CN104744391B - The synthetic method of a kind of medicine intermediate azoles alkyl compound - Google Patents
The synthetic method of a kind of medicine intermediate azoles alkyl compound Download PDFInfo
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- CN104744391B CN104744391B CN201510104717.5A CN201510104717A CN104744391B CN 104744391 B CN104744391 B CN 104744391B CN 201510104717 A CN201510104717 A CN 201510104717A CN 104744391 B CN104744391 B CN 104744391B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/44—Two oxygen atoms
Abstract
The present invention provides the synthetic method of azoles alkyl compound shown in a kind of following formula (I),Described method comprises: under binary composite catalyst, alkali and activator exist, in carbon dioxide atmosphere, following formula (II) compound and formula (III) compound react in a solvent, thus obtain upper formula (I) azoles alkyl compoundWherein, R1And R2It is H, C independently of one another1-C6Alkyl, C1-C6Alkoxy or halogen. Described method is by constructing novel catalyzer, alkali, activator and solvent reaction system, thus greatly improves product yield, has prospects for commercial application very widely in organic chemical synthesis and pharmaceutical intermediate synthesis field.
Description
Technical field
The present invention relates to the synthetic method of a kind of heterocyclic compound that can be used as medicine intermediate, relate more specifically to the synthetic method of a kind of azoles alkyl compound, belong to organic synthesis and pharmaceutical intermediate compound synthesis technical field.
Background technology
Azoles alkane class formation formula is the function fragment of many bioactive compoundss, and many medical compoundss containing this type of structure fragment are applied in the middle of the development and production of medical preparation. Such as, it can be used among anticonvulsant drug, sodium-ion channel inhibitor, the preparation treating diabetes and cancer therapy drug or medicament or synthesis, such as:
DirkA.Heerding etc. (" NewBenzylidenethiazolidinedionesasAntibacterialAgents ", Bioorganic&MedicinalChemistryLetters, 2003,13,3771-3773) reporting a kind of novel antimicrobial compounds, its structure is as follows:
KoichiroHarada etc. (" Identificationofoxazolidinedionesandthiazolidinedionesas potent17 ��-hydroxysteroiddehydrogenasetype3inhibitors ", Bioorganic&MedicinalChemistryLetters, 2012,22,504-507) report a kind of 17 novel beta-hydroxy sterol class dehydrogenase inhibitors, it can be used for the preparation of cancer therapy drug, and structure is as follows:
As mentioned above, it is necessary, prior art has existed the method for multiple synthesis oxazolidinedione class, but the research still necessity existing for such compou nd synthesis method, this is also one of research focus and emphasis in this field current.
Based on this kind of thinking, the present inventor is intended to a kind of novel method efficiently preparing azoles alkyl compound of exploitation, thus reach the object of efficient synthesis azoles alkyl compound, fully meet the widespread demand of current medicine, chemical intermediate, there is application prospect extremely widely.
Summary of the invention
For many demands of above-mentioned existence, the present inventor, after having paid a large amount of creative works, proposes the synthetic method of a kind of azoles alkyl compound that can be used as pharmaceutical intermediate compound, thus completes the present invention through further investigation.
Specifically, the present invention provides the synthetic method of azoles alkyl compound shown in following formula (I),
Described method comprises: under binary composite catalyst, alkali and activator exist, in carbon dioxide atmosphere, following formula (II) compound and formula (III) compound react in a solvent, thus obtain upper formula (I) azoles alkyl compound
Wherein, R1And R2It is H, C independently of one another1-C6Alkyl, C1-C6Alkoxy 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 then refers to " C defined above1-C6Alkyl " be connected with O atom after group.
In the described synthetic method of the present invention, halogen is fluorine, chlorine, bromine or iodine.
In the described synthetic method of the present invention, described binary composite catalyst is two (triphenylphosphine) Palladous chloride (PdCl2(PPh3)2) and acetylacetone copper (Cu (acac)2) mixture, both mol ratios are 1:2-3, such as, can be 1:2,1:2.5 or 1:3.
In the described synthetic method of the present invention, described alkali is any one in sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert.-butoxide, sodium phosphate, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus etc., it is most preferred that be sodium phosphate.
In the described synthetic method of the present invention, described activator is polyamine compound, it is any one in 1,4-diazabicylo [2.2.2] octane (DABCO), Tetramethyl Ethylene Diamine (TMEDA), quadrol, hexanediamine, it is most preferred that be TMEDA.
In the described synthetic method of the present invention, described solvent is any one in N-Methyl pyrrolidone (NMP), dioxane, dimethyl sulfoxide (DMSO) (DMSO), toluene, dimethyl formamide (DMF), it is most preferred that be N-Methyl pyrrolidone.
In the described synthetic method of the present invention, the consumption of described solvent is not particularly limited, and those skilled in the art can select suitable consumption, reacting balance is such as made to carry out, or aftertreatment is easy to the amount carried out, and this belongs to ordinary skill in the art means, and this is no longer going to repeat them.
In the described synthetic method of the present invention, the mol ratio of described formula (II) compound and formula (III) compound 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 mol ratio of described formula (II) compound and catalyzer is 1:0.02-0.06, i.e. the mole dosage of described formula (II) compound and two (triphenylphosphine) Palladous chloride (PdCl forming catalyzer2(PPh3)2) and acetylacetone copper (Cu (acac)2) the ratio of mole dosage paper sum be 1:0.02-0.06, such as can be 1:0.02,1:0.03,1:0.04,1:0.05 or 1:0.06.
In the described synthetic method of the present invention, the mol ratio of described formula (II) compound and alkali is 1:1.5-2.5, such as, can be 1:1.5,1:2 or 1:2.5.
In the described synthetic method of the present invention, the mol ratio of described formula (II) compound and activator 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, carbon dioxide atmosphere realizes by continuing to blast carbonic acid gas in reaction system, and this is also ordinary skill in the art means, and this is no longer going to repeat them.
In the described synthetic method of the present invention, temperature of reaction is 80-110 DEG C, such as, can be 80 DEG C, 90 DEG C, 100 DEG C or 110 DEG C
In the described synthetic method of the present invention, the reaction times is 6-10 hour, such as, can be 6 hours, 7 hours, 8 hours, 9 hours or 10 hours.
In the described synthetic method of the present invention, react the aftertreatment after terminating as follows: after reaction terminates, naturally cool to room temperature, in reaction system, then add enough saturated sodium bicarbonate aqueous solutions, fully vibration, mixing, stratification, separate organic phase, again wash with water, by again separate organic phase anhydrous sodium sulfate drying, filtration, removal of solvent under reduced pressure, residue recrystallisation from isopropanol, obtains object product.
As mentioned above, the present invention provides the synthetic method of a kind of azoles alkyl compound, in the process, by the suitable selection of catalyzer, alkali, activator and solvent and combination, thus the azoles alkyl compound that can be used as pharmaceutical intermediate is obtained with high yield, have broad application prospects and industrialization potential in organic chemical synthesis and pharmaceutical synthesis field.
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.
Embodiment 1
To, in the appropriate solvent NMP of reactor, adding 100mmol formula (II) compound and 200mmol formula (III) compound, blow with carbon dioxide and sweep repeatedly, until becoming carbon dioxide atmosphere; Adding 2mmol binary composite catalyst under continuous stirring (is 0.6mmolPdCl2(PPh3)2With 1.4mmolCu (acac)2Mixture), 150mmol sodium phosphate and 10mmolTMEDA; Continue to lead to into carbon dioxide in reaction system, and it is warming up to 80 DEG C, at such a temperature stirring reaction 10 hours.
After reaction terminates, naturally cool to room temperature, then in reaction system, enough saturated sodium bicarbonate aqueous solutions are added, fully vibration, mixing, stratification, separate organic phase, again wash with water, by again separate organic phase anhydrous sodium sulfate drying, filtration, removal of solvent under reduced pressure, residue recrystallisation from isopropanol, obtaining formula (I) compound on object product, product rate is 97.8%.
1H-NMR(600MHz,CDCl3)��:3.91(s,3H,-OCH3), 6.92 (s, 1H), 7.02 (d, J=8.4Hz, 2H), 7.51-7.53 (m, 4H), 7.78 (d, J=8.4Hz, 2H).
MSm/z:329 (M+1,100).
Embodiment 2
To, in the appropriate solvent NMP of reactor, adding 100mmol formula (II) compound and 250mmol formula (III) compound, blow with carbon dioxide and sweep repeatedly, until becoming carbon dioxide atmosphere; Adding 4mmol binary composite catalyst under continuous stirring (is 1mmolPdCl2(PPh3)2With 3mmolCu (acac)2Mixture), 180mmol sodium phosphate and 15mmolTMEDA; Continue to lead to into carbon dioxide in reaction system, and it is warming up to 90 DEG C, at such a temperature stirring reaction 9 hours.
After reaction terminates, naturally cool to room temperature, then in reaction system, enough saturated sodium bicarbonate aqueous solutions are added, fully vibration, mixing, stratification, separate organic phase, again wash with water, by again separate organic phase anhydrous sodium sulfate drying, filtration, removal of solvent under reduced pressure, residue recrystallisation from isopropanol, obtaining formula (I) compound on object product, product rate is 97.3%.
1H-NMR(600MHz,CDCl3) ��: 2.44 (s, 3H), 6.91 (s, 1H), 7.35 (d, J=7.8Hz, 2H), 7.43 (d, J=8.4Hz, 2H), 7.48-7.54 (m, 3H), 7.87 (d, J=7.2Hz, 2H).
MSm/z:279 (M+1,100).
Embodiment 3
To, in the appropriate solvent NMP of reactor, adding 100mmol formula (II) compound and 300mmol formula (III) compound, blow with carbon dioxide and sweep repeatedly, until becoming carbon dioxide atmosphere; Adding 6mmol binary composite catalyst under continuous stirring (is 1.8mmolPdCl2(PPh3)2With 4.2mmolCu (acac)2Mixture), 200mmol sodium phosphate and 20mmolTMEDA; Continue to lead to into carbon dioxide in reaction system, and it is warming up to 110 DEG C, at such a temperature stirring reaction 6 hours.
After reaction terminates, naturally cool to room temperature, then in reaction system, enough saturated sodium bicarbonate aqueous solutions are added, fully vibration, mixing, stratification, separate organic phase, again wash with water, by again separate organic phase anhydrous sodium sulfate drying, filtration, removal of solvent under reduced pressure, residue recrystallisation from isopropanol, obtaining formula (I) compound on object product, product rate is 97.5%.
1H-NMR(600MHz,CDCl3) ��: 2.41 (s, 3H), 3.83 (s, 3H), 6.89 (s, 1H), 7.05 (d, J=9.0Hz, 2H), 7.24 (d, J=9.0Hz, 2H), 7.35 (d, J=9.0Hz, 2H), 7.68 (d, J=8.4Hz, 2H).
MSm/z:309 (M+1,100).
Embodiment 4
To, in the appropriate solvent NMP of reactor, adding 100mmol formula (II) compound and 220mmol formula (III) compound, blow with carbon dioxide and sweep repeatedly, until becoming carbon dioxide atmosphere; Adding 5mmol binary composite catalyst under continuous stirring (is 1.5mmolPdCl2(PPh3)2With 3.5mmolCu (acac)2Mixture), 180mmol sodium phosphate and 13mmolTMEDA; Continue to lead to into carbon dioxide in reaction system, and it is warming up to 100 DEG C, at such a temperature stirring reaction 7 hours.
After reaction terminates, naturally cool to room temperature, then in reaction system, enough saturated sodium bicarbonate aqueous solutions are added, fully vibration, mixing, stratification, separate organic phase, again wash with water, by again separate organic phase anhydrous sodium sulfate drying, filtration, removal of solvent under reduced pressure, residue recrystallisation from isopropanol, obtaining formula (I) compound on object product, product rate is 96.9%.
1H-NMR(600MHz,CDCl3) ��: 6.85 (s, 1H), 7.44 (d, J=8.4Hz, 2H), 7.48-7.53 (m, 4H), 7.74 (d, J=8.4Hz, 2H).
MSm/z:334 (M+1,100).
Embodiment 5-12: the investigation using single catalyst component
Embodiment 5-8: except binary composite catalyst wherein is all replaced the PdCl into same amount2(PPh3)2Outward, other operation is all constant, and to implement embodiment 5-8 respectively with the same procedure of embodiment 1-4.
Embodiment 9-12: except binary composite catalyst wherein all being replaced the Cu into same amount (acac)2Outward, other operation is all constant, and implements embodiment 9-12 with the same procedure with embodiment 1-4.
Concrete outcome sees the following form 1.
Table 1: the result of single catalyst
As seen from the above table, when adopting one-component catalyzer, product product rate, by significantly reducing, thus demonstrates in the described method of the present invention, adopts two (triphenylphosphine) Palladous chloride (PdCl only simultaneously2(PPh3)2) and acetylacetone copper (Cu (acac)2) mixture as binary composite catalyst, the excellent technique effect of the present invention could be obtained.
Embodiment 13-20: change PdCl2(PPh3)2Time investigation
Except by PdCl wherein2(PPh3)2Replace as, outside the corresponding palladium compound in following table 2, other is all constant, and implements embodiment 13-20 with the same way with embodiment 1-4, is used palladium compound, corresponding relation and product product rate to see the following form 2.
Table 2: change PdCl2(PPh3)2Time result
As seen from the above table, when by PdCl2(PPh3)2When replacing other palladium compounds, all cause product rate to have remarkable reduction, this demonstrate that only PdCl2(PPh3)2The excellent effect of the present invention could be obtained, even if the Pd (PPh also containing triphenylphosphine3)4, its product rate also has and significantly reduces.
Embodiment 21-28: change Cu (acac)2Time investigation
Except by Cu (acac) wherein2Replace as, outside the corresponding copper compound in following table 3, other is all constant, and implements embodiment 21-28 with the same way with embodiment 1-4, is used copper compound, corresponding relation and product product rate to see the following form 3.
Table 3: change Cu (acac)2Time result
As seen from the above table, when by Cu (acac)2Replace for replace other copper compounds time, all cause product rate to have remarkable reduction, even if with Cu (acac)2Very similar trifluoroacetylacetone copper, its product rate is also significantly reduced to 62.1% by the 97.8% of embodiment 1, this demonstrate that only Cu (acac)2The excellent effect of the present invention could be obtained.
Embodiment 29-36: the investigation of alkali
Replace as, except other alkali in following table 4, other is all constant, and implements embodiment 29-36 with the same way with embodiment 1-4, is used alkali, corresponding relation and product product rate to see the following form 4 except by sodium phosphate wherein.
Table 4: change result during alkali
As seen from the above table, when sodium phosphate is replaced as other alkali, all cause product rate to have and significantly reduce.
Embodiment 37-48: the investigation of activator
Embodiment 37-40: all replace except the DABCO into same amount except by TMEDA wherein, other operation is all constant, and to implement embodiment 37-40 respectively with the same procedure of embodiment 1-4.
Embodiment 41-44: all replace except the quadrol into same amount except by TMEDA wherein, other operation is all constant, and to implement embodiment 41-44 respectively with the same procedure of embodiment 1-4.
Embodiment 45-48: all replace except the hexanediamine into same amount except by TMEDA wherein, other operation is all constant, and to implement embodiment 45-48 respectively with the same procedure of embodiment 1-4.
The results are shown in following table 5.
Table 5: the result of different activator
It thus is seen that the kind of activator has remarkably influenced for product product rate, wherein TMEDA has best activation effect, even if the quadrol very similar with it, its product rate also has remarkable reduction.
Embodiment 49-64: the investigation of solvent
Embodiment 49-52: except solvent NMP wherein all being replaced into, except dioxane, other operation is all constant, and to implement embodiment 49-52 respectively with the same procedure of embodiment 1-4.
Embodiment 53-56: except solvent NMP wherein all being replaced into, except DMSO, other operation is all constant, and to implement embodiment 53-56 respectively with the same procedure of embodiment 1-4.
Embodiment 57-60: except solvent NMP wherein all being replaced into, except toluene, other operation is all constant, and to implement embodiment 57-60 respectively with the same procedure of embodiment 1-4.
Embodiment 61-64: except solvent NMP wherein all being replaced into, except DMF, other operation is all constant, and to implement embodiment 61-64 respectively with the same procedure of embodiment 1-4.
The results are shown in following table 6.
Table 6: the result of different solvents
It thus is seen that the kind of solvent has certain impact for product product rate, wherein NMP has best effect.
In sum, the present invention is by constructing novel catalyzer, alkali, activator and solvent reaction system, thus greatly improves product yield, has prospects for commercial application very widely in organic chemical synthesis and pharmaceutical intermediate synthesis field.
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 (6)
1. a synthetic method for azoles alkyl compound shown in following formula (I),
Described method comprises: under binary composite catalyst, alkali and activator exist, in carbon dioxide atmosphere, following formula (II) compound and formula (III) compound react in a solvent, thus obtain upper formula (I) azoles alkyl compound
Wherein, R1And R2It is H, C independently of one another1-C6Alkyl, C1-C6Alkoxyl group or chlorine;
Described binary composite catalyst is the mixture of two (triphenylphosphine) Palladous chlorides and acetylacetone copper, and both mol ratios are 1:2-3;
Described alkali is sodium phosphate;
Described activator is Tetramethyl Ethylene Diamine;
Described solvent is N-Methyl pyrrolidone.
2. synthetic method according to claim 1, it is characterised in that: the mol ratio of described formula (II) compound and formula (III) compound is 1:2-3.
3. synthetic method according to claim 1, it is characterised in that: the mol ratio of described formula (II) compound and catalyzer is 1:0.02-0.06.
4. synthetic method according to claim 1, it is characterised in that: the mol ratio of described formula (II) compound and alkali is 1:1.5-2.5.
5. synthetic method according to claim 1, it is characterised in that: the mol ratio of described formula (II) compound and activator is 1:0.1-0.2.
6. synthetic method according to the arbitrary item of claim 1-5, it is characterised in that: temperature of reaction is 80-110 DEG C; Reaction times is 6-10 hour.
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Non-Patent Citations (3)
| Title |
|---|
| Chemical fixation of carbon dioxide by copper catalyzed multicomponent reactions for oxazolidinedione syntheses;Siddharth Sharma et al.;《Green Chemistry》;20141223;第17卷;第1404-1407页 * |
| Simple and Efficient Copper-Catalyzed Approach to 2,4-Disubstituted Imidazolones;Xiaoyu Gong et al.;《Organic Letters》;20100618;第12卷(第14期);第3128-3131页 * |
| Synthesis of oxazolidine-2,4-diones by a tandem phosphorus-mediated carboxylative condensation-cyclization reaction using atmospheric carbon dioxide;Wen-Zhen Zhang et al.;《Chem. Commun.》;20150303;第51卷;第6175-6178页 * |
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