CN105646116A - Method for synthesizing medical intermediate phenanthrene compound from palladium chloride - Google Patents

Method for synthesizing medical intermediate phenanthrene compound from palladium chloride Download PDF

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CN105646116A
CN105646116A CN201610216416.6A CN201610216416A CN105646116A CN 105646116 A CN105646116 A CN 105646116A CN 201610216416 A CN201610216416 A CN 201610216416A CN 105646116 A CN105646116 A CN 105646116A
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翟学研
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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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Abstract

The invention relates to a method for synthesizing a phenanthrene compound from palladium chloride, and the phenanthrene compound is as shown in the formula (I) in the specification. The method comprises the following steps: in inert gas atmosphere and in the presence of a catalyst containing palladium chloride, an organic ligand and alkali, enabling a compound as shown in the formula (II) and a compound as shown in the formula (III) to react in a solvent, thereby obtaining the compound as shown in the formula (I), wherein R1 and R2 are independently H, C1-C6 alkyl groups, C1-C6 alkoxy groups or halogen; R3 is C6-C10 aryl group or C5-C8 ceteroary; C6-C10 aryl groups or C4-C8 ceteroary are randomly substituted by 1-3 substituent groups; the substituent groups are C1-C6 alkyl groups or halogen. Due to selection of the appropriate catalyst, organic ligand, alkali and the solvent, a good effect is achieved, and the method is wide in industrial application prospect.

Description

A kind of method applying Palladous chloride. synthesis medicine intermediate phenanthrene compound
The present patent application is the divisional application of the patent application that application number is 201510100568.5 (synthetic methods of a kind of medicine intermediate phenanthrene compounds) of application on March 6th, 2015.
Technical field
The present invention relates to the synthetic method of a kind of fused ring compound, relate more specifically to a kind of method applying Palladous chloride. synthesis medicine intermediate phenanthrene compound, belong to organic synthesis and medicine intermediate synthesis field.
Background technology
The fused ring compound such as compound such as naphthalene, anthracene, phenanthrene receives attention and the concern of medicine research staff due to its ubiquitous biological activity. Wherein, luxuriant and rich with fragrance and derivant is the phenolic compound that a class is important, has been widely used in drug design and synthesis, material development field.
Just because of such excellent in performance and the potentiality of phenanthrene compound, thus luxuriant and rich with fragrance and derivant the novel method for synthesizing of research be also always up organic chemical synthesis worker hot issue very deeply concerned.
Up to the present, having there is the preparation technology of multiple phenanthrene compound in prior art, it have studied, from multiple angles, the synthetic method that phenanthrene compound is suitable for. Such as:
XiaoTiebo etc. (" PhenanthreneSynthesisbyEosinY-Catalyzed; VisibleLight-Induced [4+2] BenzannulationofBiaryldiazoniumSaltswithAlkynes ", Adv.Synth.Catal., 2012,354,3195-3199) a kind of [4+2] benzo cyclization without metal catalytic, visible light-inducing diaryl diazo salt is reported. Its equation is as follows:
YeFei etc. (" ExpeditiousSynthesisofPhenanthrenesviaCuBr2-CatalyzedCou plingofTerminalAlkynesandN-TosylhydrazonesDerivedfromO-F ormylBiphenyls "; OrganicLetters; 2011; 13; 5020-5023) disclose the coupling/cyclization of a kind of benzyl CuBr2 catalysis; its N-Tosylhydrazone being derived from adjacent formyl biphenyl is raw material, and reaction equation is as follows:
KwonYongseok etc. (" ExpedientSynthesisofPhenanthrenesviaIn (III)-Catalyzed6-Exo-DigCycloisomerization ", OrganicLetters, 2013,15,920-923) report the reaction preparing phenanthrene compound of a kind of In (III) catalysis, its have reaction efficiently, the advantage of wide application range of substrates, its reaction equation is as follows:
As mentioned above, although the preparation method having been disclosed for various types of phenanthrene compound in prior art, but these methods still can not meet the Production requirement in medicine, chemical industry synthesis field, and this is due to problems such as its intrinsic production efficiency are low, raw material can not make full use of.
In view of this, the present inventor has aimed to provide the new catalytic synthetic method of a kind of phenanthrene compound by substantial amounts of experimentation, has reached yield purpose high, willing, has had prospects for commercial application very widely.
Summary of the invention
For many defects of above-mentioned existence, the present inventor is after having paid substantial amounts of creative work, through further investigation, and develops the synthetic method of a kind of phenanthrene compound that can be used as pharmaceutical intermediate, and then completes the present invention.
Specifically, the invention provides the synthetic method of phenanthrene compound shown in a kind of following formula (I),
Described method includes: under inert atmosphere, and under catalyst, organic ligand and alkali exist, in solvent, following formula (II) compound and formula (III) compound react, thus obtaining formula (I) compound;
Wherein, R1��R2It is each independently H, C1-C6Alkyl, C1-C6Alkoxy or halogen;
R3For C6-C10Aryl or C5-C8Heteroaryl, described C6-C10Aryl or C4-C8Heteroaryl is optionally replaced by 1-3 substituent group, for instance can be replaced by 1,2 or 3 substituent groups, and described substituent group is C1-C6Alkyl or halogen.
In the described synthetic method of the present invention, C1-C6Alkyl refers to the alkyl with 1-6 carbon atom, for instance can be methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, n-hexyl etc.
In the described synthetic method of the present invention, C1-C6Alkoxyl refers to " C defined above1-C6Alkyl " be connected with O atom after group.
In the described synthetic method of the present invention, described halogen can be such as fluorine, chlorine, bromine or iodine.
In the described synthetic method of the present invention, described C6-C10Aryl refers to the aryl with 6-10 carbon atom, for instance can be phenyl or naphthyl.
In the described synthetic method of the present invention, described C4-C8Heteroaryl refers to the heteroaryl with 4-8 carbon atom, for instance can be pyridine radicals, furan thiophene base or thienyl etc.
In the described synthetic method of the present invention, described catalyst is the mixture of organic palladium compound and organocopper compound, and both mol ratios are 1:2-4, for instance can be 1:2,1:3 or 1:4.
Wherein, described organic palladium compound example is acid chloride (Pd (OAc)2), Palladous chloride. (PdCl2), palladium acetylacetonate (Pd (acac)2), (1,5-cyclo-octadiene) Palladous chloride. (PdCl2(cod)), palladium trifluoroacetate (Pd (TFA)2), [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (PdCl2(dppf)), two (triphenylphosphine) Palladous chloride. (PdCl2(PPh3)2) in any or any multiple mixture, it is most preferred that for PdCl2(dppf)��
Wherein, described organocopper compound is hexafluorophosphoric acid four acetonitrile copper ([(CH3CN)4Cu]PF6), copper trifluoromethanesulfcomposite (Cu (OTf)2), acetylacetone copper (Cu (acac)2), in copper acetate any one or multiple, it is most preferred that for hexafluorophosphoric acid four acetonitrile copper ([(CH3CN)4Cu]PF6)��
In the described synthetic method of the present invention, described organic ligand is nitrogenous bidentate ligand, for instance can be substituted or unsubstituted bipyridyl, substituted or unsubstituted Phen etc., for instance can be following L1-L4:
It most preferably is L1.
In the described synthetic method of the present invention, described alkali is Na2CO3��K2CO3��NaOH��KOH��K3PO4��Na3PO4��NaHCO3��KHCO3, sodium acetate, Sodium ethylate, potassium tert-butoxide, diisopropylamine, any or any multiple mixture in diisopropyl ethanolamine etc.; It most preferably is diisopropyl ethanolamine.
In the described synthetic method of the present invention, described solvent is the mixture of PEG-400 and 1-pi-allyl-3-methyl imidazolium tetrafluoroborate, and both volume ratios are 1:0.1-0.3, for instance can be 1:0.1,1:0.2 or 1:0.3.
In the described synthetic method of the present invention, described inert atmosphere can be such as nitrogen atmosphere or argon atmosphere.
In the described synthetic method of the present invention, the mol ratio of described formula (II) compound and formula (III) compound is 1:2-4, for instance can be 1:2,1:3 or 1:4.
In the described synthetic method of the present invention, the mol ratio of described formula (II) compound and catalyst is 1:0.08-0.15, namely the mole dosage of described formula (II) compound is 1:0.08-0.15 with the ratio of the mole dosage sum of the two kinds of components constituting described catalyst, for instance can be 1:0.08,1:0.1,1:0.12,1:0.14 or 1:0.15.
In the described synthetic method of the present invention, the mol ratio of described formula (II) compound and organic ligand is 1:0.1-0.2, for instance can be 1:0.1,1:0.15 or 1:0.2.
In the described synthetic method of the present invention, the mol ratio of described formula (II) compound and alkali is 1:2-3, for instance can be 1:2,1:2.5 or 1:3.
In the described synthetic method of the present invention, the consumption of described solvent does not have strict restriction, and its consumption can be carried out suitable selection by those skilled in the art, for instance can according to making post processing be prone to carry out, be enough to react to be smoothed out.
In the described synthetic method of the present invention, reaction temperature is 60-80 DEG C, for instance can be 60 DEG C, 70 DEG C or 80 DEG C.
In the described synthetic method of the present invention, the response time is 8-12 hour, for instance can be 8 hours, 10 hours or 12 hours.
In the described synthetic method of the present invention, react the post processing after terminating specific as follows: after reaction terminates, in reaction system, add deionized water, fully vibrate, wash, separate organic layer, again with deionized water wash, separate organic layer; By organic layer concentrating under reduced pressure, remove, silica gel column chromatography on gained residue, carry out eluting using the mixed solvent of hexanol and chloroform that volume ratio is 1:2-4 as eluting solvent, detect through TLC, merge same composition, remove eluting solvent, obtain target compound.
As mentioned above, the invention provides the synthetic method of a kind of phenanthrene compound as medicine intermediate, described method by suitable catalyst, You Jipei, alkali and solvent selection/combination/work in coordination with, thus obtaining purpose product with high yield, the actual production of the intermediate such as medicine, chemical industry is of great advantage, there is prospects for commercial application widely.
Detailed description of the invention
Below by specific embodiment, the present invention is described in detail; but the purposes of these exemplary embodiments and purpose are only used for enumerating the present invention; not the real protection scope of the present invention is constituted any type of any restriction, more non-protection scope of the present invention is limited thereto.
Wherein, in all embodiments, unless otherwise prescribed, the ligand L 1 used is the above formula L1 part referred to.
Embodiment 1
In reactor, add the mixed solvent (both volume ratios are 1:0.1) being made up of PEG-400 and 1-pi-allyl-3-methyl imidazolium tetrafluoroborate in right amount, then replace twice with nitrogen so that be nitrogen atmosphere in reactor; Be subsequently adding the bromo-4 '-chlordiphenyl of 100mmol above formula (II) compound 2-, 200mmol above formula (III) compound styrene, by 3mmolPdCl2And the composite catalyst of 6mmol hexafluorophosphoric acid four acetonitrile copper composition, 10mmol ligand L 1 and 200mmol diisopropyl ethanolamine (dppf), 60 DEG C under stirring, it are warming up to, and reaction 12 hours at such a temperature.
After reaction terminates, in reaction system, add deionized water, fully vibration, washing, separate organic layer, again with deionized water wash, separate organic layer; By organic layer concentrating under reduced pressure, remove, silica gel column chromatography on gained residue, eluting is carried out as eluting solvent using the mixed solvent of hexanol and chloroform that volume ratio is 1:2, detect through TLC, merge same composition, remove eluting solvent, obtaining the chloro-10-phenyl of target compound 2-luxuriant and rich with fragrance, productivity is 95.3%.
1H-NMR (300MHz, CDCl3) ��: 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
In reactor, add the mixed solvent (both volume ratios are 1:0.2) being made up of PEG-400 and 1-pi-allyl-3-methyl imidazolium tetrafluoroborate in right amount, then replace twice with nitrogen so that be nitrogen atmosphere in reactor; Be subsequently adding 100mmol above formula (II) compound 2-bromo biphenyl, 300mmol above formula (III) compound 1-methyl-3-vinyl benzene, by 3mmolPdCl2And the composite catalyst of 9mmol hexafluorophosphoric acid four acetonitrile copper composition, 15mmol ligand L 1 and 250mmol diisopropyl ethanolamine (dppf), 70 DEG C under stirring, it are warming up to, and reaction 10 hours at such a temperature.
After reaction terminates, in reaction system, add deionized water, fully vibration, washing, separate organic layer, again with deionized water wash, separate organic layer; By organic layer concentrating under reduced pressure, remove, silica gel column chromatography on gained residue, eluting is carried out as eluting solvent using the mixed solvent of hexanol and chloroform that volume ratio is 1:3, detect through TLC, merge same composition, remove eluting solvent, obtaining tolyl between target compound 9-luxuriant and rich with fragrance, productivity is 94.7%.
1H-NMR (300MHz, CDCl3) ��: 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
In reactor, add the mixed solvent (both volume ratios are 1:0.3) being made up of PEG-400 and 1-pi-allyl-3-methyl imidazolium tetrafluoroborate in right amount, then replace twice with nitrogen so that be nitrogen atmosphere in reactor; Be subsequently adding 100mmol above formula (II) compound 2-bromo biphenyl, 400mmol above formula (III) compound 1-vinyl naphthalene, by 3mmolPdCl2And the composite catalyst of 12mmol hexafluorophosphoric acid four acetonitrile copper composition, 20mmol ligand L 1 and 300mmol diisopropyl ethanolamine (dppf), 80 DEG C under stirring, it are warming up to, and reaction 8 hours at such a temperature.
After reaction terminates, in reaction system, add deionized water, fully vibration, washing, separate organic layer, again with deionized water wash, separate organic layer; By organic layer concentrating under reduced pressure, remove, silica gel column chromatography on gained residue, eluting is carried out as eluting solvent using the mixed solvent of hexanol and chloroform that volume ratio is 1:4, detect through TLC, merge same composition, remove eluting solvent, obtaining target compound 9-(naphthalene-1-base) luxuriant and rich with fragrance, productivity is 95.7%.
1H-NMR (300MHz, CDCl3) ��: 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
In reactor, add the mixed solvent (both volume ratios are 1:0.2) being made up of PEG-400 and 1-pi-allyl-3-methyl imidazolium tetrafluoroborate in right amount, then replace twice with nitrogen so that be nitrogen atmosphere in reactor; Be subsequently adding 100mmol above formula (II) compound 2-bromo biphenyl, 300mmol above formula (III) compound 2-vinylpyridine, by 2mmolPdCl2And the composite catalyst of 6mmol hexafluorophosphoric acid four acetonitrile copper composition, 20mmol ligand L 1 and 200mmol diisopropyl ethanolamine (dppf), 70 DEG C under stirring, it are warming up to, and reaction 12 hours at such a temperature.
After reaction terminates, in reaction system, add deionized water, fully vibration, washing, separate organic layer, again with deionized water wash, separate organic layer; By organic layer concentrating under reduced pressure, remove, silica gel column chromatography on gained residue, eluting is carried out as eluting solvent using the mixed solvent of hexanol and chloroform that volume ratio is 1:3, detect through TLC, merge same composition, remove eluting solvent, obtaining target compound 9-(pyridine-2-base) luxuriant and rich with fragrance, productivity is 94.9%.
1H-NMR (300MHz, CDCl3) ��: 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) replacing with acid chloride (Pd (OAc) 2) outward, other operation is all constant, implements embodiment 5-8 with the same way with embodiment 1-4.
Embodiment 9-12: except respectively by PdCl therein2(dppf) replacing with Palladous chloride. (PdCl2) outward, other operation is all constant, implements embodiment 9-12 with the same way with embodiment 1-4.
Embodiment 13-16: except respectively by PdCl therein2(dppf) palladium acetylacetonate (Pd (acac) is replaced with2) outward, other operation is all constant, implements embodiment 13-16 with the same way with embodiment 1-4.
Embodiment 17-20: except respectively by PdCl therein2(dppf) (1,5-cyclo-octadiene) Palladous chloride. (PdCl is replaced with2(cod)) outward, other operation is all constant, implements embodiment 17-20 with the same way with embodiment 1-4.
Embodiment 21-24: except respectively by PdCl therein2(dppf) palladium trifluoroacetate (Pd (TFA) is replaced with2) outward, other operation is all constant, implements embodiment 21-24 with the same way with embodiment 1-4.
Embodiment 25-28: except respectively by PdCl therein2(dppf) two (triphenylphosphine) Palladous chloride. (PdCl2 (PPh3) is replaced with2) outward, other operation is all constant, implements embodiment 25-28 with the same way with embodiment 1-4.
The productivity of products therefrom is as shown in table 1 below:
Table 1: the investigation of palladium compound component
As can be seen here, when by the PdCl in composite catalyst2(dppf), when replacing with other palladium compound, all cause that productivity is greatly lowered, and this demonstrate that PdCl2(dppf) can have best catalytic effect together with hexafluorophosphoric acid four acetonitrile copper.
Embodiment 29-40: the investigation of catalyst copper compound component
Embodiment 29-32: except respectively hexafluorophosphoric acid four acetonitrile copper therein being replaced with copper trifluoromethanesulfcomposite (Cu (OTf)2) outward, other operation is all constant, implements embodiment 29-32 with the same way with embodiment 1-4.
Embodiment 33-36: except respectively hexafluorophosphoric acid four acetonitrile copper therein being replaced with acetylacetone copper (Cu (acac)2) outward, other operation is all constant, implements embodiment 33-36 with the same way with embodiment 1-4.
Embodiment 37-40: except respectively hexafluorophosphoric acid four acetonitrile copper therein being replaced with copper acetate, other operation is all constant, implements embodiment 37-40 with the same way with embodiment 1-4.
The productivity of products therefrom is as shown in table 2 below:
Table 2: the investigation of copper compound component
As can be seen here, when the hexafluorophosphoric acid four acetonitrile copper in composite catalyst is replaced with other copper compound, all cause that productivity is greatly lowered, this demonstrate that hexafluorophosphoric acid four acetonitrile copper can with PdCl2(dppf) best catalytic effect is played together.
Embodiment 41-52: the investigation of organic ligand
Embodiment 41-44: except respectively organic ligand therein being replaced with L2 by L1, other operation is all constant, implements embodiment 41-44 with the same way with embodiment 1-4.
Embodiment 45-48: except respectively organic ligand therein being replaced with L3 by L1, other operation is all constant, implements embodiment 45-48 with the same way with embodiment 1-4.
Embodiment 49-52: except respectively organic ligand therein being replaced with L4 by L1, other operation is all constant, implements embodiment 49-52 with the same way with embodiment 1-4.
The productivity of products therefrom is as shown in table 3 below:
Table 3: the investigation of organic ligand
As can be seen here, in all of part, L1 has best reaction effect, even if the L2 very similar with L1 structure, its productivity also has suitable reduction.
Embodiment 53-64: the investigation of alkali
Except alkali therein is replaced with other alkali by diisopropyl ethanolamine, other all constant and with embodiment 1-4 same way implements embodiment 53-64, and used alkali, corresponding relation and products collection efficiency are shown in table 4 below:
Table 4: the investigation of alkali
As can be seen here, when using other alkali, all causing that productivity is greatly lowered, even if the diisopropylamine that diisopropyl ethanolamine used with embodiment 1-4 is very similar, its productivity also significantly reduces.
Embodiment 65-72: the investigation of solvent
Embodiment 65-68: respectively the mixed solvent in embodiment 1-4 is replaced with PEG-400, other is all constant, and obtains embodiment 65-68.
Embodiment 69-72: the mixed solvent in embodiment 1-4 replaces with 1-pi-allyl-3-methyl imidazolium tetrafluoroborate respectively, and other is all constant, and obtains embodiment 69-72.
The productivity of products therefrom is as shown in table 5 below:
Table 5: the investigation of solvent
As can be seen here, when using the solvent of one-component, productivity has suitable reduction, when only using both compositionss, could obtain the excellent effect of the present invention.
Embodiment 73-80: the investigation of single catalyst component
Embodiment 73-76: respectively the composite catalyst in embodiment 1-4 is replaced with the PdCl of same amount2(dppf), i.e. PdCl2(dppf) consumption is total consumption of original two kinds of components, and obtains embodiment 73-76.
Embodiment 77-80: the composite catalyst in embodiment 1-4 replaces with the hexafluorophosphoric acid four acetonitrile copper of same amount respectively, and namely the consumption of hexafluorophosphoric acid four acetonitrile copper is total consumption of original two kinds of components, and obtains embodiment 77-80.
The productivity of products therefrom is as shown in table 6 below:
Table 6: the investigation of single catalyst component
As can be seen here, when using one-component catalyst, productivity has suitable reduction, when only using both mixture, has played the synergism of uniqueness each other, thus achieving the excellent catalytic effect of the present invention, this is non-obvious.
In sum, the invention provides the synthetic method of a kind of medicine intermediate phenanthrene compound, in the method, by the combined selection of catalyst, organic ligand, alkali and solvent and/or collaborative, thus obtaining purpose product with high yield, and when changing any component or being omitted, all cause that products collection efficiency significantly reduces. As can be seen here, the method for the present invention has good, commercial Application potentiality widely, can be applicable to the synthesis field of medicine intermediate.
Should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limit the scope of the invention. In addition; it is also contemplated that; after the technology contents having read the present invention, the present invention can be made various change, amendment and/or modification by those skilled in the art, and all these equivalent form of value falls within the application appended claims protection defined equally.

Claims (7)

1. a method for phenanthrene compound shown in application Palladous chloride. synthesis following formula (I),
Described method includes: under inert atmosphere, and under catalyst, organic ligand and alkali exist, in solvent, following formula (II) compound and formula (III) compound react, thus obtaining formula (I) compound;
Wherein, R1��R2It is each independently H, C1-C6Alkyl, C1-C6Alkoxy or halogen;
R3 is C6-C10Aryl or C5-C8Heteroaryl, described C6-C10Aryl or C4-C8Heteroaryl is optionally replaced by 1-3 substituent group, and described substituent group is C1-C6Alkyl or halogen;
Described catalyst is the mixture of organic palladium compound and organocopper compound, and both mol ratios are 1:2-4, and wherein, described organic palladium compound is PdCl2, described organocopper compound is hexafluorophosphoric acid four acetonitrile copper;
Described organic ligand is the one in following L1-L4:
Described alkali is diisopropyl ethanolamine;
Described solvent is the mixture of PEG-400 and 1-pi-allyl-3-methyl imidazolium tetrafluoroborate, and both volume ratios are 1:0.1-0.3.
2. the method for the described phenanthrene compound of synthesis according to claim 1, it is characterised in that described organic ligand is L1.
3. the method for the described phenanthrene compound of synthesis according to claim 1 and 2, it is characterised in that the mol ratio of described formula (II) compound and formula (III) compound is 1:2-4.
4. the method for the described phenanthrene compound of synthesis according to claim 1 and 2, it is characterised in that the mol ratio of described formula (II) compound and catalyst is 1:0.08-0.15.
5. the method for the described phenanthrene compound of synthesis according to claim 1 and 2, it is characterised in that the mol ratio of described formula (II) compound and organic ligand is 1:0.1-0.2.
6. the method for the described phenanthrene compound of synthesis according to claim 1 and 2, it is characterised in that the mol ratio of described formula (II) compound and alkali is 1:2-3.
7. the method for the described phenanthrene compound of synthesis according to claim 1 and 2, it is characterised in that reaction temperature is 60-80 DEG C; Response time is 8-12 hour.
CN201610216416.6A 2015-03-06 2015-03-06 Method for synthesizing medical intermediate phenanthrene compound from palladium chloride Withdrawn CN105646116A (en)

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Application publication date: 20160608