CN105669336A - Method for synthesizing medical intermediate phenanthrene compound in sodium ethoxide environment - Google Patents

Method for synthesizing medical intermediate phenanthrene compound in sodium ethoxide environment Download PDF

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CN105669336A
CN105669336A CN201610217180.8A CN201610217180A CN105669336A CN 105669336 A CN105669336 A CN 105669336A CN 201610217180 A CN201610217180 A CN 201610217180A CN 105669336 A CN105669336 A CN 105669336A
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fragrance
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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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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention relates to a method for synthesizing a medical intermediate phenanthrene compound shown in a formula (I) in the description in a sodium ethoxide environment.The method comprises the steps that in an inert atmosphere, in the presence of a catalyst, an organic ligand and sodium ethoxide and in solvent, a compound of a formula (II) is reacted with a compound of a formula (III), and the compound of the formula (I) is obtained, wherein the formulas are in the description, R1 and R2 independently adopt H or C1-C6 alkyl groups or C1-C6 alkoxy or halogens, R3 adopts C6-C10 aryl groups or C5-C8 heteroaryl, C6-C10 aryl groups or C4-C8 heteroaryl is optionally substituted for 1-3 substituent groups, and the substituent groups adopt the C1-C6 alkyl groups or halogens.According to the method for synthesizing the medical intermediate phenanthrene compound shown in the formula (I) in the description in the sodium ethoxide environment, by means of proper selection of the catalyst, the organic ligand, alkali and the solvent, the good effect is achieved, and a wide industrial application prospect is achieved.

Description

The method of the luxuriant and rich with fragrance compound of medicine intermediate is synthesized under a kind of sodium ethylate environment
The present patent application is the application number of application the be 201510100568.5 point case application of patent application of (synthetic methods of the luxuriant and rich with fragrance compounds of a kind of medicine intermediate) 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 the synthetic method of the luxuriant and rich with fragrance compound of a kind of medicine intermediate, belong to organic synthesis and medicine intermediate synthesis field.
Background technology
Fused ring compound such as the compounds such as naphthalene, anthracene, phenanthrene receive attention and the concern of medicine research staff due to its biological activity generally existed. Wherein, luxuriant and rich with fragrance and derivative is the important phenolic compound of a class, has been widely used in medicinal design and synthesis, material development field.
Just due to excellent in performance like this and the potentiality of luxuriant and rich with fragrance compound, thus research novel method for synthesizing that is luxuriant and rich with fragrance and derivative be also always organic chemical synthesis worker hot issue very deeply concerned.
Up to the present, having there is the preparation technology of multiple luxuriant and rich with fragrance compound in prior art, it have studied, from multiple angle, the synthetic method that luxuriant and rich with fragrance compound is applicable to. Such as:
XiaoTiebo etc. (" PhenanthreneSynthesisbyEosinY-Catalyzed; VisibleLight-Induced [4+2] BenzannulationofBiaryldiazoniumSaltswithAlkynes ", Adv.Synth.Catal., 2012,354,3195-3199) report a kind of without metal catalytic, [4+2] benzo cyclization of the diaryl diazo salt of visible light-inducing. 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; it is derived from the N-Tosylhydrazone of adjacent formyl biphenyl is raw material, and reaction formula is as follows:
KwonYongseok etc. (" ExpedientSynthesisofPhenanthrenesviaIn (III)-Catalyzed6-Exo-DigCycloisomerization ", OrganicLetters, 2013,15,920-923) report the reaction of the luxuriant and rich with fragrance compound of preparation of a kind of In (III) catalysis, it has, and reaction is efficient, the advantage of wide application range of substrates, and its reaction formula is as follows:
As mentioned above, although prior art has disclosed the preparation method of various types of luxuriant and rich with fragrance compound, 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 luxuriant and rich with fragrance compound by a large amount of experiments research, reaches receipts rate height, reacts object rapidly, has prospects for commercial application very widely.
Summary of the invention
For many defects of above-mentioned existence, the present inventor, after having paid a large amount of creative works, through further investigation, and develops the synthetic method of a kind of luxuriant and rich with fragrance compound that can be used as pharmaceutical intermediate, and then completes the present invention.
Specifically, the present invention provides the synthetic method of luxuriant and rich with fragrance compound shown in a kind of following formula (I),
Described method comprises: under inert atmosphere, and under catalyzer, organic ligand and alkali exist, in solvent, following formula (II) compound and formula (III) compound react, thus obtain formula (I) compound;
Wherein, R1、R2It is H, C independently of one another1-C6Alkyl, C1-C6Alkoxy or halogen;
R3For C6-C10Aryl or C5-C8Heteroaryl, described C6-C10Aryl or C4-C8Heteroaryl is optionally replaced by 1-3 substituting group, such as, can be replaced by 1,2 or 3 substituting groups, and described substituting 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 methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, just own base etc.
In the described synthetic method of the present invention, C1-C6Alkoxyl group refers to " C defined above1-C6Alkyl " be connected with O atom after group.
In the described synthetic method of the present invention, described halogen such as can be 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, 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, such as, can be pyridyl, furan thiophene base or thienyl etc.
In the described synthetic method of the present invention, described catalyzer is the mixture of organic palladium compound and organocopper compound, and 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-cyclooctadiene) 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 a kind of or any multiple mixture, it is most preferred that be PdCl2(dppf)。
Wherein, described organocopper compound is phosphofluoric acid four acetonitrile copper ([(CH3CN)4Cu]PF6), copper trifluoromethanesulfcomposite (Cu (OTf)2), acetylacetone copper (Cu (acac)2), in venus crystals any one or multiple, it is most preferred that be phosphofluoric acid four acetonitrile copper ([(CH3CN)4Cu]PF6)。
In the described synthetic method of the present invention, described organic ligand is nitrogenous bitooth ligand, such as, can be substituted or unsubstituted dipyridyl, substituted or unsubstituted phenanthroline etc., such as, 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 a kind of 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-allyl group-3-methyl imidazolium tetrafluoroborate, and 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 such as can be 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, such as, 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 catalyzer 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 forming described catalyzer, 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, the mol ratio of described formula (II) compound and 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, the mol ratio of described formula (II) compound and alkali is 1:2-3, such as, can be 1:2,1:2.5 or 1:3.
In the described synthetic method of the present invention, the restriction that the consumption of described solvent is not strict, its consumption can be carried out suitable selection by those skilled in the art, such as, can carry out according to making aftertreatment be easy to, be enough to reaction and carry out smoothly.
In the described synthetic method of the present invention, temperature of reaction 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 reaction times is 8-12 hour, such as, can be 8 hours, 10 hours or 12 hours.
In the described synthetic method of the present invention, reacting the aftertreatment after terminating specific as follows: reaction adds deionized water after terminating in reaction system, fully vibration, washing, separate organic layer, again with deionized water wash, separate organic layer; By organic layer concentrating under reduced pressure, removing, silica gel column chromatography on gained residue is that the n-hexyl alcohol of 1:2-4 and the mixed solvent of chloroform carry out wash-out as eluting solvent taking volume ratio, through TLC detection, merges same composition, removes eluting solvent, obtain target compound.
As mentioned above, the present invention provides the synthetic method of a kind of luxuriant and rich with fragrance compound being used as medicine intermediate, described method is by the selection/combination of suitable catalyst, You Jipei, alkali and solvent/work in coordination with, thus obtain object product with high yield, the actual production of the intermediates such as medicine, chemical industry is of great advantage, there is prospects for commercial application widely.
Embodiment
Below by specific embodiment, the present invention is described in detail; but the purposes of these exemplary enforcement modes and object are only used for enumerating the present invention; not the real protection scope of the present invention is formed any type of any restriction, more non-protection scope of the present invention is confined to this.
Wherein, in all embodiments, unless otherwise prescribed, the ligand L 1 used is the part of formula L1 designate.
Embodiment 1
In reactor, add the mixed solvent (both volume ratios are 1:0.1) being made up of PEG-400 and 1-allyl group-3-methyl imidazolium tetrafluoroborate in right amount, then replace twice with nitrogen so that be nitrogen atmosphere in reactor; Then add the bromo-4 '-chlordiphenyl of formula on 100mmol (II) compound 2-, 200mmol upper formula (III) compound vinylbenzene, by 3mmolPdCl2And the composite catalyst of 6mmol phosphofluoric acid four acetonitrile copper composition, 10mmol ligand L 1 and 200mmol diisopropyl ethanolamine, (dppf) it is warming up to 60 DEG C under stirring, and reacts 12 hours at such a temperature.
Reaction adds deionized water after terminating in reaction system, and 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, it is that the n-hexyl alcohol of 1:2 and the mixed solvent of chloroform carry out wash-out as eluting solvent taking volume ratio, through TLC detection, merge same composition, remove eluting solvent, obtaining the chloro-10-phenyl of target compound 2-luxuriant and rich with fragrance, product rate 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, add the mixed solvent (both volume ratios are 1:0.2) being made up of PEG-400 and 1-allyl group-3-methyl imidazolium tetrafluoroborate in right amount, then replace twice with nitrogen so that be nitrogen atmosphere in reactor; Then add formula on 100mmol (II) compound 2-bromo biphenyl, 300mmol upper formula (III) compound 1-methyl-3-vinyl benzene, by 3mmolPdCl2And the composite catalyst of 9mmol phosphofluoric acid four acetonitrile copper composition, 15mmol ligand L 1 and 250mmol diisopropyl ethanolamine, (dppf) it is warming up to 70 DEG C under stirring, and reacts 10 hours at such a temperature.
Reaction adds deionized water after terminating in reaction system, and 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, it is that the n-hexyl alcohol of 1:3 and the mixed solvent of chloroform carry out wash-out as eluting solvent taking volume ratio, through TLC detection, merge same composition, remove eluting solvent, obtaining tolyl between target compound 9-luxuriant and rich with fragrance, product rate 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, add the mixed solvent (both volume ratios are 1:0.3) being made up of PEG-400 and 1-allyl group-3-methyl imidazolium tetrafluoroborate in right amount, then replace twice with nitrogen so that be nitrogen atmosphere in reactor; Then add formula on 100mmol (II) compound 2-bromo biphenyl, 400mmol upper formula (III) compound 1-vinyl naphthalene, by 3mmolPdCl2And the composite catalyst of 12mmol phosphofluoric acid four acetonitrile copper composition, 20mmol ligand L 1 and 300mmol diisopropyl ethanolamine, (dppf) it is warming up to 80 DEG C under stirring, and reacts 8 hours at such a temperature.
Reaction adds deionized water after terminating in reaction system, and 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, it is that the n-hexyl alcohol of 1:4 and the mixed solvent of chloroform carry out wash-out as eluting solvent taking volume ratio, through TLC detection, merge same composition, remove eluting solvent, obtaining target compound 9-(naphthalene-1-base) luxuriant and rich with fragrance, product rate 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, add the mixed solvent (both volume ratios are 1:0.2) being made up of PEG-400 and 1-allyl group-3-methyl imidazolium tetrafluoroborate in right amount, then replace twice with nitrogen so that be nitrogen atmosphere in reactor; Then add formula on 100mmol (II) compound 2-bromo biphenyl, 300mmol upper formula (III) compound 2-vinyl pyridine, by 2mmolPdCl2And the composite catalyst of 6mmol phosphofluoric acid four acetonitrile copper composition, 20mmol ligand L 1 and 200mmol diisopropyl ethanolamine, (dppf) it is warming up to 70 DEG C under stirring, and reacts 12 hours at such a temperature.
Reaction adds deionized water after terminating in reaction system, and 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, it is that the n-hexyl alcohol of 1:3 and the mixed solvent of chloroform carry out wash-out as eluting solvent taking volume ratio, through TLC detection, merge same composition, remove eluting solvent, obtaining target compound 9-(pyridine-2-base) luxuriant and rich with fragrance, product rate 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 wherein2(dppf) replace for 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 wherein2(dppf) replace for 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 wherein2(dppf) replace as palladium acetylacetonate (Pd (acac)2) 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 wherein2(dppf) replace as (1,5-cyclooctadiene) Palladous chloride (PdCl2) outward, (cod) other operation is all constant, implements embodiment 17-20 with the same way with embodiment 1-4.
Embodiment 21-24: except respectively by PdCl wherein2(dppf) replace as palladium trifluoroacetate (Pd (TFA)2) 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 wherein2(dppf) replacing is two (triphenylphosphine) Palladous chloride (PdCl2 (PPh3)2) outward, other operation is all constant, implements embodiment 25-28 with the same way with embodiment 1-4.
The product rate of products therefrom is as shown in table 1 below:
Table 1: the investigation of palladium compound component
It thus is seen that when by the PdCl in composite catalyst2(dppf), when replacing as other palladium compound, all cause product rate to have and significantly reduce, this demonstrate that PdCl2(dppf) can have best catalytic effect together with phosphofluoric acid four acetonitrile copper.
Embodiment 29-40: the investigation of catalyzer copper compound component
Embodiment 29-32: except respectively phosphofluoric acid four acetonitrile copper wherein being replaced as 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 phosphofluoric acid four acetonitrile copper wherein being replaced as 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 phosphofluoric acid four acetonitrile copper wherein being replaced as, except venus crystals, other operation is all constant, implements embodiment 37-40 with the same way with embodiment 1-4.
The product rate of products therefrom is as shown in table 2 below:
Table 2: the investigation of copper compound component
It thus is seen that when by composite catalyst phosphofluoric acid four acetonitrile copper replace for other copper compound time, all cause product rate to have and significantly reduce, this demonstrate that phosphofluoric 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 being replaced by L1 by organic ligand wherein respectively and being L2, other operation is all constant, implements embodiment 41-44 with the same way with embodiment 1-4.
Embodiment 45-48: except being replaced by L1 by organic ligand wherein respectively and being L3, other operation is all constant, implements embodiment 45-48 with the same way with embodiment 1-4.
Embodiment 49-52: except being replaced by L1 by organic ligand wherein respectively and being L4, other operation is all constant, implements embodiment 49-52 with the same way with embodiment 1-4.
The product rate of products therefrom is as shown in table 3 below:
Table 3: the investigation of organic ligand
It thus is seen that in all parts, L1 has best reaction effect, even if the L2 very similar with L1 structure, its product rate also has suitable reduction.
Embodiment 53-64: the investigation of alkali
Except alkali wherein is replaced as, except other alkali, other is all constant and same way with embodiment 1-4 implements embodiment 53-64, is used alkali, corresponding relation and product product rate to see the following form 4 by diisopropyl ethanolamine:
Table 4: the investigation of alkali
It thus is seen that when use other alkali time, all cause product rate to have and significantly reduce, even if with embodiment 1-4 in used diisopropyl ethanolamine very similar diisopropylamine, its product rate also has remarkable reduction.
Embodiment 65-72: the investigation of solvent
Embodiment 65-68: replacing the mixed solvent in embodiment 1-4 for PEG-400 respectively, other is all constant, and obtains embodiment 65-68.
Embodiment 69-72: replacing the mixed solvent in embodiment 1-4 for 1-allyl group-3-methyl imidazolium tetrafluoroborate respectively, other is all constant, and obtains embodiment 69-72.
The product rate of products therefrom is as shown in table 5 below:
Table 5: the investigation of solvent
It thus is seen that when using the solvent of one-component, product rate has suitable reduction, when only using both compositions, 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 the PdCl for 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: respectively the composite catalyst in embodiment 1-4 being replaced the phosphofluoric acid four acetonitrile copper for same amount, namely the consumption of phosphofluoric acid four acetonitrile copper is total consumption of original two kinds of components, and obtains embodiment 77-80.
The product rate of products therefrom is as shown in table 6 below:
Table 6: the investigation of single catalyst component
It thus is seen that when using one-component catalyzer, product rate has suitable reduction, when only using both mixtures, having played unique synergy each other, thus achieved the excellent catalytic effect of the present invention, this is non-obvious.
In sum, the present invention provides the synthetic method of the luxuriant and rich with fragrance compound of a kind of medicine intermediate, in the method, by the comprehensive selection of catalyzer, organic ligand, alkali and solvent and/or collaborative, thus obtain object product with high yield, and when changing any a kind of component or omitted, all cause product product rate to have remarkable reduction. It thus is seen that the method for the present invention has good, industrial application potentiality widely, can be applicable to the synthesis field of medicine intermediate.
It is to be understood that the purposes of these embodiments only is not intended to for illustration of the present invention limit the scope of the invention. In addition; also should understand; 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 these all equivalent form of values fall within the protection domain that the application's appended claims limits equally.

Claims (7)

1. under sodium ethylate environment, synthesize a method for luxuriant and rich with fragrance compound shown in following formula (I),
Described method comprises: under inert atmosphere, and under catalyzer, organic ligand and alkali exist, in solvent, following formula (II) compound and formula (III) compound react, thus obtain formula (I) compound;
Wherein, R1、R2It is H, C independently of one another1-C6Alkyl, C1-C6Alkoxy or halogen;
R3 is C6-C10Aryl or C5-C8Heteroaryl, described C6-C10Aryl or C4-C8Heteroaryl is optionally replaced by 1-3 substituting group, and described substituting group is C1-C6Alkyl or halogen;
Described catalyzer 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(dppf), described organocopper compound is phosphofluoric acid four acetonitrile copper;
Described organic ligand is the one in following L1-L4:
Described alkali is sodium ethylate;
Described solvent is the mixture of PEG-400 and 1-allyl group-3-methyl imidazolium tetrafluoroborate, and both volume ratios are 1:0.1-0.3.
2. the method for the described luxuriant and rich with fragrance compound of synthesis according to claim 1, it is characterised in that, described organic ligand is L1.
3. the method for the described luxuriant and rich with fragrance 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 luxuriant and rich with fragrance compound of synthesis according to claim 1 and 2, it is characterised in that, the mol ratio of described formula (II) compound and catalyzer is 1:0.08-0.15.
5. the method for the described luxuriant and rich with fragrance 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 luxuriant and rich with fragrance 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 luxuriant and rich with fragrance compound of synthesis according to claim 1 and 2, it is characterised in that, temperature of reaction is 60-80 DEG C; Reaction times is 8-12 hour.
CN201610217180.8A 2015-03-06 2015-03-06 Method for synthesizing medical intermediate phenanthrene compound in sodium ethoxide environment Withdrawn CN105669336A (en)

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Application publication date: 20160615