CN105061484B - A kind of synthetic method of medicine intermediate alkynyl substituted quinolinones compound - Google Patents
A kind of synthetic method of medicine intermediate alkynyl substituted quinolinones compound Download PDFInfo
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Abstract
The present invention relates to the synthetic method method there is provided alkynyl substituted quinolinones compound shown in a kind of formula (III), methods described includes：At room temperature into the organic solvent of reactor, formula (I) compound and formula (II) compound are added, and stirs mixing 10 15 minutes, catalyst and auxiliary agent is then added, is warming up to 50 60 DEG C and insulated and stirred is reacted 68 hours；After completion of the reaction, reactant mixture is filtered, deionized water is added in filtrate and is fully vibrated, is extracted with dichloromethane 23 times, merge organic phase, vacuum distillation, residue crosses silica gel column chromatography, isolated formula (III) compound,Wherein, R1Selected from C1‑C6Alkyl or benzyl, R2Selected from H, C1‑C6Alkoxy, nitro or halogen.Methods described, so as to play the synergy of uniqueness, can be obtained purpose product with high yield, be had a good application prospect and industrial production value in organic synthesis field by the appropriately selected with combining of catalyst, auxiliary agent and organic solvent.
Description
Technical field
The present invention relates to a kind of synthetic method of quinolinones compound, relate more particularly to a kind of alkynyl substituted quinolinone
The synthetic method of class compound, belongs to medicine intermediate synthesis field.
Background technology
In organic chemistry and pharmaceutical chemistry, quinolinones compound be build natural or synthetic medicine, lead compound,
It is the centre for preparing biologically active drug that the important feature unit of functional material etc., such as C5- alkynyls quinolinone, which have been reported,
Body,
Such important effect and application potential just because of quinolinone compounds, therefore, develop quinolinones chemical combination
The selective alkynylation reaction of thing turns into one of the critical problem in synthesis field increasingly.
In addition, alkynyl is due to being unsaturated group, with good reactivity, can further occur a variety of reactions,
So as to the basic group extended as group.In recent years, scientists have been developed that a variety of by directly reacting come structure
The reaction method of the construction module containing alkynyl is built, for example：
(" Palladium-Cataly zed Direct Ethynylation of C (sp3) H such as Ano Yusuke
Bonds in Aliphatic Carboxylic Acid Derivatives”,J.Am.Chem.Soc.,2011,133,
A kind of alkynylation reaction of the torpescence c h bond of palladium chtalyst 12984-12986) is reported, is replaced by heterocyclic amine compound and bromine
TIPS alkynyl compounds reacted, so as to obtain the compound of alkynyl substituted, its reaction equation is as follows：
He Jian etc. (" Palladium (0)-Catalyzed Alkynylation of C (sp3)-H Bonds ",
J.Am.Chem.Soc., 2013,135,3387-3390) report and a kind of entered using [AlkynylPd (II) Ln] activation c h bond
And the reaction of alkynyl compound is prepared, its reaction equation is as follows：
(" the Formal Inverse Sonogashira Reaction such as Alexander S.Dudnik:Direct
Alkynylation of Arenes and Heterocycles with Alkynyl Halides”,
Angew.Chem.Int.Ed., 2010,49,2096-2098) summarize using alkynyl halogen compound and aromatic hydrocarbons or heterocyclic
The direct alkynylation reaction method of compound.
However, being but rarely reported for the selective alkynylation reaction of quinolinones compound in the prior art.
The present inventor by depth study with after experimental exploring, it is proposed that a kind of quinolinones compound C-H alkynyls
Reaction method, this method directly carries out C-H alkynylation reactions with quinolinones compound reaction using TIPS reagents and realized, should
The method of kind has the advantages that high selectivity, high yield, shows to be widely applied prospect.
The content of the invention
In order to overcome many defects as indicated above, present inventor has performed in-depth study and exploration, paying
After enough creative works, so as to complete the present invention.
Specifically, technical scheme and content are related to alkynyl substituted quinolinones shown in a kind of lower formula (III)
The synthetic method method of compound, methods described includes：At room temperature into the organic solvent of reactor, lower formula (I) chemical combination is added
Thing and lower formula (II) compound, and mixing 10-15 minutes is stirred, catalyst and auxiliary agent are then added, 50-60 DEG C is warming up to and protects
Warm stirring reaction 6-8 hours；After completion of the reaction, reactant mixture is filtered, deionized water is added in filtrate and is fully vibrated, with two
Chloromethanes is extracted 2-3 times, merges organic phase, vacuum distillation, and residue crosses silica gel column chromatography, and the isolated formula (III) is changed
Compound,
Wherein, R1Selected from C1-C6Alkyl or benzyl, R2Selected from H, C1-C6Alkoxy, nitro or halogen.
In the synthetic method of the present invention, the C1-C6The implication of alkyl refers to the straight chain with 1-6 carbon atom
Or branched alkyl, for example can be methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, uncle in non-limiting manner
Butyl, n-pentyl, isopentyl or n-hexyl etc..
In the synthetic method of the present invention, the C1-C6Alkoxy refers to " C defined above1-C6Alkyl " is former with O
Group after son is connected.
In the synthetic method of the present invention, the implication of the halogen refers to halogen, for example can be non-exclusively
F, Cl, Br or I.
In the synthetic method of the present invention, in formula (II) compound and the formula (III) compound
" TIPS " is triisopropylsilyl, and this is the Conventional abbreviations in this area, belongs to common knowledge.
In the synthetic method of the present invention, the catalyst is that mol ratio is 4:1 rhodium compound and AgBF4It is mixed
Compound.
Wherein, the rhodium compound is [RhCp*Cl2]2Or [RhCp* (MeCN)3(SbF6)2] in any one, it is optimal
Elect [RhCp*Cl as2]2。
In the synthetic method of the present invention, the auxiliary agent is cucurbit [6] urea (CB [6]), cucurbit [7] urea (CB [7])
Or any one in cucurbit [8] urea (CB [8]), most preferably cucurbit [7] urea.
In the synthetic method of the present invention, the organic solvent is that volume ratio is 5:1 solvent composition A and solvent group
Divide B mixture.
Wherein, the solvent composition A is benzene, toluene, DMF (DMF), acetonitrile, DMSO (dimethyl Asias
Sulfone), ethanol, NMP (1-METHYLPYRROLIDONE), paraxylene, chlorobenzene, any one in propyl alcohol etc., most preferably NMP.
Wherein, the solvent composition B is PEG-200.
In the synthetic method of the present invention, the consumption of the organic solvent is not particularly limited, this area skill
Suitable consumption may be selected in art personnel, for example, reacting balance is carried out, or post processing is easy to the amount of progress, and this belongs to ability
The conventional technical means in domain, this is no longer going to repeat them.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and formula (II) compound is 1:1-
1.5, in non-limiting manner for example can 1:1、1:1.2、1:1.4 or 1:1.5.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and catalyst is 1:0.03-
0.05, i.e., the mole dosage and the rhodium compound and AgBF of the composition catalyst of described formula (I) compound4Both total moles
The ratio of consumption is 1:0.03-0.05, for example, can be 1:0.03、1:0.04 or 1:0.05.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and auxiliary agent is 1:0.08-0.12,
For example can be 1:0.08、1:0.1 or 1:0.12.
In the synthetic method of the present invention, reaction terminates rear purification of products and belongs to conventional technology, such as institute
The silica gel of 300-400 mesh can be loaded by stating silica gel chromatographic column, and eluent is also that can carry out conventional selection, and it is suitable for example to can be used
Organic solvent or mixed organic solvents eluted (can be used volume ratio be 1:2 ethyl acetate and acetone mixture conduct
Eluent).These technological means those skilled in the art can suitably be selected, and be no longer described in detail herein.
In summary, the invention provides a kind of synthetic method of alkynyl substituted quinolinone compounds, methods described passes through
Appropriately selected with combining, especially being applied in combination of catalyst, the specific adjuvant and organic of catalyst, auxiliary agent and organic solvent
The selection of solvent, so as to play the synergy of uniqueness, can obtain purpose product with very high yield, significantly larger than existing
Any known report in technology, so as to have good application in organic synthesis field especially medicine intermediate synthesis field
Prospect and industrial production value.
Embodiment
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and
Purpose only be used for enumerate the present invention, not to the present invention real protection scope constitute it is any type of it is any limit, it is more non-will
Protection scope of the present invention is confined to this.
Embodiment 1
Appropriate organic solvent at room temperature into reactor (is that volume ratio is 5:1 NMP and PEG-200 mixture)
In, formula (II) compound on the upper formula (I) compounds of 100mmol and 100mmol is added, and stir and mix 10 minutes, then add
3mmol catalyst (is 2.4mmol [RhCp*Cl2]2With 0.6mmolAgBF4Mixture) and 8mmol auxiliary agents cucurbit [7] urea, rise
Temperature to 50 DEG C and insulated and stirred is reacted 8 hours；After completion of the reaction, reactant mixture is filtered, deionized water is added in filtrate and is filled
Point vibration, is extracted 2-3 time, merging organic phase, vacuum distillation, residue crosses silica gel column chromatography with dichloromethane, it is isolated on
Formula (III) compound (Bn therein is benzyl), yield is 96.5%.
1H NMR(CDCl3,400MHz):δ 7.66 (d, J=9.3Hz, 1H), 7.46 (d, J=7.9Hz, 1H), 7.41-
7.27 (m, 3H), 7.18 (d, J=9.3Hz, 1H), 7.09 (ddd, J=7.1,1.6,0.8Hz, 2H), 6.27 (d, J=7.8Hz,
1H),5.28(s,2H),1.18(s,21H)。
Embodiment 2
Appropriate organic solvent at room temperature into reactor (is that volume ratio is 5:1 NMP and PEG-200 mixture)
In, formula (II) compound on the upper formula (I) compounds of 100mmol and 120mmol is added, and stir and mix 12 minutes, then add
4mmol catalyst (is 3.2mmol [RhCp*Cl2]2With 0.8mmolAgBF4Mixture) and 12mmol auxiliary agents cucurbit [7] urea,
It is warming up to 55 DEG C and insulated and stirred is reacted 7 hours；After completion of the reaction, reactant mixture is filtered, deionized water is added in filtrate
Fully vibration, is extracted 2-3 times with dichloromethane, merges organic phase, vacuum distillation, residue crosses silica gel column chromatography, isolated
Upper formula (III) compound (Bn therein is benzyl), yield is 96.3%.
1H NMR(CDCl3,400MHz):δ 7.44 (d, J=7.8Hz, 1H), 7.34-7.23 (m, 3H), 7.19-7.07 (m,
2H), 7.02 (dd, J=7.8,1.8Hz, 2H), 6.16 (d, J=7.7Hz, 1H), 5.25 (s, 2H), 1.17 (s, 21H).
Embodiment 3
Appropriate organic solvent at room temperature into reactor (is that volume ratio is 5:1 NMP and PEG-200 mixture)
In, formula (II) compound on the upper formula (I) compounds of 100mmol and 150mmol is added, and stir and mix 15 minutes, then add
5mmol catalyst (is 4mmol [RhCp*Cl2]2With 1mmolAgBF4Mixture) and 10mmol auxiliary agents cucurbit [7] urea, heating
Reacted 6 hours to 60 DEG C and insulated and stirred；After completion of the reaction, reactant mixture is filtered, deionized water is added in filtrate abundant
Vibration, is extracted 2-3 times with dichloromethane, merges organic phase, and vacuum distillation, residue crosses silica gel column chromatography, isolated above formula
(III) compound, yield is 96.2%.
1H NMR(CDCl3,400MHz):δ 7.57-7.43 (m, 2H), 7.29 (d, J=7.7Hz, 1H), 7.24 (dd, J=
8.3,1.5Hz, 1H), 6.13 (d, J=7.7Hz, 1H), 3.72 (s, 3H), 1.24 (s, 21H).
Embodiment 4
Appropriate organic solvent at room temperature into reactor (is that volume ratio is 5:1 NMP and PEG-200 mixture)
In, formula (II) compound on the upper formula (I) compounds of 100mmol and 110mmol is added, and stir and mix 12 minutes, then add
5mmol catalyst (is 4mmol [RhCp*Cl2]2With 1mmolAgBF4Mixture) and 9mmol auxiliary agents cucurbit [7] urea, be warming up to
55 DEG C and insulated and stirred are reacted 8 hours；After completion of the reaction, reactant mixture is filtered, deionized water is added in filtrate and is fully shaken
Swing, extracted 2-3 times with dichloromethane, merge organic phase, vacuum distillation, residue crosses silica gel column chromatography, isolated above formula
(III) compound, yield is 95.9%.
1H NMR(CDCl3,400MHz):δ7.32-7.26(m,1H),7.11-7.01(m,1H),6.63-6.49(m,1H),
6.18-6.03 (m, 1H), 3.94 (d, J=0.9Hz, 3H), 3.66 (d, J=1.1Hz, 3H), 1.23 (s, 21H).
Embodiment 5-16
Embodiment 5-8：Except by the rhodium compound in catalyst by [RhCp*Cl2]2Replace with [RhCp* (MeCN)3
(SbF6)2] outside, other operations are constant, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 5-8.
Embodiment 9-12：Except by catalyst by [RhCp*Cl2]2And AgBF4Mixture replace with consumption for original two kinds
One-component [the RhCp*Cl of the total consumption of component2]2Outside, other operations are constant, so as to repeat to implement embodiment 1-4, sequentially
Obtain embodiment 9-12.
Embodiment 13-16：Except by catalyst by [RhCp*Cl2]2And AgBF4Mixture replace with consumption for original two kinds
The one-component AgBF of the total consumption of component4Outside, other operations are constant, so as to repeat to implement embodiment 1-4, sequentially obtain reality
Apply a 13-16.
As a result it see the table below 1.
Table 1
Note：" -- " represents to be not present.
From table 1, [RhCp*Cl is only used simultaneously2]2With AgBF4The bicomponent catalyst of composition, could obtain this
The excellent effect of invention.When using one-component, yield, which has, significantly to be significantly reduced, and even loses the value of research
(see embodiment 13-16).It is also seen that working as [RhCp*Cl2]2Replace with [RhCp*Cl2]2When, yield equally has significantly
Reduction.
Embodiment 17-28
Embodiment 17-20：Except by auxiliary agent by addition to cucurbit [7] urea replaces with cucurbit [6] urea, other operations are constant so that
Repetition implements embodiment 1-4, sequentially obtains embodiment 17-20.
Embodiment 21-24：Except by auxiliary agent by addition to cucurbit [7] urea replaces with cucurbit [8] urea, other operations are constant so that
Repetition implements embodiment 1-4, sequentially obtains embodiment 21-24.
Embodiment 25-28：(i.e. without using any auxiliary agent) in addition to auxiliary agent is omitted, so as to repeat to implement embodiment
81-4, sequentially obtains embodiment 25-28.
As a result 2 be see the table below.
Table 2
Note：" -- " represents to be not present.
As can be seen here, in all auxiliary agents, cucurbit [7] urea has a best collaboration facilitation effect, and cucurbit [6] urea and
Cucurbit [8] urea is significantly reduced.On the other hand, when not being used additives, products collection efficiency reduction is the most notable, this demonstrate that
The necessity that auxiliary agent is present.
Embodiment 29-68
Embodiment 29-32：Except by the solvent composition A in organic solvent by addition to NMP replaces with benzene, other operations are constant,
So as to repeat to implement embodiment 1-4, embodiment 29-32 is sequentially obtained.
Embodiment 33-36：Except by the solvent composition A in organic solvent by addition to NMP replaces with toluene, other operations are not
Become, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 33-36.
Embodiment 37-40：Except by the solvent composition A in organic solvent by addition to NMP replaces with DMF, other operations are constant,
So as to repeat to implement embodiment 1-4, embodiment 37-40 is sequentially obtained.
Embodiment 41-44：Except by the solvent composition A in organic solvent by addition to NMP replaces with DMSO, other operations are not
Become, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 41-44.
Embodiment 45-48：Except by the solvent composition A in organic solvent by addition to NMP replaces with ethanol, other operations are not
Become, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 45-48.
Embodiment 49-52：Except by the solvent composition A in organic solvent by addition to NMP replaces with paraxylene, other operations are equal
It is constant, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 49-52.
Embodiment 53-56：Except by the solvent composition A in organic solvent by addition to NMP replaces with chlorobenzene, other operations are not
Become, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 53-56.
Embodiment 57-60：Except by the solvent composition A in organic solvent by addition to NMP replaces with propyl alcohol, other operations are not
Become, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 57-60.
Embodiment 61-64：Except by organic solvent by addition to NMP and PEG-200 mixture replaces with single solvent NMP, its
His operation is constant, so as to repeat to implement embodiment 1-4, sequentially obtains embodiment 61-64.
Embodiment 65-68：Except organic solvent is replaced with into single solvent PEG-200 by NMP and PEG-200 mixture
Outside, other operations are constant, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 65-68.
As a result 3 be see the table below.
Table 3
As shown in Table 3, present invention employs binary mixed solvent, and the species of each component has been screened, when progress species
Replace or can cause being remarkably decreased for reaction yield when lacking, wherein, only using NMP and PEG-200 double solvents, ability
Obtain the excellent effect of the present invention；Even if being single use NMP or PEG-200, also leading to yield significantly reduces.
Summary, the present inventor proposes a kind of alkynyl substituted quinolinones chemical combination that can be used as medicine intermediate first
The synthetic method of thing, methods described is by the appropriately selected with combining of catalyst, auxiliary agent and organic solvent, so as to play solely
Special synergy, can obtain purpose product with high yield, have a good application prospect and industrialize in organic synthesis field
Productive value.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limitation protection model of the invention
Enclose.In addition, it will also be appreciated that after the technology contents of the present invention have been read, those skilled in the art can make each to the present invention
Change, modification and/or variation are planted, all these equivalent form of values equally fall within the guarantor that the application appended claims are limited
Within the scope of shield.
Claims (4)
1. a kind of synthetic method of alkynyl substituted quinolinones compound shown in lower formula (III), methods described includes：At room temperature to
In the organic solvent of reactor, lower formula (I) compound and lower formula (II) compound are added, and stirs mixing 10-15 minutes, then
Catalyst and auxiliary agent are added, 50-60 DEG C is warming up to and insulated and stirred is reacted 6-8 hours；After completion of the reaction, by reactant mixture mistake
Deionized water is added in filter, filtrate fully to vibrate, and is extracted 2-3 times with dichloromethane, is merged organic phase, vacuum distillation, residue
Cross silica gel column chromatography, isolated formula (III) compound,
Wherein, R1Selected from C1-C6Alkyl or benzyl, R2Selected from H, C1-C6Alkoxy, nitro or halogen；
The catalyst is that mol ratio is 4:1 rhodium compound and AgBF4Mixture；
The rhodium compound is [RhCp*Cl2]2；
The auxiliary agent is cucurbit [7] urea；
The organic solvent is that volume ratio is 5:1 solvent composition A and solvent composition B mixture；
The solvent composition A is 1-METHYLPYRROLIDONE；
The solvent composition B is PEG-200.
2. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound is rubbed with formula (II) compound
You are than being 1:1-1.5.
3. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound and the mol ratio of catalyst are
1:0.03-0.05。
4. the synthetic method as described in claim any one of 1-3, it is characterised in that：Formula (I) compound and auxiliary agent rub
You are than being 1:0.08-0.12.
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Non-Patent Citations (1)
| Title |
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| Rh(III) and Ru(II)-Catalyzed Site-Selective C-H Alkynylation of Quinolones;Dahye Kang et al.;《Organic Letters》;20150330;第17卷;摘要，scheme2，表1 * |
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