CN104016936A - Application of chiral aminophenol ligand to asymmetric synthesis of efavirenz - Google Patents
Application of chiral aminophenol ligand to asymmetric synthesis of efavirenz Download PDFInfo
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- CN104016936A CN104016936A CN201410273032.9A CN201410273032A CN104016936A CN 104016936 A CN104016936 A CN 104016936A CN 201410273032 A CN201410273032 A CN 201410273032A CN 104016936 A CN104016936 A CN 104016936A
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- naphthalene
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
- C07C215/50—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
- B01J31/182—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine comprising aliphatic or saturated rings
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2217—At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
- B01J31/2252—Sulfonate ligands
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
- B01J2231/34—Other additions, e.g. Monsanto-type carbonylations, addition to 1,2-C=X or 1,2-C-X triplebonds, additions to 1,4-C=C-C=X or 1,4-C=-C-X triple bonds with X, e.g. O, S, NH/N
- B01J2231/341—1,2-additions, e.g. aldol or Knoevenagel condensations
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/20—Complexes comprising metals of Group II (IIA or IIB) as the central metal
- B01J2531/26—Zinc
Abstract
The invention relates to an application of a chiral aminophenol ligand to asymmetric synthesis of efavirenz. A chiral aminophenol ligand compound is used for inducing asymmetric synthesis of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone (Efavirenz). The ligand is cheap, easily available, safe and recoverable, is used in asymmetric synthesis of efavirenz, and has the advantages of high yield, good enantioselectivity, simplicity and convenience in operation, capability of realizing industrialized production and good product quality.
Description
Technical field
The present invention relates to the application of a kind of chiral aminophenol part in efavirenz asymmetric synthesis, chiral aminophenol ligand compound is encircled to the third ethynyl-4-Trifluoromethyl-1 for the chloro-4-of induction (S)-6-, 4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz).This part is cheap and easy to get, and safety is recyclable; Be used in the asymmetric synthesis of efavirenz, have that yield is high, enantioselectivity good, easy and simple to handle, can suitability for industrialized production, the advantage of good product quality.
Background technology
Aminophenols, just just has been synthesized out as far back as eighties of last century, but relatively lags behind for its chiral separation and application.1998, the people such as Naso reported chiral aminophenol asymmetric addition to aromatic aldehyde for zinc ethyl, can obtain 99% enantioselectivity.Afterwards these years in, the application of chiral aminophenol in asymmetric synthesis is more and more.Make a general survey of its application in asymmetric synthesis, main or by means of alkyl zinc reagent, after first activating again with simple aromatic aldehydes substrate reactions, in can obtaining, wait until good enantioselectivity.Simultaneously also there is report, use it for the fractionation of BINOL, or set it as chiral auxiliary and use.The synthetic method of chiral aminophenol is simple, and there is very suitable coordination structure and group, can catalysis and the polytype organic reaction of induction, be the very potential and efficient chiral catalyst of a class, believe that its fixed meeting show outstanding glamour in fields such as medicine, agricultural chemicals, chemical industry in the near future.
Acquired immune deficiency syndrome (AIDS) is to perplex at present the large disease of the mankind one, and countries in the world scientist has carried out a large amount of research to the medicine for its treatment.Synthetic methodology and the process study of Jiang Biao seminar antagonism hiv reverse transcriptase inhibitor efavirenz, develop the one kettle way asymmetric synthesis technique [CN102584801A18Jul2012 of hiv reverse transcriptase inhibitor efavirenz compounds, 30pp], be research and the industrial production huge step of efavirenz.
The present invention finds out a class chiral aminophenol part, and all very stable to strong acid and strong base, its raw materials is cheap, and method is simple, and can be close to quantitative recovery part, and the part of recovery can directly use, and chiral induction effect is still excellent.
Summary of the invention
The present invention relates to the asymmetric synthesis of a kind of chiral aminophenol part for hiv reverse transcriptase inhibitor efavirenz, it is cheap and easy to get that the method has raw material, and part is stable, and yield is high, easy and simple to handle, the advantage of good product quality.
Described amino phenol and analogue structural formula thereof are as follows:
Wherein, R
1, R
2it is identical or different groups; R
1, R
2for R
4the C replacing
1-C
15alkyl, R
4the benzyl, the R that replace
4the 1-phenyl C replacing
2-C
15alkyl; Or R
1, R
2for-(CH
2)
nx (CH
2)
m-and R
4replace-(CH
2)
nx (CH
2)
m-, wherein X is CH
2, O or S; N, m is 1 to 5 integer;
Described substituent R
4refer to H, F, Cl, Br, CH
3, CH
3cH
2, i-Pr, i-Bu, t-Bu, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH
3o, CH
3cH
2o, i-PrO, t-BuO, BnO, NO
2, CO
2et, CN, CF
3, CHF
2, CH
2f, CF
3o, CHF
2o or CH
2fO;
R
3for phenyl, naphthyl, heteroaryl, benzo heteroaryl, R
4the phenyl, the R that replace
4the naphthyl, the R that replace
4the heteroaryl, the benzo heteroaryl that replace; Described R
4definition as previously shown;
Described heteroaryl refers to five yuan or hexa-atomic containing N, O or the heteroatomic ring-type aromatic compound of S;
Z is hydrogen, monosubstituted or polysubstituted electrophilic or electron-donating group; Described electron-withdrawing group is F, Cl, Br, NO
2, CF
3, CHF
2, CH
2f, CF
3o, CHF
2o, CH
2fO, PhC (O) or Ac; Described electron-donating group is C
1-C
5alkoxyl group, NH
2or C
1-C
6alkyl.
Above-mentioned R
1, R
2, R
3, Z typical example be:
Work as R
1, R
2for-(CH
2)
4-, R
3for phenyl, Z is hydrogen, formula I corresponding compound 1, i.e. 1-(phenyl (pyrrolidin-1-yl) methyl) naphthalene-2-alcohol;
Work as R
1, R
2for-(CH
2)
4-, R
3for phenyl, Z is hydrogen, formula II corresponding compound 2, i.e. 2-(phenyl (pyrrolidin-1-yl) methyl) naphthalene-1-alcohol;
Work as R
1, R
2for-(CH
2)
4-, R
3for phenyl, Z is hydrogen, formula III corresponding compound 3, i.e. 2-(phenyl (pyrrolidin-1-yl) methyl) phenol;
Work as R
1, R
2for-(CH
2)
2o (CH
2)
2-, R
3for phenyl, Z is hydrogen, formula I corresponding compound 4, i.e. 1-(morpholino (phenyl) methyl) naphthalene-2-alcohol;
Work as R
1for Bn, R
2for Bn, R
3for p-methylphenyl, Z is 4-nitro, formula III corresponding compound 5, i.e. 2-((benzyl (methyl) amino) (p-methylphenyl) methyl)-4-nitrophenols;
Work as R
1, R
2for-(CH
2)
5-, R
3for phenyl, Z is 4-methyl, formula III corresponding compound 6, i.e. 4-methyl-2-(phenyl (piperidin-1-yl) methyl) phenol;
Work as R
1, R
2for-(CH
2)
2o (CH
2)
2-, R
3for rubigan, Z is H, formula III corresponding compound 7, i.e. 2-((4-chloro-phenyl-) (morpholino) methyl) phenol;
Work as R
1, R
2for-(CH
2)
4-, R
3for phenyl, Z is 2,4-dichloro, the corresponding compound 8 of formula III, 2, the chloro-6-of 4-bis-(phenyl (pyrrolidin-1-yl) methyl) phenol;
Work as R
1for Me, R
2for 1-phenylethyl, R
3for phenyl, Z is H, formula I corresponding compound 9, i.e. 1-((methyl (1-phenylethyl) amino) (phenyl) methyl) naphthalene-2-alcohol;
Work as R
1, R
2for-(CH
2)
5-, R
3for to bromophenyl, Z is H, formula I corresponding compound 10, i.e. 1-((4-bromophenyl) (piperidin-1-yl) methyl) naphthalene-2-alcohol;
Work as R
1, R
2for-(CH
2)
2o (CH
2)
2-, R
3for p-nitrophenyl, Z is H, formula I corresponding compound 11, i.e. 1-(morpholino (4-nitrophenyl) methyl) naphthalene-2-alcohol;
Work as R
1, R
2for-(CH
2)
2o (CH
2)
2-, R
3for p-trifluoromethyl phenyl, Z is 7-methoxyl group, formula I corresponding compound 12, i.e. 7-methoxyl group-1-(morpholino (4-(trifluoromethyl) phenyl) methyl) naphthalene-2-alcohol;
Work as R
1, R
2for-(CH
2)
5-, R
3be 2,4-Dimethoxyphenyl, Z is 5-methoxyl group, formula II corresponding compound 13, i.e. 2-((2,4-Dimethoxyphenyl) (piperidin-1-yl) methyl)-5-methoxynaphthalene-1-alcohol;
Work as R
1, R
2for-(CH
2)
2o (CH
2)
2-, R
3for 2-p-methoxy-phenyl, Z is 5-methoxyl group, formula II corresponding compound 14, i.e. 5-methoxyl group-2-((2-p-methoxy-phenyl) (morpholinyl) methyl) naphthalene-1-alcohol;
Work as R
1, R
2for-(CH
2)
2o (CH
2)
2-, R
3for thiene-3-yl-, Z is H, formula II corresponding compound 15, i.e. 2-(morpholino base (thiene-3-yl-) methyl) naphthalene-1-alcohol;
Work as R
1for Me, R
2for 1-styroyl, R
3for naphthalene-1-base, Z is H, formula I corresponding compound 16, i.e. 1-((methyl (1-styroyl) amino) (naphthalene-1-yl) methyl) naphthalene-2-alcohol;
Work as R
1, R
2for-(CH
2)
2s (CH
2)
2-, R
3for p-methylphenyl, Z is H, the corresponding compound 17 of formula I, i.e. 1-(thiomorpholine generation (p-tolyl) methyl) naphthalene-2-alcohol;
Work as R
1for Me, R
2for cyclohexyl methyl, R
3for phenyl, Z is H, formula I corresponding compound 18, i.e. 1-(((cyclohexyl methyl) (methyl) amino) (phenyl) methyl) naphthalene-2-alcohol;
Work as R
1, R
2for-(CH
2)
2n (CH
3) (CH
2)
2-, R
3for to Trifluoromethoxyphen-l, it is the protection of diphenol methylene radical that Z is 4,5, the corresponding compound 19 of formula III, be 6-((4-methylpiperazine-1-yl) (4-(trifluoromethoxy) phenyl) methyl) benzo [d] [1,3] dioxole-5-alcohol;
Work as R
1, R
2for Me, R
3for phenyl, Z is 6-benzoyl, formula I corresponding compound 20, i.e. (5-((dimethylamino) (phenyl) methyl)-6-hydroxyl naphthalene-2-yl) (phenyl) ketone;
Work as R
1for Me, R
2for Bn, R
3for cumarone-3-base, Z is H, formula III corresponding compound 21, i.e. 2-(cumarone-3-base (benzyl (methyl) amino) methyl) phenol;
Work as R
1, R
2for-(CH
2)
5-, R
3for 2-Methyl-1H-indole-3-base, Z is 2-methoxyl group, formula III corresponding compound 22, i.e. 2-methoxyl group-6-((2-Methyl-1H-indole-3-yl) (piperidin-1-yl) methyl) phenol;
Work as R
1, R
2for-(CH
2)
2o (CH
2)
2-, R
3for to benzyloxy phenyl, Z is 4-nitro, formula III corresponding compound 23, i.e. 2-(((benzyloxy) phenyl) (morpholino) methyl)-4-nitrophenols;
Work as R
1, R
2for-CH
2cH (COOEt) (CH
2)
3-, R
3for 7-Methyl-1H-indole-3-base, Z is H, formula III corresponding compound 24, i.e. 1-((2-hydroxy phenyl) (7-Methyl-1H-indole-3-yl) methyl) piperidines-3-ethyl formate;
Work as R
1, R
2for Me, R
3for phenyl, Z is 4-NH
2formula II corresponding compound 25, i.e. 4-amino-2-((dimethylamino) (phenyl) methyl) naphthalene-1-alcohol.
At a certain temperature, above-mentioned chiral aminophenol part and cyclopropyl acethlene, Lewis acid and organic bases are mixed in organic solvent;
In this mixed solution, add (the chloro-2-trifluoroacetyl group of 4-phenyl) urethanum, reaction expression is as follows:
Recommendation response temperature is-30 DEG C～30 DEG C, is particularly recommended as room temperature, and the recommendation response time is 1～72 hour;
In described method, Lewis acid is Zn (II) salt, Cu (I) salt or Cu (II) salt, is recommended as ZnBr
2, ZnCl
2, ZnF
2, Zn (OTs)
2, Zn (PhSO
3)
2, Zn (OAc)
2, Zn (C
11h
23cO
2)
2, Zn (C
17h
35cO
2)
2, Zn (acac)
2, ZnSO
4, Zn (OH)
2, Zn (OTf)
2, Zn (ODf)
2, Zn (OMs)
2, CuBr, CuCl, CuBr
2, CuCl
2, Cu (OTs)
2, Cu (PhSO
3)
2, Cu (OTf)
2, Cu (ODf)
2or Cu (OMs)
2; Especially recommending Zn (II) salt is Zn (OTs)
2.Zn (OTs)
2represent tosic acid zinc, Zn (OAc)
2represent zinc acetate, Zn (acac)
2represent zinc acetylacetonate, Zn (OTf)
2represent trifluoromethanesulfonic acid zinc, Zn (ODf)
2represent Difluore methane-sulfonic acid zinc, Zn (OMs)
2represent methylsulfonic acid zinc, Cu (OTs)
2represent copper p-toluenesulfonate, Cu (OTf)
2represent copper trifluoromethanesulfcomposite, Cu (ODf)
2represent Difluore methane-sulfonic acid copper, Cu (OMs)
2represent copper methane sulfonate.
Described organic solvent is selected from the mixed solvent of alcoholic solvent, ketones solvent, esters solvent, ether solvent, varsol, above solvent or solvent-free; Recommend 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, methylene dichloride or above-mentioned solvent; Especially recommend toluene or solvent-free;
Described organic bases is recommended as MeN (i-Pr)
2, HNEt
2, N (i-Pr)
3, pyridine, NEt
3, piperidines, EtN (i-Pr)
2or N (n-Bu)
3; Further recommending organic bases is NEt
3;
In aforesaid method, the amino phenol part of chirality: (the chloro-2-trifluoroacetyl group of 4-phenyl) urethanum: cyclopropyl acethlene: Lewis acid: the mol ratio of organic bases is 1:(0.5-3): (1-40): (0.5-2): (0.5-10); Especially recommend 1:(0.8-1.5): (5-20): (0.7-1.4): (3-8).
After reacting completely, with HCl recovery chiral aminophenol part, then heat, cyclization obtains final efavirenz;
In aforesaid method, the concentration of hydrochloric acid is 1-12mol/L; Recommend 4-8mol/L;
Recommend ring-closure reaction temperature to be 40 DEG C and arrive reflux temperature, further recommendation response temperature is 50 DEG C and arrives reflux temperature.
Compared with the method for existing synthetic efavirenz, technique of the present invention relates to the asymmetric addition that chiral aminophenol part participates in.Amino phenol is synthetic simple, split efficiently, and part is to ph stability, recovery that can be quantitative after use, keeps original chirality, directly drops in next batch synthetic, reduce production costs, economic benefit and social benefit are maximized, be applicable to large-scale industrial production.
Embodiment
Following examples will further illustrate method provided by the invention, but the present invention is not limited.
Embodiment 1:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
In tube sealing, add (R)-1-(phenyl (pyrrolidin-1-yl) methyl) naphthalene-2 – alcohol (23mg; 0.75mmol); tosic acid zinc (20mg; 0.5mmol); substitute gas; add cyclopropyl acethlene (0.4mL); triethylamine (0.14mL; 10mmol); stirring reaction 3h; add (the chloro-2-trifluoroacetyl group of 4-phenyl) urethanum (30mg, 0.1mmol), in stirring at room temperature reaction 24h.Organic solvent shifts as ethyl acetate (EA), 6M salt acid elution, saturated sodium-chloride washing, anhydrous sodium sulfate drying.Column chromatography obtains, (S)-(the chloro-2-of 4-(4-cyclopropyl-1, the fluoro-2-hydroxyl fourth-3-of 1,1-tri-alkynes-2-yl) phenyl) urethanum 35.5mg, productive rate 96%, ee value 81%.(separate is only data analysis herein, when actual synthesizing, can not carry out this step separation)
1H?NMR(300MHz,CDCl
3)δ8.54(s,1H),8.05(d,J＝8.4Hz,1H),7.66(s,1H),7.32(dd,J＝9.0,2.2Hz,1H),4.19(q,J＝7.1Hz,2H),4.04(s,1H),1.37(td,J＝8.2,4.1Hz,1H),1.29(t,J＝7.1Hz,3H),0.96–0.86(m,2H),0.82(dd,J＝7.3,4.2Hz,2H).
19F?NMR(282MHz,CDCl
3)：δ-80.35；
MS(EI)m/z:361[M]
+(33.12).
Ee adopts HPLC analytical procedure to measure [as determined by HPLC analysis] (chiral column Chiralcel AD-H, drip washing organic solvent volume ratio iPrOH/hexane=7/93, flow 1mL/min, 254nm, t
f5.524 (main peak major), 6.395 (secondary peak minor).
By above-mentioned gained (S)-(the chloro-2-of 4-(4-cyclopropyl-1, the fluoro-2-hydroxyl fourth-3-of 1,1-tri-alkynes-2-yl) phenyl) urethanum, 5mL reflux in toluene reaction 4 hours, obtain efavirenz 31.0mg, quantitative yield, ee value 81%.
1H?NMR(300MHz,CDCl
3)：δ8.98(s,1H),7.49(s,1H),7.36(dd,J＝8.5,2.2Hz,1H),6.82(d,J＝8.6Hz,1H),1.45–1.35(m,1H),0.98–0.81(m,4H).
19F?NMR(282MHz,CDCl
3)：δ-81.35.
MS(EI)m/z:315[M]
+(38.38).
ee?as?determined?by?HPLC?analysis(Chiralcel?AD-H,iPrOH/hexane＝7/93,1mL/min,254nm),t
f8.2(minor),7.5(major).
Embodiment 2:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
In tube sealing, add (R)-1-(phenyl (pyrrolidin-1-yl) methyl) naphthalene-2 – alcohol (68mg; 2.25mmol); tosic acid zinc (61mg; 1.5mmol); substitute gas; add cyclopropyl acethlene (0.4mL); triethylamine (0.14mL; 10mmol); stirring reaction 8h; add (the chloro-2-trifluoroacetyl group of 4-phenyl) urethanum (30mg, 0.1mmol), in stirring at room temperature reaction 24h.The cancellation that adds water, EA extraction, 6M salt acid elution, saturated sodium-chloride washing, anhydrous sodium sulfate drying.After concentrated, add refluxing toluene reaction 4 hours, obtain efavirenz 31.1mg, productive rate 98%, ee value 91%.
Embodiment 3:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
In tube sealing, add (R)-2-(phenyl (pyrrolidin-1-yl) methyl) naphthalene-1-alcohol (68mg; 2.25mmol); tosic acid zinc (61mg; 1.5mmol); substitute gas; add cyclopropyl acethlene (0.4mL); triethylamine (0.14mL; 10mmol); move into 40 DEG C of oil baths, stirring reaction 3h, adds (the chloro-2-trifluoroacetyl group of 4-phenyl) urethanum (30mg; 0.1mmol), in stirring at room temperature reaction 24h.The cancellation that adds water, EA extraction, 6M salt acid elution, saturated sodium-chloride washing, anhydrous sodium sulfate drying.After concentrated, add refluxing toluene reaction 4 hours, obtain efavirenz 31.5mg, productive rate 94%, ee value 95%.
Embodiment 4:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
In tube sealing, add (R)-2-(phenyl (pyrrolidin-1-yl) methyl) phenol (57mg; 2.25mmol); tosic acid zinc (61mg; 1.5mmol); substitute gas; add cyclopropyl acethlene (0.4mL); triethylamine (0.14mL; 10mmol); stirring reaction 3h; add (the chloro-2-trifluoroacetyl group of 4-phenyl) urethanum (30mg, 0.1mmol), in stirring at room temperature reaction 24h.The cancellation that adds water, EA extraction, 6M salt acid elution, saturated sodium-chloride washing, anhydrous sodium sulfate drying.After concentrated, add refluxing toluene reaction 4 hours, obtain efavirenz 31.4mg, productive rate 89%, ee value 95%.
Embodiment 5:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
In 50mL egg type bottle, add (R)-1-(phenyl (pyrrolidin-1-yl) methyl) naphthalene-2 – alcohol (3.64g; 0.012mol); tosic acid zinc (4.48g; 0.011mol); substitute gas; add cyclopropyl acethlene (3.4mL; 0.04mol); triethylamine (5.58mL, 0.04mol), toluene (30g); stirring reaction 24h; add (the chloro-2-trifluoroacetyl group of 4-phenyl) urethanum (2.96g, 0.01mol), in stirring at room temperature reaction 48h.With after HCl recovery part, to toluene phase back flow reaction, obtain efavirenz, to thick product recrystallization purifying, can obtain target compound 2.94g, productive rate 93%, ee value 99%.
Embodiment 6:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-1-(morpholino (phenyl) methyl) naphthalene-2-alcohol, and zinc salt uses ZnBr
2, alkali uses MeN (i-Pr)
2, solvent uses tetrahydrofuran (THF), and productive rate is that 85%, ee value is 91%.
Embodiment 7:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-2-((benzyl (methyl) amino) (p-methylphenyl) methyl)-4-nitrophenols, and zinc salt uses Zn (OTf)
2, alkali uses pyridine, and solvent uses ethyl acetate, and productive rate is that 85%, ee value is 89%.
Embodiment 8:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-4-methyl-2-(phenyl (piperidin-1-yl) methyl) phenol, and zinc salt uses Zn (ODf)
2, alkali uses piperidines, and solvent uses ether, and productive rate is that 79%, ee value is 88%.
Embodiment 9:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-2-((4-chloro-phenyl-) (morpholino) methyl) phenol, and zinc salt uses CuBr, and alkali uses N (n-Bu)
3, solvent uses methylene dichloride, and productive rate is that 85%, ee value is 83%.
Embodiment 10:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-2, the chloro-6-of 4-bis-(phenyl (pyrrolidin-1-yl) methyl) phenol, and zinc salt uses Cu (PhSO
3)
2, alkali uses NEt
3, solvent uses normal hexane, and productive rate is that 78%, ee value is 87%.
Embodiment 11:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses 1-((R)-(methyl ((R)-1-phenylethyl) amino) (phenyl) methyl) naphthalene-2-alcohol, and zinc salt uses ZnCl
2, alkali uses N (i-Pr)
3, solvent uses ethyl acetate and normal hexane mixed solvent, and productive rate is that 75%, ee value is 79%.
Embodiment 12:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-1-((4-bromophenyl) (piperidin-1-yl) methyl) naphthalene-2-alcohol, and zinc salt uses ZnBr
2, alkali uses MeN (i-Pr)
2, solvent uses toluene, and productive rate is that 88%, ee value is 91%.
Embodiment 13:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-1-(morpholino (4-nitrophenyl) methyl) naphthalene-2-alcohol, and zinc salt uses ZnCl
2, alkali uses N (i-Pr)
3, solvent uses ethyl acetate, and productive rate is that 85%, ee value is 92%.
Embodiment 14:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-7-methoxyl group-1-(morpholino (4-(trifluoromethyl) phenyl) methyl) naphthalene-2-alcohol, and zinc salt uses ZnCl
2, alkali uses HNEt
2, solvent uses normal hexane, and productive rate is that 86%, ee value is 79%.
Embodiment 15:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-2-((2,4-Dimethoxyphenyl) (piperidin-1-yl) methyl)-5-methoxynaphthalene-1-alcohol, and zinc salt uses Zn (OTs)
2, alkali uses NEt
3, solvent uses methylene dichloride and normal hexane mixed solvent, and productive rate is that 81%, ee value is 85%.
Embodiment 16:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-5-methoxyl group-2-((2-p-methoxy-phenyl) (morpholinyl) methyl) naphthalene-1-alcohol, and zinc salt uses Zn (OTs)
2, alkali uses N (n-Bu)
3, solvent uses methanol solvate, and productive rate is that 92%, ee value is 74%.
Embodiment 17:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-2-(morpholino base (thiene-3-yl-) methyl) naphthalene-1-alcohol, and zinc salt uses Zn (PhSO
3)
2, alkali uses piperidines, and solvent uses ethanol, and productive rate is that 80%, ee value is 71%.
Embodiment 18:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-1-((methyl (1-styroyl) amino) (naphthalene-1-yl) methyl) naphthalene-2-alcohol, and zinc salt uses Zn (PhSO
3)
2, alkali uses piperidines, and solvent uses acetone, and productive rate is that 81%, ee value is 85%.
Embodiment 19:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-1-(thiomorpholine generation (p-tolyl) methyl) naphthalene-2-alcohol, and zinc salt uses Zn (OTf)
2, alkali uses pyridine, and solvent uses tetrahydrofuran (THF), and productive rate is that 79%, ee value is 69%.
Embodiment 20:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-1-(((cyclohexyl methyl) (methyl) amino) (phenyl) methyl) naphthalene-2-alcohol, and zinc salt uses Zn (ODf)
2, alkali uses pyridine, and solvent uses tetrahydrofuran (THF), and productive rate is that 92%, ee value is 95%.
Embodiment 21:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-6-((4-methylpiperazine-1-yl) (4-(trifluoromethoxy) phenyl) methyl) benzo [d] [1,3] dioxole-5-alcohol, zinc salt uses CuBr, and alkali uses N (i-Pr)
3, solvent uses toluene, and productive rate is that 71%, ee value is 74%.
Embodiment 22:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-(5-((dimethylamino) (phenyl) methyl)-6-hydroxyl naphthalene-2-yl) (phenyl) ketone, and zinc salt uses CuBr
2, alkali uses MeN (i-Pr)
2, solvent uses the mixed solvent of toluene and tetrahydrofuran (THF), and productive rate is that 83%, ee value is 86%.
Embodiment 23:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-2-(cumarone-3-base (benzyl (methyl) amino) methyl) phenol, and zinc salt uses Cu (OTs)
2, alkali uses NEt
3, solvent uses toluene, and productive rate is that 71%, ee value is 69%.
Embodiment 24:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-2-methoxyl group-6-((2-Methyl-1H-indole-3-yl) (piperidin-1-yl) methyl) phenol, and zinc salt uses Cu (OTs)
2, alkali uses N (i-Pr)
3, solvent uses solvent-free, and productive rate is that 80%, ee value is 75%.
Embodiment 25:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-2-(((benzyloxy) phenyl) (morpholino) methyl)-4-nitrophenols, and zinc salt uses Cu (PhSO
3)
2, alkali uses pyridine, and solvent uses solvent-free, and productive rate is that 81%, ee value is 88%.
Embodiment 26:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-1-((2-hydroxy phenyl) (7-Methyl-1H-indole-3-yl) methyl) piperidines-3-ethyl formate, and zinc salt uses Cu (OTf)
2, alkali uses EtN (i-Pr)
2, solvent uses toluene, and productive rate is that 75%, ee value is 77%.
Embodiment 27:
(S) the chloro-4-of-6-encircles the third ethynyl-4-Trifluoromethyl-1,4-dihydro-2H-1, the asymmetric synthesis of 3-benzoxazine-2-ketone (efavirenz Efavirenz)
With reference to the method for embodiment 5, amino phenol part uses (R)-4-amino-2-((dimethylamino) (phenyl) methyl) naphthalene-1-alcohol, and zinc salt uses Cu (OTf)
2, alkali uses HNEt
2, solvent uses tetrahydrofuran (THF), and productive rate is that 81%, ee value is 70%.
Claims (9)
1. the application of chiral aminophenol part in efavirenz asymmetric synthesis, is characterised in that described chiral aminophenol part has following structural formula:
Wherein, R
1, R
2it is identical or different groups; R
1, R
2for R
4the C replacing
1-C
15alkyl, R
4the benzyl, the R that replace
4the 1-phenyl C replacing
2-C
15alkyl; Or R
1, R
2for-(CH
2)
nx (CH
2)
m-and R
4replace-(CH
2)
nx (CH
2)
m-, wherein X is CH
2, O or S; N, m is 1 to 5 integer;
Described substituent R
4refer to H, F, Cl, Br, CH
3, CH
3cH
2, i-Pr, i-Bu, t-Bu, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH
3o, CH
3cH
2o, i-PrO, t-BuO, BnO, NO
2, CO
2et, CN, CF
3, CHF
2, CH
2f, CF
3o, CHF
2o or CH
2fO;
R
3for phenyl, naphthyl, heteroaryl, benzo heteroaryl, R
4the phenyl, the R that replace
4the naphthyl, the R that replace
4the heteroaryl, the benzo heteroaryl that replace; Described R
4definition as previously shown;
Described heteroaryl refers to five yuan or hexa-atomic containing N, O or the heteroatomic ring-type aromatic compound of S;
Z is hydrogen, monosubstituted or polysubstituted electrophilic or electron-donating group; Described electron-withdrawing group is F, Cl, Br, NO
2, CF
3, CHF
2, CH
2f, CF
3o, CHF
2o, CH
2fO, PhC (O) or Ac; Described electron-donating group is C
1-C
5alkoxyl group, NH
2or C
1-C
6alkyl.
2. the application of chiral aminophenol part according to claim 1 in efavirenz asymmetric synthesis, it is characterized in that described chiral aminophenol part is 1-(phenyl (pyrrolidin-1-yl) methyl) naphthalene-2-alcohol, 2-(phenyl (pyrrolidin-1-yl) methyl) naphthalene-1-alcohol, 2-(phenyl (pyrrolidin-1-yl) methyl) phenol, 1-(morpholino (phenyl) methyl) naphthalene-2-alcohol, 2-((benzyl (methyl) amino) (p-methylphenyl) methyl)-4-nitrophenols, 4-methyl-2-(phenyl (piperidin-1-yl) methyl) phenol, 2-((4-chloro-phenyl-) (morpholino) methyl) phenol, 2, the chloro-6-of 4-bis-(phenyl (pyrrolidin-1-yl) methyl) phenol, 1-((methyl (1-phenylethyl) amino) (phenyl) methyl) naphthalene-2-alcohol, 1-((4-bromophenyl) (piperidin-1-yl) methyl) naphthalene-2-alcohol, 1-(morpholino (4-nitrophenyl) methyl) naphthalene-2-alcohol, 7-methoxyl group-1-(morpholino (4-(trifluoromethyl) phenyl) methyl) naphthalene-2-alcohol, 2-((2, 4-Dimethoxyphenyl) (piperidin-1-yl) methyl)-5-methoxynaphthalene-1-alcohol, 5-methoxyl group-2-((2-p-methoxy-phenyl) (morpholinyl) methyl) naphthalene-1-alcohol, 2-(morpholino base (thiene-3-yl-) methyl) naphthalene-1-alcohol, 1-((methyl (1-styroyl) amino) (naphthalene-1-yl) methyl) naphthalene-2-alcohol, 1-(thiomorpholine generation (p-tolyl) methyl) naphthalene-2-alcohol, 1-(((cyclohexyl methyl) (methyl) amino) (phenyl) methyl) naphthalene-2-alcohol, 6-((4-methylpiperazine-1-yl) (4-(trifluoromethoxy) phenyl) methyl) benzo [d] [1, 3] dioxole-5-alcohol, (5-((dimethylamino) (phenyl) methyl)-6-hydroxyl naphthalene-2-yl) (phenyl) ketone, 2-(cumarone-3-base (benzyl (methyl) amino) methyl) phenol, 2-methoxyl group-6-((2-Methyl-1H-indole-3-yl) (piperidin-1-yl) methyl) phenol, 2-(((benzyloxy) phenyl) (morpholino) methyl)-4-nitrophenols, 1-((2-hydroxy phenyl) (7-Methyl-1H-indole-3-yl) methyl) piperidines-3-ethyl formate, 4-amino-2-((dimethylamino) (phenyl) methyl) naphthalene-1-alcohol.
3. the application of chiral aminophenol part according to claim 1 in efavirenz asymmetric synthesis, it is characterized in that described application comprises following steps: in organic solvent or when solvent-free, described chiral aminophenol part, (the chloro-2-trifluoroacetyl group of 4-phenyl) urethanum, cyclopropyl acethlene, Lewis acid and organic bases are at-30 DEG C～30 DEG C, react 1～72 hour, the acid adding shrend reaction of going out, then organic phase is continued under 40 DEG C～reflux temperature to reaction 4～48 hours, obtain the efavirenz of high enantioselectivity; The mol ratio of described chiral aminophenol part, (the chloro-2-trifluoroacetyl group of 4-phenyl) urethanum, cyclopropyl acethlene, Lewis acid and organic bases is followed successively by 1:(0.5-3): (1-40): (0.5-2): (0.5-10).
4. according to application claimed in claim 3, it is characterized in that described organic solvent is alcoholic solvent, ketones solvent, esters solvent, ether solvent, varsol or above-mentioned mixed solvent.
5. application according to claim 3, is characterized in that described Lewis acid is Zn (II) salt, Cu (I) salt or Cu (II) salt.
6. according to application claimed in claim 5, it is characterized in that described Zn (II) salt, Cu (I) salt or Cu (II) salt are specially ZnBr
2, ZnCl
2, ZnF
2, Zn (OTs)
2, Zn (PhSO
3)
2, Zn (OAc)
2, Zn (C
11h
23cO
2)
2, Zn (C
17h
35cO
2)
2, Zn (acac)
2, ZnSO
4, Zn (OH)
2, Zn (OTf)
2, Zn (ODf)
2, Zn (OMs)
2, CuBr, CuCl, CuBr
2, CuCl
2, Cu (OTs)
2, Cu (PhSO
3)
2, Cu (OTf)
2, Cu (ODf)
2or Cu (OMs)
2; Wherein, Zn (OTs)
2represent tosic acid zinc, Zn (OAc)
2represent zinc acetate, Zn (acac)
2represent zinc acetylacetonate, Zn (OTf)
2represent trifluoromethanesulfonic acid zinc, Zn (ODf)
2represent Difluore methane-sulfonic acid zinc, Zn (OMs)
2represent methylsulfonic acid zinc, Cu (OTs)
2represent copper p-toluenesulfonate, Cu (OTf)
2represent copper trifluoromethanesulfcomposite, Cu (ODf)
2represent Difluore methane-sulfonic acid copper, Cu (OMs)
2represent copper methane sulfonate.
7. application according to claim 3, is characterized in that described organic bases is MeN (i-Pr)
2, HNEt
2, N (i-Pr)
3, pyridine, NEt
3, piperidines, EtN (i-Pr)
2or N (n-Bu)
3.
8. application according to claim 3, is characterized in that the HCl aqueous solution that described sour water is 1～12mol/L.
9. application according to claim 3 after it is characterized in that described cancellation reaction, is reclaimed the chiral aminophenol part described in claim 1 or 2 from the aqueous solution.
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| WO2015192774A1 (en) * | 2014-06-18 | 2015-12-23 | 中国科学院上海有机化学研究所 | Application of chiral aminophenol ligand in asymmetric synthesis of efavirenz |
| CN110382470A (en) * | 2017-02-23 | 2019-10-25 | 纳尔逊·曼德拉都市大学 | The preparation method of efavirenz |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1185146A (en) * | 1995-05-25 | 1998-06-17 | 麦克公司 | Asymmetric synthesis of (-) 6 -chloro-4-cyclopropyl-ethynyl-4-trifluoromethyl-1, 4dihydro-2H-3, 1-benzoxazin-2-one |
| WO1998027034A1 (en) * | 1996-12-16 | 1998-06-25 | Du Pont Pharmaceuticals Company | An improved synthesis of cyclopropylacetylene |
| CN1245493A (en) * | 1996-12-16 | 2000-02-23 | 杜邦药品公司 | Asymmetric synthesis of benzoxazinones |
| CN103664816A (en) * | 2011-01-06 | 2014-03-26 | 中国科学院上海有机化学研究所 | One-pot asymmetric synthetic process of HIV (Human Immunodeficiency Virus) reverse transcriptase inhibitor efavirenz compound |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104016936B (en) * | 2014-06-18 | 2016-08-17 | 中国科学院上海有机化学研究所 | The application in efavirenz asymmetric synthesis of the chiral aminophenol part |
-
2014
- 2014-06-18 CN CN201410273032.9A patent/CN104016936B/en active Active
-
2015
- 2015-06-17 WO PCT/CN2015/081701 patent/WO2015192774A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1185146A (en) * | 1995-05-25 | 1998-06-17 | 麦克公司 | Asymmetric synthesis of (-) 6 -chloro-4-cyclopropyl-ethynyl-4-trifluoromethyl-1, 4dihydro-2H-3, 1-benzoxazin-2-one |
| WO1998027034A1 (en) * | 1996-12-16 | 1998-06-25 | Du Pont Pharmaceuticals Company | An improved synthesis of cyclopropylacetylene |
| CN1245493A (en) * | 1996-12-16 | 2000-02-23 | 杜邦药品公司 | Asymmetric synthesis of benzoxazinones |
| CN103664816A (en) * | 2011-01-06 | 2014-03-26 | 中国科学院上海有机化学研究所 | One-pot asymmetric synthetic process of HIV (Human Immunodeficiency Virus) reverse transcriptase inhibitor efavirenz compound |
Non-Patent Citations (2)
| Title |
|---|
| WEN-YONG HAN等: "Enantioselective Organocatalytic Three-Component Petasis Reaction among Salicylaldehydes, Amines, and Organoboronic Acids", 《ORGANIC LETTERS》, vol. 14, no. 4, 30 April 2012 (2012-04-30), pages 978 - 2 * |
| 刘丰良等: "手性氨基酚配体及其衍生物在不对称催化中的应用", 《有机化学》, vol. 25, no. 9, 30 September 2005 (2005-09-30) * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015192774A1 (en) * | 2014-06-18 | 2015-12-23 | 中国科学院上海有机化学研究所 | Application of chiral aminophenol ligand in asymmetric synthesis of efavirenz |
| CN110382470A (en) * | 2017-02-23 | 2019-10-25 | 纳尔逊·曼德拉都市大学 | The preparation method of efavirenz |
| CN110382470B (en) * | 2017-02-23 | 2023-06-06 | 纳尔逊·曼德拉都市大学 | Preparation method of efavirenz |
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| CN104016936B (en) | 2016-08-17 |
| WO2015192774A1 (en) | 2015-12-23 |
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