction after reacting completely, extraction into ethyl acetate, organic phase merges dry rear concentrating and to obtain product (95% productive rate, 99.1%ee), with rear recovery part in aqueous phase sodium hydroxide.
Embodiment 48
(S)-6-methoxyl group-4-(2 '-furans alkynyl)-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone
At 25 DEG C, amino alcohol ligands (1R, 2R)-3-tertiary butyl dimethyl Si base-2-N-pyrrolidyl-1-p-nitrophenyl-1-propyl alcohol (2.7g, 7mmol) and Zn(OTs) 2(2.1g, 5mmol) is dissolved in the mixed solution of normal heptane (5mL) and benzene (5mL), then adds piperidines (1.9g, 22mmol).Add formic acid ring propyl ester (1.5g, 5mmol) of 2-furans acetylene (644mg, 7mmol) and 4-methoxyl group-2-trifluoroacetyl group-aniline afterwards again.18hr is reacted at 25 DEG C, mixture.After raw material aniline reacts completely, direct raised temperature backflow, about 12 to 32 hours all can generate cyclisation product, with dilute hydrochloric acid cancellation reaction after reacting completely, extraction into ethyl acetate, organic phase merges dry rear concentrating and to obtain product (95% productive rate, 99.1%ee), with rear recovery part in aqueous phase sodium hydroxide.
Embodiment 49
(S)-6-trifluoromethoxy-4-(2 '-pyridinylethynyl)-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone
At 25 DEG C, amino alcohol ligands (1R, 2S)-3-acetoxyl group-2-N, N-dimethylamino-1-p-nitrophenyl-1-propyl alcohol (4.23g, 15mmol) and Cu(OTf) 2(3.6g, 10mmol) is dissolved in benzene (10mL), then adds diethylamine (2.6mL, 50mmol).Add the cyclohexyl formate (4.0g, 10mmol) of 2-pyridine acetylene (1.6g, 15mmol) and 4-trifluoromethoxy-2-trifluoroacetyl group-aniline afterwards again.18hr is reacted at 25 DEG C, mixture.After raw material aniline reacts completely, direct raised temperature backflow, about 12 to 32 hours all can generate cyclisation product, with dilute hydrochloric acid cancellation reaction after reacting completely, extraction into ethyl acetate, organic phase merges dry rear concentrating and to obtain product (95% productive rate, 99.1%ee), with rear recovery part in aqueous phase sodium hydroxide.
Embodiment 50
(S)-6-chloro-4-ortho-nitrophenyl acetylene-4-Trifluoromethyl-1; 4-dihydro-2H-1; at 3-benzoxazine-2-ketone 25 DEG C; amino alcohol ligands (1R, 2R)-3-trityloxy-2-N, N-dimethylamino-1-are to methanesulfonylphenYl-1-propyl alcohol (7.7g; 15mmol) with ZnF2 (1.03g; 10mmol) be dissolved in benzene (10mL), then add pyridine (3.6g, 45mmol).Add the pentyl formate (3.4g, 10mmol) of ortho-nitrophenyl acetylene (2.2g, 15mmol) and the chloro-2-trifluoroacetyl group-aniline of 4-afterwards again.18hr is reacted at 25 DEG C, mixture.After raw material aniline reacts completely, direct raised temperature backflow, about 12 to 32 hours all can generate cyclisation product, with dilute hydrochloric acid cancellation reaction after reacting completely, extraction into ethyl acetate, organic phase merges dry rear concentrating and to obtain product (95% productive rate, 99.1%ee), with rear recovery part in aqueous phase sodium hydroxide.
Embodiment 51
(S)-6-trifluoromethyl-4-ring third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone
At 25 DEG C, amino alcohol ligands (1R, 2R)-3-pyridyl-2-N, N-dimethylamino-1-p-trifluoromethyl phenyl-1-propyl alcohol (6.2g, 15mmol) and Zn(OMs) 2(2.6g, 10mmol) is dissolved in methyltetrahydrofuran (10mL), then adds tri-isopropyl amine (6.4g, 45mmol).Add formic acid ring butyl ester (3.9g, 10mmol) of ring third acetylene (0.99g, 15mmol) and the chloro-2-trifluoroacetyl group-aniline of 4-trifluoromethyl-5-afterwards again.18hr is reacted at 25 DEG C, mixture.After raw material aniline reacts completely, direct raised temperature backflow, about 12 to 32 hours all can generate cyclisation product, with dilute hydrochloric acid cancellation reaction after reacting completely, extraction into ethyl acetate, organic phase merges dry rear concentrating and to obtain product (95% productive rate, 99.1%ee), with rear recovery part in aqueous phase sodium hydroxide.
Embodiment 52
(S)-6-chloro-4-cyclopropyl acethlene base-4-Trifluoromethyl-1, the synthesis example 1 of 4-dihydro-2H-1,3-benzoxazine-2-ketone (Sustiva Efavirenz, formula I):
At 25 DEG C, amino alcohol ligands (1R, 2R)-3-tert.-butoxy-2-N-Benzyl-N-methylamino-1-to nitre phenyl-1-propanol (3.72g, 10mmol) and Zn(OTf) 2(3.6g, 10mmol) is dissolved in hexanaphthene (10mL), then adds NEt 3(2.1mL, 15mmol).Add the ethyl formate (2.95g, 10mmol) of cyclopropyl acethlene (1.2mL, 12mmol) and the chloro-2-trifluoroacetyl group-aniline of 4-afterwards again.10hr is reacted at 25 DEG C, mixture.After raw material aniline reacts completely, direct raised temperature backflow, about 12 to 20 hours all can generate cyclisation product Sustiva Efavirenz, with dilute hydrochloric acid cancellation reaction after reacting completely, extraction into ethyl acetate, organic phase merges dry rear concentrating and to obtain product (95% productive rate, 99.3%ee), with rear recovery part in aqueous phase sodium hydroxide.
Embodiment 53
(S)-6-chloro-4-cyclopropyl acethlene base-4-Trifluoromethyl-1, the synthesis example 2 of 4-dihydro-2H-3,1-benzoxazine-2-ketone (Sustiva Efavirenz, formula I):
With reference to the method for embodiment 31, amino alcohol ligands uses (1R, 2S, 3R, 4R)-3-N, N-dimethylamino-4-methyl-7-oxabicyclo [2,2,1]-2-alcohol in heptan, and zinc salt uses Zn(OTs) 2, alkali pyridine, the formic acid ring propyl ester of the chloro-2-trifluoroacetyl group-aniline of substrate 4-, solvent is dimethylbenzene, and productive rate is 90%, ee value is 99.1%.
Embodiment 54
(S)-6-chloro-4-cyclopropyl acethlene base-4-Trifluoromethyl-1, the synthesis example 3 of 4-dihydro-2H-3,1-benzoxazine-2-ketone (Sustiva Efavirenz, formula I):
With reference to the method for embodiment 31, amino alcohol ligands uses (1R, 2R)-2-N-Benzyl-N-methylamino-1-indanol, and zinc salt uses Cu(OTf) 2, alkali NBu 3, the n-propyl formate of the chloro-2-trifluoroacetyl group-aniline of substrate 4-, solvent is benzene, and productive rate is 90%, ee value is 99.1%.
Embodiment 55
(S)-6-chloro-4-cyclopropyl acethlene base-4-Trifluoromethyl-1, the synthesis example 4 of 4-dihydro-2H-3,1-benzoxazine-2-ketone (Sustiva Efavirenz, formula I):
With reference to the method for embodiment 31, amino alcohol ligands uses (1R, 2R)-3-tertiary butyl dimethyl Si base-2-N-pyrrolidyl-1-to nitre phenyl-1-propanol, and zinc salt uses Zn(PhSO 3) 2, alkali is with MeN (i-Pr) 2, the positive heptyl ester of formic acid of substrate 4-chloro-2-trifluoroacetyl group-aniline, solvent is tetrahydrofuran (THF), and productive rate is 90%, ee value is 99.1%.
Embodiment 56
(S)-6-chloro-4-cyclopropyl acethlene base-4-Trifluoromethyl-1, the synthesis example 5 of 4-dihydro-2H-3,1-benzoxazine-2-ketone (Sustiva Efavirenz, formula I):
With reference to the method for embodiment 31, amino alcohol ligands uses (1R, 2R)-3-tert.-butoxy-2-N-piperidyl-1-to nitre phenyl-1-propanol, and zinc salt uses Zn(ODf) 2, alkali NHEt 2, the formic acid ring pentyl ester of the chloro-2-trifluoroacetyl group-aniline of substrate 4-, solvent is methyltetrahydrofuran, and productive rate is 96%, ee value is 99.1%.
Embodiment 57
(S)-6-chloro-4-cyclopropyl acethlene base-4-Trifluoromethyl-1, the synthesis example 6 of 4-dihydro-2H-3,1-benzoxazine-2-ketone (Sustiva Efavirenz, formula I):
With reference to the method for embodiment 31, amino alcohol ligands uses (1R, 2R)-3-tert.-butoxy-2-N, and N-dimethylamino-1-is to nitre phenyl-1-propanol, and zinc salt uses CuBr 2, alkali piperidines, the formic acid of the chloro-2-trifluoroacetyl group-aniline of substrate 4-is to p-Nitrobenzyl, and solvent is dioxane, and productive rate is 90%, ee value is 99.3%.
Embodiment 58
(S)-6-chloro-4-cyclopropyl acethlene base-4-Trifluoromethyl-1, the synthesis example 7 of 4-dihydro-2H-3,1-benzoxazine-2-ketone (Sustiva Efavirenz, formula I):
With reference to the method for embodiment 31, amino alcohol ligands uses (1R, 2R)-3-acetoxyl group-2-N, and N-dimethylamino-1-is to nitre phenyl-1-propanol, and zinc salt uses Cu(OTf), alkali NHEt 2, the methyl-formiate of the chloro-2-trifluoroacetyl group-aniline of substrate 4-, solvent is normal heptane, and productive rate is 94%, ee value is 99.1%.
Embodiment 59
(S)-6-chloro-4-cyclopropyl acethlene base-4-Trifluoromethyl-1, the synthesis example 8 of 4-dihydro-2H-3,1-benzoxazine-2-ketone (Sustiva Efavirenz, formula I):
At 0-60 DEG C, amino alcohol ligands (1R, 2R)-3-tert.-butoxy-2-N, N-dimethylamino-1-are to nitre phenyl-1-propanol (2.96g, 10mmol) and Zn(OMs) 2(5.08g, 20mmol) is dissolved in normal hexane (10mL), then adds diethylamine (2.6mL, 25mmol).Add the tetryl formate (3.23g, 10mmol) of cyclopropyl acethlene (1.2mL, 12mmol) and the chloro-2-trifluoroacetyl group-aniline of 4-afterwards again.10hr is reacted at mixture 0-50 DEG C.After raw material aniline reacts completely, direct raised temperature backflow, about 12 to 20 hours all can generate cyclisation product Sustiva Efavirenz, with dilute hydrochloric acid cancellation reaction after reacting completely, extraction into ethyl acetate, organic phase merges dry rear concentrating and to obtain product, and productive rate is 92%, ee value is 99.5%.With rear recovery part in aqueous phase sodium hydroxide.

Claims (11)

1. be there is by the asymmetric synthesis of continuous print one pot reaction a method for the compound of following general structure,
In formula, Y is hydrogen, monosubstituted or polysubstitutedly draw electronics or electron-donating group; Y be positioned at phenyl ring neighbour, or contraposition;
Rf is C 1-C 20perfluoroalkyl;
R is R 6the C replaced 1-C 20alkyl, R 6the C replaced 3-C 7cycloalkyl, R 6the phenyl, the R that replace 6the benzyl, the R that replace 6the naphthyl, the R that replace 6the furans, the R that replace 6the thiophene, the R that replace 6the pyrroles replaced, R 6the thiazole, the R that replace 6the pyrazoles, the R that replace 6the imidazoles, the R that replace 6the pyridine, the R that replace 6the pyrimidine, the R that replace 6the triazole replaced or R 6the tetrazole replaced;
Described substituent R 6refer to hydrogen, halogen, nitro, methyl, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy, CN, CF 3, CHF 2, CF 3o, CHF 2o, CH 3sO 2or CH 3cH 2sO 2; Replacement mode is monosubstituted, two replacement or three replacements;
Described halogen is F, Cl or Br;
It is characterized in that being obtained by following step (b) or step (a) and (b) two kinds of methods:
(a). amino protection: by formula II compound or its salt hydrochlorate,
In the presence of a base, in the mixed solvent of organic solvent and water, temperature 0 DEG C at 60 DEG C, with ClCOOR 5reaction 1-72 hour, extraction also concentrating under reduced pressure evaporate to dryness can obtain formula (III) compound,
Wherein, R 5r 6the C replaced 1-C 20alkyl, R 6the C replaced 3-C 7cycloalkyl, benzyl, to nitrobenzyl, p-chlorobenzyl, 2,4-dichloro benzyls, R 6the phenyl replaced or R 6the naphthyl replaced; Described R 6definition as previously mentioned;
The reaction mol ratio of described organic solvent and water is (20-1): 1;
Described alkali is mineral alkali or organic bases; Wherein mineral alkali is selected from alkali-metal oxyhydroxide, alkali-metal carbonate, alkali-metal supercarbonate, alkali-metal phosphoric acid salt or alkali-metal hydrophosphate; Organic bases is selected from alkali alcoholate, MeN (i-Pr) 2, HNEt 2, N (i-Pr) 3, pyridine, NEt 3, piperidines, EtN (i-Pr) 2or Bu 3n;
Described formula II compound or hydrochloride: alkali: ClCOOR 5mol ratio is 1:(1-20): (1-20);
(b). the amino alcohol ligands of chirality and Terminal Acetylenes and Zn salt or Cu salt and organic bases are mixed in organic solvent, asymmetric addition is there is at 0-60 DEG C with the compound of formula III, react and within 1-48 hour, obtain asymmetric addition product without separation, directly raised temperature in reaction system, in 60 DEG C to reflux temperature generation cyclisation, react and obtain target compound after 5-48 hour:
Described Terminal Acetylenes is the definition of described R as previously mentioned;
Described in step a or b, organic solvent is selected from acetonitrile, tetrahydrofuran (THF), methyltetrahydrofuran, dioxane, Et 2o, dme, methyl tertiary butyl ether, ethyl acetate, n-butyl acetate, isopropyl acetate, benzene,toluene,xylene, normal hexane, normal heptane, octane, hexanaphthene, CH 2cl 2, 1,2-ethylene dichloride, DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, acetone, methyl alcohol, ethanol, Virahol or their mixture;
Described formula III compound: the amino alcohol ligands of chirality: Terminal Acetylenes: Zn salt or Cu salt: the mol ratio of organic bases is 1:(0.1-3): (0.1-3): (0.1-3): (0.1-4);
The amino alcohol ligands of described chirality has compound or its whole mapping or the diastereomer of following structural formula:
Wherein, R 1, R 2it is identical or different group; R 6the C replaced 1-C 20alkyl, R 6the benzyl replaced; Or R 1, R 2for-(CH 2) nx (CH 2) m-, wherein X is CH 2, O or NH; N, m are the integer of 1 to 6; Described R 6definition as previously shown;
Z is hydrogen, monosubstituted or polysubstitutedly draw electronics or electron-donating group, Z be positioned at phenyl ring neighbour, or contraposition; Described drawing electron group is halogen, NO 2, CN, CF 3, CHF 2, CF 3o, CHF 2o, CH 3sO 2, CH 3cH 2sO 2or AcO; Described electron-donating group is C 1-C 3alkoxyl group, OH, NH 2or C 1-C 4alkyl;
When described chiral amino alcohol ligand is following structure:
R 3for R 6the benzyl replaced or CH 2oR 4; Wherein R 4for hydrogen, R 6the C replaced 1-C 20alkyl, R 6the C replaced 3-C 7cycloalkyl, three (C 1-C 4) alkyl silyl, tert-butyl diphenyl are silica-based, R 6the benzyl, the R that replace 6the phenyl, the R that replace 6the trityl, the R that replace 6the naphthyl, the R that replace 6the pyrimidyl, the R that replace 6the pyridyl replaced or R 6the thiazolyl replaced; Described R 6definition as previously shown;
When described chiral amino alcohol ligand is following structure:
R 3for hydrogen, R 6the C replaced 1-C 20alkyl, R 6the benzyl replaced or CH 2oR 4; Wherein R 4for hydrogen, R 6the C replaced 1-C 20alkyl, R 6the C replaced 3-C 7cycloalkyl, three (C 1-C 4) alkyl silyl, tert-butyl diphenyl are silica-based, R 6the benzyl, the R that replace 6the phenyl, the R that replace 6the trityl, the R that replace 6the naphthyl, the R that replace 6the pyrimidyl, the R that replace 6the pyridyl replaced or R 6the thiazolyl replaced; Described R 6definition as previously shown.
2. the method for claim 1, is characterized in that described Y is H, F, Cl, Br, I, CF 3, CN, CHF 2, CF 3o, CHF 2o, CH 3sO 2, CH 3cH 2sO 2, AcO, MeO, EtO, t-Bu, i-Pr, NH 2or NO 2.
3. the method for claim 1, is characterized in that described Y is H, F, Cl, Br, CF 3, CN, CHF 2, CF 3o, CHF 2o, CH 3sO 2, CH 3cH 2sO 2or NO 2;
Rf is C 1-C 4perfluoroalkyl;
R is R 6the C replaced 1-C 4alkyl, R 6the C replaced 3-C 7cycloalkyl, R 6the phenyl, the R that replace 6the benzyl replaced, furans, thiophene, pyrroles, pyridine, pyrimidine, thiazole, pyrazoles or imidazoles; Described R 6definition as claimed in claim 1;
R 1and R 2for R 6the C replaced 1-C 4alkyl, R 6the benzyl replaced; Or R 1, R 2cyclisation is-(CH 2) 2o (CH 2) 2-,-(CH 2) 2nH (CH 2) 2-,-(CH 2) 4-,-(CH 2) 5-or-(CH 2) 6-;
R 5for C 1-C 7alkyl, C 3-C 5cycloalkyl, phenyl, benzyl, naphthyl, p-nitrophenyl, to nitrobenzyl, rubigan, p-chlorobenzyl, 2,4 dichloro benzene base or 2,4-dichloro benzyl;
Z is H, F, Cl, Br, OH, NO 2, CN, CF 3, CHF 2, CF 3o, CHF 2o, CH 3sO 2or CH 3cH 2sO 2; When described chiral amino alcohol ligand is following structure:
R 3for R 6the benzyl replaced or CH 2oR 4; Wherein R 4for hydrogen, R 6the C replaced 1-C 4alkyl, R 6the benzyl, the R that replace 6the phenyl, the R that replace 6the trityl, the three (C that replace 1-C 4) alkyl silyl or tert-butyl diphenyl silica-based; Described R 6definition as previously shown;
When described chiral amino alcohol ligand is following structure:
R 3hydrogen, R 6the C replaced 1-C 4alkyl, R 6the benzyl replaced or CH 2oR 4; Wherein R 4for hydrogen, R 6the C replaced 1-C 4alkyl, R 6the C replaced 3-C 7cycloalkyl, R 6the benzyl, trityl, the three (C that replace 1-C 4) alkyl silyl or tert-butyl diphenyl silica-based; R 6definition as claimed in claim 1.
4. the method for claim 1, is characterized in that step (a) compound of formula III can obtain pure formula III compound by recrystallization in organic solvent; Described organic solvent refers to sherwood oil, Skellysolve A, normal hexane, normal heptane, octane, nonane, hexanaphthene, methylcyclohexane or suberane; Formula III compound as claimed in claim 1.
5. the method for claim 1, described zinc salt is selected from ZnCl 2, ZnBr 2, ZnF 2, ZnI 2, Zn (OTf) 2, Zn (ODf) 2, Zn (OMs) 2, Zn (OTs) 2or Zn (PhSO 3) 2; Described mantoquita is selected from CuCl 2, CuBr 2, CuI 2, CuCl, CuBr, CuI, Cu (OTf) 2, Cu (OTf), Cu (PhSO 3), Cu (PhSO 3) 2, Cu (OTs) 2, Cu (OTs), Cu (OMs) 2or Cu (OMs); Described Tf, Df, Ts and Ms refer to trifluoromethanesulfonic acid, Difluore methane-sulfonic acid, tosic acid and methylsulfonic acid respectively.
6. the method for claim 1, described zinc salt is selected from Zn (OTf) 2; Described Tf as claimed in claim 5.
7. the method for claim 1, is characterized in that when b step reactant is all converted into cyclisation product, adds proton source cancellation reaction, by extracting and separating organic phase and aqueous phase; Proton source is saturated aqueous ammonium chloride, water, dilute hydrochloric acid, dilute sulphuric acid, acetic acid, formic acid or aqueous citric acid solution.
8. the method as described in any one of claim 1 to 7, is characterized in that without being separated the compound (formula I) by continuous one pot reaction asymmetric synthesis with following general structure:
9. method as claimed in claim 8, is characterized in that obtaining Sustiva as follows:
A. amino chloro-formic ester protection:
In the presence of a base, the mixed solvent neutral temperature 0 DEG C of organic solvent and water at 30 DEG C, by formula IV compound or its salt hydrochlorate,
With ClCOOR 5reaction, in 1 to 48 hours reaction times, obtains the compound of formula V;
Wherein, R 5for C 1-C 7alkyl, C 3-C 5cycloalkyl, phenyl or naphthyl;
Described alkali is basic metal one hydrogen orthophosphate, alkaline carbonate, alkali metal hydrocarbonate, alkali metal hydroxide or alkali metal alcoholates, and described alcohol is methyl alcohol, ethanol or the trimethyl carbinol, and described basic metal is Na, K or Li;
Described compound IV or hydrochloride: alkali: ClCOOR 5mol ratio be 1:(1-10): (1-10);
B. Terminal Acetylenes is to the asymmetric addition cyclization of the trifluorumethylketone that chloro-formic ester is protected:
In organic solvent with at 0-30 DEG C, the amino alcohol ligands of formula V compound, chirality, Terminal Acetylenes, Zn (II) salt, Cu (I) salt or Cu (II) salt and organic bases reaction 1-48 hour; Then continue reaction 5-48 hour at 60 DEG C to reflux temperature, obtain crystal formation, yield is greater than 95% and the ee value Sustiva that is greater than 99%;
Wherein, the amino alcohol ligands of described chirality has compound or its whole mapping or the diastereomer of following structural formula:
Described Terminal Acetylenes is;
Wherein R 1, R 2, R 3with the description of Z as claimed in claim 1;
Formula V compound described in step b: the amino alcohol ligands of chirality: Terminal Acetylenes: Zn salt or Cu salt: the mol ratio of organic bases is 1:(0.5-3): (0.5-3): (0.5-3): (2-3.5).
10. method as claimed in claim 9, is characterized in that chloro-formic ester protection employing formula IV compound or its salt hydrochlorate amino in described step a,
In the presence of a base, in the mixed solvent of organic solvent and water, temperature 0 DEG C at 30 DEG C, with the C of chloroformic acid 1-C 7alkyl ester, C 3-C 5cycloalkyl ester, phenylester or naphthyl ester react, 1 to 48 hours reaction times, and extraction is concentrating under reduced pressure evaporate to dryness also, and further recrystallization obtains the sterling compound of formula V;
The described solvent for recrystallization refers to sherwood oil, normal hexane, normal heptane, hexanaphthene or methylcyclohexane;
The reaction mol ratio of described organic solvent and water is (10-1): 1;
Described compound IV or hydrochloride: alkali: the C of chloroformic acid 1-C 7alkyl ester, C 3-C 5the mol ratio of cycloalkyl ester, phenylester or naphthyl ester is 1:(1-10): (1-10);
Described alkyl chloroformate or cycloalkyl ester are methyl-chloroformate, Vinyl chloroformate or chloroformic acid ring propyl ester;
Organic solvent in described step a or b is selected from the arbitrary combination solvent of tetrahydrofuran (THF), 2-methyltetrahydrofuran, ethyl acetate, n-butyl acetate, isopropyl acetate, ether, methyl tertiary butyl ether, Isosorbide-5-Nitrae-dioxane, normal hexane, normal heptane, hexanaphthene, benzene,toluene,xylene, acetonitrile or above-mentioned solvent;
Zinc salt in described step b or mantoquita are selected from ZnCl 2, ZnBr 2, ZnF 2, CuCl 2, CuBr 2, Cu (OTf) 2, Cu (OTf), Cu (PhSO 3) 2, Cu (OTs) 2, Cu (OTs), Cu (OMs) 2, Zn (OTf) 2, Zn (OMs) 2, Zn (OTs) 2or Zn (PhSO 3) 2; Described Tf, Ms are as claimed in claim 5;
Organic bases in described step b is selected from MeN (i-Pr) 2, diethylamide, triisopropylamine, pyridine, NEt 3, piperidines, NBu 3or EtN (i-Pr) 2;
Formula V compound described in step b: the amino alcohol ligands of chirality: Terminal Acetylenes: Zn salt or Cu salt: the mol ratio of organic bases is 1:(0.5-3): (0.5-3): (0.5-3): (2-3.5).
11. 1 kinds of chiral amino alcohol ligands synthesizing Sustiva compounds, is characterized in that compound or its whole mapping or the diastereomer with following structure:
When the amino alcohol ligands of chirality is, time, wherein R 1, R 2it is identical or different group; R 1and R 2for benzyl, C 1-C 4the benzyl that alkyl replaces, the benzyl of halogen substiuted, to methoxy-benzyl, to nitrobenzyl; Or R 1, R 2cyclisation is-(CH 2) 2o (CH 2) 2-or-(CH 2) 2nH (CH 2) 2-;
Described R 3hydrogen, C 1-C 4alkyl, benzyl or CH 2oR 4; Wherein R 4for hydrogen, C 1-C 4alkyl, C 3-C 7cycloalkyl, benzyl, trityl, three (C 1-C 4) alkyl silyl or tert-butyl diphenyl silica-based;
When the amino alcohol ligands of chirality is, time, wherein R 1, R 2it is identical or different group; R 1and R 2for C 1-C 4alkyl, benzyl; Or R 1, R 2cyclisation is-(CH 2) 2o (CH 2) 2-or-(CH 2) 2nH (CH 2) 2-;
Described R 3hydrogen, C 1-C 4alkyl, benzyl or CH 2oR 4; Wherein R 4for hydrogen, C 1-C 4alkyl, C 3-C 7cycloalkyl, benzyl, trityl, three (C 1-C 4) alkyl silyl or tert-butyl diphenyl silica-based
Described Z as claimed in claim 1.
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