CN112094218A - Synthetic method of pyrrole derivative - Google Patents
Synthetic method of pyrrole derivative Download PDFInfo
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- CN112094218A CN112094218A CN202010922735.5A CN202010922735A CN112094218A CN 112094218 A CN112094218 A CN 112094218A CN 202010922735 A CN202010922735 A CN 202010922735A CN 112094218 A CN112094218 A CN 112094218A
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- isocyanate
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- ylide
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- 150000003233 pyrroles Chemical class 0.000 title claims abstract description 18
- 238000010189 synthetic method Methods 0.000 title claims description 5
- 238000003756 stirring Methods 0.000 claims abstract description 54
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- -1 amine compounds Chemical class 0.000 claims abstract description 45
- 239000002904 solvent Substances 0.000 claims abstract description 40
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 36
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000000926 separation method Methods 0.000 claims abstract description 19
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 18
- 239000000047 product Substances 0.000 claims abstract description 17
- 238000004440 column chromatography Methods 0.000 claims abstract description 15
- 239000012948 isocyanate Substances 0.000 claims abstract description 15
- 229910001961 silver nitrate Inorganic materials 0.000 claims abstract description 15
- 239000012043 crude product Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- 150000002513 isocyanates Chemical class 0.000 claims abstract description 10
- 238000004821 distillation Methods 0.000 claims abstract description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- 238000001035 drying Methods 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000012074 organic phase Substances 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 11
- 238000003786 synthesis reaction Methods 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 10
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 6
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 6
- 235000011152 sodium sulphate Nutrition 0.000 claims description 6
- 238000001308 synthesis method Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- MGYGFNQQGAQEON-UHFFFAOYSA-N 4-tolyl isocyanate Chemical compound CC1=CC=C(N=C=O)C=C1 MGYGFNQQGAQEON-UHFFFAOYSA-N 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- DZSGDHNHQAJZCO-UHFFFAOYSA-N 1-isocyanato-3,5-dimethylbenzene Chemical compound CC1=CC(C)=CC(N=C=O)=C1 DZSGDHNHQAJZCO-UHFFFAOYSA-N 0.000 claims description 4
- FMDGXCSMDZMDHZ-UHFFFAOYSA-N 1-isocyanato-4-methoxybenzene Chemical compound COC1=CC=C(N=C=O)C=C1 FMDGXCSMDZMDHZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 4
- NOHQUGRVHSJYMR-UHFFFAOYSA-N 1-chloro-2-isocyanatobenzene Chemical compound ClC1=CC=CC=C1N=C=O NOHQUGRVHSJYMR-UHFFFAOYSA-N 0.000 claims description 3
- ADAKRBAJFHTIEW-UHFFFAOYSA-N 1-chloro-4-isocyanatobenzene Chemical compound ClC1=CC=C(N=C=O)C=C1 ADAKRBAJFHTIEW-UHFFFAOYSA-N 0.000 claims description 3
- DSVGFKBFFICWLZ-UHFFFAOYSA-N 1-fluoro-4-isocyanatobenzene Chemical compound FC1=CC=C(N=C=O)C=C1 DSVGFKBFFICWLZ-UHFFFAOYSA-N 0.000 claims description 3
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 claims description 3
- 150000001409 amidines Chemical class 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 3
- 238000012544 monitoring process Methods 0.000 claims description 3
- 229960005181 morphine Drugs 0.000 claims description 3
- UVKNSPCUKBUVDH-UHFFFAOYSA-N 1,1,2-tribenzyl-2-methylhydrazine Chemical compound C=1C=CC=CC=1CN(CC=1C=CC=CC=1)N(C)CC1=CC=CC=C1 UVKNSPCUKBUVDH-UHFFFAOYSA-N 0.000 claims description 2
- XXFUZSHTIOFGNV-UHFFFAOYSA-N 1-bromoprop-1-yne Chemical compound CC#CBr XXFUZSHTIOFGNV-UHFFFAOYSA-N 0.000 claims description 2
- SUVCZZADQDCIEQ-UHFFFAOYSA-N 1-isocyanato-2-methoxybenzene Chemical group COC1=CC=CC=C1N=C=O SUVCZZADQDCIEQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000005936 piperidyl group Chemical group 0.000 claims description 2
- 238000009987 spinning Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 3
- 239000000758 substrate Substances 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 description 7
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000005580 one pot reaction Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 150000002527 isonitriles Chemical class 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- LNNXOEHOXSYWLD-UHFFFAOYSA-N 1-bromobut-2-yne Chemical compound CC#CCBr LNNXOEHOXSYWLD-UHFFFAOYSA-N 0.000 description 1
- CPPGZWWUPFWALU-UHFFFAOYSA-N 1-isocyanato-3-methylbenzene Chemical compound CC1=CC=CC(N=C=O)=C1 CPPGZWWUPFWALU-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 238000010499 C–H functionalization reaction Methods 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 238000006086 Paal-Knorr synthesis reaction Methods 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001345 alkine derivatives Chemical group 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000006452 multicomponent reaction Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000005691 oxidative coupling reaction Methods 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a method for preparing pyrrole derivatives, which comprises the following steps of adding a proper reaction solvent into a container filled with phosphine ylide, sequentially adding isocyanate and amine compounds, stirring at normal temperature, then adding silver nitrate, continuously stirring until the reaction is finished, carrying out reduced pressure distillation and concentration to remove the solvent, and carrying out column chromatography separation on a crude product to obtain a target product pyrrole derivative, wherein the reaction formula is as follows:
the method has the advantages of simple and convenient operation, mild conditions, wide substrate application range, cheap and easily-obtained raw materials, low cost, high yield of target products and the like.
Description
Technical Field
The invention relates to the field of chemical intermediates, in particular to a polysubstituted pyrrole organism and a synthesis method thereof.
Background
Disadvantages and inadequacies of the prior art (object of the invention): polysubstituted pyrrole is an important nitrogen-containing heterocyclic compound and widely exists in a plurality of natural products and high-activity medicaments. The heterocyclic ring system generally has good biological activities of resisting fungi, inflammation, convulsion and the like.
In view of the importance of pyrrole derivatives, they have attracted considerable attention in the field of synthetic chemistry and have evolved a number of different synthetic strategies. In addition to the classical Paal-Knorr or Hantazsch reactions, there are several new synthetic methods including 1, 3-dipolar cycloaddition, C-H activation, multicomponent reactions, oxidative coupling cyclization reactions, etc.
For example, tin and Leeiwinia topics simultaneously report the preparation of a versatile and practical pyrrole construction method by silver-catalyzed cycloaddition of isocyanides to non-activated terminal alkynes (Angew. chem. int. Ed.,2013,52, 6953-6967; Angew. chem. int. Ed.,2013,52, 6958-6961.).
Pagadala describes an efficient process for the catalyst-free reaction of four components, aromatic aldehydes, malononitrile, isocyanides and cyclic secondary amines, to give functionalized pyrroles with antitumor activity (org. biomol. chem.,2015,13, 1800-1806.).
In 2019, Li reports a palladium-catalyzed alpha-p-toluenesulfonamide allene oxidation reaction for one-pot pyrrole ring synthesis (ACS Catal.,2019,9, 5184-substituted 5190.). Although there are many advantages in the synthesis of azoles in the literature, we cannot ignore that these methods are often accompanied by some drawbacks, such as too high reaction temperature, need of peracid or over-alkali environment, addition of toxic additives, complicated operation, etc. Therefore, the new and simple pyrrole synthesis method still has important application value in pharmaceutical chemistry and synthetic chemistry.
Disclosure of Invention
The invention provides a synthesis method of pyrrole compounds, which utilizes simple and easily obtained raw materials to synthesize polysubstituted pyrrole compounds with novel structures by a one-pot method.
The technical scheme of the invention is as follows:
a synthetic method of pyrrole derivatives comprises the following steps: adding a proper reaction solvent into a container filled with phosphine ylide, sequentially adding isocyanate and amine compounds, stirring at normal temperature, then adding silver nitrate, continuously stirring until the reaction is finished, carrying out reduced pressure distillation and concentration to remove the solvent, and carrying out column chromatography separation on the crude product to obtain the target product pyrrole derivative, wherein the reaction formula is as follows:
wherein the content of the first and second substances,
R1is any one of methyl and ethyl;
R2: any one of hydrogen and methyl;
R3: any one of phenyl, 4-methylphenyl, 3, 5-dimethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl and 2-chlorophenyl.
NR4R5: any one of piperidyl, diethylamino, tetrahydropyrrolyl, morphinyl, dibenzylamino, N-methylbenzylamine, tert-butylamino, N-butylamino, benzylamino and isopropylamino;
the reaction temperature is normal temperature;
the molar ratio of the phosphine ylide compound to the isocyanate compound to the amine compound is 1:1: 1.
Further, the isocyanate is any one selected from the group consisting of phenyl isocyanate, 4-methylphenyl isocyanate, 3, 5-dimethylphenyl isocyanate, 4-methoxyphenyl isocyanate, 4-fluorophenyl isocyanate, 4-chlorophenyl isocyanate and 2-chlorophenyl isocyanate.
The amine may be any one selected from piperidine, diethylamine, tetrahydropyrrolidine, morphine, dibenzylamine, N-methylbenzylamine, tert-butylamine, N-butylamine, benzylamine, and isopropylamine.
Further, the reaction solvent is any one selected from dichloromethane and tetrahydrofuran.
Further, the preparation method of the phosphine ylide comprises the following steps: dissolving bromoacetate ylide 1 in chloroform, adding bromopropyne 2, and stirring and refluxing at 60 deg.C overnight; then cooling the reaction system, spin-drying the solvent, adding a large amount of water, dropwise adding a sodium hydroxide solution to adjust the solution to be alkaline, and stirring the reaction system for 5 minutes; extracting with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate to obtain an organic phase, and concentrating the organic phase to obtain the raw material phosphine ylide;
a method for synthesizing pyrrole derivatives comprises the steps of adding a ylide raw material and a solvent I into a round-bottom flask, then adding isocyanate, stirring and reacting for 4-6 hours at normal temperature to obtain an intermediate 4, directly adding amine into a system without separation, continuously stirring for 1-2 hours to obtain an amidine intermediate 5, spin-drying the solvent, adding a solvent II into the system, adding a catalyst silver nitrate, stirring for 12-24 hours at normal temperature, monitoring by TLC (thin layer chromatography), concentrating a reaction liquid under reduced pressure to remove the solvent, and separating residues by column chromatography to obtain a target product;
further, the first solvent is dichloromethane; solvent II is tetrahydrofuran; the molar ratio of the phosphine ylide compound to the isocyanate compound to the amine compound is 1:1: 1.
Synthesis of 2- (diethylamino) -1- (4-methoxyphenyl) -5-methyl-1H-pyrrole-3-carboxylic acid ethyl ester further, the above raw material was ylide 3b, the added material was methoxyphenyl isocyanate, stirred at room temperature for 4 hours, and then diethylamine was directly added to the system without separation, and stirred for 1 hour, and stirred at room temperature for 12 hours;
the structural formula of ylide 3b is:
compared with the prior art, the invention has the following beneficial effects:
the invention provides a method for preparing a polysubstituted pyrrole compound by a one-pot method, which starts from simple raw materials, can carry out reaction at normal temperature, omits the step of intermediate separation, and has the advantages of simpler and more convenient operation, mild conditions, wide substrate application range, cheap and easily available raw materials, low cost and high yield of target products.
Drawings
FIG. 1 is a chemical reaction formula of a polysubstituted pyrrole compound of the invention;
FIG. 2 is a 1HNMR picture of methyl 2- (diethylamino) -1- (3, 5-dimethylphenyl) -5-methyl-1H-pyrrole-3-carboxylate;
FIG. 3 is a 13C NMR chart of methyl 2- (diethylamino) -1- (3, 5-dimethylphenyl) -5-methyl-1H-pyrrole-3-carboxylate.
Detailed Description
The invention is further described with reference to the accompanying drawings in which:
the synthesis method of the pyrrole derivative is characterized by comprising the following steps:
adding a proper reaction solvent into a container filled with phosphine ylide, sequentially adding isocyanate and amine compounds, stirring at normal temperature, then adding silver nitrate, continuously stirring until the reaction is finished, carrying out reduced pressure distillation and concentration to remove the solvent, and carrying out column chromatography separation on the crude product to obtain the target product pyrrole derivative, wherein the reaction formula is as follows:
wherein: the reaction solvent is any one selected from dichloromethane and tetrahydrofuran;
the reaction temperature may be normal temperature;
the molar ratio of the phosphine ylide compound to the isocyanate compound to the amine compound is 1:1: 1;
the isocyanate may be any one selected from phenyl isocyanate, 4-methylphenyl isocyanate, 3, 5-dimethylphenyl isocyanate, 4-methoxyphenyl isocyanate, 4-fluorophenyl isocyanate, 4-chlorophenyl isocyanate and 2-chlorophenyl isocyanate.
The amine may be any one selected from piperidine, diethylamine, tetrahydropyrrolidine, morphine, dibenzylamine, N-methylbenzylamine, tert-butylamine, N-butylamine, benzylamine, and isopropylamine.
Example 1, preparation of the starting phosphine ylide 3: the references ((a) B.M.Trost, G.D.Probst and A.Schoop, J.Am.chem.Soc.1998,120,9228-9236.(b) D.Scholz, S.Weber-roth, E.Macoratti and E.Francotte, Synthetic Communications,1999,29, 1143. 1155.(c) C.Zhu, B.Yang, T.Jiang and J.E.Backval, Angew.chem.int.Ed.,2015,54, 9066. and 9069.(d) N.Britto, V.G.Gore, R.S.Mali and A.C.Rana, Synthetic Communications,1989,19,1899 1910. acetate), 10mmol of methyl bromide (10mmol) were added to toluene under reflux at 10 ℃ and stirred overnight. Then cooling the reaction system, spin-drying the solvent, adding a large amount of water, dropwise adding a sodium hydroxide solution to adjust to alkalinity, and stirring the reaction system for 5 minutes. Extraction with dichloromethane, drying of the organic phase over anhydrous sodium sulfate, filtration of the sodium sulfate to give an organic phase, and concentration of the organic phase to give starting material 3 in yield.
Preparation of phosphine ylide 3 a: 2- (triphenyl-lambda)5Methyl (10mmol) phosphoranylidene acetate was dissolved in chloroform, 3-bromopropyne (10mmol) was added thereto, and the mixture was stirred and refluxed at 60 ℃ for 12 hours. Then cooling the reaction system, spin-drying the solvent, adding a large amount of water, dropwise adding a sodium hydroxide solution to adjust to alkalinity, and stirring the reaction system for 5 minutes. Extracting with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate to obtain organic phase, and concentrating the organic phase to obtain 2- (triphenyl-lambda)5-phosphono) pentyl-4-acetic acid methyl ester 3a, yield 67%.
Preparation of phosphine ylide 3 b: 2- (triphenyl-lambda)5Ethyl (10mmol) phosphoranylidene acetate was dissolved in chloroform, and 3-bromopropyne (10mmol) was added thereto, followed by stirring and refluxing at 60 ℃ for 12 hours. Then cooling the reaction system, spin-drying the solvent, adding a large amount of water, dropwise adding a sodium hydroxide solution to adjust to alkalinity, and stirring the reaction system for 5 minutes. Extracting with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate to obtain organic phase, and concentrating the organic phase to obtain 2- (triphenyl-lambda)5-phosphonoethylene) pentyl-4-nonanoate 3b in 68% yield.
Preparation of phosphine ylide 3 c: 2- (triphenyl-lambda)5Methyl (10mmol) phosphoranylidene acetate was dissolved in chloroform, and 1-bromo-2-butyne (10mmol) was added thereto, followed by stirring and refluxing at 60 ℃ for 12 hours. Then cooling the reaction system, spin-drying the solvent, adding a large amount of water, dropwise adding a sodium hydroxide solution to adjust the solution to be alkaline, and stirring the reaction system for 5 minutes. Extracting with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate to obtain organic phase, and concentrating the organic phase to obtain 2- (triphenyl-lambda)5Phosphinomethylene) hexyl-4-nonanoate 3c, yield 65%.
Wherein the phosphine ylide 3 can be represented by the following structural formula:
example 2, preparation of pyrrole 6, illustrated by the following schematic reaction scheme, detailed description: adding ylide 3(2mmol) and 10mL dichloromethane into a 50mL round bottom flask, adding isocyanate (2mmol), stirring and reacting for 4-6 hours at normal temperature to obtain an intermediate 4, directly adding 2mmol amine into the system without separation, continuing stirring for 1-2 hours to obtain an amidine intermediate 5, spinning off the solvent, adding 10mL tetrahydrofuran and silver nitrate (0.2mmol), stirring for 12-24 hours at normal temperature, after the reaction is completed through TLC monitoring, concentrating the reaction liquid under reduced pressure to remove the solvent, and separating the residue through column chromatography (the elution solvent is ethyl acetate/petroleum ether is 1:10) to obtain the target product 6.
Embodiment 3
Synthesis of 5-methyl-1-phenyl-2- (piperidin-1-yl) -1H-pyrrole-3-carboxylic acid methyl ester
Adding 2mmol of raw material ylide 3a into a reaction container, dissolving in 10ml of dichloromethane, then adding 2mmol of phenyl isocyanate, stirring for 4 hours at normal temperature, directly adding 2mmol of piperidine into the system without separation, continuously stirring for 1 hour, spin-drying the solvent, adding 10ml of tetrahydrofuran and silver nitrate (0.2mmol) into the system, stirring for 24 hours at normal temperature, concentrating by reduced pressure distillation after the reaction is finished to remove the solvent, and separating the crude product by column chromatography to obtain the target product with the yield of 83%.
Example 4
2- (diethylamino) -5-methyl-1- (p-tolyl) -1H-pyrrole-3-carboxylic acid methyl ester is synthesized by adding 2mmol of raw material ylide 3a into a reaction vessel to be dissolved in 10ml of dichloromethane, then adding 2mmol of 4-methylphenyl isocyanate, stirring at normal temperature for 4 hours, directly adding 2mmol of diethylamine into the system without separation, continuously stirring for 1 hour, spin-drying the solvent, adding 10ml of tetrahydrofuran and silver nitrate (0.2mmol) into the system, stirring at normal temperature for 16 hours, removing the solvent by reduced pressure distillation and concentration after the reaction is finished, and separating the crude product by column chromatography to obtain the target product with the yield of 86%.
Example 5
5-methyl-2- (piperidin-1-yl) -1- (m-tolyl) -1H-pyrrole-3-carboxylic acid methyl ester
Adding 2mmol of raw material ylide 3a into a reaction container, dissolving in 10ml of dichloromethane, then adding 2mmol of m-methylphenyl isocyanate, stirring for 6 hours at normal temperature, directly adding 2mmol of piperidine into the system without separation, continuing stirring for 1 hour, spin-drying the solvent, adding 10ml of tetrahydrofuran and silver nitrate (0.2mmol) into the system, stirring for 16 hours at normal temperature, concentrating by reduced pressure distillation after the reaction is finished, removing the solvent, and separating the crude product by column chromatography to obtain the target product with the yield of 86%.
Example 6
Synthesis of methyl 2- (tert-butylamino) -5-methyl-1-phenyl-1H-pyrrole-3-carboxylate
Adding 2mmol of raw material ylide 3a into a reaction container, dissolving in 10ml of dichloromethane, then adding 2mmol of phenyl isocyanate, stirring for 5 hours at normal temperature, then directly adding 2mmol of tert-butylamine into the system without separation, continuing stirring for 1 hour, spin-drying the solvent, adding 10ml of tetrahydrofuran and silver nitrate (0.2mmol) into the system, stirring for 20 hours at normal temperature, decompressing, distilling and concentrating after the reaction is finished, removing the solvent, and separating the crude product by column chromatography to obtain the target product with the yield of 74%.
Example 7
Synthesis of ethyl 2- (diethylamino) -1- (4-methoxyphenyl) -5-methyl-1H-pyrrole-3-carboxylate
Adding 2mmol of raw material ylide 3b into a reaction container, dissolving in 10ml of dichloromethane, then adding 2mmol of p-methoxyphenyl isocyanate, stirring for 4 hours at normal temperature, directly adding 2mmol of diethylamine into the system without separation, continuing stirring for 1 hour, spin-drying the solvent, adding 10ml of tetrahydrofuran and silver nitrate (0.2mmol) into the system, stirring for 12 hours at normal temperature, decompressing, distilling and concentrating to remove the solvent after the reaction is finished, and separating the crude product by column chromatography to obtain the target product with the yield of 90%.
Example 8
Synthesis of methyl 2- (diethylamino) -1- (3, 5-dimethylphenyl) -5-methyl-1H-pyrrole-3-carboxylate
Adding 2mmol of raw material ylide 3b into a reaction container, dissolving in 10ml of dichloromethane, then adding 2mmol of 3, 5-dimethylphenyl isocyanate, stirring for 4 hours at normal temperature, directly adding 2mmol of diethylamine into the system without separation, continuously stirring for 1 hour, spin-drying the solvent, adding 10ml of tetrahydrofuran and silver nitrate (0.2mmol) into the system, stirring for 18 hours at normal temperature, distilling under reduced pressure after the reaction is finished, concentrating to remove the solvent, and separating the crude product by column chromatography to obtain the target product with the yield of 86%.
Example 9
Synthesis of methyl 1- (4-chlorophenyl) -2- (dipropylamino) -5-methyl-1H-pyrrole-3-carboxylate
Adding 2mmol of raw material ylide 3a into a reaction container, dissolving in 10ml of dichloromethane, then adding 2mmol of 4-dichlorophenyl isocyanate, stirring for 6 hours at normal temperature, directly adding 2mmol of diethylamine into the system without separation, continuing stirring for 1 hour, spin-drying the solvent, adding 10ml of tetrahydrofuran and silver nitrate (0.2mmol) into the system, stirring for 24 hours at normal temperature, decompressing, distilling and concentrating to remove the solvent after the reaction is finished, and separating the crude product by column chromatography to obtain the target product with the yield of 69%.
Synthesis of methyl 2- (benzyl (methyl) amino) -5-ethyl-1- (p-tolyl) -1H-pyrrole-3-carboxylate
Adding 2mmol of raw material ylide 3c into a reaction container, dissolving in 10ml of dichloromethane, then adding 2mmol of 4-methylphenyl isocyanate, stirring for 4 hours at normal temperature, directly adding 2mmol of N-methylbenzylamine into the system without separation, continuously stirring for 1 hour, spin-drying the solvent, adding 10ml of tetrahydrofuran and silver nitrate (0.2mmol) into the system, stirring for 20 hours at normal temperature, removing the solvent by reduced pressure distillation and concentration after the reaction is finished, and separating the crude product by column chromatography to obtain the target product with the yield of 76%.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various features described in the above embodiments may be combined in any suitable manner without departing from the scope of the invention. The invention is not described in detail in order to avoid unnecessary repetition.
In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.
Claims (7)
1. A synthetic method of pyrrole derivatives is characterized by comprising the following steps:
adding a proper reaction solvent into a container filled with phosphine ylide, sequentially adding isocyanate and amine compounds, stirring at normal temperature, then adding silver nitrate, continuously stirring until the reaction is finished, carrying out reduced pressure distillation and concentration to remove the solvent, and carrying out column chromatography separation on the crude product to obtain the target product pyrrole derivative, wherein the reaction formula is as follows:
wherein the content of the first and second substances,
R1is any one of methyl and ethyl;
R2: any one of hydrogen and methyl;
R3: any one of phenyl, 4-methylphenyl, 3, 5-dimethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl and 2-chlorophenyl.
NR4R5: any one of piperidyl, diethylamino, tetrahydropyrrolyl, morphinyl, dibenzylamino, N-methylbenzylamine, tert-butylamino, N-butylamino, benzylamino and isopropylamino;
the reaction temperature is normal temperature;
the molar ratio of the phosphine ylide compound to the isocyanate compound to the amine compound is 1:1: 1.
2. The method according to claim 1, wherein the isocyanate is any one selected from the group consisting of phenyl isocyanate, 4-methylphenyl isocyanate, 3, 5-dimethylphenyl isocyanate, 4-methoxyphenyl isocyanate, 4-fluorophenyl isocyanate, 4-chlorophenyl isocyanate, and 2-chlorophenyl isocyanate.
The amine is any one selected from piperidine, diethylamine, pyrrolidine, morphine, dibenzylamine, N-methylbenzylamine, tert-butylamine, N-butylamine, benzylamine and isopropylamine.
3. The method of claim 1, wherein the reaction solvent is selected from the group consisting of dichloromethane and tetrahydrofuran.
4. The synthesis method according to claim 1, characterized in that the phosphine ylide is prepared by: dissolving bromoacetate ylide 1 in chloroform, adding bromopropyne 2, and stirring and refluxing at 60 deg.C overnight; then cooling the reaction system, spin-drying the solvent, adding a large amount of water, dropwise adding a sodium hydroxide solution to adjust the solution to be alkaline, and stirring the reaction system for 5 minutes; extracting with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering to remove sodium sulfate to obtain an organic phase, and concentrating the organic phase to obtain the raw material phosphine ylide;
5. a method for synthesizing pyrrole derivatives is characterized in that a raw material ylide and a solvent I are added into a round-bottom flask, then isocyanate is added, stirring reaction is carried out for 4-6 hours at normal temperature to obtain an intermediate 4, then amine is directly added into the system without separation, stirring is continuously carried out for 1-2 hours to obtain an amidine intermediate 5, the solvent is dried in a spinning mode, a solvent II is added into the system, a catalyst silver nitrate is added, stirring is carried out for 12-24 hours at normal temperature, after TLC monitoring reaction completion, the reaction liquid is subjected to reduced pressure concentration to remove the solvent, and the residue is subjected to column chromatography separation to obtain a target product;
6. the method of synthesis according to claim 1, wherein the first solvent is dichloromethane;
the second solvent is tetrahydrofuran; the molar ratio of the phosphine ylide compound to the isocyanate compound to the amine compound is 1:1: 1. Synthesis of ethyl 2- (diethylamino) -1- (4-methoxyphenyl) -5-methyl-1H-pyrrole-3-carboxylate.
7. The synthesis method according to claim 5 or 6, wherein the raw material is ylide 3b, the added substance is methoxyphenyl isocyanate, the stirring is carried out for 4 hours at normal temperature, the diethylamine is directly added into the system without separation, the stirring is continued for 1 hour, and the stirring is carried out for 12 hours at normal temperature;
the structural formula of ylide 3b is:
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