A kind of application PdCl2(cod) method synthesizing medicine intermediate phenanthrene compound
The present patent application is Application No. 201510100568.5 (a kind of medicine filed in 6 days March in 2015
The synthetic method of intermediate phenanthrene 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 luxuriant and rich with fragrance
The synthetic method of compound, belongs 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
The attention of research staff and concern.Wherein, luxuriant and rich with fragrance and derivant is the phenolic compound that a class is important,
Through being widely used in drug 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 derivant novel
Synthetic 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 from multiple angles
Degree have studied 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 one without metal catalytic
, [4+2] benzo cyclization of the diaryl diazo salt of visible light-inducing.Its equation is as follows:
(" the Expeditious Synthesis of Phenanthrenes via such as Ye Fei
CuBr2-Catalyzed Coupling of Terminal Alkynes and N-Tosylhydrazones
Derived from O-Fo rmyl Biphenyls”,Organic Letters,2011,13,5020-5023)
Disclosing the coupling/cyclization of a kind of benzyl CuBr2 catalysis, it is derived from the N-of adjacent formyl biphenyl to toluene
Sulphonyl hydrazone 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
Having and react efficient, the advantage of wide application range of substrates, its reaction equation is 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 methods still can not meet medicine, the Production requirement in chemical industry synthesis field, and this is intrinsic due to it
The problems such as production efficiency is low, raw material can not make full use of.
In view of this, the present inventor has aimed to provide the new of a kind of phenanthrene compound by substantial amounts of experimentation
Type process for catalytic synthesis, has reached yield purpose high, willing, has had quite varied commercial Application
Prospect.
Summary of the invention
For many defects of above-mentioned existence, the present inventor, after having paid substantial amounts of creative work, passes through
Further investigation, 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,
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
Individual substituent group replaces, such as, can be replaced by 1,2 or 3 substituent groups, and described substituent group is C1-C6
Alkyl or halogen.
In the described synthetic method of the present invention, C1-C6Alkyl refers to the alkyl with 1-6 carbon atom, example
As being methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, just
Amyl group, isopentyl, n-hexyl etc..
In the described synthetic method of the present invention, C1-C6Alkoxyl refers to " C defined above1-C6Alkyl " with
Group after O atom is connected.
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 virtue with 6-10 carbon atom
Base, such as, can be phenyl or naphthyl.
In the described synthetic method of the present invention, described C4-C8Heteroaryl refers to have the miscellaneous of 4-8 carbon atom
Aryl, such as, can be pyridine radicals, furan thiophene base or thienyl etc..
In the described synthetic method of the present invention, described catalyst is organic palladium compound and organocopper compound
Mixture, 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), levulinic
Ketone palladium (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) any one of or any multiple mixture, most preferably PdCl2(dppf)。
Wherein, described organocopper compound is hexafluorophosphoric acid four acetonitrile copper ([(CH3CN)4Cu]PF6), fluoroform sulphur
Acid copper (Cu (OTf)2), acetylacetone copper (Cu (acac)2), any one or more in copper acetate, optimum
Elect hexafluorophosphoric acid four acetonitrile copper ([(CH as3CN)4Cu]PF6)。
In the described synthetic method of the present invention, described organic ligand is nitrogenous bidentate ligand, such as, can be to take
Generation or unsubstituted 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, diisopropyl second
Any one of hydramine 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.
The mixture of tetrafluoroborate, both volume ratios are 1:0.1-0.3, can be such as 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 and the mol ratio of formula (III) compound
For 1:2-4, such as, can be 1:2,1:3 or 1:4.
In the described synthetic method of the present invention, described formula (II) compound with the mol ratio of catalyst is
1:0.08-0.15, two kinds of components of the mole dosage of the most described formula (II) compound and the described catalyst of composition
The ratio of mole dosage sum is 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 with the mol ratio of organic ligand is
1:0.1-0.2, such as, can be 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, example
As being 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, this area
Its consumption can suitably be selected by technical staff, such as, can be prone to carry out, be enough to according to making post processing
Reaction is smoothed out.
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
Hour or 12 hours.
In the described synthetic method of the present invention, the post processing after reaction terminates is specific as follows: after reaction terminates,
In reaction system, add deionized water, fully vibration, washing, separate organic layer, again use deionized water
Washing, separates organic layer;By organic layer concentrating under reduced pressure, remove, silica gel column chromatography on gained residue, with
Volume ratio is that the hexanol of 1:2-4 carries out eluting with the mixed solvent of chloroform as eluting solvent, examines through TLC
Survey, merge same composition, remove eluting solvent, obtain target compound.
As it has been described above, the invention provides the synthetic method of a kind of phenanthrene compound as medicine intermediate, institute
Method of stating is by suitable catalyst, You Jipei, the selection/combination/work in coordination with of alkali and solvent, thus with high yield
Having obtained purpose product, the actual production to intermediate such as medicine, chemical industry is of great advantage, has work widely
Industry application prospect.
Detailed description of the invention
Below by specific embodiment, the present invention is described in detail, but these exemplary embodiments
Purposes and purpose are only used for enumerating the present invention, not constitute any type of to the real protection scope of the present invention
Any restriction, more non-is confined to this by protection scope of the present invention.
Wherein, in all embodiments, unless otherwise prescribed, the ligand L 1 used is above formula L1 institute
The part referred to.
Embodiment 1
In reactor, addition is made up of PEG-400 with 1-pi-allyl-3-methyl imidazolium tetrafluoroborate in right amount
Mixed solvent (both volume ratios are 1:0.1), then replaces twice with nitrogen so that be blanket of nitrogen in reactor
Enclose;It is subsequently adding the bromo-4 '-chlordiphenyl of formula (II) compound 2-on 100mmol, 200mmol upper formula (III) chemical combination
Thing styrene, by 3mmolPdCl2(dppf) and 6mmol hexafluorophosphoric acid four acetonitrile copper composition composite catalyst,
10mmol ligand L 1 and 200mmol diisopropyl ethanolamine, is warming up to 60 DEG C under stirring, and in this temperature
Lower reaction 12 hours.
After reaction terminates, in reaction system, add deionized water, fully vibration, washing, separate organic layer,
Again it is washed with deionized, separates organic layer;By organic layer concentrating under reduced pressure, remove, on gained residue
Silica gel column chromatography, the mixed solvent of the hexanol using volume ratio as 1:2 and chloroform is washed as eluting solvent
De-, detect through TLC, merge same composition, remove eluting solvent, obtain target compound 2-chloro-10-benzene
Ji Fei, 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
In reactor, addition is made up of PEG-400 with 1-pi-allyl-3-methyl imidazolium tetrafluoroborate in right amount
Mixed solvent (both volume ratios are 1:0.2), then replaces twice with nitrogen so that be blanket of nitrogen in reactor
Enclose;It is subsequently adding formula (II) compound 2-bromo biphenyl on 100mmol, 300mmol upper formula (III) compound 1-first
Base-3-vinyl benzene, by 3mmolPdCl2And compound the urging of 9mmol hexafluorophosphoric acid four acetonitrile copper composition (dppf)
Agent, 15mmol ligand L 1 and 250mmol diisopropyl ethanolamine, be warming up to 70 DEG C under stirring, and
React 10 hours at a temperature of Gai.
After reaction terminates, in reaction system, add deionized water, fully vibration, washing, separate organic layer,
Again it is washed with deionized, separates organic layer;By organic layer concentrating under reduced pressure, remove, on gained residue
Silica gel column chromatography, the mixed solvent of the hexanol using volume ratio as 1:3 and chloroform is washed as eluting solvent
De-, detect through TLC, merge same composition, remove eluting solvent, obtain tolyl between target compound 9-
Phenanthrene, 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
In reactor, addition is made up of PEG-400 with 1-pi-allyl-3-methyl imidazolium tetrafluoroborate in right amount
Mixed solvent (both volume ratios are 1:0.3), then replaces twice with nitrogen so that be blanket of nitrogen in reactor
Enclose;It is subsequently adding formula (II) compound 2-bromo biphenyl on 100mmol, 400mmol upper formula (III) compound 1-second
Thiazolinyl 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 in this temperature
Lower reaction 8 hours.
After reaction terminates, in reaction system, add deionized water, fully vibration, washing, separate organic layer,
Again it is washed with deionized, separates organic layer;By organic layer concentrating under reduced pressure, remove, on gained residue
Silica gel column chromatography, the mixed solvent of the hexanol using volume ratio as 1:4 and chloroform is washed as eluting solvent
De-, detect through TLC, merge same composition, remove eluting solvent, obtain target compound 9-(naphthalene-1-base)
Phenanthrene, 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
In reactor, addition is made up of PEG-400 with 1-pi-allyl-3-methyl imidazolium tetrafluoroborate in right amount
Mixed solvent (both volume ratios are 1:0.2), then replaces twice with nitrogen so that be blanket of nitrogen in reactor
Enclose;It is subsequently adding formula (II) compound 2-bromo biphenyl on 100mmol, 300mmol upper formula (III) compound 2-second
Thiazolinyl pyridine, by 2mmolPdCl2(dppf) and 6mmol hexafluorophosphoric acid four acetonitrile copper composition composite catalyst,
20mmol ligand L 1 and 200mmol diisopropyl ethanolamine, is warming up to 70 DEG C under stirring, and in this temperature
Lower reaction 12 hours.
After reaction terminates, in reaction system, add deionized water, fully vibration, washing, separate organic layer,
Again it is washed with deionized, separates organic layer;By organic layer concentrating under reduced pressure, remove, on gained residue
Silica gel column chromatography, the mixed solvent of the hexanol using volume ratio as 1:3 and chloroform is washed as eluting solvent
De-, detect through TLC, merge same composition, remove eluting solvent, obtain target compound 9-(pyridine-2-
Base) luxuriant and rich with fragrance, 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
Operate the most constant, implement embodiment 5-8 with the same way with embodiment 1-4.
Embodiment 9-12: except respectively by PdCl therein2(dppf) Palladous chloride. (PdCl2) is replaced with outward, other behaviour
Make the most 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,
Other 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. is replaced with
(PdCl2(cod)) outward, other operation is the most constant, implements embodiment with the same way with embodiment 1-4
17-20。
Embodiment 21-24: except respectively by PdCl therein2(dppf) palladium trifluoroacetate (Pd (TFA) is replaced with2) outward,
Other operation is the most 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. is replaced with
(PdCl2(PPh3)2) outward, other operation is the most constant, implements embodiment with the same way with embodiment 1-4
25-28。
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 lead
Cause productivity to be greatly lowered, this demonstrate that PdCl2(dppf) can have together with hexafluorophosphoric acid four acetonitrile copper
Good catalytic effect.
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 behaviour
Make the most constant, 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 cause productivity to be greatly lowered, this demonstrate that hexafluorophosphoric acid four acetonitrile copper can be with PdCl2(dppf) one rise
Wave best catalytic 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 not
Become, implement embodiment 41-44 with the same way with embodiment 1-4.
Embodiment 45-48: in addition to respectively organic ligand therein being replaced with L3 by L1, other operation is the most not
Become, implement embodiment 45-48 with the same way with embodiment 1-4.
Embodiment 49-52: in addition to respectively organic ligand therein being replaced with L4 by L1, other operation is the most not
Become, implement 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 with L1 structure
Very similar 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 and embodiment
The same way of 1-4 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 using other alkali, productivity is all caused to be greatly lowered, even and if embodiment
The diisopropylamine that used in 1-4, 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 is replaced with PEG-400, other is the most not
Become, and obtained embodiment 65-68.
Embodiment 69-72: respectively the mixed solvent in embodiment 1-4 is replaced with 1-pi-allyl-3-Methylimidazole.
Tetrafluoroborate, 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 both
Compositions 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 same amount
PdCl2(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 hexafluoro phosphorus of same amount
Acid four acetonitrile copper, the i.e. consumption of hexafluorophosphoric acid four acetonitrile copper are total consumption of original two kinds of components, and obtain
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
During mixture, play the synergism of uniqueness each other, thus achieved the excellent catalysis effect of the present invention
Really, this is non-obvious.
In sum, the invention provides the synthetic method of a kind of medicine intermediate phenanthrene compound, in the method
In, by the combined selection of catalyst, organic ligand, alkali and solvent and/or collaborative, thus obtain with high yield
Arrive purpose product, and when changing any component or being omitted, all cause products collection efficiency to have aobvious
Write and reduce.As can be seen here, the method for the present invention has good, commercial Application potentiality widely, can apply
Synthesis field in 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 guarantor of the present invention
Protect scope.Additionally, it will also be appreciated that after the technology contents having read the present invention, those skilled in the art
The present invention can make various change, amendment and/or modification, and all these equivalent form of value falls within this Shen equally
Please be within the protection domain that limited of appended claims.