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CN105777461B - A kind of method that medicine intermediate phenanthrene compound is synthesized under sodium carbonate environment - Google Patents

A kind of method that medicine intermediate phenanthrene compound is synthesized under sodium carbonate environment Download PDF

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CN105777461B
CN105777461B CN201610216498.4A CN201610216498A CN105777461B CN 105777461 B CN105777461 B CN 105777461B CN 201610216498 A CN201610216498 A CN 201610216498A CN 105777461 B CN105777461 B CN 105777461B
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phenanthrene
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catalyst
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CN105777461A (en
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翟学研
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Zhejiang Aolanding Biotechnology Co ltd
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Huang Zhemin
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
    • C07B37/10—Cyclisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
    • C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
    • C07C17/266—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions of hydrocarbons and halogenated hydrocarbons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2/00—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms
    • C07C2/02—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by addition between unsaturated hydrocarbons
    • C07C2/42—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by addition between unsaturated hydrocarbons homo- or co-oligomerisation with ring formation, not being a Diels-Alder conversion
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/127—Preparation from compounds containing pyridine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2531/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • C07C2531/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • C07C2531/22—Organic complexes

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  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to a kind of method for synthesizing phenanthrene compound shown in lower formula (I) under sodium carbonate environment,The method includes：Under inert atmosphere, in the presence of catalyst, organic ligand and sodium carbonate, in solvent, lower formula (II) compound reacts with formula (III) compound, to obtain formula (I) compound；Wherein, R1、R2It is each independently H, C1‑C6Alkyl, C1‑C6Alkoxy or halogen；R3 is C6‑C10Aryl or C5‑C8Heteroaryl, the C6‑C10Aryl or C4‑C8Heteroaryl is optionally replaced by 13 substituent groups, and the substituent group is C1‑C6Alkyl or halogen.The method achieves good effect by the selection of suitable catalyst, organic ligand, alkali and solvent, has extensive prospects for commercial application.

Description

A kind of method that medicine intermediate phenanthrene compound is synthesized under sodium carbonate environment
The present patent application is that application No. is 201510100568.5, (a kind of medicine intermediate is luxuriant and rich with fragrance filed in 6 days March in 2015 The synthetic method of class compound) patent application divisional application.
Technical field
The present invention relates to a kind of synthetic methods of fused ring compound, relate more specifically to a kind of medicine intermediate phenanthrene compound Synthetic method, belong to organic synthesis and medicine intermediate synthesis field.
Background technology
The compounds such as fused ring compound such as naphthalene, anthracene, phenanthrene are researched and developed people due to the bioactivity of its generally existing by medicine The attention and concern of member.Wherein, luxuriant and rich with fragrance and its derivative is a kind of important phenolic compound, has been widely used in medicine Object designs and synthesis, material development field.
Just because of the such excellent in performance and potentiality of phenanthrene compound, thus study luxuriant and rich with fragrance and its derivative novel synthesis side Method also be always organic chemical synthesis worker hot issue very deeply concerned.
Up to the present, the preparation process for having existed a variety of phenanthrene compounds in the prior art, from multiple angle researchs The synthetic method that phenanthrene compound is suitble to.Such as：
(" Phenanthrene Synthesis by the Eosin Y-Catalyzed, Visible such as Xiao Tiebo Light-Induced [4+2] Benzannulation of Biaryldiazonium Salts with Alkynes ", Adv.Synth.Catal., 2012,354,3195-3199) report a kind of no metal catalytic, visible light-inducing diaryl [4+2] benzo cyclization of diazo salt.Its equation is as follows：
(" the Expeditious Synthesis of Phenanthrenes via CuBr2-Catalyzed such as Ye Fei Coupling of Terminal Alkynes and N-Tosylhydrazones Derived from O-Fo rmyl Biphenyls ", Organic Letters, 2011,13,5020-5023) disclose a kind of coupling/cyclisation of benzyl CuBr2 catalysis Reaction, the N- Tosylhydrazones derived from adjacent formyl biphenyl are raw material, and reaction equation is as follows：
(" the Expedient Synthesis of Phenanthrenes via In (III)-such as Kwon Yongseok Catalyzed 6-Exo-DigCycloisomerization ", Organic Letters, 2013,15,920-923) it reports A kind of reaction for preparing phenanthrene compound of In (III) catalysis, has the advantages that react efficient, wide application range of substrates, anti- Answer formula as follows：
As described above, although having been disclosed for the preparation method of various types of phenanthrene compounds in the prior art, these Method still cannot meet medical, chemical industry synthesis field production requirement, this is because its intrinsic low production efficiency, raw material are not It the problems such as can make full use of.
In view of this, the present inventor studies and has been intended to provide a kind of new catalytic of phenanthrene compound through a large number of experiments Synthetic method has reached high income, willing purpose, has very extensive prospects for commercial application.
Invention content
For above-mentioned many defects, the present inventor is after having paid a large amount of creative work, by deeply grinding Study carefully, and develop a kind of synthetic method for the phenanthrene compound can be used as pharmaceutical intermediate, and then completes the present invention.
Specifically, the present invention provides a kind of synthetic method of phenanthrene compound shown in lower formula (I),
The method includes：Under inert atmosphere, in the presence of catalyst, organic ligand and alkali, in solvent, lower formula (II) Compound reacts with formula (III) compound, to obtain formula (I) compound；
Wherein, R1、R2It is each independently H, C1-C6Alkyl, C1-C6Alkoxy or halogen；
R3For C6-C10Aryl or C5-C8Heteroaryl, the C6-C10Aryl or C4-C8Heteroaryl is optionally by 1-3 substituent group Substitution, such as can be replaced by 1,2 or 3 substituent group, the substituent group is C1-C6Alkyl or halogen.
In the synthetic method of the present invention, C1-C6Alkyl refers to the alkyl for having 1-6 carbon atom, may be, for example, first Base, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, tertiary butyl, n-pentyl, isopentyl, n-hexyl etc..
In the synthetic method of the present invention, C1-C6Alkoxy refers to " C defined above1-C6Alkyl " and O atom phase Group after even.
In the synthetic method of the present invention, the halogen may be, for example, fluorine, chlorine, bromine or iodine.
In the synthetic method of the present invention, the C6-C10Aryl refers to the aryl for having 6-10 carbon atom, such as It can be phenyl or naphthyl.
In the synthetic method of the present invention, the C4-C8Heteroaryl refers to the heteroaryl for having 4-8 carbon atom, example Such as can be pyridyl group, furan thiophene base or thienyl.
In the synthetic method of the present invention, the catalyst is the mixing of organic palladium compound and organocopper compound The molar ratio of object, the two is 1:2-4 may be, for example, 1:2、1:3 or 1:4.
Wherein, organic palladium compound example is acid chloride (Pd (OAc)2), palladium bichloride (PdCl2), palladium acetylacetonate (Pd (acac)2), (1,5- cyclo-octadiene) palladium bichloride (PdCl2(cod)), palladium trifluoroacetate (Pd (TFA)2), [1,1 '-bis- (diphenyl Phosphino-) ferrocene] palladium chloride (PdCl2(dppf)), two (triphenylphosphine) palladium bichloride (PdCl2(PPh3)2Any one of) Or any a variety of mixture, most preferably PdCl2(dppf)。
Wherein, the organocopper compound is four acetonitrile copper ([(CH of hexafluorophosphoric acid3CN)4Cu]PF6), copper trifluoromethanesulfcomposite (Cu(OTf)2), acetylacetone copper (Cu (acac)2), any one or more in copper acetate, most preferably hexafluorophosphoric acid tetrem Nitrile copper ([(CH3CN)4Cu]PF6)。
The present invention the synthetic method in, the organic ligand be nitrogenous bidentate ligand, may be, for example, substitution or not Substituted bipyridyl, substituted or unsubstituted Phen etc., may be, for example, following L1-L4：
Most preferably L1.
In the synthetic method of the present invention, the alkali is Na2CO3、K2CO3、NaOH、KOH、K3PO4、Na3PO4、 NaHCO3、KHCO3, sodium acetate, sodium ethoxide, potassium tert-butoxide, diisopropylamine, any one of diisopropyl ethanolamine etc. or Any a variety of mixture；Most preferably diisopropyl ethanolamine.
In the synthetic method of the present invention, the solvent is PEG-400 and 1- allyl -3- methylimidazole tetrafluoro boron The mixture of hydrochlorate, the two volume ratio are 1:0.1-0.3 may be, for example, 1:0.1、1:0.2 or 1:0.3.
In the synthetic method of the present invention, the inert atmosphere may be, for example, nitrogen atmosphere or argon atmosphere.
In the synthetic method of the present invention, the molar ratio of formula (II) compound and formula (III) compound is 1: 2-4 may be, for example, 1:2、1:3 or 1:4.
In the synthetic method of the present invention, the molar ratio of formula (II) compound and catalyst is 1:0.08- 0.15, i.e., the ratio of the mole dosage and the sum of the mole dosage of two kinds of components of the composition catalyst of described formula (II) compound It is 1:0.08-0.15 may be, for example, 1:0.08、1:0.1、1:0.12、1:0.14 or 1:0.15.
In the synthetic method of the present invention, the molar ratio of formula (II) compound and organic ligand is 1:0.1- 0.2, it may be, for example, 1:0.1、1:0.15 or 1:0.2.
In the synthetic method of the present invention, the molar ratio of formula (II) compound and alkali is 1:2-3 may be, for example, 1:2、1:2.5 or 1:3.
In the synthetic method of the present invention, there is no stringent restriction, people in the art for the dosage of the solvent Member can suitably select its dosage, such as can be easy to carry out, be enough to react and be smoothed out according to post-process.
In the synthetic method of the present invention, reaction temperature is 60-80 DEG C, may be, for example, 60 DEG C, 70 DEG C or 80 DEG C.
In the synthetic method of the present invention, the reaction time is 8-12 hours, be may be, for example, 8 hours, 10 hours or 12 Hour.
In the synthetic method of the present invention, post-processing after reaction is specific as follows：After reaction, to reaction Deionized water is added in system, fully oscillation, washing, separates organic layer, be washed with deionized again, separate organic layer；It will Organic layer is concentrated under reduced pressure, and removes, silica gel column chromatography on gained residue, with volume ratio for 1:The n-hexyl alcohol of 2-4 and mixing for chloroform Bonding solvent is eluted as eluting solvent, is detected through TLC, and same composition is merged, and is removed eluting solvent, is obtained target chemical combination Object.
As described above, the present invention provides a kind of synthetic method of the phenanthrene compound as medicine intermediate, the method It is right to obtain purpose product with high yield by selection/combination/collaboration of suitable catalyst, You Jipei, alkali and solvent The actual production of the intermediates such as medicine, chemical industry is of great advantage, has extensive prospects for commercial application.
Specific implementation mode
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and Purpose is only used for enumerating the present invention, not constitutes any type of any restriction to the real protection scope of the present invention, more non-to incite somebody to action Protection scope of the present invention is confined to this.
Wherein, in all embodiments, unless otherwise prescribed, used ligand L 1 is matching of being referred to of above formula L1 Body.
Embodiment 1
The mixing being made of in right amount PEG-400 and 1- allyl -3- methyl imidazolium tetrafluoroborates is added into reactor (the two volume ratio is 1 to solvent:0.1) it, is then replaced twice with nitrogen so that be nitrogen atmosphere in reactor；Then it is added The bromo- 4 '-chlordiphenyls of the upper formula (II) compound 2- of 100mmol, the upper formula (III) compound styrene of 200mmol, by 3mmolPdCl2 (dppf) and four acetonitrile copper of 6mmol hexafluorophosphoric acids composition composite catalyst, 10mmol ligand Ls 1 and 200mmol diisopropyl second Hydramine is warming up to 60 DEG C, and reacts 12 hours at such a temperature under stirring.
After reaction, deionized water is added into reaction system, fully oscillation, washing, separates organic layer, spends again Ion water washing, separates organic layer；Organic layer is concentrated under reduced pressure, is removed, silica gel column chromatography on gained residue is with volume ratio 1:2 n-hexyl alcohol and the mixed solvent of chloroform are eluted as eluting solvent, are detected through TLC, and same composition is merged, and removing is washed Desolventizing obtains the chloro- 10- phenyl phenanthrene of target compound 2-, yield 95.3%.
1H-NMR (300MHz, CDCl3)δ:8.63 (d, J=8.9Hz, 1H), 8.49-8.44 (m, 2H), 7.84 (d, J= 2.2Hz, 1H), 7.71 (d, J=8.1Hz, 1H), 7.63 (s, 1H), 7.52 (dd, J=8.9,2.3Hz, 1H), 7.51-7.41 (m, 6H).
Embodiment 2
The mixing being made of in right amount PEG-400 and 1- allyl -3- methyl imidazolium tetrafluoroborates is added into reactor (the two volume ratio is 1 to solvent:0.2) it, is then replaced twice with nitrogen so that be nitrogen atmosphere in reactor；Then it is added The upper formula (II) compound 2- bromo biphenyls of 100mmol, the upper formula (III) compound 1- methyl -3- vinyl benzenes of 300mmol, by 3mmolPdCl2(dppf) and four acetonitrile copper of 9mmol hexafluorophosphoric acids composition composite catalyst, 15mmol ligand Ls 1 and 250mmol Diisopropyl ethanolamine is warming up to 70 DEG C, and reacts 10 hours at such a temperature under stirring.
After reaction, deionized water is added into reaction system, fully oscillation, washing, separates organic layer, spends again Ion water washing, separates organic layer；Organic layer is concentrated under reduced pressure, is removed, silica gel column chromatography on gained residue is with volume ratio 1:3 n-hexyl alcohol and the mixed solvent of chloroform are eluted as eluting solvent, are detected through TLC, and same composition is merged, and removing is washed Desolventizing, tolyl is luxuriant and rich with fragrance between obtaining target compound 9-, yield 94.7%.
1H-NMR (300MHz, CDCl3) δ:8.72 (dd, J=8.3,1.2Hz, 1H), 8.51 (d, J=1.6Hz, 1H), 7.96 (dd, J=8.3,1.4Hz, 1H), 7.83 (d, J=8.0Hz, 1H), 7.68-7.61 (m, 2H), 7.52 (ddd, J=8.2, 6.9,1.3Hz, 1H), 7.45-7.31 (m, 4H), 7.27-7.22 (m, 2H), 2.63 (s, 3H).
Embodiment 3
The mixing being made of in right amount PEG-400 and 1- allyl -3- methyl imidazolium tetrafluoroborates is added into reactor (the two volume ratio is 1 to solvent:0.3) it, is then replaced twice with nitrogen so that be nitrogen atmosphere in reactor；Then it is added The upper formula (II) compound 2- bromo biphenyls of 100mmol, the upper formula (III) compound 1- vinyl naphthalenes of 400mmol, by 3mmolPdCl2 (dppf) and four acetonitrile copper of 12mmol hexafluorophosphoric acids composition composite catalyst, 20mmol ligand Ls 1 and 300mmol diisopropyls Ethanol amine is warming up to 80 DEG C, and reacts 8 hours at such a temperature under stirring.
After reaction, deionized water is added into reaction system, fully oscillation, washing, separates organic layer, spends again Ion water washing, separates organic layer；Organic layer is concentrated under reduced pressure, is removed, silica gel column chromatography on gained residue is with volume ratio 1:4 n-hexyl alcohol and the mixed solvent of chloroform are eluted as eluting solvent, are detected through TLC, and same composition is merged, and removing is washed Desolventizing obtains target compound 9- (naphthalene -1- bases) phenanthrene, yield 95.7%.
1H-NMR (300MHz, CDCl3)δ:8.82 (d, J=8.2Hz, 2H), 8.61 (s, 1H), 8.02-7.95 (m, 2H), 7.83 (d, J=8.0Hz, 1H), 7.74 (s, 1H), 7.65-7.31 (m, 9H).
Embodiment 4
The mixing being made of in right amount PEG-400 and 1- allyl -3- methyl imidazolium tetrafluoroborates is added into reactor (the two volume ratio is 1 to solvent:0.2) it, is then replaced twice with nitrogen so that be nitrogen atmosphere in reactor；Then it is added The upper formula (II) compound 2- bromo biphenyls of 100mmol, the upper formula (III) compound 2- vinylpyridines of 300mmol, by 2mmolPdCl2 (dppf) and four acetonitrile copper of 6mmol hexafluorophosphoric acids composition composite catalyst, 20mmol ligand Ls 1 and 200mmol diisopropyl second Hydramine is warming up to 70 DEG C, and reacts 12 hours at such a temperature under stirring.
After reaction, deionized water is added into reaction system, fully oscillation, washing, separates organic layer, spends again Ion water washing, separates organic layer；Organic layer is concentrated under reduced pressure, is removed, silica gel column chromatography on gained residue is with volume ratio 1:3 n-hexyl alcohol and the mixed solvent of chloroform are eluted as eluting solvent, are detected through TLC, and same composition is merged, and removing is washed Desolventizing obtains target compound 9- (pyridine -2- bases) phenanthrene, yield 94.9%.
1H-NMR (300MHz, CDCl3)δ:8.83 (d, J=4.9Hz, 1H), 8.76 (dd, J=8.3,1.3Hz, 1H), 8.57-8.51 (m, 1H), 8.07 (dd, J=8.2,1.4Hz, 1H), 7.89-7.83 (m, 3H), 7.71-7.62 (m, 2H), 7.58-7.52 (m, 1H), 7.45 (dd, J=8.1Hz, 1.6Hz, 1H), 7.41-7.35 (m, 2H).
Embodiment 5-28：The investigation of palladium catalyst compound component
Embodiment 5-8：Except respectively by PdCl therein2(dppf) acid chloride (Pd (OAc) 2) is replaced with outside, other operations It is constant, embodiment 5-8 is implemented with the same way with embodiment 1-4.
Embodiment 9-12：Except respectively by PdCl therein2(dppf) palladium bichloride (PdCl2) is replaced with outside, other operations are equal It is constant, embodiment 9-12 is implemented with the same way with embodiment 1-4.
Embodiment 13-16：Except respectively by PdCl therein2(dppf) palladium acetylacetonate (Pd (acac) is replaced with2) outside, Its operation is constant, and embodiment 13-16 is implemented with the same way with embodiment 1-4.
Embodiment 17-20：Except respectively by PdCl therein2(dppf) (1,5- cyclo-octadiene) palladium bichloride (PdCl is replaced with2 (cod)) outside, other operations are constant, and embodiment 17-20 is implemented with the same way with embodiment 1-4.
Embodiment 21-24：Except respectively by PdCl therein2(dppf) palladium trifluoroacetate (Pd (TFA) is replaced with2) outside, it is other Operation is constant, and embodiment 21-24 is implemented with the same way with embodiment 1-4.
Embodiment 25-28：Except respectively by PdCl therein2(dppf) two (triphenylphosphine) palladium bichloride (PdCl2 are replaced with (PPh3)2) outside, other operations are constant, and embodiment 25-28 is implemented with the same way with embodiment 1-4.
The yield of products therefrom is as shown in table 1 below：
Table 1：The investigation of palladium compound component
It can be seen that working as the PdCl in composite catalyst2(dppf) when replacing with other palladium compounds, lead to yield It is greatly lowered, this demonstrate that PdCl2(dppf) there can be best catalytic effect together with four acetonitrile copper of hexafluorophosphoric acid.
Embodiment 29-40：The investigation of catalyst copper compound component
Embodiment 29-32：Except four acetonitrile copper of hexafluorophosphoric acid therein is replaced with copper trifluoromethanesulfcomposite (Cu respectively (OTf)2) outside, other operations are constant, and embodiment 29-32 is implemented with the same way with embodiment 1-4.
Embodiment 33-36：Except four acetonitrile copper of hexafluorophosphoric acid therein is replaced with acetylacetone copper (Cu (acac) respectively2) Outside, other operations are constant, and embodiment 33-36 is implemented with the same way with embodiment 1-4.
Embodiment 37-40：In addition to four acetonitrile copper of hexafluorophosphoric acid therein is replaced with copper acetate respectively, other operations are not Become, embodiment 37-40 is implemented with the same way with embodiment 1-4.
The yield of products therefrom is as shown in table 2 below：
Table 2：The investigation of copper compound component
It can be seen that when the four acetonitrile copper of hexafluorophosphoric acid in composite catalyst is replaced with other copper compounds, lead Yield is caused to be greatly lowered, this demonstrate that four acetonitrile copper of hexafluorophosphoric acid can be with PdCl2(dppf) best catalysis is played together Effect.
Embodiment 41-52：The investigation of organic ligand
Embodiment 41-44：In addition to organic ligand therein is replaced with L2 by L1 respectively, it is other operation it is constant, with The same way of embodiment 1-4 implements embodiment 41-44.
Embodiment 45-48：In addition to organic ligand therein is replaced with L3 by L1 respectively, it is other operation it is constant, with The same way of embodiment 1-4 implements embodiment 45-48.
Embodiment 49-52：In addition to organic ligand therein is replaced with L4 by L1 respectively, it is other operation it is constant, with The same way of embodiment 1-4 implements embodiment 49-52.
The yield of products therefrom is as shown in table 3 below：
Table 3：The investigation of organic ligand
It can be seen that in all ligands, L1 has best reaction effect, even very similar with L1 structures L2, yield also have comparable reduction.
Embodiment 53-64：The investigation of alkali
In addition to alkali therein is replaced with other alkali by diisopropyl ethanolamine, it is other constant and with embodiment 1-4's Same way implements embodiment 53-64, and institute see the table below 4 using alkali, correspondence and products collection efficiency：
Table 4：The investigation of alkali
It can be seen that when using other alkali when, yield is caused to be greatly lowered, even with institute in embodiment 1-4 Using the very similar diisopropylamine of diisopropyl ethanolamine, yield also has significant decrease.
Embodiment 65-72：The investigation of solvent
Embodiment 65-68：The mixed solvent in embodiment 1-4 is replaced with into PEG-400 respectively, it is other constant, and obtain Embodiment 65-68 is arrived.
Embodiment 69-72：The mixed solvent in embodiment 1-4 is replaced with into 1- allyl -3- methylimidazole tetrafluoros respectively Borate, it is other constant, and obtained embodiment 69-72.
The yield of products therefrom is as shown in table 5 below：
Table 5：The investigation of solvent
It can be seen that when using the solvent of one-component, yield has comparable reduction, only uses the composition of the two When, the excellent effect of the present invention could be obtained.
Embodiment 73-80：The investigation of single catalyst component
Embodiment 73-76：Composite catalyst in embodiment 1-4 is replaced with to the PdCl of same amount respectively2(dppf), That is PdCl2(dppf) dosage is total dosage of original two kinds of components, and has obtained embodiment 73-76.
Embodiment 77-80：Composite catalyst in embodiment 1-4 is replaced with to the hexafluorophosphoric acid tetrem of same amount respectively Nitrile copper, the i.e. dosage of four acetonitrile copper of hexafluorophosphoric acid are total dosage of original two kinds of components, and have obtained embodiment 77-80.
The yield of products therefrom is as shown in table 6 below：
Table 6：The investigation of single catalyst component
It can be seen that when using one-component catalyst, yield has comparable reduction, only uses the two mixture When, unique synergistic effect has been played between each other, and to achieve the excellent catalytic effect of the present invention, this is non-obvious 's.
In conclusion the present invention provides a kind of synthetic methods of medicine intermediate phenanthrene compound to pass through in the method Comprehensive selection and/or the collaboration of catalyst, organic ligand, alkali and solvent to obtain purpose product with high yield, and are worked as and are changed When becoming any type component or being omitted, products collection efficiency is caused to have significant decrease.It can be seen that the method tool of the present invention There is good, extensive commercial application potentiality, can be applied to the synthesis field of medicine intermediate.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limitation protection model of the invention It encloses.In addition, it should also be understood that, after reading the technical contents of the present invention, those skilled in the art can make the present invention each Kind change, modification and/or variation, all these equivalent forms equally fall within and are protected defined by the application the appended claims Within the scope of shield.

Claims (6)

1. a kind of method that phenanthrene compound shown in lower formula (I) is synthesized under sodium carbonate environment,
The method includes：Under inert atmosphere, in the presence of catalyst, organic ligand and alkali, in solvent, lower formula (II) chemical combination Object reacts with formula (III) compound, to obtain formula (I) compound；
Wherein, R1、R2It is each independently H, C1-C6Alkyl, C1-C6Alkoxy or halogen；
R3For C6-C10Aryl or C5-C8Heteroaryl, the C6-C10Aryl or C5-C8Heteroaryl is optionally replaced by 1-3 substituent group, The substituent group is C1-C6Alkyl or halogen；
The catalyst is the mixture of organic palladium compound and organocopper compound, and the molar ratio of the two is 1:2-4, wherein Organic palladium compound is PdCl2(dppf), the organocopper compound is four acetonitrile copper of hexafluorophosphoric acid；
The organic ligand is following L1：
The alkali is Na2CO3；
The solvent is the mixture of PEG-400 and 1- allyl -3- methyl imidazolium tetrafluoroborates, and the two volume ratio is 1: 0.1-0.3。
2. the method for the synthesis according to claim 1 phenanthrene compound, which is characterized in that formula (II) compound with The molar ratio of formula (III) compound is 1:2-4.
3. the method for the synthesis according to claim 1 phenanthrene compound, which is characterized in that formula (II) compound with The molar ratio of catalyst is 1:0.08-0.15.
4. the method for the synthesis according to claim 1 phenanthrene compound, which is characterized in that formula (II) compound with The molar ratio of organic ligand is 1:0.1-0.2.
5. the method for the synthesis according to claim 1 phenanthrene compound, which is characterized in that formula (II) compound with The molar ratio of alkali is 1:2-3.
6. the method for the synthesis phenanthrene compound according to claim 1, which is characterized in that reaction temperature is 60-80 DEG C； Reaction time is 8-12 hours.
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Copper-Catalyzed Oxytrifluoromethylation of Unactivated Alkenes;Rong Zhu等;《Journal of the American chemical society》;20120717;第134卷(第30期);第12463页table 1 *
Palladium-catalyzed double cross-coupling reaction of 1,2-bis(pinacolatoboryl)alkenes and –arenes with 2,2’-dibromobiaryls: annulative approach to functionalized polycyclic aromatic hydrocarbons;Masaki Shimizu等;《Tetrahedron》;20110812;第67卷(第41期);第8016页table 2 *

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