CN105801340A - Method for synthesizing pharmaceutical intermediate phenanthrene compound in sodium phosphate environment - Google Patents

Method for synthesizing pharmaceutical intermediate phenanthrene compound in sodium phosphate environment Download PDF

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CN105801340A
CN105801340A CN201610216435.9A CN201610216435A CN105801340A CN 105801340 A CN105801340 A CN 105801340A CN 201610216435 A CN201610216435 A CN 201610216435A CN 105801340 A CN105801340 A CN 105801340A
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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
    • C07C2/86—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by condensation between a hydrocarbon and a non-hydrocarbon
    • C07C2/861—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by condensation between a hydrocarbon and a non-hydrocarbon the non-hydrocarbon contains only halogen as hetero-atoms
    • 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 pharmaceutical intermediate phenanthrene compound shown in formula (I) in a sodium phosphate environment. The method comprises steps as follows: in the inert atmosphere, in the presence of a catalyst, an organic ligand and sodium phosphate, a compound shown in formula (II) reacts with a compound shown in formula (III) in a solvent, so that the compound shown in formula (I) is obtained, wherein R1 and R2 are independently H, C1-C6 alkyl groups, C1-C6 alkoxy groups or halogen; R3 is C6-C10 aryl groups or C5-C8 heterocyclic aryl groups, 1-3 substituent groups substitute for C6-C10 aryl groups or C4-C8 heterocyclic aryl groups optionally, and the substituent groups are C1-C6 alkyl groups or halogen. The method realizes a good effect through proper selection of the catalyst, the organic ligand, alkali and the solvent and has broad industrial application prospect.

Description

A kind of method synthesizing medicine intermediate phenanthrene compound under sodium phosphate environment
The present patent application is that (a kind of medicine intermediate is luxuriant and rich with fragrance for Application No. 201510100568.5 filed in 6 days March in 2015 The synthetic method of compounds) the divisional application of patent application.
Technical field
The present invention relates to the synthetic method of a kind 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 fused ring compound biological activity that such as compound such as naphthalene, anthracene, phenanthrene generally exists due to it and by medicine research and development people The attention of member and concern.Wherein, luxuriant and rich with fragrance and derivant is the phenolic compound that a class is important, has been widely used in medicine Thing design and synthesis, material development field.
Just because of such excellent in performance and the potentiality of phenanthrene compound, thus research is luxuriant and rich with fragrance and the novel synthesis side of derivant Method also be always organic chemical synthesis worker hot issue the most deeply concerned.
Up to the present, there is the preparation technology of multiple phenanthrene compound in prior art, it is studied from multiple angles The synthetic method that phenanthrene compound is suitable for.Such as:
(" Phenanthrene Synthesis by Eosin Y-Catalyzed, the 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 without 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 coupling/cyclisation that a kind of benzyl CuBr2 is catalyzed Reaction, its N-Tosylhydrazone being derived from adjacent formyl biphenyl is raw material, and reaction equation is as follows:
(" Expedient Synthesis of Phenanthrenes via In (the III)-C such as Kwon Yongseok Atalyzed 6-Exo-DigCycloisomerization ", Organic Letters, 2013,15,920-923) report The reaction preparing phenanthrene compound that a kind of In (III) is catalyzed, its have reaction efficiently, the advantage of wide application range of substrates, it is anti- Answer formula as follows:
Although as it has been described above, prior art has been disclosed for the preparation method of various types of phenanthrene compound, but these Method still can not meet medicine, the Production requirement in chemical industry synthesis field, this be owing to its intrinsic production efficiency is low, raw material not The problems such as can make full use of.
In view of this, the present inventor has aimed to provide the new catalytic of a kind of phenanthrene compound by substantial amounts of experimentation Synthetic method, has reached yield purpose high, willing, has had quite varied prospects for commercial application.
Summary of the invention
For many defects of above-mentioned existence, the present inventor is after having paid substantial amounts of creative work, through deeply grinding Study carefully, and develop the synthetic method of a kind of phenanthrene compound that can be used as pharmaceutical intermediate, and then complete the present invention.
Specifically, the invention provides the synthetic method of phenanthrene compound shown in a kind of lower formula (I),
Described method includes: under inert atmosphere, in the presence of catalyst, organic ligand and alkali, in solvent, and lower formula (II) Compound reacts with formula (III) compound, thus obtains 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 by 1-3 substituent group Replacing, such as, can be replaced by 1,2 or 3 substituent groups, 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, such as, can be first Base, 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 " with O atom phase Group after Lian.
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, such as It 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, example As being pyridine radicals, furan thiophene base or thienyl etc..
In the described synthetic method of the present invention, described catalyst is the mixing of organic palladium compound and organocopper compound Thing, both mol ratios are 1:2-4, such as, 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-(diphenyl Phosphino-) ferrocene] palladium chloride (PdCl2(dppf)), two (triphenylphosphine) Palladous chloride. (PdCl2(PPh3)2Any one of) Or any multiple mixture, most preferably 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), any one or more in copper acetate, most preferably hexafluorophosphoric acid tetrem Nitrile copper ([(CH3CN)4Cu]PF6)。
In the described synthetic method of the present invention, described organic ligand is nitrogenous bidentate ligand, can be such as replace or not Substituted bipyridyl, substituted or unsubstituted Phen etc., such as, can be following L1-L4:
Most preferably 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 one of diisopropyl ethanolamine etc. or Any multiple mixture；Most preferably diisopropyl ethanolamine.
In the described synthetic method of the present invention, described solvent is PEG-400 Yu 1-pi-allyl-3-Methylimidazole. tetrafluoro boron The mixture of hydrochlorate, both volume ratios are 1:0.1-0.3, such as, 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, described formula (II) compound is 1 with the mol ratio of formula (III) compound: 2-4, such as, can be 1:2,1:3 or 1:4.
In the described synthetic method of the present invention, described formula (II) compound is 1:0.08-with the mol ratio of catalyst 0.15, the ratio of mole dosage sum of the mole dosage of the most described formula (II) compound and the two kinds of components constituting described catalyst For 1:0.08-0.15, such as, 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, described formula (II) compound is 1:0.1-with the mol ratio of organic ligand 0.2, can be such as 1:0.1,1:0.15 or 1:0.2.
In the described synthetic method of the present invention, described formula (II) compound is 1:2-3 with the mol ratio of alkali, such as, 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 has strict restriction, people in the art Its consumption can suitably be selected by member, such as, can be smoothed out according to making post processing be prone to carry out, be enough to react.
In the described synthetic method of the present invention, reaction temperature is 60-80 DEG C, such as, 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, such as, can be 8 hours, 10 hours or 12 Hour.
In the described synthetic method of the present invention, the post processing after reaction terminates is specific as follows: after reaction terminates, to reaction System adds deionized water, fully vibration, washing, separates organic layer, be again washed with deionized, separate organic layer；Will Organic layer concentrating under reduced pressure, removes, silica gel column chromatography on gained residue, and the hexanol with volume ratio as 1:2-4 is mixed with chloroform Bonding solvent carries out eluting as eluting solvent, detects through TLC, merges same composition, removes eluting solvent, obtains target chemical combination Thing.
As it has been described above, the invention provides the synthetic method of a kind of phenanthrene compound as medicine intermediate, described method By the selection/combination of suitable catalyst, You Jipei, alkali and solvent/collaborative, thus obtain purpose product with high yield, right The actual production of the intermediate such as medicine, chemical industry is of great advantage, has 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 is only used for enumerating the present invention, and not the real protection scope to the present invention constitutes any type of any restriction, more non-general Protection scope of the present invention is confined to this.
Wherein, in all embodiments, unless otherwise prescribed, what the ligand L 1 used was that above formula L1 referred to joins Body.
Embodiment 1
The mixing being made up of in right amount is added PEG-400 with 1-pi-allyl-3-methyl imidazolium tetrafluoroborate in reactor Solvent (both volume ratios are 1:0.1), then replaces twice with nitrogen so that be nitrogen atmosphere in reactor；It is subsequently adding 100mmol upper the formula (II) bromo-4 '-chlordiphenyl of compound 2-, 200mmol upper formula (III) compound styrene, by 3mmolPdCl2 (dppf) and 6mmol hexafluorophosphoric acid four acetonitrile copper composition composite catalyst, 10mmol ligand L 1 and 200mmol diisopropyl second Hydramine, is warming up to 60 DEG C under stirring, and reaction 12 hours at such a temperature.
After reaction terminates, in reaction system, add deionized water, fully vibration, washing, separate organic layer, again spend Ionized water washs, and separates organic layer；By organic layer concentrating under reduced pressure, remove, silica gel column chromatography on gained residue, with volume ratio be The hexanol of 1:2 and the mixed solvent of chloroform carry out eluting as eluting solvent, detect through TLC, merge same composition, and removing is washed Desolventizing, obtains target compound 2-chloro-10-phenyl luxuriant and rich with fragrance, and productivity is 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 up of in right amount is added PEG-400 with 1-pi-allyl-3-methyl imidazolium tetrafluoroborate in reactor Solvent (both volume ratios are 1:0.2), then replaces twice with nitrogen so that be nitrogen atmosphere in reactor；It is subsequently adding 100mmol upper formula (II) compound 2-bromo biphenyl, 300mmol upper formula (III) compound 1-methyl-3-vinyl benzene, by 3mmolPdCl2(dppf) and 9mmol hexafluorophosphoric acid four acetonitrile copper composition composite catalyst, 15mmol ligand L 1 and 250mmol Diisopropyl ethanolamine, is warming up to 70 DEG C under stirring, and reaction 10 hours at such a temperature.
After reaction terminates, in reaction system, add deionized water, fully vibration, washing, separate organic layer, again spend Ionized water washs, and separates organic layer；By organic layer concentrating under reduced pressure, remove, silica gel column chromatography on gained residue, with volume ratio be The hexanol of 1:3 and the mixed solvent of chloroform carry out eluting as eluting solvent, detect through TLC, merge same composition, and removing is washed Desolventizing, obtains tolyl between target compound 9-luxuriant and rich with fragrance, and productivity is 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 up of in right amount is added PEG-400 with 1-pi-allyl-3-methyl imidazolium tetrafluoroborate in reactor Solvent (both volume ratios are 1:0.3), then replaces twice with nitrogen so that be nitrogen atmosphere in reactor；It is subsequently adding 100mmol upper formula (II) compound 2-bromo biphenyl, 400mmol upper formula (III) compound 1-vinyl naphthalene, by 3mmolPdCl2 (dppf) and 12mmol hexafluorophosphoric acid four acetonitrile copper composition composite catalyst, 20mmol ligand L 1 and 300mmol diisopropyl Ethanolamine, is warming up to 80 DEG C under stirring, and reaction 8 hours at such a temperature.
After reaction terminates, in reaction system, add deionized water, fully vibration, washing, separate organic layer, again spend Ionized water washs, and separates organic layer；By organic layer concentrating under reduced pressure, remove, silica gel column chromatography on gained residue, with volume ratio be The hexanol of 1:4 and the mixed solvent of chloroform carry out eluting as eluting solvent, detect through TLC, merge same composition, and removing is washed Desolventizing, obtains target compound 9-(naphthalene-1-base) luxuriant and rich with fragrance, and productivity is 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 up of in right amount is added PEG-400 with 1-pi-allyl-3-methyl imidazolium tetrafluoroborate in reactor Solvent (both volume ratios are 1:0.2), then replaces twice with nitrogen so that be nitrogen atmosphere in reactor；It is subsequently adding 100mmol upper formula (II) compound 2-bromo biphenyl, 300mmol upper formula (III) compound 2-vinylpyridine, by 2mmolPdCl2 (dppf) and 6mmol hexafluorophosphoric acid four acetonitrile copper composition composite catalyst, 20mmol ligand L 1 and 200mmol diisopropyl second Hydramine, is warming up to 70 DEG C under stirring, and reaction 12 hours at such a temperature.
After reaction terminates, in reaction system, add deionized water, fully vibration, washing, separate organic layer, again spend Ionized water washs, and separates organic layer；By organic layer concentrating under reduced pressure, remove, silica gel column chromatography on gained residue, with volume ratio be The hexanol of 1:3 and the mixed solvent of chloroform carry out eluting as eluting solvent, detect through TLC, merge same composition, and removing is washed Desolventizing, obtains target compound 9-(pyridine-2-base) luxuriant and rich with fragrance, and productivity is 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 outward, other operation The most constant, implement 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, implement 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, its Its operation is the most 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 the most 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 Operate the most constant, implement 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 is replaced with (PPh3)2) outward, other operation is the most 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, productivity is all caused It is greatly lowered, 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 the most 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 the most constant, implements embodiment 33-36 with the same way with embodiment 1-4.
Embodiment 37-40: in addition to respectively hexafluorophosphoric acid four acetonitrile copper therein being replaced with copper acetate, other operation is the most not Become, implement 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 lead Cause productivity to be greatly lowered, this demonstrate that hexafluorophosphoric acid four acetonitrile copper 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 respectively organic ligand therein being replaced with L2 by L1, other operation is the most constant, with The same way of embodiment 1-4 implements embodiment 41-44.
Embodiment 45-48: in addition to respectively organic ligand therein being replaced with L3 by L1, other operation is the most constant, with The same way of embodiment 1-4 implements embodiment 45-48.
Embodiment 49-52: in addition to respectively organic ligand therein being replaced with L4 by L1, other operation is the most constant, with The same way of embodiment 1-4 implements embodiment 49-52.
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 similar with L1 structure L2, its productivity also has suitable reduction.
Embodiment 53-64: the investigation of alkali
In addition to alkali therein is replaced with other alkali by diisopropyl ethanolamine, other the most constant and with embodiment 1-4 Same way implements embodiment 53-64, and used alkali, corresponding relation and products collection efficiency see table 4:
Table 4: the investigation of alkali
As can be seen here, when use other alkali time, all cause productivity to be greatly lowered, even if with institute in embodiment 1-4 Using the diisopropylamine that diisopropyl ethanolamine is similar to very much, its productivity also significantly reduces.
Embodiment 65-72: the investigation of solvent
Embodiment 65-68: respectively the mixed solvent in embodiment 1-4 being replaced with PEG-400, other is the most constant, and obtains Arrive embodiment 65-68.
Embodiment 69-72: respectively the mixed solvent in embodiment 1-4 is replaced with 1-pi-allyl-3-Methylimidazole. tetrafluoro Borate, other is the most constant, and has obtained 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, only uses a combination of both thing Time, the excellent effect of the present invention could be obtained.
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 has obtained embodiment 73-76.
Embodiment 77-80: respectively the composite catalyst in embodiment 1-4 is replaced with the hexafluorophosphoric acid tetrem of same amount Nitrile copper, the i.e. consumption of hexafluorophosphoric acid four acetonitrile copper are total consumption of original two kinds of components, and have obtained 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, only uses both mixture Time, playing the synergism of uniqueness each other, thus achieved the excellent catalytic effect of the present invention, this is non-obvious 's.
In sum, the invention provides the synthetic method of a kind of medicine intermediate phenanthrene compound, in the method, pass through The combined selection of catalyst, organic ligand, alkali and solvent and/or collaborative, thus obtained purpose product with high yield, and when change When becoming any component or omitted, products collection efficiency is all caused to significantly reduce.As can be seen here, the method tool of the present invention There are 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 protection model of the present invention Enclose.Additionally, it will also be appreciated that after the technology contents having read the present invention, the present invention can be made respectively by those skilled in the art Planting change, amendment and/or modification, all these equivalent form of value falls within the guarantor that the application appended claims is limited equally Within the scope of protecting.

Claims (7)

1. a method for phenanthrene compound shown in the lower formula (I) of synthesis under sodium phosphate environment,
Described method includes: under inert atmosphere, in the presence of catalyst, organic ligand and alkali, in solvent, and lower formula (II) chemical combination Thing reacts with formula (III) compound, thus obtains 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, 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, wherein, Described organic palladium compound is PdCl2(dppf), described organocopper compound is hexafluorophosphoric acid four acetonitrile copper；
Described organic ligand is the one in following L1-L4:
Described alkali is Na3PO4；
Described solvent is the mixture of PEG-400 Yu 1-pi-allyl-3-methyl imidazolium tetrafluoroborate, and both volume ratios are 1: 0.1-0.3。
The method of the described phenanthrene compound of synthesis the most according to claim 1, it is characterised in that described organic ligand is L1.
The method of the described phenanthrene compound of synthesis the most according to claim 1 and 2, it is characterised in that described formula (II) chemical combination Thing is 1:2-4 with the mol ratio of formula (III) compound.
The method of the described phenanthrene compound of synthesis the most according to claim 1 and 2, it is characterised in that described formula (II) chemical combination Thing is 1:0.08-0.15 with the mol ratio of catalyst.
The method of the described phenanthrene compound of synthesis the most according to claim 1 and 2, it is characterised in that described formula (II) chemical combination Thing is 1:0.1-0.2 with the mol ratio of organic ligand.
The method of the described phenanthrene compound of synthesis the most according to claim 1 and 2, it is characterised in that described formula (II) chemical combination Thing is 1:2-3 with the mol ratio of alkali.
The method of the described phenanthrene compound of synthesis the most according to claim 1 and 2, it is characterised in that reaction temperature is 60-80 ℃；Response time is 8-12 hour.
CN201610216435.9A 2015-03-06 2015-03-06 Method for synthesizing pharmaceutical intermediate phenanthrene compound in sodium phosphate environment Withdrawn CN105801340A (en)

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Application publication date: 20160727