CN103012239A - Preparation method of 2-nitro-4-(1H-pyrrylmethyl)-N-substituted aniline derivatives - Google Patents
Preparation method of 2-nitro-4-(1H-pyrrylmethyl)-N-substituted aniline derivatives Download PDFInfo
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- -1 2-nitro-4-(1H-pyrrylmethyl)-N-substituted aniline Chemical class 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 14
- 150000003335 secondary amines Chemical class 0.000 claims abstract description 13
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 claims abstract description 9
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 claims abstract description 9
- PMMYEEVYMWASQN-IMJSIDKUSA-N trans-4-Hydroxy-L-proline Natural products O[C@@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-IMJSIDKUSA-N 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 150000003053 piperidines Chemical class 0.000 claims description 12
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- IQQRAVYLUAZUGX-UHFFFAOYSA-N 1-butyl-3-methylimidazolium Chemical compound CCCCN1C=C[N+](C)=C1 IQQRAVYLUAZUGX-UHFFFAOYSA-N 0.000 claims description 4
- FUFZNHHSSMCXCZ-UHFFFAOYSA-N 5-piperidin-4-yl-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical compound FC(F)(F)C1=CC=CC(C=2N=C(ON=2)C2CCNCC2)=C1 FUFZNHHSSMCXCZ-UHFFFAOYSA-N 0.000 claims description 4
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 claims description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 4
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 4
- BXOAIZOIDUQOFA-UHFFFAOYSA-M 1-butyl-3-methylimidazol-3-ium;hydroxide Chemical compound [OH-].CCCC[N+]=1C=CN(C)C=1 BXOAIZOIDUQOFA-UHFFFAOYSA-M 0.000 claims description 3
- SQPFPKSOPRMSDP-UHFFFAOYSA-N C(CCC)N1CN(C=C1)C.O Chemical compound C(CCC)N1CN(C=C1)C.O SQPFPKSOPRMSDP-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 239000003049 inorganic solvent Substances 0.000 claims description 3
- 229910001867 inorganic solvent Inorganic materials 0.000 claims description 3
- 239000002608 ionic liquid Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 2
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- 150000003935 benzaldehydes Chemical class 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 claims description 2
- 210000002615 epidermis Anatomy 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000002466 imines Chemical class 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000012429 reaction media Substances 0.000 claims description 2
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 claims description 2
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 claims description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 2
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- 239000000543 intermediate Substances 0.000 abstract description 3
- 238000005899 aromatization reaction Methods 0.000 abstract description 2
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 229940041181 antineoplastic drug Drugs 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
- 229960002429 proline Drugs 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
- ILKWFRCNNILIJW-UHFFFAOYSA-N 4-fluoro-3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC(C=O)=CC=C1F ILKWFRCNNILIJW-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 238000000926 separation method Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000004900 laundering Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- HETBKLHJEWXWBM-UHFFFAOYSA-N 4-chloro-3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC(C=O)=CC=C1Cl HETBKLHJEWXWBM-UHFFFAOYSA-N 0.000 description 2
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- QXNDZONIWRINJR-UHFFFAOYSA-N azocane Chemical compound C1CCCNCCC1 QXNDZONIWRINJR-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 0 *c1ccc(C[n]2cccc2)cc1[N+]([O-])=O Chemical compound *c1ccc(C[n]2cccc2)cc1[N+]([O-])=O 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical class C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 description 1
- SAFSVELFSYQXOV-UHFFFAOYSA-N 4-bromo-3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC(C=O)=CC=C1Br SAFSVELFSYQXOV-UHFFFAOYSA-N 0.000 description 1
- 235000001018 Hibiscus sabdariffa Nutrition 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical class C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 235000005291 Rumex acetosa Nutrition 0.000 description 1
- 240000007001 Rumex acetosella Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- HSOHBWMXECKEKV-UHFFFAOYSA-N cyclooctanamine Chemical compound NC1CCCCCCC1 HSOHBWMXECKEKV-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 235000003513 sheep sorrel Nutrition 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Abstract
The invention relates to a preparation method of 2-nitro-4-(1H-pyrrylmethyl)-N-substituted aniline derivatives, which mainly comprises the following steps: reacting 3-nitro-4-halo-benzaldehyde, trans-4-hydroxy-L-proline or trans-4-benzoyloxy-L-proline, secondary amine and solvent at 25-140 DEG C in a redox aromatization reaction and SN2 substitution reaction mode to synthesize the target compounds by a one-pot method. The compounds are important intermediates for synthesizing anticancer drugs EGFRis and HDACis. The method provided by the invention can quickly and effectively prepare the compounds, and lower the synthesis cost.
Description
Technical field
The present invention relates to the preparation method of 2-nitro-4-(1H-pyrroles's methyl)-N-substituted aniline derivative.
Background technology
2-nitro-4-(1H-pyrroles's methyl) N-substituted aniline derivative is the important intermediate of synthetic epidermis factor acceptor inhibitor (EGFRis) and NSC 630176 (HDACis).What 2-nitro-4-(1H-pyrroles's methyl) N-substituted aniline derivative document synthetic method was taked is the method for fractional steps, that is: utilize first secondary amine and 3-nitro-4-chlorobenzaldehyde to react, generate 3-nitro-4-Serenase formaldehyde take Pd and dipyridyl as catalyzer, yield 54% (Chinese Chemical Letters, 2010,21:935-938):
Or adopt Cs
2CO
3Be alkaline reagents, take DMSO as solvent, room temperature to 100 ℃ lower reaction 30min, yield 43% (PCT Int.Appl., 2008057282):
Or in water, react, yield 56% (Vestnik Moskovskogo Universiteta, Seriya 2:Khimiya, 1984,25:583-588):
Adopt again intermolecular reduction amination aromatization to obtain target product: to utilize 2,5-dihydro-1H-pyrroles and aldehyde (alkanoic and aromatic aldehyde) reaction, generate N-alkyl pyrrole derivative take acid as catalyzer, yield 60～94% (Nirmal K.Pahadi, Miranda Paley, Ranjan Jana, Shelli R.Waetzig, and Jon A.Tunge.J. Am.Chem.Soc.2009,131:16626-16627)
Or utilize trans-4-hydroxy-l-proline and aldehyde reaction, under microwave condition, generate N-alkyl pyrrole derivative, yield 42～73% (Indubhusan Deb, Daniel J. Coiro and Daniel Seidel.Chem.Commun.2011 take acid as catalyzer, 47,6473)
The aforesaid method reactions steps is many, and the reaction times is long, and it is unstable to separate the intermediate product obtain, and total recovery is low, and wherein some reaction conditions is harsh, and the catalyzer such as employed Pd and dipyridyl and reagent are expensive.
Summary of the invention
The object of the invention is to, provide a kind of " one kettle way " redox aromizing-nucleophilic substitution cascade reaction to prepare the method for 2-nitro-4-(1H-pyrroles's methyl)-N-substituted aniline derivative.This method need not separation of intermediates, and is economical, efficient, practical, and environmental protection has overcome many-sided deficiencies such as reaction process complexity, severe reaction conditions in the prior art.
The present invention 2-nitro-4-to be prepared (1H-pyrroles's methyl) N-substituted aniline derivative, its structure is suc as formula shown in the I:
Among the formula I, R
1R
2Can be respectively straight chain length C 1～C6 aliphatic carbon chain (main nail base, ethyl, n-propyl or-CH
2CH
2-OH); Or R
1R
2Be expressed as the ring-type carbochain of same C4～C9, C4～C9 contain heteroatoms (N, O, S) the ring-type carbochain (for example-CH
2CH
2OCH
2CH
2-,-CH
2CH
2N (CH
3)-CH
2CH
2-).
The method of compound shown in the preparation formula I provided by the present invention, its key step is: with 3-nitro-4-halogen phenyl aldehyde (its structure is suc as formula shown in the II), trans-4-hydroxy-l-proline or trans-4-benzoyloxy-L-PROLINE (structure is shown in formula III), secondary amine (structure is suc as formula shown in the IV) and solvent, 25～140 ℃ of reactions, obtain target compound (compound shown in the formula I).
What the X of its Chinese style II represented is halogen: F, Cl, Br, I;
Among the formula IV, R
1R
2Definition described identical with preamble;
Embodiment
In preferred technical scheme of the present invention, the mol ratio of compound shown in compound of benzaldehyde category shown in the formula II and the formula III is 1: 1～1: 3, and the mol ratio of compound is 1: 1～1: 2 shown in compound of benzaldehyde category shown in the formula II and the formula IV.
The best molar ratio that uses, formula II is 1: 1.5 than formula III, formula II is 1: 1 than formula IV.
In a further preferred technical solution of the present invention, said reaction medium is inorganic solvent, organic solvent or ionic liquid, such as (but being not limited to): dithiocarbonic anhydride, water, ethanol, acetonitrile, toluene, dimethylbenzene, 1,4-dioxane, N, dinethylformamide (DMF), N,N-dimethylacetamide, methyl-sulphoxide (DMSO), tetramethylene sulfone, hydroxide 1-butyl-3-methylimidazole salt ([bmIm] OH), 1-butyl-3-methyl imidazolium tetrafluoroborate ([bmIm] BF
4) or 1-butyl-3-Methylimidazole hexafluorophosphate ([bmIm] PF
6) etc.;
The organic solvent of recommendation of the present invention is: ethanol, acetonitrile, DMF (DMF), N,N-dimethylacetamide, and methyl-sulphoxide (DMSO), hydroxide 1-butyl-3-methylimidazole salt ([bmIm] OH).
The suggestion consumption of described organic solvent is 15mL～20mL/g halogenated benzaldehyde, that is: the fragrant propenal of every gram (compound shown in the formula II) needs the described organic solvent with 15mL～20mL.
In a further preferred technical solution of the present invention, R
1R
2Can be respectively straight chain length C 1～C6 aliphatic carbon chain (main nail base, ethyl, n-propyl or-CH
2CH
2-OH); Or R
1R
2Be expressed as the ring-type carbochain of same C4～C9, C4～C9 contain heteroatoms (N, O, S) the ring-type carbochain (for example-CH
2CH
2OCH
2CH
2-,-CH
2CH
2N (CH
3)-CH
2CH
2-), namely operable secondary amine can be the also secondary amine of ring-type of secondary amine of open chain.
The best open chain secondary amine that uses has dimethylamine, diethylamine, dipropyl amine, dibutylamine, diethanolamine.
The best cyclic secondary amine that uses has Pyrrolidine, piperidines, morpholine, piperazine, 4-methylpiperazine, 4-benzyl diethylenediamine, 4-Boc piperazine, 4-piperidine methyl formate, 4-piperidine ethyl formate, U-4527, ring imines in heptan.
In preparation method of the present invention, can adopt thin-layer chromatography (TLC) to judge the terminal point (petrol ether/ethyl acetate=5: 1 (v/v)) of preparation feedback; And the crude product of compound shown in the prepared formula I can adopt the purification process of the existing routine such as column chromatography to carry out purifying (column chromatography adopts silicagel column, and eluent is petrol ether/ethyl acetate=10: 1 (v/v)).
The method for preparing 2-nitro-4-(1H-pyrroles's methyl)-N-substituted aniline derivative of the present invention, it is extensive that it has raw material sources, cheap and easy to get, easy to operation, need not protection of inert gas and yield advantages of higher in whole preparation process.
Below by embodiment the present invention is further set forth, purpose only is better to understand content of the present invention.Therefore, listed embodiment does not limit protection scope of the present invention:
The preparation of embodiment 11-(2-nitro-4-(1H-pyrroles's methyl) phenyl) piperidines
Be connected to thermowell, in the 25ml there-necked flask of reflux condensing tube, add 4-fluoro-3-nitrobenzaldehyde (0.1691g, 1.0mmol), trans-4-hydroxy-l-proline (0.1966g, 1.5mmol), N, dinethylformamide (6ml) and piperidines (0.0989ml, 1.0mmol) after, stirring heating, be warming up to 140 ℃ of reaction 5h, the reaction of TLC tracing display finishes, reaction solution naturally cools to room temperature, and the reaction solution massive laundering is used dichloromethane extraction, anhydrous sodium sulfate drying, filter, column chromatography for separation gets 1-(2-nitro-4-(1H-pyrroles's methyl) phenyl) piperidines 0.2309g, sorrel oily liquids, yield 81% after the removal of solvent under reduced pressure.
Calcd.HRMS?for?C
16H
20N
3O
2(M+H)，286.1556；Found，286.1555；
1H?NMR(400MHz，CDC1
3)ppm?7.57(s，1H，ArH)，7.18(d，J＝8.58Hz，1H，ArH)，7.08(d，J＝8.52Hz，1H，ArH)，6.70(s，2H，ArH)，6.22(s，2H，ArH)，5.03(s，2H，CH
2)，3.02(t，4H，CH
2)，1.72(dd，J＝10.54，5.50Hz，4H，CH
2)，1.61(t，J＝11.08Hz，2H，CH
2).；
13C?NMR(100MHz，CDCl
3)ppm?146.5，142.3，131.9，130.6，124.6，121.3，120.9，109.0，53.4，52.9，25.9，24.0.
The preparation of embodiment 2 1-(2-nitro-4-(1H-pyrroles's methyl) phenyl) piperidines
Substitute outside the DMF the other the same as in Example 1, yield 60% divided by ethanol.
The preparation of embodiment 3 1-(2-nitro-4-(1H-pyrroles's methyl) phenyl) piperidines
Substitute outside the DMF the other the same as in Example 1, yield 79% divided by acetonitrile.
The preparation of embodiment 4 1-(2-nitro-4-(1H-pyrroles's methyl) phenyl) piperidines
Substitute DMF, the other the same as in Example 1, yield 80% divided by toluene.
The preparation of embodiment 5 1-(2-nitro-4-(1H-pyrroles's methyl) phenyl) piperidines
Substitute DMF, the other the same as in Example 1, yield 78% divided by methyl-sulphoxide.
The preparation of embodiment 6 1-(2-nitro-4-(1H-pyrroles's methyl) phenyl) piperidines
Substitute 4-fluoro-3-nitrobenzaldehyde, the other the same as in Example 1, yield 84% divided by 4-chloro-3-nitrobenzaldehyde.
The preparation of embodiment 7 1-(2-nitro-4-(1H-pyrroles's methyl) phenyl) piperidines
Substitute 4-fluoro-3-nitrobenzaldehyde, the other the same as in Example 1, yield 85% divided by 4-bromo-3-nitrobenzaldehyde.
The preparation of embodiment 8 1-(2-nitro-4-(1H-pyrroles's methyl) phenyl) piperidines
Substitute trans-4-hydroxy-l-proline, the other the same as in Example 1, yield 83% divided by trans-4-benzoyloxy-L-PROLINE.
The preparation of embodiment 9 4-(2-nitro-4-(1H-pyrroles's methyl) phenyl) morpholine
Be connected to thermowell, in the 25ml there-necked flask of reflux condensing tube, add 4-fluoro-3-nitrobenzaldehyde (0.1691g, 1.0mmol), trans-4-hydroxy-l-proline (0.1966g, 1.5mmol), N, dinethylformamide (6ml) and morpholine (0.0877ml, 1.0mmol) after, stirring heating, be warming up to 140 ℃ of reaction 5h, the reaction of TLC tracing display finishes, reaction solution naturally cools to room temperature, and the reaction solution massive laundering is used dichloromethane extraction, anhydrous sodium sulfate drying, filter, column chromatography for separation gets 4-(2-nitro-4-(1H-pyrroles's methyl) phenyl) morpholine 0.2155g, red solid, yield 75% after the removal of solvent under reduced pressure.
Calcd.HRMS?for?C
15H
18N
3O
3(M+H)，288.1348；Found，288.1346；
1H?NMR(400MHz，CDCl
3)δppm?7.55(d，J＝1.98Hz，1H，ArH)，7.20(dd，J＝8.46，2.05Hz，1H，ArH)，7.11-7.08(m，1H，ArH)，6.67(t，J＝2.04，2.04Hz，2H，ArH)，6.20(t，J＝2.05，2.05Hz，2H，ArH)，5.04(s，2H，CH
2)，3.84-3.81(m，4H，CH
2)，3.04-3.01(m，4H，CH
2)；
13C?NMR(100MHz，CDCl
3)δppm?145.2，143.5，132.7，132.0，124.3，121.4，121.0，109.2，66.8，52.1，52.0.
Embodiment 10 1-(3-nitro-4-pyrrolidyl)-N-benzyl-1H-pyrroles's preparation
Be connected to thermowell, in the 25ml there-necked flask of reflux condensing tube, add 4-fluoro-3-nitrobenzaldehyde (0.1691g, 1.0mmol), trans-4-hydroxy-l-proline (0.1966g, 1.5mmol), N, dinethylformamide (6ml) and tetrahydro pyrrolidine (0.0833ml, 1.0mmol) after, stirring heating, be warming up to 140 ℃ of reaction 5h, the reaction of TLC tracing display finishes, reaction solution naturally cools to room temperature, and the reaction solution massive laundering is used dichloromethane extraction, anhydrous sodium sulfate drying, filter, column chromatography for separation gets 1-(3-nitro-4-pyrrolidyl)-N-benzyl-1H-pyrroles 0.2388g, yellow solid, yield 88% after the removal of solvent under reduced pressure.
Calcd.HRMS?for?C
15H
18N
3O
2(M+H)，272.1399；Found，272.1391；
1H?NMR(400MHz，CDCl
3)δppm?7.59(d，J＝2.13Hz，1H，ArH)，7.13(dd，J＝8.81，2.20Hz，1H，ArH)，6.87-6.84(m，1H，ArH)，6.67(t，J＝2.08，2.08Hz，2H，ArH)，6.17(t，J＝2.09，2.09Hz，2H，ArH)，4.97(s，2H，CH
2)，3.19(t，J＝6.50，6.50Hz，4H，CH
2)，1.99-1.95(m，4H，CH
2)；
13C?NMR(100MHz，CDCl1
3)δppm?142.3，136.6，132.0，125.5，125.2，120.8，116.5，108.8，52.1，50.5，25.7.
The preparation of embodiment 11 1-(2-nitro-4-(1H-pyrroles's methyl)-phenyl) Azacyclooctane
Be connected to thermowell, in the 25ml there-necked flask of reflux condensing tube, add 4-fluoro-3-nitrobenzaldehyde (0.1691g, 1.0mmol), trans-4-hydroxy-l-proline (0.1966g, 1.5mmol), N, dinethylformamide (6ml) and cyclooctylamine (0.1220ml, 1.0mmol) after, stirring heating, be warming up to 140 ℃ of reaction 5h, the reaction of TLC tracing display finishes, reaction solution naturally cools to room temperature, and the reaction solution massive laundering is used dichloromethane extraction, anhydrous sodium sulfate drying, filter, column chromatography for separation gets 1-(4-((1H-pyrroles-1-yl) methyl)-2) nitrophenyl after the removal of solvent under reduced pressure) Azacyclooctane 0.2507g, red solid, yield 80%.
Calcd.HRMS?for?C
18H
24N
3O
2(M+H)，314.1869；Found，314.1865；
1H?NMR(400MHz，CDC1
3)δppm?7.42(d，J＝1.95Hz，1H，ArH)，7.10(dd，J＝8.82，2.09Hz，1H，ArH)，7.08-7.05(m，1H，ArH)，6.68(t，J＝2.09，2.09Hz，2H，ArH)，6.19(t，J＝2.10，2.10Hz，2H，ArH)，4.97(s，2H，CH
2)，3.30(t，J＝4.00，4.00Hz，4H，CH
2)，1.74-1.69(m，4H，CH
2)，1.56-1.53(m，6H，CH
2)；
13C?NMR(100MHz，CDCl
3)δppm?144.1，131.5，128.4，127.0，125.0，120.9，119.9，108.8，52.7，52.0，27.1，27.0，24.8.
Claims (7)
1. a class is suc as formula the 2-nitro-4-(1H-pyrroles's methyl) of the structure representative of I-N-substituted aniline derivative,
It is the important intermediate of synthetic epidermis factor acceptor inhibitor (EGFRis) and NSC 630176 (HDACis); its synthetic key step is: with 3-nitro-4-halogen phenyl aldehyde (its structure is suc as formula shown in the II); trans-4-hydroxy-l-proline or trans-4-benzoyloxy-L-PROLINE (structure is shown in formula III); secondary amine (structure is suc as formula shown in the IV) and solvent; in 25～140 ℃ " one kettle way " reaction, obtain target compound (compound shown in the formula I):
Wherein, R
1R
2Can be respectively straight chain length C 1～C6 aliphatic carbon chain (main nail base, ethyl, n-propyl or-CH
2CH
2-OH); Or R
1R
2Be expressed as the ring-type carbochain of same C4～C9, C4～C9 contain heteroatoms (N, O, S) the ring-type carbochain (for example-CH
2CH
2OCH
2CH
2-,-CH
2CH
2N (CH
3)-CH
2CH
2-).
2. method claimed in claim 1, what the X in the employed aldehyde compound (its structure is suc as formula shown in the II) represented is halogen: F, Cl, Br, I.
3. method claimed in claim 1, the R in the employed secondary amine (its structure is suc as formula shown in the IV)
1R
2Can be respectively straight chain length C 1～C6 aliphatic carbon chain (main nail base, ethyl, n-propyl or-CH
2CH
2-OH); Or R
1R
2Be expressed as the ring-type carbochain of same C4～C9, C4～C9 contain heteroatoms (N, O, S) the ring-type carbochain (for example-CH
2CH
2OCH
2CH
2-,-CH
2CH
2N (CH
3)-CH
2CH
2-).
4. method claimed in claim 1, the mol ratio of compound shown in compound of benzaldehyde category and the formula III is 1: 1～1: 3 shown in its Chinese style II, and the mol ratio of compound is 1: 1～1: 2 shown in compound of benzaldehyde category shown in the formula II and the formula IV.
5. the method for claim 1, wherein said reaction medium is inorganic solvent, organic solvent or ionic liquid; Wherein said inorganic solvent is: dithiocarbonic anhydride, water; Organic solvent is: ethanol, acetonitrile, toluene, dimethylbenzene, acetic acid, Isosorbide-5-Nitrae-dioxane, DMF, N,N-dimethylacetamide, methyl-sulphoxide or tetramethylene sulfone; Said ionic liquid is: hydroxide 1-butyl-3-methylimidazole salt ([bmIm] OH), 1-butyl-3-methyl imidazolium tetrafluoroborate ([bmIm] BF
4) or 1-butyl-3-Methylimidazole hexafluorophosphate ([bmIm] PF
6).
6. the method for claim 1, the suggestion consumption of organic solvent is 15mL～20mL/g halogenated benzaldehyde, that is: the fragrant propenal of every gram (compound shown in the formula II) needs the described organic solvent with 15mL～20mL.
7. the method for claim 1, R
1R
2Can be respectively straight chain length C 1～C6 aliphatic carbon chain (main nail base, ethyl, n-propyl or-CH
2CH
2-OH); Or R
1R
2Be expressed as the ring-type carbochain of same C4～C9, C4～C9 contain heteroatoms (N, O, S) the ring-type carbochain (for example-CH
2CH
2OCH
2CH
2-,-CH
2CH
2N (CH
3)-CH
2CH
2-), namely operable secondary amine can be the also secondary amine of ring-type of secondary amine of open chain;
The best open chain secondary amine that uses has dimethylamine, diethylamine, dipropyl amine, dibutylamine, diethanolamine;
The best cyclic secondary amine that uses has Pyrrolidine, piperidines, morpholine, piperazine, 4-methylpiperazine, 4-benzyl diethylenediamine, 4-Boc piperazine, 4-piperidine methyl formate, 4-piperidine ethyl formate, U-4527, ring imines in heptan.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003030902A1 (en) * | 2001-10-09 | 2003-04-17 | Tularik Inc. | Imidazole derivates as anti-inflammatory agents |
| CN102180824A (en) * | 2011-02-18 | 2011-09-14 | 华东理工大学 | Method for preparing pyrrole derivative |
| CN102250040A (en) * | 2011-06-01 | 2011-11-23 | 华东理工大学 | Method for preparing N-(3'-aryl allyl)pyrrole derivatives |
| CN102558098A (en) * | 2011-11-23 | 2012-07-11 | 华东理工大学 | Preparation method of alpha-cyano-3-nitro-4-substituted aminophenylacrylic acid derivatives |
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2013
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003030902A1 (en) * | 2001-10-09 | 2003-04-17 | Tularik Inc. | Imidazole derivates as anti-inflammatory agents |
| CN102180824A (en) * | 2011-02-18 | 2011-09-14 | 华东理工大学 | Method for preparing pyrrole derivative |
| CN102250040A (en) * | 2011-06-01 | 2011-11-23 | 华东理工大学 | Method for preparing N-(3'-aryl allyl)pyrrole derivatives |
| CN102558098A (en) * | 2011-11-23 | 2012-07-11 | 华东理工大学 | Preparation method of alpha-cyano-3-nitro-4-substituted aminophenylacrylic acid derivatives |
Non-Patent Citations (1)
| Title |
|---|
| A.VIJAY KUMAR和K.RAMA RAO: "trans-4-Hydroxy-L-proline:a novel starting material for N-alkylpyrroles synthesis", 《TETRAHEDRON LETTERS》, vol. 52, 18 April 2011 (2011-04-18), pages 3237 - 3239 * |
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