CN104016936B - The application in efavirenz asymmetric synthesis of the chiral aminophenol part - Google Patents

The application in efavirenz asymmetric synthesis of the chiral aminophenol part Download PDF

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CN104016936B
CN104016936B CN201410273032.9A CN201410273032A CN104016936B CN 104016936 B CN104016936 B CN 104016936B CN 201410273032 A CN201410273032 A CN 201410273032A CN 104016936 B CN104016936 B CN 104016936B
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methyl
phenyl
naphthalene
alcohol
base
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CN104016936A (en
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姜标
李晓贤
李金华
邢萍
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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    • 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
    • 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

Abstract

The present invention relates to the application in efavirenz asymmetric synthesis of a kind of chiral aminophenol part, use chiral aminophenol ligand compound, for inducing (S) 6 chlorine 4 ring the third acetenyl 4 trifluoromethyl 1, the asymmetric synthesis of 4 dihydro 2H 1,3 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 is good, easy and simple to handle, can industrialized production, the advantage of good product quality.

Description

The application in efavirenz asymmetric synthesis of the chiral aminophenol part
Technical field
The present invention relates to the application in efavirenz asymmetric synthesis of a kind of chiral aminophenol part, by chirality ammonia Base phenol ligand compound is used for inducing (S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3- The asymmetric synthesis of benzoxazine-2-ketone (efavirenz Efavirenz).This part is cheap and easy to get, and safety can Reclaim；It is used in the asymmetric synthesis of efavirenz, has that yield is high, enantioselectivity is good, easy and simple to handle, Can industrialized production, the advantage of good product quality.
Background technology
Aminophenols, as far back as being synthesized at the beginning of eighties of last century, but for its chiral separation And application is the most delayed.1998, Naso et al. reported chiral aminophenol for diethyl zinc to fragrance The asymmetric addition of aldehyde, it is possible to obtain the enantioselectivity of 99%.Afterwards these years in, chiral aminophenol exists Application in asymmetric synthesis gets more and more.Make a general survey of its application in asymmetric synthesis, be the most also by mean of Alkyl zinc reagent, after first activating again with simple aromatic aldehydes substrate reactions, can wait until good in obtaining Enantioselectivity.Also have been reported that simultaneously, use it for the fractionation of BINOL, or as chirality Prothetic group uses.The synthetic method of chiral aminophenol is simple, and has the coordination structure and group being particularly suitable for, Can be catalyzed and induce polytype organic reaction, be the most potential and efficient chiral catalyst of a class, Believe that its fixed meeting show outstanding glamour in fields such as medicine, pesticide, chemical industry in the near future.
Acquired immune deficiency syndrome (AIDS) is to perplex the big disease of the mankind one at present, and the medicine treated for it is entered by countries in the world scientist Go substantial amounts of research.The methodology of Jiang Biao seminar antagonism hiv reverse transcriptase inhibitor efavirenz synthesis And process study, develop the one kettle way of hiv reverse transcriptase inhibitor efavirenz compounds not Symmetrical synthesis technique [CN102584801A18Jul2012,30pp], for research and the commercial production of efavirenz Huge step.
The present invention finds out a class chiral aminophenol part, and the most stable to strong acid and strong base, it prepares cost of material Cheap, method is simple, and can directly can use with the recovery part of near quantitative, the part of recovery, hands Property inducing effect is the most excellent.
Summary of the invention
The present invention relates to the most right for hiv reverse transcriptase inhibitor efavirenz of a kind of chiral aminophenol part Claiming synthesis, 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, good product quality Advantage.
Described amino phenols and the like structural formula is as follows:
Wherein, R1, R2It it is identical or different groups；R1, R2For R4Substituted C1-C15Alkyl, R4 Substituted benzyl, R4Substituted 1-phenyl C2-C15Alkyl；Or R1, R2For-(CH2)nX(CH2)m-and R4Substituted-(CH2)nX(CH2)m-, wherein X is CH2, O or S；N, m are the integer of 1 to 5；
Described substituent R4Refer to H, F, Cl, Br, CH3、CH3CH2, i-Pr, i-Bu, t-Bu, ring Propyl group, cyclobutyl, cyclopenta, cyclohexyl, CH3O、CH3CH2O、i-PrO、t-BuO、BnO、NO2、 CO2Et、CN、CF3、CHF2、CH2F、CF3O、CHF2O or CH2FO；
R3For phenyl, naphthyl, heteroaryl, benzo heteroaryl, R4Substituted phenyl, R4Substituted naphthyl, R4Substituted heteroaryl, benzo heteroaryl；Described R4As defined above shown in；
Described heteroaryl refers to five yuan or hexa-atomic containing N, O or S heteroatomic cyclic aromatic compound；
Z is hydrogen, monosubstituted or polysubstituted electrophilic or electron donating group；Described electron withdraw group be F, Cl, Br、NO2、CF3、CHF2、CH2F、CF3O、CHF2O、CH2FO, PhC (O) or Ac；Described give Electron group is C1-C5Alkoxyl, NH2Or C1-C6Alkyl.
Above-mentioned R1、R2、R3, the typical example of Z be:
Work as R1、R2For-(CH2)4-,R3For phenyl, Z is hydrogen, Formulas I correspondence compound 1, i.e. 1-(phenyl (pyrrole Cough up alkane-1-base) methyl) naphthalene-2-alcohol；
Work as R1、R2For-(CH2)4-, R3For phenyl, Z is hydrogen, Formula II correspondence compound 2, i.e. 2-(phenyl (pyrrolidin-1-yl) methyl) naphthalene-1-alcohol；
Work as R1、R2For-(CH2)4-, R3For phenyl, Z is hydrogen, formula III correspondence compound 3, i.e. 2-(benzene Base (pyrrolidin-1-yl) methyl) phenol；
Work as R1、R2For-(CH2)2O(CH2)2-, R3For phenyl, Z is hydrogen, Formulas I correspondence compound 4, i.e. 1-(morpholino (phenyl) methyl) naphthalene-2-alcohol；
Work as R1For Bn, R2For Bn, R3For p-methylphenyl, Z is 4-nitro, formula III correspondence compound 5, I.e. 2-((benzyl (methyl) amino) (p-methylphenyl) methyl)-4-nitrophenol；
Work as R1、R2For-(CH2)5-, R3For phenyl, Z is 4-methyl, formula III correspondence compound 6, i.e. 4 -methyl-2-(phenyl (piperidin-1-yl) methyl) phenol；
Work as R1、R2For-(CH2)2O(CH2)2-, R3For rubigan, Z is H, formula III correspondence compound 7, I.e. 2-((4-chlorphenyl) (morpholino) methyl) phenol；
Work as R1、R2For-(CH2)4-, R3For phenyl, Z is 2,4-dichloro, formula III correspondence compound 8, i.e. The chloro-6-of 2,4-bis-(phenyl (pyrrolidin-1-yl) methyl) phenol；
Work as R1For Me, R2For 1-phenylethyl, R3For phenyl, Z is H, Formulas I correspondence compound 9, I.e. 1-((methyl (1-phenylethyl) amino) (phenyl) methyl) naphthalene-2-alcohol；
Work as R1、R2For-(CH2)5-,R3For p-bromophenyl, Z is H, Formulas I correspondence compound 10, i.e. 1-((4 -bromophenyl) (piperidin-1-yl) methyl) naphthalene-2-alcohol；
Work as R1、R2For-(CH2)2O(CH2)2-,R3For p-nitrophenyl, Z is H, Formulas I correspondence compound 11, I.e. 1-(morpholino (4-nitrobenzophenone) methyl) naphthalene-2-alcohol；
Work as R1、R2For-(CH2)2O(CH2)2-,R3For p-trifluoromethyl phenyl, Z is 7-methoxyl group, Formulas I Corresponding compound 12, i.e. 7-methoxyl group-1-(morpholino (4-(trifluoromethyl) phenyl) methyl) naphthalene-2-alcohol；
Work as R1、R2For-(CH2)5-,R3Being 2,4-Dimethoxyphenyl, Z is 5-methoxyl group, and Formula II is corresponding Compound 13, i.e. 2-((2,4-Dimethoxyphenyl) (piperidin-1-yl) methyl)-5-methoxynaphthalene-1- Alcohol；
Work as R1、R2For-(CH2)2O(CH2)2-,R3For 2-methoxyphenyl, Z is 5-methoxyl group, Formula II Corresponding compound 14, i.e. 5-methoxyl group-2-((2-methoxyphenyl) (morpholinyl) methyl) naphthalene-1-alcohol；
Work as R1、R2For-(CH2)2O(CH2)2-,R3For thiene-3-yl, Z is H, Formula II correspondence compound 15, I.e. 2-(morpholino base (thiene-3-yl) methyl) naphthalene-1-alcohol；
Work as R1For Me, R2For 1-phenethyl, R3For naphthalene-1-base, Z is H, Formulas I correspondence compound 16, I.e. 1-((methyl (1-phenethyl) amino) (naphthalene-1-base) methyl) naphthalene-2-alcohol；
Work as R1、R2For-(CH2)2S(CH2)2-,R3For p-methylphenyl, Z is H, Formulas I correspondence compound 17, I.e. 1-(thiomorpholine generation (p-tolyl) methyl) naphthalene-2-alcohol；
Work as R1For Me, R2For cyclohexyl methyl, R3For phenyl, Z is H, Formulas I correspondence compound 18, i.e. 1-(((cyclohexyl methyl) (methyl) amino) (phenyl) methyl) naphthalene-2-alcohol；
Work as R1、R2For-(CH2)2N(CH3)(CH2)2-,R3For to Trifluoromethoxyphen-l, Z is 4, and 5 is two Phenol methylene is protected, formula III correspondence compound 19, i.e. 6-((4-methylpiperazine-1-yl) (4-(trifluoro Methoxyl group) phenyl) methyl) benzo [d] [1,3] dioxole-5-alcohol；
Work as R1、R2For Me, R3For phenyl, Z is 6-benzoyl, Formulas I correspondence compound 20, i.e. (5- ((dimethylamino) (phenyl) methyl)-6-hydroxyl naphthalene-2-base) (phenyl) ketone；
Work as R1For Me, R2For Bn, R3For benzofuran-3-base, Z is H, formula III correspondence compound 21, I.e. 2-(benzofuran-3-base (benzyl (methyl) amino) methyl) phenol；
Work as R1、R2For-(CH2)5-,R3For 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-base) (piperidin-1-yl) first Base) phenol；
Work as R1、R2For-(CH2)2O(CH2)2-,R3For to benzyloxy-phenyl, Z is 4-nitro, and formula III is corresponding Compound 23, i.e. 2-(((benzyloxy) phenyl) (morpholino) methyl)-4-nitrophenol；
Work as R1、R2For-CH2CH(COOEt)(CH2)3-,R3For 7-Methyl-1H-indole-3-base, Z is H, Formula III correspondence compound 24, i.e. 1-((2-hydroxy phenyl) (7-Methyl-1H-indole-3-base) methyl) piperidines-3-Ethyl formate；
Work as R1、R2For Me, R3For phenyl, Z is 4-NH2Formula II correspondence compound 25, i.e. 4-amino-2- ((dimethylamino) (phenyl) methyl) naphthalene-1-alcohol.
At a certain temperature, above-mentioned chiral aminophenol part mixes with cyclopropyl acethlene, Lewis acid and organic base In organic solvent；
In this mixed liquor, add (4-chloro-2-trifluoroacetyl group phenyl) urethanes, reaction expression As follows:
Recommendation response temperature is-30 DEG C～30 DEG C, is particularly recommended as room temperature, it is recommended that the response time is 1～72 hour；
In described method, Lewis acid is Zn (II) salt, Cu (I) salt or Cu (II) salt, it is recommended that for ZnBr2、ZnCl2、 ZnF2、Zn(OTs)2、Zn(PhSO3)2、Zn(OAc)2、Zn(C11H23CO2)2、Zn(C17H35CO2)2、 Zn(acac)2、ZnSO4、Zn(OH)2、Zn(OTf)2、Zn(ODf)2、Zn(OMs)2、CuBr、CuCl、 CuBr2、CuCl2、Cu(OTs)2、Cu(PhSO3)2、Cu(OTf)2、Cu(ODf)2Or Cu (OMs)2；Especially It recommends Zn (II) salt to be Zn (OTs)2。Zn(OTs)2Represent p-methyl benzenesulfonic acid zinc, Zn (OAc)2Represent zinc acetate, Zn(acac)2Represent zinc acetylacetonate, Zn (OTf)2Represent trifluoromethanesulfonic acid zinc, Zn (ODf)2Represent difluoro first Sulfonic acid zinc, Zn (OMs)2Represent methanesulfonic acid zinc, Cu (OTs)2Represent copper p-toluenesulfonate, Cu (OTf)2Generation Table copper trifluoromethanesulfcomposite, Cu (ODf)2Represent Difluore methane-sulfonic acid copper, Cu (OMs)2Represent copper methane sulfonate.
Described organic solvent selected from alcohols solvent, ketones solvent, esters solvent, ether solvent, varsol, The mixed solvent or solvent-free of above solvent；Recommend oxolane, 2-methyltetrahydrofuran, ethyl acetate, second Acid N-butyl, isopropyl acetate, ether, methyl tertiary butyl ether(MTBE), 1,4-dioxane, normal hexane, normal heptane, The combination in any solvent of hexamethylene, benzene,toluene,xylene, dichloromethane or above-mentioned solvent；Especially recommend Toluene or solvent-free；
Described organic base is recommended as MeN (i-Pr)2、HNEt2、N(i-Pr)3, pyridine, NEt3, piperidines, EtN(i-Pr)2Or N (n-Bu)3；It is further recommended that organic base is NEt3；
In said method, the amino phenols part of chirality: (4-chloro-2-trifluoroacetyl group phenyl) urethanes: Cyclopropyl acethlene: Lewis acid: the mol ratio of organic base 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 reaction completely, with HCl recovery chiral aminophenol part, then heating, cyclization obtains final depending on Fa Weilun；
In said 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, it is further recommended that reaction temperature is 50 DEG C arrives backflow Temperature.
Compared with the method for existing synthesis efavirenz, present invention process relates to what chiral aminophenol part participated in Asymmetric addition.Amino phenols synthesis is simple, splits efficiently, and part is to ph stability, can determine after using Amount recovery, keep original chirality, direct plunge in the synthesis of next batch, reduce production cost, make through Ji benefit and social benefit maximize, and are suitable for large-scale industrial production.
Detailed description of the invention
Following example will be further illustrated the method that the present invention provides, but the present invention is not limited.
Embodiment 1:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
In tube sealing add (R)-1-(phenyl (pyrrolidin-1-yl) methyl) naphthalene-2 alcohol (23mg, 0.75 Mmol), p-methyl benzenesulfonic acid zinc (20mg, 0.5mmol), substitute gas, add cyclopropyl acethlene (0.4mL), Triethylamine (0.14mL, 10mmol), stirring reaction 3h, add (4-chloro-2-trifluoroacetyl group phenyl) ammonia Base Ethyl formate (30mg, 0.1mmol), is stirred at room temperature reaction 24h.Organic solvent such as ethyl acetate (EA) Transfer, 6M salt acid elution, saturated sodium-chloride washs, and anhydrous sodium sulfate is dried.Column chromatography obtains, (S)-(4 -chloro-2-(4-cyclopropyl-1,1,1-three fluoro-2-hydroxyl butyl-3-alkynes-2-base) phenyl) urethanes 35.5mg, productivity 96%, ee value 81%.(separate is only data analysis herein, can not carry out during actual synthesis This step separates)
1H NMR(300MHz,CDCl3) δ 8.54 (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,CDCl3): δ-80.35；
MS(EI)m/z:361[M]+(33.12).
Ee uses HPLC to analyze method and measures [as determined by HPLC analysis] (chiral column Chiralcel AD-H, drip washing organic solvent volume than iPrOH/hexane=7/93, flow 1mL/min, 254nm, tf5.524 (main peak major), 6.395 (secondary peak minor).
By above-mentioned gained (S)-(the chloro-2-of 4-(4-cyclopropyl-1,1,1-three fluoro-2-hydroxyl butyl-3-alkynes-2- Base) phenyl) urethanes, reacts 4 hours in 5mL reflux in toluene, obtains efavirenz 31.0 Mg, quantitative yield, ee value 81%.
1H NMR(300MHz,CDCl3): δ 8.98 (s, 1H), 7.49 (s, 1H), 7.36 (dd, J=8.5,2.2 Hz, 1H), 6.82 (d, J=8.6Hz, 1H), 1.45 1.35 (m, 1H), 0.98 0.81 (m, 4H).
19F NMR(282MHz,CDCl3): δ-81.35.
MS(EI)m/z:315[M]+(38.38).
Ee as determined by HPLC analysis (Chiralcel AD-H, iPrOH/hexane=7/93,1 mL/min,254nm),tf8.2(minor),7.5(major).
Embodiment 2:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
In tube sealing add (R)-1-(phenyl (pyrrolidin-1-yl) methyl) naphthalene-2 alcohol (68mg, 2.25 Mmol), p-methyl benzenesulfonic acid zinc (61mg, 1.5mmol), substitute gas, add cyclopropyl acethlene (0.4mL), Triethylamine (0.14mL, 10mmol), stirring reaction 8h, add (4-chloro-2-trifluoroacetyl group phenyl) ammonia Base Ethyl formate (30mg, 0.1mmol), is stirred at room temperature reaction 24h.Add water cancellation, and EA extracts, 6M Salt acid elution, saturated sodium-chloride washs, and anhydrous sodium sulfate is dried.After concentration, add refluxing toluene and react 4 hours, Obtain efavirenz 31.1mg, productivity 98%, ee value 91%.
Embodiment 3:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
(R)-2-(phenyl (pyrrolidin-1-yl) methyl) naphthalene-1-alcohol (68mg, 2.25mmol) is added in tube sealing, P-methyl benzenesulfonic acid zinc (61mg, 1.5mmol), substitutes gas, adds cyclopropyl acethlene (0.4mL), triethylamine (0.14mL, 10mmol), moves into 40 DEG C of oil baths, stirring reaction 3h, adds (4-chloro-2-trifluoroacetyl Base phenyl) urethanes (30mg, 0.1mmol), reaction 24h is stirred at room temperature.Add water cancellation, EA extracts, 6M salt acid elution, and saturated sodium-chloride washs, and anhydrous sodium sulfate is dried.After concentration, add toluene Back flow reaction 4 hours, obtains efavirenz 31.5mg, productivity 94%, ee value 95%.
Embodiment 4:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
(R)-2-(phenyl (pyrrolidin-1-yl) methyl) phenol (57mg, 2.25mmol) is added in tube sealing, P-methyl benzenesulfonic acid zinc (61mg, 1.5mmol), substitutes gas, adds cyclopropyl acethlene (0.4mL), triethylamine (0.14mL, 10mmol), stirring reaction 3h, add (4-chloro-2-trifluoroacetyl group phenyl) carbamic acid Ethyl ester (30mg, 0.1mmol), is stirred at room temperature reaction 24h.Add water cancellation, and EA extracts, 6M hydrochloric acid Washing, saturated sodium-chloride washs, and anhydrous sodium sulfate is dried.After concentration, add refluxing toluene and react 4 hours, Efavirenz 31.4mg, productivity 89%, ee value 95%.
Embodiment 5:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
(R)-1-(phenyl (pyrrolidin-1-yl) methyl) naphthalene-2 alcohol (3.64 is added in 50mL egg type bottle G, 0.012mol), p-methyl benzenesulfonic acid zinc (4.48g, 0.011mol), substitute gas, add cyclopropyl acethlene (3.4 ML, 0.04mol), triethylamine (5.58mL, 0.04mol), toluene (30g), stirring reaction 24h, add Enter (4-chloro-2-trifluoroacetyl group phenyl) urethanes (2.96g, 0.01mol), be stirred at room temperature anti- Answer 48h.After HCl recovery part, to toluene phase back flow reaction, obtain efavirenz, thick product is heavily tied Brilliant purification, can obtain target compound 2.94g, productivity 93%, ee value 99%.
Embodiment 6:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-1-(morpholino (phenyl) methyl) naphthalene -2-alcohol, zinc salt uses ZnBr2, alkali uses MeN (i-Pr)2, solvent uses oxolane, and productivity is 85%, Ee value is 91%.
Embodiment 7:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-2-, and ((benzyl (methyl) amino) is (right Tolyl) methyl)-4-nitrophenol, zinc salt uses Zn (OTf)2, alkali uses pyridine, and solvent uses acetic acid Ethyl ester, productivity is 85%, and ee value is 89%.
Embodiment 8:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-4-methyl-2-(phenyl (piperidin-1-yl) Methyl) phenol, zinc salt uses Zn (ODf)2, alkali uses piperidines, and solvent uses ether, and productivity is 79%, Ee value is 88%.
Embodiment 9:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-2-((4-chlorphenyl) (morpholino) Methyl) phenol, zinc salt uses CuBr, and alkali uses N (n-Bu)3, solvent uses dichloromethane, and productivity is 85%, Ee value is 83%.
Embodiment 10:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-2,4-bis-chloro-6-(phenyl (pyrrolidine -1-base) methyl) phenol, zinc salt uses Cu (PhSO3)2, alkali uses NEt3, solvent uses normal hexane, Productivity is 78%, and ee value is 87%.
Embodiment 11:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses 1-((R)-(methyl ((R)-1-phenyl second Base) amino) (phenyl) methyl) naphthalene-2-alcohol, zinc salt uses ZnCl2, alkali uses N (i-Pr)3, solvent makes With ethyl acetate and normal hexane mixed solvent, productivity is 75%, and ee value is 79%.
Embodiment 12:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-1-((4-bromophenyl) (piperidin-1-yl) Methyl) naphthalene-2-alcohol, zinc salt uses ZnBr2, alkali uses MeN (i-Pr)2, solvent uses toluene, and productivity is 88%, ee value is 91%.
Embodiment 13:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-1-(morpholino (4-nitrobenzophenone) Methyl) naphthalene-2-alcohol, zinc salt uses ZnCl2, alkali uses N (i-Pr)3, solvent uses ethyl acetate, and productivity is 85%, ee value is 92%.
Embodiment 14:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-7-methoxyl group-1-(morpholino (4-(three Methyl fluoride) phenyl) methyl) naphthalene-2-alcohol, zinc salt uses ZnCl2, alkali uses HNEt2, solvent is just using Hexane, productivity is 86%, and ee value is 79%.
Embodiment 15:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-2-((2,4-Dimethoxyphenyl) (piperazine Pyridine-1-base) methyl)-5-methoxynaphthalene-1-alcohol, zinc salt uses Zn (OTs)2, alkali uses NEt3, solvent Using dichloromethane and normal hexane mixed solvent, productivity is 81%, and ee value is 85%.
Embodiment 16:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-5-methoxyl group-2-((2-methoxybenzene Base) (morpholinyl) methyl) naphthalene-1-alcohol, zinc salt uses Zn (OTs)2, alkali uses N (n-Bu)3, solvent makes With methanol solvate, productivity is 92%, and ee value is 74%.
Embodiment 17:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-2-(morpholino base (thiene-3-yl) Methyl) naphthalene-1-alcohol, zinc salt uses Zn (PhSO3)2, alkali uses piperidines, and solvent uses ethanol, and productivity is 80%, ee value is 71%.
Embodiment 18:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-1-((methyl (1-phenethyl) amino) (naphthalene-1-base) methyl) naphthalene-2-alcohol, zinc salt uses Zn (PhSO3)2, alkali uses piperidines, and solvent uses third Ketone, productivity is 81%, and ee value is 85%.
Embodiment 19:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-1-(thiomorpholine generation (p-toluene Base) methyl) naphthalene-2-alcohol, zinc salt uses Zn (OTf)2, alkali uses pyridine, and solvent uses oxolane, produces Rate is 79%, and ee value is 69%.
Embodiment 20:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-1-(((cyclohexyl methyl) (methyl) Amino) (phenyl) methyl) naphthalene-2-alcohol, zinc salt uses Zn (ODf)2, alkali uses pyridine, and solvent uses four Hydrogen furan, productivity is 92%, and ee value is 95%.
Embodiment 21:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-6-((4-methylpiperazine-1-yl) (4- (trifluoromethoxy) phenyl) methyl) benzo [d] [1,3] dioxole-5-alcohol, zinc salt uses CuBr, Alkali uses N (i-Pr)3, solvent uses toluene, and productivity is 71%, and ee value is 74%.
Embodiment 22:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-(5-((dimethylamino) (phenyl) Methyl)-6-hydroxyl naphthalene-2-base) (phenyl) ketone, zinc salt uses CuBr2, alkali uses MeN (i-Pr)2, Solvent uses toluene and the mixed solvent of oxolane, and productivity is 83%, and ee value is 86%.
Embodiment 23:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-2-(benzofuran-3-base (benzyl (first Base) amino) methyl) phenol, zinc salt uses Cu (OTs)2, alkali uses NEt3, solvent uses toluene, produces Rate is 71%, and ee value is 69%.
Embodiment 24:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-2-methoxyl group-6-((2-methyl isophthalic acid H- Indol-3-yl) (piperidin-1-yl) methyl) phenol, zinc salt uses Cu (OTs)2, alkali uses N (i-Pr)3, Solvent uses solvent-free, and productivity is 80%, and ee value is 75%.
Embodiment 25:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-2-(((benzyloxy) phenyl) (morpholine Generation) methyl)-4-nitrophenol, zinc salt uses Cu (PhSO3)2, alkali uses pyridine, and solvent uses solvent-free, Productivity is 81%, and ee value is 88%.
Embodiment 26:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-1-((2-hydroxy phenyl) (7-methyl -1H-indol-3-yl) methyl) piperidines-3-Ethyl formate, zinc salt uses Cu (OTf)2, alkali uses EtN (i-Pr)2, Solvent uses toluene, and productivity is 75%, and ee value is 77%.
Embodiment 27:
(S)-6-chloro-4-ring the third acetenyl-4-Trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone is (in accordance with the law Wei Lun Efavirenz) asymmetric synthesis
With reference to the method for embodiment 5, amino phenols part uses (R)-4-amino-2-((dimethylamino) (benzene Base) methyl) naphthalene-1-alcohol, zinc salt uses Cu (OTf)2, alkali uses HNEt2, solvent uses oxolane, Productivity is 81%, and ee value is 70%.

Claims (9)

1. a chiral aminophenol part application in efavirenz asymmetric synthesis, is characterised by described Chiral aminophenol part has a following structural formula:
Wherein, R1, R2It it is identical or different groups；R1, R2It is respectively C1-C15Alkyl, benzyl, 1-phenyl C2-C15Alkyl；Or R1, R2It is collectively forming-(CH2)nX(CH2)m-, wherein X is CH2、O Or S；N, m are the integer of 1 to 5；
R3For phenyl, naphthyl, heteroaryl, R4Substituted phenyl, R4Substituted naphthyl, R4Substituted heteroaryl Base, benzo heteroaryl；
Described substituent R4Refer to F, Cl, Br, CH3、CH3CH2、i-Pr、i-Bu、t-Bu、CH3O、 CH3CH2O、i-PrO、t-BuO、BnO、CO2Et、CF3、CHF2、CH2F、CF3O、CHF2O or CH2FO；
Described heteroaryl refers to five yuan or hexa-atomic containing N, O or S heteroatomic cyclic aromatic compound；
Z is hydrogen, monosubstituted or polysubstituted electrophilic or electron donating group；Described electron withdraw group be F, Cl, Br、NO2, PhC (O) or Ac；Described electron donating group is C1-C5Alkoxyl, NH2Or C1-C6Alkyl.
2. the chiral aminophenol part application in efavirenz asymmetric synthesis, it is characterised in that described Chiral aminophenol part be 1-(phenyl (pyrrolidin-1-yl) methyl) naphthalene-2-alcohol, 2-(phenyl (pyrrole Cough up alkane-1-base) methyl) naphthalene-1-alcohol, 2-(phenyl (pyrrolidin-1-yl) methyl) phenol, 1-(morpholine Generation (phenyl) methyl) naphthalene-2-alcohol, 2-((benzyl (methyl) amino) (p-methylphenyl) methyl)-4-nitre Base phenol, 4-methyl-2-(phenyl (piperidin-1-yl) methyl) phenol, 2-((4-chlorphenyl) (morpholine Generation) methyl) phenol, the chloro-6-of 2,4-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-nitrobenzophenone) 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-methoxyphenyl) (morpholinyl) methyl) naphthalene-1-alcohol, 2-(morpholino base (thiene-3-yl) methyl) naphthalene-1-alcohol, 1- (in thiomorpholine generation, is (right for ((methyl (1-phenethyl) amino) (naphthalene-1-base) methyl) naphthalene-2-alcohol, 1- -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-base) (benzene Base) ketone, 2-(benzofuran-3-base (benzyl (methyl) amino) methyl) phenol, 2-methoxyl group -6-((2-Methyl-1H-indole-3-base) (piperidin-1-yl) methyl) phenol, 2-(((benzyloxy) benzene Base) (morpholino) methyl)-4-nitrophenol, 1-((2-hydroxy phenyl) (7-Methyl-1H-indole-3- Base) methyl) piperidines-3-Ethyl formate, 4-amino-2-((dimethylamino) (phenyl) methyl) naphthalene-1- Alcohol.
The chiral aminophenol part the most according to claim 1 application in efavirenz asymmetric synthesis, It is characterized in that described application comprises the steps of: in organic solvent or solvent-free time, described chirality ammonia Base phenol part, (4-chloro-2-trifluoroacetyl group phenyl) urethanes, cyclopropyl acethlene, Lewis acid and Organic base, at-30 DEG C～30 DEG C, reacts 1～72 hour, and acid adding shrend is gone out reaction, then by organic facies at 40 DEG C ～under reflux temperature, continue reaction 4～48 hours, obtain efavirenz；Described chiral aminophenol part, (4- Chloro-2-trifluoroacetyl group phenyl) urethanes, cyclopropyl acethlene, Lewis acid and the mol ratio of organic base It is followed successively by 1:(0.5-3): (1-40): (0.5-2): (0.5-10).
4., according to the application described in claim 3, it is characterized in that described organic solvent is alcohols solvent, ketone Solvent, esters solvent, ether solvent, varsol or above-mentioned mixed solvent.
Application the most 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 the application described in claim 5, it is characterized in that described Zn (II) salt, Cu (I) salt or Cu (II) Salt is specially ZnBr2、ZnCl2、ZnF2、Zn(OTs)2、Zn(PhSO3)2、Zn(OAc)2、Zn(C11H23CO2)2、 Zn(C17H35CO2)2、Zn(acac)2、ZnSO4、Zn(OH)2、Zn(OTf)2、Zn(ODf)2、Zn(OMs)2、 CuBr、CuCl、CuBr2、CuCl2、Cu(OTs)2、Cu(PhSO3)2、Cu(OTf)2、Cu(ODf)2Or Cu(OMs)2；Wherein, Zn (OTs)2Represent p-methyl benzenesulfonic acid zinc, Zn (OAc)2Represent zinc acetate, Zn (acac)2 Represent zinc acetylacetonate, Zn (OTf)2Represent trifluoromethanesulfonic acid zinc, Zn (ODf)2Represent Difluore methane-sulfonic acid zinc, Zn(OMs)2Represent methanesulfonic acid zinc, Cu (OTs)2Represent copper p-toluenesulfonate, Cu (OTf)2Represent fluoroform sulphur Acid copper, Cu (ODf)2Represent Difluore methane-sulfonic acid copper, Cu (OMs)2Represent copper methane sulfonate.
Application the most according to claim 3, is characterized in that described organic base is MeN (i-Pr)2、HNEt2、 N(i-Pr)3, pyridine, NEt3, piperidines, EtN (i-Pr)2Or N (n-Bu)3。
Application the most according to claim 3, is characterized in that the HCl that described sour water is 1～12mol/L Aqueous solution.
Application the most according to claim 3, after it is characterized in that described cancellation reaction, from aqueous solution Middle recovery chiral aminophenol part as described in claim 1 or 2.
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