CN103242223B - Preparation method of 2-pyridineoxydiaryl ketone derivative - Google Patents

Preparation method of 2-pyridineoxydiaryl ketone derivative Download PDF

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CN103242223B
CN103242223B CN201310153763.5A CN201310153763A CN103242223B CN 103242223 B CN103242223 B CN 103242223B CN 201310153763 A CN201310153763 A CN 201310153763A CN 103242223 B CN103242223 B CN 103242223B
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pyridyloxy
nmr
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pyridineoxydiaryl
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CN103242223A (en
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张玉红
姚金忠
冯若昆
刘占祥
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Zhejiang University ZJU
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Abstract

The invention discloses a preparation method of 2-pyridineoxydiaryl ketone derivative. The preparation method comprises the following steps of: adding a catalyst, an oxidant, a 2-pyridineoxydiaryl compound and aryl oxoacetic acid to an organic solvent; heating up to 90-120 DEG C; and posttreating to obtain 2-pyridineoxydiaryl ketone derivative after the reaction is completed. The preparation method of the pyridineoxydiaryl ketone derivative disclosed by the invention is easy to operate, simple in posttreatment, strong in substrate designability, capable of designing a compound for synthesizing the needed structure according to actual needs, and stronger in practicability. Meanwhile, the compound prepared by the preparation method is good in bioactivity, can be used as the material for synthesizing various 2-pyridineoxydiaryl ketone derivative compounds and is higher in economic value.

Description

A kind of preparation method of 2-pyridyloxy diaryl ketone derivatives
Technical field
The invention belongs to organic synthesis field, be specifically related to a kind of preparation method of 2-pyridyloxy diaryl ketone derivatives.
Background technology
2-pyridyloxy diaryl ketone is the very important organic intermediate of a class, and it, as a kind of important nitrogen heterocyclic ring, is extensively present in natural product.The mother nucleus structure of the multiple inhibitor against colon carcinoma cells compound such as, extracted during Garcinia Xanthochymus is real is exactly diaryl ketone.（Bioactive Benzophenonesfrom Garcinia xanthochymus Fruits,J.Nat.Prod.2005,68,354-360）
The derivative functionalization of this compounds causes the interest of a large amount of study on the synthesis persons.Such as its derivative can as the non-nucleoside reverse transcriptase inhibitor of anti-HIV-1 (NNRTI). (Practical snthesis of a benzophenone-based NNRT inhibitor of HIV-1, Org.Process Res.Dev.2012,16,561-566)
In addition, 2-pyridyloxy diaryl ketone will produce 2-hydroxy diaryl methanone compounds through hydrolysis, hydrolytic process simply, easy handling with realize industrialization.2-hydroxy diaryl methanone compounds is very important organic raw material, it can as the raw material of some medicines of synthesis, such as patent application WO2012041860A1 discloses a kind of method that the 2-of use dihydroxy benaophenonel synthesizes a class indole derivatives, and such indole derivatives can as a kind of histamine H 4receptor antibody.
Summary of the invention
The invention provides a kind of preparation method of 2-pyridyloxy diaryl ketone derivatives, the method step is simple, and the by product of reaction is carbonic acid gas and water, and environmental pollution is little.
A kind of preparation method of 2-pyridyloxy diaryl ketone derivatives, comprise: by catalyzer, oxygenant, 2-pyridyloxy aryl compound and aryl GA join in organic solvent, be heated to 90 ~ 120 DEG C, after reacting completely, obtain described 2-pyridyloxy diaryl ketone derivatives through aftertreatment;
The structure of described 2-pyridyloxy aryl compound is as shown in the formula (II):
（II）；
The structure of described aryl GA is as shown in the formula (III):
（III）；
The structure of described 2-pyridyloxy diaryl ketone derivatives is as shown in the formula (I):
（I）；
In formula (I)-Shi (III): R 1for hydrogen, halogen, C 1~ C 5alkyl or C 1~ C 5alkoxyl group;
R 2for hydrogen, halogen, C 1~ C 5alkyl, C 1~ C 5alkoxyl group or trifluoromethyl;
Described catalyzer is divalent palladium catalyzer;
Described oxygenant is monovalence silver oxygenant.
Above-mentioned reaction process is shown below:
As shown in Figure 1, the possible reaction mechanism of preparation method of the present invention is as follows: described divalent palladium catalyzer and 2-pyridyloxy diaryl ketone derivatives are (with R 1=H is example) in pyridine atom N carry out coordination after, intermediate A is generated after the ortho position c h bond of 2-pyridyloxy is activated, intermediate B is formed after intermediate A and aryl GA generation metal exchange, and then there is decarboxylic reaction, generate intermediate C, there is reduction and eliminate the 2-pyridyloxy diaryl ketone derivatives described in generating in intermediate C, and discharges zeroth order palladium, then zeroth order palladium regenerates divalent palladium catalyzer under the effect of oxygenant, completes catalytic cycle.In this preparation method, having reacted rear by product is water and carbonic acid gas, and environmental pollution is little, and reaction raw materials becomes more readily available, and cost is lower.
As preferably, described R 1for hydrogen, fluorine, chlorine, bromine, methyl or methoxy, now, these 2-pyridyloxy aryl compounds (II) can select existing method to prepare, such as, 2-bromopyridine and fragrant phenol can be selected to obtain under the effect of monovalence copper and alkali.
As further preferred, described R 2for hydrogen, fluorine, chlorine, bromine, methyl, methoxyl group or trifluoromethyl, now starting aryl GA is cheaply easy to get, and reaction yield is higher.
As preferably, described organic solvent is dioxane, acetic acid or methyl-sulphoxide, and raw material, without requirement strict especially, can fully dissolve by the consumption of reaction solvent.
As preferably, described divalent palladium catalyzer comprises palladium, dichlorodiethyl nitrile palladium (Pd (CH 3cN) 2cl 2) or Palladous chloride, these divalent palladium catalyzer can be buied easily from the market.
As preferably, described monovalence silver oxygenant is Silver monoacetate, silver carbonate, silver suboxide or Silver Nitrate, and these oxygenants can be buied easily from the market.
In above-mentioned reaction, for economizing in raw materials, ensure carrying out completely of reaction, as preferably, the mol ratio of described 2-pyridyloxy aryl compound, aryl GA, catalyzer and oxygenant is 1:2-4:0.1-0.3:1-3 simultaneously.
Reacting the degree of carrying out can by TLC(thin-layer chromatography) monitor, as preferably, the reaction times is 6-12 hour, reaction times long increase reaction cost, is then difficult on the contrary ensure the complete of reaction.
As further preferred, described divalent palladium catalyzer is dichlorodiethyl nitrile palladium;
Described monovalence silver oxygenant is silver suboxide;
Temperature of reaction is 110 ~ 115 ° of C, and now, the productive rate of reaction is the highest, and side reaction is minimum.
As preferably, described 2-pyridyloxy diaryl ketone derivatives is selected from the one in compound shown in formula (I-1)-Shi (I-10):
（I-1）
（I-2）
（I-3）
（I-4）
（I-5）
（I-6）
（I-7）
（I-8）
（I-9）
（I-10）。
After above-mentioned reaction completes, available last handling process comprises: filter, silica gel mixed sample, eventually passes column chromatography purification and obtain corresponding 2-pyridyloxy diaryl ketone derivatives.
The preparation method of 2-pyridyloxy diaryl ketone derivatives of the present invention, easy handling, aftertreatment is easy, and substrate designability is strong, and can go out the compound of desired structure by design and synthesis according to actual needs, practicality is stronger.Meanwhile, the compound biological activity prepared by aforesaid method is good, can be used as Material synthesis various 2-hydroxy diaryl methanone compounds simultaneously, has higher economic worth.
Accompanying drawing explanation
Fig. 1 is the reaction mechanism figure of the preparation method of 2-pyridyloxy diaryl ketone derivatives of the present invention.
Embodiment
Embodiment 1 ~ 10
In the Schlenk pipe of 35ml, catalyzer, oxygenant, 2-pyridyloxy aryl compound (II), aryl GA (III) and organic solvent 2ml is added according to the proportioning raw materials of table 1, mixing and stirring, after having reacted according to the reaction conditions of table 2, filter, silica gel mixed sample, obtain corresponding 2-pyridyloxy diaryl ketone derivatives (I) through column chromatography (eluent is sherwood oil) purifying, reaction process is shown below:
Table 1
Table 2
In table 1 and table 2, T is temperature of reaction, and t is the reaction times, and Me is methyl, and OMe is methoxyl group, and p represents para-orientation, and m represents that ortho position replaces.
Application examples 1
The preparation of 2-dihydroxy benaophenonel (No. CAS: 117-99-7): the compound (I-1) (138mg, 0.5mmol) embodiment 1 prepared is dissolved in the toluene of 5 milliliters, adds 0.1mL Methyl triflate.Be heated to 100 ° of C, react 2 hours stopped reaction, revolve except toluene.Residue is dissolved in the methyl alcohol of 5 milliliters, adds sodium methylate (270mg, 5mmol), be heated to 80 ° of C and react 0.5 hour.Reaction solution cool to room temperature, with water and ethyl acetate layering, organic phase is collected, saturated common salt water washing, anhydrous magnesium sulfate drying, and filter, be spin-dried for and namely obtain product 2-dihydroxy benaophenonel 81mg, productive rate 82%, the nuclear magnetic data of products obtained therefrom is as follows:
1H NMR(400MHz,CDCl 3,TMS)δ12.1(s,1H),7.69-7.67(m,2H),7.61-7.58(m,2H),7.51-7.49(m,3H),7.08(d,J=8.4Hz,1H),6.90-6.86(m,1H);
13C NMR(100MHz,CDCl 3)δ201.6,163.2,137.8,136.3,133.6,131.9,129.1,128.3,119.1,118.6,118.4.
Application examples 2
The preparation of 4-methoxyl group-2-dihydroxy benaophenonel (No. CAS: 131-57-7): the compound (I-9) (153mg, 0.5mmol) embodiment 9 prepared is dissolved in the toluene of 5 milliliters, adds 0.1mL Methyl triflate.Be heated to 100 ° of C, react 2 hours stopped reaction, revolve except toluene.Residue is dissolved in the methyl alcohol of 5 milliliters, adds sodium methylate (270mg, 5mmol), be heated to 80 ° of C and react 0.5 hour.Reaction solution cool to room temperature, with water and ethyl acetate layering, organic phase is collected, saturated common salt water washing, anhydrous magnesium sulfate drying, and filter, be spin-dried for and namely obtain product 2-dihydroxy benaophenonel 96mg, productive rate 84%, the nuclear magnetic data of products obtained therefrom is as follows:
1H NMR(400MHz,CDCl 3,TMS)δ12.20(s,1H),7.69-7.54(m,2H),7.56-7.51(m,1H),7.47-7.43(m,2H),7.15(d,J=8.0Hz,1H),7.06(d,J=8.0Hz,1H),6.78-6.76(m,1H),3.89(s,3H);
13C NMR(100MHz,CDCl 3)δ201.6,153.2,148.8,137.7,131.8,128.1,124.6,124.3,119.1,117.9,116.9,56.1.
Embodiment 1 ~ 10 prepares the structure confirmation data of compound:
The structure detection data of the 2-pyridyloxy diaryl ketone derivatives prepared by embodiment 1 ~ 10 are respectively:
The nucleus magnetic resonance of the 2-pyridyloxy diaryl ketone derivatives (I-1, No. CAS: 1173294-85-3) prepared by embodiment 1 ( 1h NMR and 13c NMR) detect data and be:
（I-1）
1H NMR(400MHz,CDCl 3,TMS)δ8.01(d,J=4.0Hz,1H),7.75(d,J=8.0Hz,2H),7.59-7.45(m,4H),7.35-7.28(m,4H),6.87(t,J=6.4Hz,1H),6.60(d,J=8.4Hz,1H); 13C NMR(100MHz,CDCl 3)δ195.3,162.8,151.5,146.9,139.3,137.4,132.7,132.1,130.2,129.7,127.9,124.6,122.7,118.4,111.4.
The nucleus magnetic resonance of the 2-pyridyloxy diaryl ketone derivatives (I-2, No. CAS: 1173294-97-7) prepared by embodiment 2 ( 1h NMR and 13c NMR) detect data and be:
（I-2）
1H NMR(400MHz,CDCl 3,TMS)δ8.01(d,J=4.0Hz,1H),7.67(d,J=8.0Hz,2H),7.56-7.49(m,3H),7.31-7.24(m,2H),7.13(d,J=8.4Hz,2H),6.86(t,J=7.2Hz,1H),6.64(d,J=8.4Hz,1H),2.35(s,3H);
13C NMR(100MHz,CDCl 3)δ194.5,162.9,151.4,146.9,143.6,139.2,134.7,132.4,131.7,130.0,129.9,128.7,124.5,122.6,118.4,111.4,21.6.
The nucleus magnetic resonance of 2-pyridyloxy diaryl ketone derivatives (I-3) prepared by embodiment 3 ( 1h NMR and 13c NMR) detect data and be:
（I-3）
1H NMR(400MHz,CDCl 3,TMS)δ8.01(d,J=4.0Hz,1H),7.55-7.51(m,3H),7.33-7.27(m,3H),7.25-7.19(m,2H),7.01(d,J=8.0,4.0Hz,1H),6.87(d,J=8.0Hz,1H),6.62(d,J=8.0Hz,1H),3.75(s,3H);
13C NMR(100MHz,CDCl 3)δ195.0,162.9,159.3,151.5,146.9,139.3,138.7,132.1,132.0,130.1,128.9,124.5,122.9,122.7,119.6,118.4,113.1,111.4,55.3.
The nucleus magnetic resonance of 2-pyridyloxy diaryl ketone derivatives (I-4) prepared by embodiment 4 ( 1h NMR and 13c NMR) detect data and be:
（I-4）
1H NMR(400MHz,CDCl 3,TMS)δ8.00(d,J=4.0Hz,1H),7.78(d,J=8.4,2.8Hz,2H),7.59-7.51(m,3H),7.31(t,J=7.6Hz,1H),7.25(d,J=7.6Hz,1H),6.99(t,J=8.8Hz,2H),6.88(t,J=6.4Hz,1H),6.62(d,J=8.4Hz,1H);
13C NMR(100MHz,CDCl 3)δ193.7,165.5(J=253Hz),162.7,151.4,146.9,139.4,133.7(J=2.0Hz),132.4(J=8.9Hz),132.2,131.9,130.0,124.7,122.6,118.6,115.1(J=21.5Hz),111.4.
The nucleus magnetic resonance of 2-pyridyloxy diaryl ketone derivatives (I-5) prepared by embodiment 5 ( 1h NMR and 13c NMR) detect data and be:
（I-5）
1H NMR(400MHz,CDCl 3,TMS)δ8.01(d,J=4.4Hz,1H),7.70(d,J=7.2Hz,2H),7.59-7.52(m,3H),7.34-7.25(m,4H),6.89(t,J=6.4Hz,1H),6.62(d,J=8.0Hz,1H);
13C NMR(100MHz,CDCl 3)δ194.1,162.7,151.5,146.9,139.4,139.1,135.8,132.4,131.7,131.1,130.1,128.3,124.8,122.7,118.6,111.5.
The nucleus magnetic resonance of the 2-pyridyloxy diaryl ketone derivatives (I-6, No. CAS: 1173294-98-8) prepared by embodiment 6 ( 1h NMR and 13c NMR) detect data and be:
（I-6）
1H NMR(400MHz,CDCl 3,TMS)δ8.00(d,J=4.0Hz,1H),7.63-7.53(m,5H),7.46(d,J=8.8Hz,2H),7.31(t,J=7.6Hz,1H),7.26-7.24(m,1H),6.89(t,J=5.6Hz,1H),6.62(d,J=8.8Hz,1H);
13C NMR(125MHz,CDCl 3)δ194.2,162.7,151.5,146.9,139.4,136.2,132.4,131.6,131.3,131.2,130.1,127.8,124.7,122.7,118.6,111.5.
The nucleus magnetic resonance of 2-pyridyloxy diaryl ketone derivatives (I-7) prepared by embodiment 7 ( 1h NMR and 13c NMR) detect data and be:
（I-7）
1H NMR(400MHz,CDCl 3,TMS)δ8.00-7.98(m,2H),7.93(d,J=8.0Hz,1H),7.70(d,J=8.0Hz,1H),7.61-7.59(m,2H),7.50-7.46(m,2H),7.35(t,J=7.2Hz,1H),7.28-7.26(m,1H),6.90-6.87(m,1H),6.55(d,J=8.0Hz,1H);
13C NMR(100MHz,CDCl 3)δ194.0,162.6,151.7,147.0,139.4,138.3,132.8(2C),131.2,130.6(q,J=33.4Hz),130.1,129.0(q,J=3.7Hz),128.6,126.5(q,J=3.4Hz),124.9,123.6(q,J=265Hz),122.8,118.7,111.3.
The nucleus magnetic resonance of 2-pyridyloxy diaryl ketone derivatives (I-8) prepared by embodiment 8 ( 1h NMR and 13c NMR) detect data and be:
（I-8）
1H NMR(400MHz,CDCl 3,TMS)δ8.01(d,J=4.0Hz,1H),7.74(d,J=7.6Hz,2H),7.48-7.44(m,2H),7.38-7.36(m,2H),7.31(t,J=7.6Hz,2H),7.15(d,J=8.8Hz,1H),6.85(t,J=6.8Hz,1H),6.55(d,J=8.0Hz,1H),2.40(s,3H);
13C NMR(100MHz,CDCl 3)δ195.5,163.1,149.2,146.9,139.1,137.5,134.5,132.8,132.6,131.9,130.5,129.8,127.9,122.6,118.2,111.2,20.8.
The nucleus magnetic resonance of the 2-pyridyloxy diaryl ketone derivatives (I-9, No. CAS: 1173294-88-6) prepared by embodiment 9 ( 1h NMR and 13c NMR) detect data and be:
（I-9）
1H NMR(400MHz,CDCl 3,TMS)δ8.01(d,J=5.2Hz,1H),7.74(d,J=8.0Hz,2H),7.48-7.44(m,2H),7.31(t,J=7.6Hz,2H),7.19(d,J=8.8Hz,1H),7.12-7.07(m,2H),6.84(t,J=6.4Hz,1H),6.52(d,J=8.4Hz,1H),3.83(s,3H);
13C NMR(100MHz,CDCl 3)δ195.0,163.3,156.3,146.9,144.8,139.1,137.3,132.9,132.8,129.7,127.9,124.1,118.1,118.0,114.4,111.0,55.7.
The nucleus magnetic resonance of 2-pyridyloxy diaryl ketone derivatives (I-10) prepared by embodiment 10 ( 1h NMR and 13c NMR) detect data and be:
（I-10）
1H NMR(400MHz,CDCl 3,TMS)δ8.00(d,J=3.6Hz,1H),7.75(d,J=7.2Hz,2H),7.53-7.48(m,2H),7.34(t,J=8.0Hz,2H),7.28-7.26(m,3H),6.88(t,J=6.0Hz,1H),6.58(d,J=8.4Hz,1H);
13C NMR(100MHz,CDCl 3)δ193.8,162.8,159.0(J=245.3Hz),147.2(J=3.2Hz),146.8,139.4,136.8,133.5(J=7.2Hz),133.1,129.7,128.1,124.6(J=8.9Hz),118.8(J=23.9Hz),118.5,116.6(J=24.6Hz),111.3。

Claims (1)

1. a preparation method for 2-dihydroxy benaophenonel, is characterized in that, comprising:
(1) in the Schlenk pipe of 35ml, 0.3mmol Pd (OAc) is added 2, 3mmol Silver monoacetate, 1mmol 2-pyridyloxy benzene, 2mmol phenyl GA and dioxane 2ml, mixing and stirring, at 110 DEG C of temperature, react 12 hours, filter, silica gel mixed sample, 2-pyridyloxy diphenylmethanone is obtained, productive rate 82% through column chromatography purification;
Wherein, the eluent of column chromatography is sherwood oil;
(2) the 2-pyridyloxy diphenylmethanone that 138mg step (1) prepares is dissolved in the toluene of 5 milliliters, add 0.1mL Methyl triflate, be heated to 100 DEG C, react 2 hours stopped reaction, revolve except toluene, residue is dissolved in the methyl alcohol of 5 milliliters, add 270mg sodium methylate, be heated to 80 DEG C of reactions 0.5 hour, reaction solution cool to room temperature, with water and ethyl acetate layering, organic phase is collected, saturated common salt water washing, anhydrous magnesium sulfate drying, filter, be spin-dried for and namely obtain product 2-dihydroxy benaophenonel 81mg.
CN201310153763.5A 2013-04-27 2013-04-27 Preparation method of 2-pyridineoxydiaryl ketone derivative Expired - Fee Related CN103242223B (en)

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