CN104725267B - The synthetic method of imide analog compounds - Google Patents
The synthetic method of imide analog compounds Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 42
- 238000010189 synthetic method Methods 0.000 title claims abstract description 18
- 150000003949 imides Chemical class 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 239000012752 auxiliary agent Substances 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 10
- 229910021577 Iron(II) chloride Inorganic materials 0.000 claims abstract description 7
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims abstract description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000000741 silica gel Substances 0.000 claims description 7
- 229910002027 silica gel Inorganic materials 0.000 claims description 7
- 229960001866 silicon dioxide Drugs 0.000 claims description 7
- 208000035126 Facies Diseases 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 3
- 229910052736 halogen Chemical group 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 abstract description 14
- -1 imide compound Chemical class 0.000 abstract description 14
- 238000002360 preparation method Methods 0.000 abstract description 6
- 238000005516 engineering process Methods 0.000 abstract description 4
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 238000002474 experimental method Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 7
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 238000011938 amidation process Methods 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- UXKCLTPQRBKROC-UHFFFAOYSA-N C(C)(C)C1=C(C(=CC(=C1)C(C)C)C(C)C)C1=CC=CC=C1.[P] Chemical group C(C)(C)C1=C(C(=CC(=C1)C(C)C)C(C)C)C1=CC=CC=C1.[P] UXKCLTPQRBKROC-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000032825 Ring chromosome 2 syndrome Diseases 0.000 description 1
- ZYPGADGCNXOUJP-CXVPHVKISA-N Variotin Chemical compound CCCC[C@@H](O)\C=C(/C)\C=C\C=C\C(=O)N1CCCC1=O ZYPGADGCNXOUJP-CXVPHVKISA-N 0.000 description 1
- XSWALQKVYPLUJA-UHFFFAOYSA-N [Ru].N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 Chemical compound [Ru].N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 XSWALQKVYPLUJA-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- ZXNRTKGTQJPIJK-UHFFFAOYSA-N aniracetam Chemical compound C1=CC(OC)=CC=C1C(=O)N1C(=O)CCC1 ZXNRTKGTQJPIJK-UHFFFAOYSA-N 0.000 description 1
- 229960000793 aniracetam Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002505 iron Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229960000599 pecilocin Drugs 0.000 description 1
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003140 primary amides Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to the synthetic method of a kind of imide analog compounds; described method promotes 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 optimal Complex catalyst system; this preparation technology has opened up the preparation method of imide compound; and reaction yield is high, there is wide scale application prospect and market potential is worth.
Description
Technical field
The application is filing date " on 04 10th, 2014 ", and Application No. " 201410142432.6 ", 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 in reality
Pharmaceutical synthesis field in receive significant attention, such as, pecilocin, aniracetam and many comprise the natural product of heterocyclic compound
The synthesis of thing.
It is known that it is the most traditional synthesis strategy that acyl chlorides is used for constructing imide compound as acylating reagent, so
And the acyl chlorides reagent involved by this kind of method has many shortcoming such as unstability, corrosivity.In addition, by c h bond and N-H
Direct oxidation coupling between key is also the method that prior art is commonly used for the structure of C-N key, the NH nucleophilic that it mainly uses
Reagent has aminated compounds or specific amide (such as picolinamide or primary amide etc.), and example is as follows:
(" the EfficientDiastereoselectiveIntermolecularRhodium-such as LiangChungen
CatalyzedC-HAmination ", Angew.Chem.Int.Ed., 2006,45,4641-4644) report a kind of rhodium catalysis
C-H aminating reaction, its use sulfimide amide compound be nitrene precursor and containing c h bond substrate as limit component,
For the intramolecular C-H aminating reaction of rhodium catalysis, reaction equation is as follows:
(" the HighlyEfficientRuthenium (II) such as PhilipWaiHongChan
PhorphyrinCatalyzedAmidationofAldehydes”,Angew.Chem.Int.Ed.,2008,47,1138-
1140) report a kind of with PhI=NTs for nitrogen source, under the catalysis of ruthenium-porphyrin complex, realize the amidation process of C-H, its
Reaction equation is as follows:
(" the SynthesisofImidesbyPalladium-CatalyzedC-H such as BianYong-Jun
FunctionalizationofAldehydeswithSecondaryAmides”,Chem.Eur.J.2013,19,
1129-1133) reporting a kind of aldehyde compound is raw material with N-substituted N-aromatic ring-2-Methanamide, in palladium catalyst effect
The method of lower synthesizing secondary imide compound, its reaction equation is as follows:
(" the HighlyEfficientCopper-CatalyzedAmidationofAldehydesbyC-such as WangLong
HActivation ", Chem.Eur.J.2008,14,10722-10726) disclose a kind of aldehydes of copper catalysis in the presence of NBS
The amidation process of compound, 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 the most not high enough;2, catalyst relates generally to noble metal or the network of costliness
Compound, hence it is evident that add production cost.The defect that the present inventor exists for prior art, it is intended to by Design Theory and experiment
Research and explore a kind of practical, novel preparation process of imide compound that reaction yield is high, thus fully satisfiedization
The Production requirement of work medicine and other fields.
Summary of the invention
In order to overcome many defects as indicated above, this is conducted in-depth research by the present inventor, a large amount of having paid
After creative work, thus develop the novel preparation process of a kind of imide compound, and then complete the present invention.
Specifically, technical scheme and content relate to the synthetic method of a kind of formula III compound, described side
Method comprises the steps: to add formula I compound and FeCl in reactor2, stir and be passed through nitrogen and maintain nitrogen atmosphere, so
Backward system adds solvent toluene, adds formula II compound, TBHP (tert-butyl hydroperoxide) and auxiliary agent under stirring, continue
Continuous logical
Sealing after being passed through nitrogen, temperature reaction, addition shrend is gone out after completion of the reaction, ether extracts, and merges warp after organic facies
Anhydrous sodium sulfate is dried, filter, be concentrated in vacuo after, residue by silicagel column chromatogram purification, i.e. can get formula III compound:
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 benzene
Base 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, and it can
For straight or branched, can be the most 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 the described synthetic method of the present invention, described C1-C6 alkoxyl refers to the base that C1-C6 alkyl is connected with oxygen atom
Group.
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, preferably 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,
Can be such as 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, be preferably
1:0.04-0.07。
In the described synthetic method of the present invention, described formula I compound is 1:2-with the mol ratio of formula II compound
5, can be 1:2,1:2.5,1:3,1:3.5,1:4,1:4.5 or 1:5, preferably 1:2.5-4 in non-limiting manner.
In the described synthetic method of the present invention, described formula I compound is 1:2-3 with the mol ratio of TBHP, such as may be used
For 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, preferably 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, i.e. every 1mol formula I compound uses 5-8L toluene, can be in non-limiting manner 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, preferably 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
For 1:8-12mol/g, i.e. every 1mol formula I compound uses 8-12g auxiliary agent, can be 1:8mol/g, 1:9mol/ in non-limiting manner
G, 1:10mol/g, 1:11mol/g or 1:12mol/g.
In the described synthetic method of the present invention, the response time is without particular limitation, such as, can be 10-14h, indefiniteness
Ground can be 10h, 11h, 12h, 13h or 14h.
In the described synthetic method of the present invention, reaction temperature is 45-55 DEG C, such as, 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 silicon as known in the art
Glue column chromatography, such as, use the silica gel of 200-400 mesh, and eluent is the mixture of normal propyl alcohol and petroleum ether, wherein normal propyl alcohol, stone
The volume ratio of oil ether is 1:1.5.Unless otherwise prescribed, the operation of the silica gel chromatography in all embodiments below is and makes
It is that volume ratio is the normal propyl alcohol of 1:1.5 and the mixture of petroleum ether is purified behaviour with the silica gel of 200-400 mesh, eluent
Make.
Compared with prior art, the invention have the benefit that
1, FeCl is used first2The catalyst system and catalyzing of/auxiliary agent, it is achieved that imidizate is prepared in amide and aldehyde compound reaction
Compound, 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, effectively assisted
Reactivity worth is improved with catalyst.
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 is only used for enumerating the present invention, and not the real protection scope to the present invention constitutes any type of any restriction, more non-general
Protection scope of the present invention is confined to this.
Embodiment 1
1mol formula I compound and 0.06mol FeCl is added in reactor2, stir and be passed through nitrogen and maintain blanket of nitrogen
Enclose, in system, then add 6L solvent toluene, under stirring, add 3mol formula II compound, 2.2molTBHP and mass ratio
For the 2-dicyclohexylphosphontetrafluoroborate-2' of 1:0.4:0.2,4', 6'-tri isopropyl biphenyl (Xphos), 1,10-o-phenanthroline and I2O5Help
Agent composition (gross mass is 10g), seals after continuing all to enter nitrogen, and heat up 50 DEG C of reaction 14h, adds shrend after completion of the reaction
Go out, use ether to extract, merge after organic facies after being dried through anhydrous sodium sulfate, filtering, be concentrated in vacuo, residue by silicagel column color
Spectrum purification, i.e. can get formula III compound, and 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 0.04mol FeCl is added in reactor2, stir and be passed through nitrogen and maintain blanket of nitrogen
Enclose, in system, then add 5.5L solvent toluene, under stirring, add 2.5mol formula II compound, 2.5molTBHP and matter
Amount is than the 2-dicyclohexylphosphontetrafluoroborate-2' for 1:0.4:0.2,4', 6'-tri isopropyl biphenyl (Xphos), 1,10-o-phenanthroline and I2O5
Agent mixture (gross mass is 12g), continue all to enter after nitrogen and seal, heats up 55 DEG C and react 12h, add after completion of the reaction
Shrend is gone out, is used ether to extract, and merges after organic facies after being dried through anhydrous sodium sulfate, filtering, be concentrated in vacuo, residue over silica gel
Column chromatography purification, i.e. can get formula III compound, and 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 0.05mol FeCl is added in reactor2, stir and be passed through nitrogen and maintain blanket of nitrogen
Enclose, in system, then add 6.5L solvent toluene, under stirring, add 4mol formula II compound, 2.4molTBHP and quality
Than the 2-dicyclohexylphosphontetrafluoroborate-2' for 1:0.4:0.2,4', 6'-tri isopropyl biphenyl (Xphos), 1,10-o-phenanthroline and I2O5's
Agent mixture (gross mass is 8g), seals after continuing all to enter nitrogen, and heat up 50 DEG C of reaction 13h, adds water after completion of the reaction
Cancellation, use ether extraction, merge after organic facies after being dried through anhydrous sodium sulfate, filtering, be concentrated in vacuo, residue by silicagel column
Chromatogram purification, i.e. can get formula III compound, and 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 0.07mol FeCl is added in reactor2, stir and be passed through nitrogen and maintain blanket of nitrogen
Enclose, in system, then add 6L solvent toluene, under stirring, add 3.5mol formula II compound, 2.3molTBHP and quality
Than the 2-dicyclohexylphosphontetrafluoroborate-2' for 1:0.4:0.2,4', 6'-tri isopropyl biphenyl (Xphos), 1,10-o-phenanthroline and I2O5's
Agent mixture (gross mass is 10g), seals after continuing all to enter nitrogen, and heat up 55 DEG C of reaction 11h, adds water after completion of the reaction
Cancellation, use ether extraction, merge after organic facies after being dried through anhydrous sodium sulfate, filtering, be concentrated in vacuo, residue by silicagel column
Chromatogram purification, i.e. can get formula III compound, and 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 FeCl2Replace with outside following component, in the way of identical with embodiment 1-4, implement embodiment respectively
5-8, component is as shown in table 1 below with the corresponding relation of experimental result.
Table 1
"--" represent without.
From embodiment 1-4 and the result of table 1, the present inventor is by experimental studies have found that: at this catalyst/auxiliary agent body
The catalyst that can produce optimum catalytic performance in system is FeCl2, and table when other similar iron salt compounds are catalyst
Reveal the low yield differed greatly or do not react.Which demonstrating catalyst type is the key factor affecting reaction process, secondly
Obvious correlation is there is likely to be 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 following component
Outward, implementing embodiment 9-12 in the way of identical with embodiment 1-4 respectively, component is as follows with the corresponding relation of experimental result
Shown in table 2.
Table 2
Embodiment 13-16
Except by 1 in auxiliary agent, 10-o-phenanthroline replaces with outside following component, in the way of identical with embodiment 1-4
Implementing embodiment 13-16 respectively, 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 I in auxiliary agent2O5Outward, in the way of identical with embodiment 1-4, embodiment 17-20, group are implemented respectively
Divide as shown in table 4 below with the corresponding relation of experimental result.
Table 4
"--" represent without.
From embodiment 1-4 and the result of table 2-table 4, between each component of auxiliary agent, there is close association and synergism, logical
Cross and study component 1 and the kind of component 2 and optimized choice goes out 2-dicyclohexylphosphontetrafluoroborate-2', 4', 6'-tri isopropyl biphenyl (Xphos)
With 1,10-o-phenanthroline, demonstrated component 3 by research component 3 indispensable in auxiliary agent, it can affect whole system
Reactivity worth.The method that the present inventor is combined with laboratory facilities by theoretical knowledge, not only constructs multiple with iron salt catalyst
The novel auxiliary system joined, but also component each to auxiliary agent has 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 system of a kind of imide compound
Standby technique, it is with FeCl2The catalyst system and catalyzing of/auxiliary agent and achieve and promote efficiently synthesizing of imide compound, and pass through Dan Yin
The best of breed of component is optimized and obtains optimal catalyst system and catalyzing by element laboratory facilities, and it is sub-that this preparation technology has opened up acyl
The preparation method of amines, 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 protection model of the present invention
Enclose.Additionally, it will also be appreciated that after the technology contents having read the present invention, the present invention can be made respectively by those skilled in the art
Planting change, amendment and/or modification, all these equivalent form of value falls within the guarantor that the application appended claims is limited equally
Within the scope of protecting.
Claims (1)
1. a synthetic method for formula (III) compound, described method comprises the steps: to add formula I in reactor
Compound and FeCl2, stir and be passed through nitrogen and maintain nitrogen atmosphere, in system, then add solvent toluene, add under stirring
Formula (II) compound, TBHP and auxiliary agent, seal after continuing to be passed through nitrogen, temperature reaction, add after completion of the reaction shrend go out, ether
Extraction, merges after organic facies after being dried through anhydrous sodium sulfate, filtering, be concentrated in vacuo, residue by silicagel column chromatogram purification,
Obtain formula (III) compound:
Wherein:
R1 is with substituent group or unsubstituted C1-C6 alkyl, with substituent group or unsubstituted phenyl;
R2, R3 be 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' in described auxiliary agent, 4', 6'-tri isopropyl biphenyl, 1,10-o-phenanthroline and I2O5Mass ratio be 1:
0.4:0.2;Described formula I compound and FeCl2Mol ratio be 1:0.05;Described formula I compound and formula (II) compound
Mol ratio be 1:4;Described formula I compound is 1:2.4 with the mol ratio of TBHP;Described formula I compound rubs with toluene
Your volume ratio is 1:6.5mol/L;Described formula I compound in mol is 1:8mol/g with the ratio of auxiliary agent in gram;Instead
It is 13h between Ying Shi;Reaction temperature is 50 DEG C.
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Effective date of registration: 20170516 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 |