CN104744290B - A kind of synthetic method of imide analog compounds - Google Patents
A kind of synthetic method of imide analog compounds Download PDFInfo
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Abstract
The present invention relates to the synthetic method of a kind of imide analog compounds; described method has promoted efficiently synthesizing of imide analog compounds with the catalyst system and catalyzing of FeCl2/ auxiliary agent; and by experiment of single factor means, the best of breed of component is optimized and obtains best Complex catalyst system; the preparation method that this preparation technology has opened up imide compound; and reaction yield is high, there is wide scale application prospect and market potential is worth.
Description
Technical field
The application is the applying date is " on 04 10th, 2014 ", and application number is " 201410142432.6 ", and patent name is the divisional application of " synthetic method of a kind of imide analog compounds ".
Background technology
At present, acid imide structure is widely present in many to be had among bioactive drug molecule, and receives significant attention in actual pharmaceutical synthesis field, for instance, pecilocin, aniracetam and many synthesis comprising heterocyclic compound natural product.
It is known that acyl chlorides is comparatively traditional synthesis strategy as acylating reagent for constructing imide compound, but the acyl chlorides reagent involved by this kind of method has many shortcoming such as unstability, corrosivity.In addition, the structure being used for C-N key by the direct oxidation coupling between c h bond and N-H key is also the method that prior art is commonly used, the NH nucleopilic reagent that it mainly adopts has aminated compounds or specific amide (such as picolinamide or primary amide etc.), and example is as follows:
LiangChungen etc. (" EfficientDiastereoselectiveIntermolecularRhodium-Catalyz edC-HAmination ", Angew.Chem.Int.Ed., 2006,45,4641-4644) report the C-H aminating reaction of a kind of rhodium catalysis, its adopt sulfimide amide compound be nitrene precursor and the substrate containing c h bond as limiting component, for C-H aminating reaction in the molecule of rhodium catalysis, reaction equation is as follows:
PhilipWaiHongChan etc. (" HighlyEfficientRuthenium (II) PhorphyrinCatalyzedAmidationofAldehydes ", Angew.Chem.Int.Ed., 2008,47,1138-1140) report one with PhI=NTs for nitrogenous source, realizing the amidation process of C-H under the catalysis of ruthenium-porphyrin complex, its reaction equation is as follows:
(" the SynthesisofImidesbyPalladium-CatalyzedC-H such as BianYong-Jun
FunctionalizationofAldehydeswithSecondaryAmides "; Chem.Eur.J.2013; 19; 1129-1133) to report the N-aromatic ring-2-Methanamide that a kind of aldehyde compound and N-replace be raw material; the method for synthesizing secondary imide compound under palladium catalyst effect, its reaction equation is as follows:
WangLong etc. (" HighlyEfficientCopper-CatalyzedAmidationofAldehydesbyC-H Activation ", Chem.Eur.J.2008,14,10722-10726) disclose a kind of amidation process of the aldehyde compound of copper catalysis under NBS exists, the method is simple, practical and economy is strong, and its reaction equation is as follows:
But, above-mentioned prior art is still not able to meet current medical intermediate, the synthesis of chemical intermediate and research and development, its mainly due to: 1, the product yield of prior art is still not high enough；2, catalyst relates generally to noble metal or the complex of costliness, hence it is evident that add production cost.The defect that the present inventor exists for prior art, it is intended to explored the novel preparation process of a kind of practical, imide compound that reaction yield is high by Design Theory and experimentation, thus fully meeting the Production requirement in the fields such as chemical and medicine industry.
Summary of the invention
In order to overcome many defects as indicated above, this is conducted in-depth research by the present inventor, after having paid a large amount of creative work, thus developing the novel preparation process of a kind of imide compound, and then completes the present invention.
Specifically, technical scheme and content relate to the synthetic method of a kind of formula III compound, and described method comprises the steps: to add formula I compound and FeCl in reactor2, stir and pass into nitrogen and maintain nitrogen atmosphere, in system, then add solvent toluene, under stirring, add formula II compound, TBHP (tert-butyl hydroperoxide) and auxiliary agent, continue logical
Pass into and seal after nitrogen, temperature reaction, add that shrend is gone out, ether extracts after completion of the reaction, dry through anhydrous sodium sulfate after merging organic facies, filter, after vacuum concentration, residue by silicagel column chromatogram purification, formula III compound can be obtained:
Wherein:
R1 is with substituent group or unsubstituted C1-C6 alkyl, with substituent group or unsubstituted phenyl；
R2, R3 are each independently with substituent group or unsubstituted C1-C6 alkyl, with substituent group or unsubstituted phenyl or benzyl；
Described substituent group in R1-R3 is C1-C6 alkyl, C1-C6 alkoxy or halogen.
In the described synthetic method of the present invention, described halogen is fluorine, chlorine, bromine or iodine atom.
In the described synthetic method of the present invention, described C1-C6 alkyl refers to the alkyl with 1-6 carbon atom, it can be straight or branched, can be such as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, n-hexyl etc. in non-limiting manner.
In the described synthetic method of the present invention, described C1-C6 alkoxyl refers to the group that C1-C6 alkyl is connected with oxygen atom.
In the described synthetic method of the present invention, described auxiliary agent is 2-dicyclohexylphosphontetrafluoroborate-2', 4', 6'-tri isopropyl biphenyl (Xphos), 1,10-o-phenanthroline and I2O5Mixture, wherein 2-dicyclohexyl phosphorus-2', 4', 6'-tri isopropyl biphenyl, 1,10-phenanthroline and I2O5Mass ratio be 1:0.2-0.5:0.1-0.3, it is preferable that 1:0.4:0.2.
In the described synthetic method of the present invention, described formula I compound and FeCl2Mol ratio be 1:0.02-0.1, for instance can be 1:0.02,1:0.03,1:0.04,1:0.05,1:0.06,1:0.07,1:0.08,1:0.09 or 1:0.1, it is preferred to 1:0.04-0.07.
In the described synthetic method of the present invention, the mol ratio of described formula I compound and formula II compound is 1:2-5, can be 1:2,1:2.5,1:3,1:3.5,1:4,1:4.5 or 1:5 in non-limiting manner, it is preferred to 1:2.5-4.
In the described synthetic method of the present invention, the mol ratio of described formula I compound and TBHP is 1:2-3, can be such as 1:2,1:2.1,1:2.2,1:2.3,1:2.4,1:2.5,1:2.6,1:2.7,1:2.8,1:2.9 or 1:3, it is preferred to 1:2.2-2.5.
In the described synthetic method of the present invention, the molal volume of described formula I compound and toluene is than for 1:5-8mol/L, namely every 1mol formula I compound uses 5-8L toluene, can be 1:5mol/L, 1:5.5mol/L, 1:6mol/L, 1:6.5mol/L, 1:7mol/L, 1:7.5mol/L or 1:8mol/L in non-limiting manner, it is preferred to 1:5.5-6.5mol/L.
In the described synthetic method of the present invention, the ratio of described formula I compound in mol and auxiliary agent in gram is 1:8-12mol/g, namely every 1mol formula I compound uses 8-12g auxiliary agent, can be 1:8mol/g, 1:9mol/g, 1:10mol/g, 1:11mol/g or 1:12mol/g in non-limiting manner.
In the described synthetic method of the present invention, the response time is without particular limitation, for instance can be 10-14h, can be 10h, 11h, 12h, 13h or 14h in non-limiting manner.
In the described synthetic method of the present invention, reaction temperature is 45-55 DEG C, for instance can be 45 DEG C, 50 DEG C or 55 DEG C.
In the described synthetic method of the present invention, described silica gel chromatography can use any silica gel column chromatography as known in the art, such as use 200-400 order silica gel, eluent is the mixture of normal propyl alcohol and petroleum ether, wherein normal propyl alcohol, petroleum ether volume ratio be 1:1.5.Unless otherwise prescribed, the operation of the silica gel chromatography in all embodiments is the use silica gel of 200-400 order below, eluent is volume ratio be the normal propyl alcohol of 1:1.5 with the mixture of petroleum ether to be purified operation.
Compared with prior art, the invention have the benefit that
1, FeCl is adopted first2The catalyst system and catalyzing of/auxiliary agent, it is achieved that imide compound is prepared in amide and aldehyde compound reaction, and reaction yield is greatly improved.
2, have studied the impact of adjuvant component this factor of kind, filtered out the best of breed of adjuvant component, effective synergistic catalyst improves reactivity worth.
Detailed description of the invention
Below by specific embodiment, the present invention is described in detail; but the purposes of these exemplary embodiments and purpose are only used for enumerating the present invention; not the real protection scope of the present invention is constituted any type of any restriction, more non-protection scope of the present invention is limited thereto.
Embodiment 1
1mol formula I compound and 0.06molFeCl is added in reactor2Stir and pass into nitrogen and maintain nitrogen atmosphere, then in system, add 6L solvent toluene, 3mol formula II compound, 2.2molTBHP and 2-dicyclohexylphosphontetrafluoroborate-2' that mass ratio is 1:0.4:0.2 is added under stirring, 4', 6'-tri isopropyl biphenyl (Xphos), 1,10-o-phenanthroline and I2O5Agent mixture (gross mass is 10g), continuation seals after all entering nitrogen, heat up 50 DEG C of reaction 14h, add shrend after completion of the reaction to go out, adopt ether to extract, merge after organic facies dry through anhydrous sodium sulfate, filter, after vacuum concentration, residue by silicagel column chromatogram purification, formula III compound can be obtained, yield is 93.8%, and purity is 98.9% (HPLC).
1HNMR(400MHz,CDCl3)δ=7.62-7.49(m,5H),3.21(s,3H),2.33(s,3H)；
MS[M+H]+:177.07。
Embodiment 2
1mol formula I compound and 0.04molFeCl is added in reactor2Stir and pass into nitrogen and maintain nitrogen atmosphere, then in system, add 5.5L solvent toluene, 2.5mol formula II compound, 2.5molTBHP and 2-dicyclohexylphosphontetrafluoroborate-2' that mass ratio is 1:0.4:0.2 is added under stirring, 4', 6'-tri isopropyl biphenyl (Xphos), 1,10-o-phenanthroline and I2O5Agent mixture (gross mass is 12g), continuation seals after all entering nitrogen, heat up 55 DEG C of reaction 12h, add shrend after completion of the reaction to go out, adopt ether to extract, merge after organic facies dry through anhydrous sodium sulfate, filter, after vacuum concentration, residue by silicagel column chromatogram purification, formula III compound can be obtained, yield is 94.6%, and purity is 98.7% (HPLC).
1HNMR(400MHz,CDCl3)δ=7.61-7.59(m,2H),7.36-7.29(m,3H),7.07-7.04(m,2H),6.82(m,2H),3.71(s,3H),2.38(s,3H)；
MS[M+H]+:269.10。
Embodiment 3
1mol formula I compound and 0.05molFeCl is added in reactor2Stir and pass into nitrogen and maintain nitrogen atmosphere, then in system, add 6.5L solvent toluene, 4mol formula II compound, 2.4molTBHP and 2-dicyclohexylphosphontetrafluoroborate-2' that mass ratio is 1:0.4:0.2 is added under stirring, 4', 6'-tri isopropyl biphenyl (Xphos), 1,10-o-phenanthroline and I2O5Agent mixture (gross mass is 8g), continuation seals after all entering nitrogen, heat up 50 DEG C of reaction 13h, add shrend after completion of the reaction to go out, adopt ether to extract, merge after organic facies dry through anhydrous sodium sulfate, filter, after vacuum concentration, residue by silicagel column chromatogram purification, formula III compound can be obtained, yield is 94.1%, and purity is 98.8% (HPLC).
1HNMR(400MHz,CDCl3)δ=7.62(d,J=8.0Hz,2H),7.41-7.22(m,6H),7.16(d,J=8.0Hz,2H),2.44(s,3H)；
MS[M+H]+:240.10。
Embodiment 4
1mol formula I compound and 0.07molFeCl is added in reactor2Stir and pass into nitrogen and maintain nitrogen atmosphere, then in system, add 6L solvent toluene, 3.5mol formula II compound, 2.3molTBHP and 2-dicyclohexylphosphontetrafluoroborate-2' that mass ratio is 1:0.4:0.2 is added under stirring, 4', 6'-tri isopropyl biphenyl (Xphos), 1,10-o-phenanthroline and I2O5Agent mixture (gross mass is 10g), continuation seals after all entering nitrogen, heat up 55 DEG C of reaction 11h, add shrend after completion of the reaction to go out, adopt ether to extract, merge after organic facies dry through anhydrous sodium sulfate, filter, after vacuum concentration, residue by silicagel column chromatogram purification, formula III compound can be obtained, yield is 94.5%, and purity is 98.4% (HPLC).
1HNMR(400MHz,CDCl3)δ=7.45-7.43(m,1H),7.38-7.36(m,1H),7.26-7.12(m,7H),4.95(s,2H),2.31(s,3H)；
MS[M+H]+:271.10。
Embodiment 5-8
Except by FeCl2Replacing with outside following component, implement embodiment 5-8 respectively in the way of identical with embodiment 1-4, component is as shown in table 1 below with the corresponding relation of experimental result.
Table 1
"--" represent without.
From the result of embodiment 1-4 and table 1, the present inventor studies discovery by experiment: the catalyst that can produce optimum catalytic performance in this catalyst/adjuvant system is FeCl2, and show the low yield differed greatly or do not react when other similar iron salt compounds are catalyst.Which demonstrating catalyst type is the key factor affecting reaction process, secondly there is likely to be obvious correlation between catalyst and auxiliary agent.
Embodiment 9-12
Except by the 2-dicyclohexylphosphontetrafluoroborate-2' in auxiliary agent, 4', 6'-tri isopropyl biphenyl (Xphos) replaces with outside following component, implements embodiment 9-12 respectively in the way of identical with embodiment 1-4, and component is as shown in table 2 below with the corresponding relation of experimental result.
Table 2
Embodiment 13-16
Except replacing with outside following component by 1,10-o-phenanthroline in auxiliary agent, implementing embodiment 13-16 respectively in the way of identical with embodiment 1-4, component is as shown in table 3 below with the corresponding relation of experimental result.
Table 3
Embodiment 17-20
Except being not added with in auxiliary agent I2O5Outward, implementing embodiment 17-20 respectively in the way of identical with embodiment 1-4, component is as shown in table 4 below with the corresponding relation of experimental result.
Table 4
"--" represent without.
Result from embodiment 1-4 and table 2-table 4, close association and synergism is there is between each component of auxiliary agent, by the kind of research component 1 and component 2, optimized choice goes out 2-dicyclohexylphosphontetrafluoroborate-2', 4', 6'-tri isopropyl biphenyl (Xphos) and 1,10-o-phenanthroline, demonstrates component 3 indispensable in auxiliary agent by studying component 3, and it can affect whole system reactivity worth.The method that the present inventor is combined with laboratory facilities by theoretical knowledge, not only constructs the novel auxiliary system composite with iron salt catalyst, but also each component of auxiliary agent has been carried out suitable selection, achieves the technique effect of excellence simultaneously.
In sum, the present inventor passes through substantial amounts of creative work, have developed the novel preparation process of a kind of imide compound, and it is with FeCl2The catalyst system and catalyzing of/auxiliary agent and achieve and promote efficiently synthesizing of imide compound, and by experiment of single factor means, the best of breed of component is optimized and obtains best catalyst system and catalyzing, the preparation method that this preparation technology has opened up imide compound, and there is certain prospects for commercial application and market potential.
Should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limit the scope of the invention.In addition; it is also contemplated that; 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 all these equivalent form of value falls within the application appended claims protection defined equally.
Claims (8)
1. a synthetic method for formula (III) compound, described method comprises the steps: to add formula I compound and FeCl in reactor2Stir and pass into nitrogen and maintain nitrogen atmosphere, then in system, add solvent toluene, add formula (II) compound, TBHP and auxiliary agent under stirring, seal after continuing to pass into nitrogen, temperature reaction, addition shrend is gone out after completion of the reaction, ether extracts, merge after organic facies dry through anhydrous sodium sulfate, filter, after vacuum concentration, residue by silicagel column chromatogram purification, formula (III) compound can be obtained:
Wherein:
R1 is with substituent group or unsubstituted C1-C6 alkyl, with substituent group or unsubstituted phenyl；
R2, R3 are each independently with substituent group or unsubstituted C1-C6 alkyl, with substituent group or unsubstituted phenyl or benzyl；
Described substituent group in R1-R3 is C1-C6 alkyl, C1-C6 alkoxy or halogen；
Described auxiliary agent is 2-dicyclohexylphosphontetrafluoroborate-2', 4', 6'-tri isopropyl biphenyl, 1,10-o-phenanthroline and I2O5Mixture；2-dicyclohexylphosphontetrafluoroborate-2', 4', 6'-tri isopropyl biphenyl, 1,10-o-phenanthroline and I in described auxiliary agent2O5Mass ratio be 1:0.2-0.5:0.1-0.3；The silica gel used in described silica gel chromatography is 200-400 order, and eluent is the mixture of normal propyl alcohol and petroleum ether, and the volume ratio of normal propyl alcohol and petroleum ether is 1:1.5.
2. synthetic method as claimed in claim 1, it is characterised in that: 2-dicyclohexylphosphontetrafluoroborate-2', 4', 6'-tri isopropyl biphenyl, 1,10-o-phenanthroline and I in described auxiliary agent2O5Mass ratio be 1:0.4:0.2.
3. synthetic method as claimed in claim 1 or 2, it is characterised in that: described formula I compound and FeCl2Mol ratio be 1:0.02-0.1.
4. synthetic method as claimed in claim 1 or 2, it is characterised in that: the mol ratio of described formula I compound and formula (II) compound is 1:2-5.
5. synthetic method as claimed in claim 1 or 2, it is characterised in that: the mol ratio of described formula I compound and TBHP is 1:2-3.
6. synthetic method as claimed in claim 1 or 2, it is characterised in that: the molal volume of described formula I compound and toluene ratio is for 1:5-8mol/L.
7. synthetic method as claimed in claim 1 or 2, it is characterised in that: the ratio of described formula I compound in mol and auxiliary agent in gram is 1:8-12mol/g.
8. synthetic method as claimed in claim 1 or 2, it is characterised in that: the response time is 10-14h；Reaction temperature is 45-55 DEG C.
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| CN101985415A (en) * | 2010-11-11 | 2011-03-16 | 江南大学 | Preparation method of verbenol and verbenone through air oxidation of a-pinene at room temperature |
| WO2012052874A1 (en) * | 2010-10-18 | 2012-04-26 | Centre National De La Recherche Scientifique | Method for functionalising surfaces for analyte detection |
| CN102516138A (en) * | 2011-10-31 | 2012-06-27 | 成都理工大学 | N-aryl t-butyl sulfonamide, synthetic method and application thereof |
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| WO2012052874A1 (en) * | 2010-10-18 | 2012-04-26 | Centre National De La Recherche Scientifique | Method for functionalising surfaces for analyte detection |
| CN101985415A (en) * | 2010-11-11 | 2011-03-16 | 江南大学 | Preparation method of verbenol and verbenone through air oxidation of a-pinene at room temperature |
| CN102516138A (en) * | 2011-10-31 | 2012-06-27 | 成都理工大学 | N-aryl t-butyl sulfonamide, synthetic method and application thereof |
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Effective date of registration: 20170505 Address after: 226000 Jiangsu province Nantong City Jiuhua high tech Industrial Development Zone, Road No. 888 Patentee after: Jiangsu Deming New Material Co., Ltd. Address before: 325600 Zhejiang city of Wenzhou province Yueqing City Yuecheng town Fortunearia hole village Patentee before: Shen Jun |