CN106242935B - A kind of synthetic method of triaryl substituted chiral compound - Google Patents

A kind of synthetic method of triaryl substituted chiral compound Download PDF

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CN106242935B
CN106242935B CN201610628195.3A CN201610628195A CN106242935B CN 106242935 B CN106242935 B CN 106242935B CN 201610628195 A CN201610628195 A CN 201610628195A CN 106242935 B CN106242935 B CN 106242935B
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synthetic method
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chiral compound
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CN106242935A (en
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王益锋
章程
许丹倩
徐振元
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Zhejiang University of Technology ZJUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/54—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The present invention provides the synthetic method of triaryl substituted chiral compound shown in a kind of formula (1), the synthetic method is：In water phase and an oil phase system; beta naphthal is reacted under the action of acid binding agent, chiral catalyst shown in (aryl (p-toluenesulfonyl) methyl) phenol of 2- shown in starting materials of formulae (2) and formula (3); TLC tracking and monitorings are to the reaction was complete; reaction solution is post-treated later, obtains triaryl substituted chiral compound shown in product formula (1)；The present invention is using the chiral catalyst containing at least one tertiary amine, nitrogen side's acid function group as catalyst system and catalyzing, it is reacted in water phase and an oil phase, isolated product triaryl substituted chiral compound is post-processed, a kind of important organic intermediate is can be used as and is applied to the fields such as medicine, pesticide；The method of the present invention solvent contamination is small, reaction speed is fast, high income, asymmetric selectivity is good, reaction substrate is in extensive range, reaction reagent is cheap and easy to get, has important application value；

Description

A kind of synthetic method of triaryl substituted chiral compound
(1) technical field
The present invention relates to a kind of synthetic methods of triaryl substituted chiral compound, and especially one kind is in water phase and an oil phase system Under, raw material beta naphthal is with 2- (aryl (p-toluenesulfonyl) methyl) phenol through being catalyzed asymmetry Friedel-Crafts alkylations The method for synthesizing triaryl substituted chiral compound.
(2) background technology
Asymmetry catalysis is current chemical developer one of field the most active, is exploitation chiral drug, material and fragrance The powerful theoretical foundation of equal chemicals and academic foundation.Enzyme and metal complex are the main and most effective catalyst of two classes, Wherein metal complex is the chemical catalyst the most universal of research, and obtains the achievement to catch people's attention, some are answered For industrial production, Nobel chemistry Prize in 2001 is granted by makes outstanding tribute in terms of metal organic catalysis asymmetric reaction William tri- people of S.Knowles, Ryoji Noyori and K.Barry Sharpless offered, it is sufficient to show asymmetry catalysis The significance of synthesis.By the development of last decade, asymmetric organocatalysis (Asymmetric organocatalysis), One of important branch through developing into asymmetry catalysis has become two kinds of conventional methods of metal organic catalysis and enzymatic Important supplement (A.Berkessel and H.Asymmetric Organocatalysis,Wiley VCH, Weinheim,2005.；P.I.Dalko,Enantioselective Organocatalysis,Wiley-VCH,Weinheim, 2007.)。
In recent years, water phase and an oil phase (Water-Oil phases) has become reaction system important in organic synthesis, because It can be such that organic compound is efficiently and quickly detached during the reaction with water-soluble ionic compounds or in conjunction with and by wide General concern.Wherein, the asymmetric catalysis under water phase and an oil phase system especially has important research and practical value.Current For research, based on the organic reaction of water phase and an oil phase system, mainly quaternary ammonium salt, crown ether-like phase transfer catalysts are to organic bottom The facilitation that object is reacted with reaction of ionic type object.For the asymmetric organocatalysis under two-phase system, be limited only at present from Sub- liquid.Therefore, develop the more asymmetry catalysis system based on two-phase, there is important practical significance.
(3) invention content
The synthesis side for the triaryl substituted chiral compound that the object of the present invention is to provide a kind of to carry out in water phase and an oil phase Method.
To achieve the above object, the present invention adopts the following technical scheme that：
The synthetic method of triaryl substituted chiral compound, the synthetic method shown in a kind of formula (1) are：
In water phase and an oil phase system, (aryl (p-toluenesulfonyl) methyl) phenol of 2- shown in starting materials of formulae (2) and formula (3) institute The beta naphthal shown is reacted under the action of acid binding agent, chiral catalyst, and TLC tracking and monitorings react later to the reaction was complete Liquid is post-treated, obtains triaryl substituted chiral compound shown in product formula (1).
Reaction equation is as follows：
In formula (2), Ts indicates p-toluenesulfonyl；
In formula (1), (2) or (3),
R1、R2Respectively stand alone as H, methoxyl group or halogen；
Ar is furyl, thienyl, naphthalene, phenyl or the phenyl being substituted by one or more substituents, and described takes Methyl, methoxyl group, trifluoromethyl or halogen are respectively stood alone as base.
In synthetic method of the present invention：
The reaction usually carries out under room temperature (20~30 DEG C).
The substance of (aryl (p-toluenesulfonyl) methyl) phenol of 2- shown in the formula (2) and beta naphthal shown in formula (3) The ratio between amount be 0.2~5：1, preferably 0.5~2：1.
The amount of the chiral catalyst and the substance of 2- (aryl (p-toluenesulfonyl) methyl) phenol shown in formula (2) it Than being 0.01~100：100, preferably 0.1~20：100.
The ratio between the amount of substance of the acid binding agent and 2- shown in formula (2) (aryl (p-toluenesulfonyl) methyl) phenol is 0.5~20：1, preferably 1~10：1.
The water phase and an oil phase system is by water and organic solvent with volume ratio 1：0.1~10 is mixed to form, and described is organic Solvent is selected from dichloromethane, 1,2- dichloroethanes, ether, toluene, ethyl acetate or isopropyl acetate.
The acid binding agent is common inorganic base, such as：Sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, bicarbonate Potassium, sodium hydroxide, potassium hydroxide or disodium hydrogen phosphate.
The post-processing approach of the reaction solution is：After reaction, by reaction solution liquid separation, organic phase is taken to be concentrated under reduced pressure laggard Row silica gel column chromatography detaches, with petrol ether/ethyl acetate volume ratio 1~10：1 mixed liquor is that eluant, eluent carries out gradient elution, The eluent containing target compound is collected, solvent and drying is evaporated off, obtains triaryl substituted chiral chemical combination shown in product formula (1) Object.
In the present invention, the chiral catalyst contains at least one of tertiary amine, nitrogen side's acid function group.
Specifically, the chiral catalyst is selected from one of compound shown in following formula (4)~(8)：
In formula (4), (5), the carbon atom for indicating * is asymmetric carbon atom.
In formula (4), (5), (6), (7) or (8),
R3、R6、R9、R12C1~C20 alkyl respectively is stood alone as, or the phenyl or benzyl being substituted by one or more substituents Base, the substituent group respectively stand alone as trifluoromethyl, nitro or halogen；
R4、R5、R7、R8Respectively stand alone as C1~C10 alkyl；
R10、R13、R16Respectively stand alone as ethyl or vinyl；
R11、R14、R15Respectively stand alone as H, hydroxyl or methoxyl group.
More preferred, the chiral catalyst is selected from one of following：
The beneficial effects of the present invention are：
In synthetic method of the present invention, with the chiral catalyst containing at least one tertiary amine, nitrogen side's acid function group It for catalyst system and catalyzing, is reacted in water phase and an oil phase, post-processes isolated product triaryl substituted chiral compound, can be used as A kind of important organic intermediate is applied to the fields such as medicine, pesticide.Synthetic method provided by the invention, solvent contamination are small, anti- It answers that speed fast, high income, asymmetric selectivity is good, reaction substrate is in extensive range, reaction reagent is cheap and easy to get, there is important answer With value.
(4) specific implementation mode
With reference to specific embodiment, the invention will be further described, but protection scope of the present invention is not limited in This.
React embodiment 1：
Catalyst (6)-a (0.005mmol, 3mg), 6- methoxyl group -2- (phenyl are sequentially added in dry glass tube (p-toluenesulfonyl) methyl) phenol (0.1mmol, 36.8mg), betanaphthol (0.12mmol, 17.3mg), potassium carbonate (0.25mmol, 34.5mg), dichloromethane (1ml), water (1ml) feed intake and finish, and reactor is closed, are existed with magnetic stirring apparatus 6h is stirred at room temperature, and TLC shows that 6- methoxyl groups -2- (phenyl (p-toluenesulfonyl) methyl) phenol is exhausted, by reaction solution Liquid separation takes organic phase to be concentrated under reduced pressure, upper silica gel column chromatography post separation, with the volume ratio of petroleum ether and ethyl acetate for 1~10：1 Mixed liquor is that eluant, eluent carries out gradient elution, collects the eluent containing target compound, solvent and drying is evaporated off, it is solid to obtain white Body product 32.7mg (yield 92%),1H NMR(500MHz,CDCl3) δ 8.10 (d, J=8.6Hz, 1H), 7.82 (dd, J= 8.1,0.7Hz, 1H), 7.76 (d, J=8.9Hz, 1H), 7.46 (ddd, J=8.4,6.8,1.3Hz, 1H), 7.41-7.22 (m, 6H), 7.12 (d, J=8.9Hz, 1H), 6.87-6.77 (m, 3H), 6.74 (s, 1H), 5.98 (s, 1H), 5.58 (s, 1H), 3.91 (s,3H).13C NMR(125MHz,CDCl3)δ153.07,146.51,143.45,141.29,133.51,129.54,129.39, 129.15,128.59,128.50,127.14,126.94,126.70,123.08,122.98,121.79,120.20,119.81, 119.68,109.60,55.98,42.39；By chiral HPLC, actual conditions are (IC-H, 1%iPrOH in hexane,flow rate 1.0ml/min):tR(master)=56.6min, tR(secondary)=70.7min, 96%ee.
Identical reactant is taken, under identical operating procedure, respectively with 0.005mmol or less catalyst alternative catalysts (6)-a is reacted, as a result as shown in table 1 below：
Table 1
Number Catalyst Reaction time (h) Yield (%)c Ee values (%)d
1 (4)-a 6 87 -83
2 (5)-a 6 68 -85
3 (6)-a 6 92 96
4 (6)-b 6 79 92
5 (6)-c 6 82 76
6 (6)-d 6 56 81
7 (6)-e 6 79 78
8 (7)-a 6 51 -72
9 (8)-a 6 59 66
In table 1, subscriptcIndicate separation yield,dIndicate the enantiomeric excess analyzed by chiral high performance liquid chromatography Value.
It takes identical reactant, under identical operating procedure, potassium carbonate is substituted with 0.25mol or less inorganic bases respectively and is carried out Reaction, as a result as shown in table 2 below：
Table 2
Number Inorganic base Reaction time (h) Yield (%)c Ee values (%)d
1 K2CO3 6 92 96
2 CsCO3 6 79 91
3 KOH 6 92 16
4 Na2HPO4 6 45 91
5 NaHCO3 6 48 89
In table 2, subscriptcIndicate separation yield,dIndicate the enantiomeric excess analyzed by chiral high performance liquid chromatography Value.
It takes identical reactant, under identical operating procedure, dichloromethane is substituted with 1ml or less organic solvents respectively and is carried out Reaction, as a result as shown in table 3 below：
Table 3
Number Solvent Reaction time (h) Yield (%)c Ee values (%)d
1 CH2Cl2 6 92 96
2 Toluene 6 89 90
3 Ethyl acetate 6 68 36
4 ClCH2CH2Cl 6 81 92
In table 3, subscriptcIndicate separation yield,dIndicate the enantiomeric excess analyzed by chiral high performance liquid chromatography Value.React embodiment 2：
With react embodiment 1 the difference is that：Substrate fortified phenol used is the bromo- 2- (phenyl of 6- methoxyl groups -4- (p-toluenesulfonyl) methyl) phenol (0.1mmol, 44.7mg), other reaction conditions and operating procedure with react 1 phase of embodiment Together, white solid product 36.5mg (yield 84%) is obtained,1H NMR(500MHz,CDCl3) δ 8.01 (d, J=8.6Hz, 1H), 7.81 (d, J=7.9Hz, 1H), 7.76 (d, J=8.9Hz, 1H), 7.49-7.42 (m, 1H), 7.34 (dt, J=12.9, 7.0Hz, 4H), 7.22 (d, J=7.5Hz, 2H), 7.10 (d, J=8.8Hz, 1H), 6.95 (d, J=2.1Hz, 1H), 6.91 (d, J=2.1Hz, 1H), 6.69 (s, 1H), 5.88 (s, 1H), 5.33 (s, 1H), 3.91 (s, 3H)13C NMR(125MHz,CDCl3) δ153.01,147.04,142.52,140.71,133.44,129.73,129.58,129.35,128.69,128.48, 128.27,127.43,126.87,124.60,123.25,122.73,119.94,119.26,113.14,112.07,56.30, 41.96；By chiral HPLC, actual conditions are (IC-H, 1%iPrOH in hexane, flow rate 1.0ml/ min):tR(master)=46.6min, tR(secondary)=38.0min, 97%ee.
React embodiment 3：
With react embodiment 1 the difference is that：Substrate fortified phenol used is the iodo- 2- (phenyl of 6- methoxyl groups -4- (p-toluenesulfonyl) methyl) phenol (0.1mmol, 49.5mg), other reaction conditions and operating procedure with react 1 phase of embodiment Together, yellow solid product 44.6mg (yield 92%) is obtained,1H NMR(500MHz,CDCl3) δ 8.01 (d, J=8.6Hz, 1H), 7.82 (dd, J=8.1,0.6Hz, 1H), 7.76 (d, J=8.9Hz, 1H), 7.46 (ddd, J=8.4,6.9,1.3Hz, 1H), 7.40-7.30 (m, 4H), 7.21 (d, J=7.6Hz, 2H), 7.15-7.00 (m, 3H), 6.67 (s, 1H), 5.92 (s, 1H), 5.34(s,1H),3.90(s,3H).13C NMR(125MHz,CDCl3)δ152.98,147.12,143.34,140.69, 133.42,130.67,129.72,129.55,129.34,129.03,128.68,128.25,127.42,126.87,123.24, 122.72,119.94,119.22,118.74,81.58,56.26,41.79；By chiral HPLC, actual conditions are (IC- H, 2%iPrOH in hexane, flow rate 1.0ml/min):tR(master)=21.2min, tR(secondary)=17.7min, 97% ee。
React embodiment 4：
With react embodiment 1 the difference is that：Substrate fortified phenol used is 6- methoxyl groups -2- (4- aminomethyl phenyls (p-toluenesulfonyl) methyl) phenol (0.1mmol, 38.2mg), other reaction conditions and operating procedure with react 1 phase of embodiment Together, white solid product 35mg (yield 95%) is obtained,1H NMR(500MHz,CDCl3) δ 8.06 (d, J=8.6Hz, 1H), 7.79 (d, J=7.9Hz, 1H), 7.74 (d, J=8.9Hz, 1H), 7.47-7.39 (m, 1H), 7.32 (dd, J=11.0, 4.0Hz, 1H), 7.15 (q, J=8.2Hz, 4H), 7.09 (d, J=8.9Hz, 1H), 6.79 (ddt, J=9.3,7.6,4.0Hz, 3H),6.67(s,1H),5.92(s,1H),5.57(s,1H),3.92(s,3H),2.35(s,3H).13C NMR(125MHz, CDCl3)δ 153.17,146.49,143.39,138.11,136.93,133.53,129.99,129.51,129.34, 128.57,128.35,127.02,126.71,123.06,122.94,121.82,120.14,119.84,119.78,109.53, 56.01,41.99,21.04；By chiral HPLC, actual conditions are (IC-H, 1%iPrOH in hexane, flow rate 1.0ml/min):tR(master)=33.8min, tR(secondary)=61.6min, 91%ee.
React embodiment 5：
With react embodiment 1 the difference is that：Substrate fortified phenol used is 6- methoxyl groups -2- (3- aminomethyl phenyls (p-toluenesulfonyl) methyl) phenol (0.1mmol, 38.2mg), other reaction conditions and operating procedure with react 1 phase of embodiment Together, white solid product 31.7mg (yield 86%) is obtained,1H NMR(500MHz,CDCl3) δ 8.10 (d, J=8.6Hz, 1H), 7.81 (d, J=7.2Hz, 1H), 7.76 (d, J=8.9Hz, 1H), 7.46 (ddd, J=8.4,6.9,1.3Hz, 1H), 7.39- 7.31 (m, 1H), 7.28-7.24 (m, 1H), 7.17-7.08 (m, 3H), 7.05 (d, J=7.7Hz, 1H), 6.87-6.76 (m, 3H),6.71(s,1H),5.97(s,1H),5.62(s,1H),3.92(s,3H),2.32(s,3H).13C NMR(125MHz, CDCl3)δ153.16,146.47,143.37,141.28,138.99,133.53,129.49,129.33,129.24,129.09, 128.56,128.12,126.93,126.72,125.34,123.06,122.93,121.85,120.11,119.84,119.83, 109.53,55.96,42.26,21.49；By chiral HPLC, actual conditions be (IC-H, 1%iPrOH in hexane, flow rate 1.0ml/min):tR(master)=32.5min, tR(secondary)=43.5min, 94%ee.
React embodiment 6：
With react embodiment 1 the difference is that：Substrate fortified phenol used is 6- methoxyl groups -2- (4- methoxybenzenes Base (p-toluenesulfonyl) methyl) phenol (0.1mmol, 39.8mg), other reaction conditions and operating procedure with react embodiment 1 It is identical, yellow solid product 34mg (yield 88%) is obtained,1H NMR(500MHz,CDCl3) δ 8.06 (d, J=8.6Hz, 1H), 7.79 (d, J=7.5Hz, 1H), 7.74 (d, J=8.9Hz, 1H), 7.44 (ddd, J=8.5,6.9,1.3Hz, 1H), 7.33 (dd, J=11.1,4.1Hz, 1H), 7.16 (d, J=8.6Hz, 2H), 7.10 (d, J=8.9Hz, 1H), 6.93-6.72 (m, 5H),6.65(s,1H),5.95(s,1H),5.63(s,1H),3.91(s,3H),3.80(s,3H).13C NMR(125MHz, CDCl3)δ 158.70,153.15,146.51,143.39,133.49,132.87,129.58,129.52,129.33, 128.57,127.25,126.69,123.06,122.93,121.75,120.16,119.81,119.76,114.63,109.55, 56.00,55.21,41.57；By chiral HPLC, actual conditions are (IC-H, 3%iPrOH in hexane, flow rate 0.6ml/min):tR(master)=58.9min, tR(secondary)=73.5min, 92%ee.
React embodiment 7：
With react embodiment 1 the difference is that：Substrate fortified phenol used is 6- methoxyl groups -2- (2- methoxybenzenes Base (p-toluenesulfonyl) methyl) phenol (0.1mmol, 39.8mg), other reaction conditions and operating procedure with react embodiment 1 It is identical, white solid product 22.2mg (yield 58%) is obtained,1H NMR(500MHz,CDCl3) δ 8.04 (d, J=8.6Hz, 1H), 7.82-7.72 (m, 1H), 7.69 (d, J=8.8Hz, 1H), 7.42 (ddd, J=8.4,6.8,1.3Hz, 1H), 7.35- 7.18 (m, 3H), 7.09 (dd, J=7.6,1.5Hz, 1H), 7.04 (d, J=8.8Hz, 1H), 6.98-6.93 (m, 1H), 6.90 (td, J=7.6,0.8Hz, 1H), 6.86-6.76 (m, 3H), 6.64 (s, 1H), 5.81 (s, 1H), 5.73 (s, 1H), 3.89 (s, 3H),3.71(s,3H).13C NMR(125MHz,CDCl3)δ157.50,153.18,146.60,143.69,133.46, 129.51,129.38 128.84,128.57,128.48,127.44,126.48,123.07,122.86,121.01,120.05, 119.45,118.92,111.11,109.68,55.95,55.66,37.66；By chiral HPLC, actual conditions are (IC- H, 3%iPrOH in hexane, flow rate 0.6ml/min):tR(master)=35.4min, tR(secondary)=43.5min, 91% ee。
React embodiment 8：
With react embodiment 1 the difference is that：Substrate fortified phenol used is 6- methoxyl groups -2- (3- methoxybenzenes Base (p-toluenesulfonyl) methyl) phenol (0.1mmol, 39.8mg), other reaction conditions and operating procedure with react embodiment 1 It is identical, yellow solid product 33mg (yield 88%) is obtained,1H NMR(500MHz,CDCl3) δ 8.05 (d, J=8.6Hz, 1H), 7.78 (dd, J=8.1,0.7Hz, 1H), 7.73 (d, J=8.9Hz, 1H), 7.43 (ddd, J=8.4,6.9,1.3Hz, 1H), 7.36-7.30 (m, 1H), 7.30-7.24 (m, 2H), 7.08 (d, J=8.8Hz, 1H), 6.87-6.71 (m, 5H), 6.66 (s, 1H),5.92(s,1H),5.59(s,1H),3.92(s,3H),3.73(s,3H).13C NMR(125MHz,CDCl3)δ160.32, 153.22,146.49,143.39,143.18,133.54,130.24,129.41,128.59,126.74,123.08,122.94, 121.82,120.68,120.19,119.86,119.60,114.51,112.46,109.62,56.01,55.15,42.36.；It is logical Chiral HPLC is crossed, actual conditions are (AD-H, 5%iPrOH in hexane, flow rate 1.0ml/min):tR(master) =89.8min, tR(secondary)=97.0min, 91%ee.
React embodiment 9：
With react embodiment 1 the difference is that：Substrate fortified phenol used is 6- methoxyl groups -2- (3,4- methylene oxygen Base phenyl (p-toluenesulfonyl) methyl) phenol (0.1mmol, 41.2mg), other reaction conditions and operating procedure with react real It is identical to apply example 1, obtains white solid product 34.6mg (yield 87%),1H NMR(500MHz,CDCl3) δ 8.03 (d, J= 8.6Hz, 1H), 7.79 (dd, J=8.1,0.6Hz, 1H), 7.74 (d, J=8.9Hz, 1H), 7.44 (ddd, J=8.4,6.9, 1.3Hz, 1H), 7.37-7.30 (m, 1H), 7.10 (d, J=8.9Hz, 1H), 6.89-6.69 (m, 5H), 6.69-6.64 (m, 1H),6.61(s,1H),5.97–5.93(m,3H),5.71(s,1H),3.91(s,3H).13C NMR(125MHz,CDCl3)δ 153.14,148.57,146.84,146.49,143.33,135.09,133.42,129.48,129.42,128.59,126.91, 126.75,123.09,122.82,121.68,121.20,120.20,119.76,119.57,109.62,109.25,108.62, 101.17,55.99,42.01；By chiral HPLC, actual conditions are (IC-H, 2%iPrOH in hexane, flow rate 1.0ml/min):tR(master)=73.3min, tR(secondary)=97.4min, 94%ee.
React embodiment 10：
With react embodiment 1 the difference is that：Substrate fortified phenol used is that (4- fluorophenyls are (right by 6- methoxyl groups -2- Tosyl) methyl) phenol (0.1mmol, 38.6mg), other reaction conditions and operating procedure with reaction embodiment 1 it is identical, White solid product 34.3mg (yield 92%) is obtained,1H NMR(500MHz,CDCl3) δ 8.05 (d, J=8.6Hz, 1H), 7.81 (dd, J=8.0,0.8Hz, 1H), 7.75 (d, J=8.8Hz, 1H), 7.44 (ddd, J=8.5,6.9,1.3Hz, 1H), 7.39- 7.31 (m, 1H), 7.25-7.17 (m, 2H), 7.10 (d, J=8.9Hz, 1H), 7.07-6.99 (m, 2H), 6.88-6.79 (m, 2H), 6.76 (dd, J=7.0,2.3Hz, 1H), 6.66 (s, 1H), 5.98 (s, 1H), 5.58 (s, 1H), 3.91 (s, 3H)13C NMR(125MHz,CDCl3) δ 161.78 (d, J=245Hz), 152.90,146.57,143.49,136.90 (d, J= 3.75Hz), 133.37,130.13 (d, J=7.5Hz), 129.60,129.52,128.66,126.98,126.73,123.15, (122.94,121.58,120.32,119.73,119.40,115.85 d, J=22.5Hz), 109.74,56.00,41.80；It is logical Chiral HPLC is crossed, actual conditions are (AS-H, 10%iPrOH in hexane, flow rate 1.0ml/min):tR (master)=42.4min, tR(secondary)=31.3min, 95%ee.
React embodiment 11：
With react embodiment 1 the difference is that：Substrate fortified phenol used is that (4- chlorphenyls are (right by 6- methoxyl groups -2- Tosyl) methyl) phenol (0.1mmol, 40.25mg), other reaction conditions and operating procedure with react 1 phase of embodiment Together, white solid product 30mg (yield 77%) is obtained,1H NMR(500MHz,CDCl3) δ 8.03 (d, J=8.6Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.75 (d, J=8.8Hz, 1H), 7.44 (ddd, J=8.5,6.9,1.2Hz, 1H), 7.38- 7.28 (m, 3H), 7.18 (d, J=8.4Hz, 2H), 7.10 (d, J=8.8Hz, 1H), 6.89-6.80 (m, 2H), 6.77 (dd, J =7.0,2.3Hz, 1H), 6.65 (s, 1H), 6.00 (s, 1H), 5.61 (s, 1H), 3.91 (s, 3H)13C NMR(125MHz, CDCl3)δ152.83,146.57,143.51,139.93,133.34,132.71,129.93,129.61,129.56,129.04, 128.67,126.73,126.69,123.16,122.97,121.59,120.33,119.68,119.20,109.77,55.99, 41.97；By chiral HPLC, actual conditions are (AS-H, 10%iPrOH in hexane, flow rate 1.0ml/ min):tR(master)=46.2min, tR(secondary)=34.5min, 95%ee.
React embodiment 12：
With react embodiment 1 the difference is that：Substrate fortified phenol used is 6- methoxyl groups -2- (4- trifluoromethyls Phenyl (p-toluenesulfonyl) methyl) phenol (0.1mmol, 43.6mg), other reaction conditions and operating procedure with react implement Example 1 is identical, obtains white solid product 33mg (yield 78%),1H NMR(500MHz,CDCl3) δ 8.05 (d, J=8.6Hz, 1H), 7.83 (d, J=7.8Hz, 1H), 7.78 (d, J=8.9Hz, 1H), 7.59 (d, J=8.3Hz, 2H), 7.48-7.43 (m, 1H), 7.36 (dd, J=11.2,4.2Hz, 3H), 7.12 (d, J=8.8Hz, 1H), 6.86 (dd, J=9.1,5.5Hz, 2H), 6.80 (dd, J=6.5,2.9Hz, 1H), 6.74 (s, 1H), 6.05 (s, 1H), 5.62 (s, 1H), 3.91 (s, 3H)13C NMR (125MHz,CDCl3)δ152.71,146.63,145.88,143.58,133.34,129.70,128.90,128.75, (126.79,126.43,125.66 q, J=3.75Hz), 125.26,123.24,123.02,121.65,120.41,119.63, 119.06,109.88,55.99,42.48；By chiral HPLC, actual conditions are (AD-H, 3%iPrOH in hexane,flow rate 0.6ml/min):tR(master)=150.9min, tR(secondary)=167.9min, 92%ee.
React embodiment 13：
With react embodiment 1 the difference is that：Substrate fortified phenol used is 6- methoxyl groups -2- (3,5- bis- trifluoros Aminomethyl phenyl (p-toluenesulfonyl) methyl) phenol (0.1mmol, 50.4mg), other reaction conditions and operating procedure with react Embodiment 1 is identical, obtains white solid product 43mg (yield 87%),1H NMR(500MHz,CDCl3) δ 8.01 (d, J= 8.6Hz, 1H), 7.83 (d, J=7.7Hz, 1H), 7.80-7.71 (m, 2H), 7.65 (s, 2H), 7.46 (ddd, J=8.4,6.9, 1.2Hz, 1H), 7.36 (dd, J=11.1,4.0Hz, 1H), 7.08 (d, J=8.8Hz, 1H), 6.90-6.83 (m, 2H), 6.78 (dd, J=6.8,2.5Hz, 1H), 6.73 (s, 1H), 6.03 (s, 1H), 5.56 (s, 1H), 3.92 (s, 3H)13C NMR (125MHz,CDCl3) δ 152.31,146.66,145.05,143.50,133.25,131.44 (q, J=33.75Hz), 130.07,129.78,128.91,128.65,126.99,125.72,124.49,123.41,122.91,122.32,121.76, (120.52,120.36 q, J=3.75Hz), 119.49,118.72,110.05,56.06,42.41；By chiral HPLC, Actual conditions are (IC-H, 1%iPrOH in hexane, flow rate 0.5ml/min):tR(master)=23.2min, tR(secondary) =18.0min, 94%ee.
React embodiment 14：
With react embodiment 1 the difference is that：Substrate fortified phenol used is that (1- naphthalenes are (to first by 6- methoxyl groups -2- Benzenesulfonyl) methyl) phenol (0.1mmol, 41.8mg), other reaction conditions and operating procedure with reaction embodiment 1 it is identical, obtain To white solid product 26mg (yield 64%),1H NMR(500MHz,CDCl3) δ 8.08 (s, 1H), 7.90 (d, J=8.1Hz, 1H), 7.83 (dd, J=14.5,7.8Hz, 3H), 7.72 (d, J=8.9Hz, 1H), 7.47 (dd, J=14.0,6.3Hz, 2H), 7.42-7.32 (m, 3H), 7.27-7.21 (m, 2H), 6.98 (d, J=8.8Hz, 1H), 6.85 (dd, J=8.1,1.3Hz, 1H), 6.79 (t, J=7.9Hz, 1H), 6.69 (s, 1H), 5.90 (s, 1H), 5.72 (s, 1H), 3.92 (s, 3H)13C NMR (125MHz,CDCl3)δ154.06,146.67,134.27,133.12,131.92,129.64,129.38,128.87, 128.73,127.04,126.60,126.09,125.56,124.10,123.14,122.63,120.24,119.60,118.60, 109.72,55.97,40.34；By chiral HPLC, actual conditions are (IC-H, 2%iPrOH in hexane, flow rate 1.0ml/min):tR(master)=41.6min, tR(secondary)=20.7min, 88%ee.
React embodiment 15：
With react embodiment 1 the difference is that：Substrate fortified phenol used is that (2- furans is (to first by 6- methoxyl groups -2- Benzenesulfonyl) methyl) phenol (0.1mmol, 35.8mg), other reaction conditions and operating procedure with reaction embodiment 1 it is identical, obtain To yellow solid product 33.7mg (yield 97%),1H NMR(500MHz,CDCl3) δ 8.05 (d, J=8.7Hz, 1H), 7.79 (d, J=7.8Hz, 1H), 7.75 (d, J=8.9Hz, 1H), 7.54-7.40 (m, 2H), 7.34 (t, J=7.2Hz, 1H), 7.14 (d, J=8.9Hz, 1H), 6.90-6.79 (m, 3H), 6.62 (s, 1H), 6.37 (dd, J=3.1,1.9Hz, 1H), 6.28 (s, 1H), 6.06 (d, J=3.2Hz, 1H), 6.02 (s, 1H), 3.89 (s, 3H)13C NMR(125MHz,CDCl3)δ154.95, 153.28,146.54,143.18,142.96,133.09,129.56,129.48,128.63,126.72,125.49,123.09, 122.61,121.14,120.21,119.62,117.09,110.35,109.80,108.59,55.98,37.21；Pass through chirality HPLC is analyzed, and actual conditions are (IC-H, 10%iPrOH in hexane, flow rate 1.0ml/min):tR(master)= 22.3min,tR(secondary)=46.2min, 91%ee.
React embodiment 16：
With react embodiment 1 the difference is that：Substrate fortified phenol used is that (2- thiophene is (to first by 6- methoxyl groups -2- Benzenesulfonyl) methyl) phenol (0.1mmol, 37.4mg), other reaction conditions and operating procedure with reaction embodiment 1 it is identical, obtain To white solid product 35mg (yield 97%),1H NMR(500MHz,CDCl3) δ 8.08 (d, J=8.6Hz, 1H), 7.78 (dd, J=21.2,8.3Hz, 2H), 7.46 (ddd, J=8.4,6.9,1.2Hz, 1H), 7.39-7.26 (m, 2H), 7.14 (d, J= 8.9Hz, 1H), 6.96 (ddd, J=14.5,5.5,3.4Hz, 2H), 6.86 (d, J=6.8Hz, 1H), 6.84 (s, 1H), 6.83 (t, J=5.5Hz, 2H), 6.02 (s, 2H), 3.91 (s, 3H)13C NMR(125MHz,CDCl3)δ153.33,146.47, (145.83,143.07,132.95,129.66,129.43,128.62,127.19,126.84 d, J=11.8Hz), 126.54, 126.15,123.16,122.66,121.12,120.20,119.90,119.31,109.82,56.00,38.00；Pass through chirality HPLC is analyzed, and actual conditions are (IC-H, 2%iPrOH in hexane, flow rate 1.0ml/min):tR(master)= 41.4min,tR(secondary)=62.8min, 65%ee.
React embodiment 17：
With react embodiment 1 the difference is that：Substrate substituted naphthol used be the bromo- beta naphthals of 3- (0.12mmol, 36.8mg), other reaction conditions and operating procedure are identical as reaction embodiment 1, obtain white solid product 40.3mg (yields 93%),1H NMR(500MHz,CDCl3) δ 8.08-8.01 (m, 2H), 7.71 (d, J=7.8Hz, 1H), 7.40 (t, J= 7.7Hz, 1H), 7.33 (dd, J=14.8,7.6Hz, 3H), 7.29-7.26 (m, 1H), 7.21 (d, J=7.3Hz, 2H), 6.85- 6.76(m,4H),6.01(s,1H),5.91(s,1H),3.91(s,3H).13C NMR(125MHz,CDCl3)δ148.57, 146.40,143.54,141.36,132.91,131.52,129.94,128.76,128.51,127.69,126.96,126.84, 126.73,124.00,123.84,122.20,122.14,119.87,113.68,109.46,56.00,42.86；Pass through chirality HPLC is analyzed, and actual conditions are (IC-H, 2%iPrOH in hexane, flow rate 1.0ml/min):tR(master)= 19.2min,tR(secondary)=54.9min, 89%ee.
React embodiment 18：
With react embodiment 1 the difference is that：Substrate substituted naphthol used be the bromo- beta naphthals of 6- (0.12mmol, 36.8mg), other reaction conditions and operating procedure are identical as reaction embodiment 1, obtain white solid product 36.8mg (yields 85%),1H NMR(500MHz,CDCl3) δ 7.95-7.90 (m, 2H), 7.64 (d, J=8.9Hz, 1H), 7.48 (dd, J=9.1, 2.2Hz, 1H), 7.38-7.29 (m, 3H), 7.23 (d, J=7.4Hz, 2H), 7.10 (d, J=8.8Hz, 1H), 6.86-6.80 (m, 2H), 6.72 (dd, J=7.5,1.7Hz, 1H), 6.63 (s, 1H), 5.94 (s, 1H), 5.59 (s, 1H), 3.92 (s, 3H) .13C NMR(125MHz,CDCl3)δ153.35,146.55,143.41,140.83,132.07,130.81,130.41, 129.81,129.23,128.49,128.45,127.30,126.69,124.98,121.61,121.01,120.31,119.95, 116.84,109.72,56.02,42.44；By chiral HPLC, actual conditions are (IC-H, 2%iPrOH in hexane,flow rate 1.0ml/min):tR(master)=27.3min, tR(secondary)=32.8min, 94%ee.
React embodiment 19：
With react embodiment 1 the difference is that：Substrate substituted naphthol used be the bromo- beta naphthals of 7- (0.12mmol, 36.8mg), other reaction conditions and operating procedure are identical as reaction embodiment 1, obtain white solid product 35.6mg (yields 85%),1H NMR(500MHz,CDCl3) δ 8.26 (d, J=1.1Hz, 1H), 7.67 (dd, J=23.7,8.7Hz, 2H), 7.41 (dd, J=8.6,1.8Hz, 1H), 7.39-7.33 (m, 2H), 7.32 (d, J=7.1Hz, 1H), 7.24 (d, J=7.5Hz, 2H), 7.10 (d, J=8.9Hz, 1H), 6.89-6.80 (m, 2H), 6.75 (dd, J=7.3,2.0Hz, 1H), 6.59 (s, 1H), 5.98 (s,1H),5.65(s,1H),3.92(s,3H).13C NMR(125MHz,CDCl3)δ153.82,146.61,143.49, 140.68,134.85,130.15,129.27,129.22,128.45,127.94,127.31,126.46,125.44,121.55, 121.36,120.27,119.17,109.76,56.01,42.33；By chiral HPLC, actual conditions be (IC-H, 2% iPrOH in hexane,flow rate 1.0ml/min):tR(master)=20.8min, tR(secondary)=25.5min, 93%ee.

Claims (7)

1. the synthetic method of triaryl substituted chiral compound shown in a kind of formula (1), which is characterized in that the synthetic method For：
In water phase and an oil phase system, shown in (aryl (p-toluenesulfonyl) methyl) phenol of 2- shown in starting materials of formulae (2) and formula (3) Beta naphthal is reacted under the action of acid binding agent, chiral catalyst, and TLC tracking and monitorings are to the reaction was complete, and reaction solution passes through later Post-processing, obtains triaryl substituted chiral compound shown in product formula (1)；
Reaction equation is as follows：
In formula (2), Ts indicates p-toluenesulfonyl；
In formula (1), (2) or (3),
R1、R2Respectively stand alone as H, methoxyl group or halogen；
Ar is furyl, thienyl, naphthalene, phenyl or the phenyl being substituted by one or more substituents, the substituent group Respectively stand alone as methyl, methoxyl group, trifluoromethyl or halogen；
In the synthetic method：
The amount of (aryl (p-toluenesulfonyl) methyl) phenol of 2- shown in the formula (2) and the substance of beta naphthal shown in formula (3) The ratio between be 0.2~5：1；
The ratio between the amount of substance of the chiral catalyst and 2- shown in formula (2) (aryl (p-toluenesulfonyl) methyl) phenol is 0.1~20：100；
The ratio between the acid binding agent and the amount of substance of 2- (aryl (p-toluenesulfonyl) methyl) phenol shown in formula (2) are 0.5 ~20：1；
The water phase and an oil phase system is by water and organic solvent with volume ratio 1：0.1~10 is mixed to form；The organic solvent Selected from dichloromethane, 1,2- dichloroethanes, ether, toluene, ethyl acetate or isopropyl acetate；
The acid binding agent is inorganic base；
The chiral catalyst is selected from one of compound shown in following formula (4)~(8)：
In formula (4), (5), the carbon atom for indicating * is asymmetric carbon atom；
In formula (4), (5), (6), (7) or (8),
R3、R6、R9、R12C1~C20 alkyl respectively is stood alone as, or the phenyl or benzyl being substituted by one or more substituents, institute The substituent group stated respectively stands alone as trifluoromethyl, nitro or halogen；
R4、R5、R7、R8Respectively stand alone as C1~C10 alkyl；
R10、R13、R16Respectively stand alone as ethyl or vinyl；
R11、R14、R15Respectively stand alone as H, hydroxyl or methoxyl group.
2. the synthetic method of triaryl substituted chiral compound shown in formula (1) as described in claim 1, which is characterized in that The reaction carries out at normal temperatures.
3. the synthetic method of triaryl substituted chiral compound shown in formula (1) as described in claim 1, which is characterized in that The ratio between the amount of substance of (aryl (p-toluenesulfonyl) methyl) phenol of 2- shown in the formula (2) and beta naphthal shown in formula (3) It is 0.5~2：1.
4. the synthetic method of triaryl substituted chiral compound shown in formula (1) as described in claim 1, which is characterized in that The ratio between the acid binding agent and the amount of substance of 2- (aryl (p-toluenesulfonyl) methyl) phenol shown in formula (2) are 1~10：1.
5. the synthetic method of triaryl substituted chiral compound shown in formula (1) as described in claim 1, which is characterized in that The acid binding agent is sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide or phosphoric acid Disodium hydrogen.
6. the synthetic method of triaryl substituted chiral compound shown in formula (1) as described in claim 1, which is characterized in that The chiral catalyst is selected from one of following：
7. the synthetic method of triaryl substituted chiral compound shown in formula (1) as described in claim 1, which is characterized in that The post-processing approach of the reaction solution is：After reaction, by reaction solution liquid separation, silicagel column is carried out after taking organic phase to be concentrated under reduced pressure Chromatography, with petrol ether/ethyl acetate volume ratio 1~10：1 mixed liquor is that eluant, eluent carries out gradient elution, collects and contains mesh The eluent for marking compound, is evaporated off solvent and drying, obtains triaryl substituted chiral compound shown in product formula (1).
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