CN117736059A - Green preparation method of N, N-disubstituted urea and derivative - Google Patents
Green preparation method of N, N-disubstituted urea and derivative Download PDFInfo
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- CN117736059A CN117736059A CN202311724474.6A CN202311724474A CN117736059A CN 117736059 A CN117736059 A CN 117736059A CN 202311724474 A CN202311724474 A CN 202311724474A CN 117736059 A CN117736059 A CN 117736059A
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- -1 N, N-disubstituted urea Chemical class 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 57
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 41
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 32
- 150000001912 cyanamides Chemical class 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000007800 oxidant agent Substances 0.000 claims abstract description 18
- 150000003672 ureas Chemical class 0.000 claims abstract description 14
- 239000003446 ligand Substances 0.000 claims abstract description 10
- 230000001590 oxidative effect Effects 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 229910000510 noble metal Inorganic materials 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 129
- 239000012074 organic phase Substances 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 28
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- 235000013877 carbamide Nutrition 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 4
- PFUVRDFDKPNGAV-UHFFFAOYSA-N sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- BZSXEZOLBIJVQK-UHFFFAOYSA-N 2-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=CC=C1C(O)=O BZSXEZOLBIJVQK-UHFFFAOYSA-N 0.000 claims description 3
- OQVYMXCRDHDTTH-UHFFFAOYSA-N 4-(diethoxyphosphorylmethyl)-2-[4-(diethoxyphosphorylmethyl)pyridin-2-yl]pyridine Chemical compound CCOP(=O)(OCC)CC1=CC=NC(C=2N=CC=C(CP(=O)(OCC)OCC)C=2)=C1 OQVYMXCRDHDTTH-UHFFFAOYSA-N 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- VKJKEPKFPUWCAS-UHFFFAOYSA-M potassium chlorate Chemical compound [K+].[O-]Cl(=O)=O VKJKEPKFPUWCAS-UHFFFAOYSA-M 0.000 claims description 3
- SATVIFGJTRRDQU-UHFFFAOYSA-N potassium hypochlorite Chemical compound [K+].Cl[O-] SATVIFGJTRRDQU-UHFFFAOYSA-N 0.000 claims description 3
- 239000012286 potassium permanganate Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 claims description 3
- 229910001488 sodium perchlorate Inorganic materials 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- 229910052786 argon Inorganic materials 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 239000012043 crude product Substances 0.000 description 22
- 229920001971 elastomer Polymers 0.000 description 21
- 239000000047 product Substances 0.000 description 17
- NWJGNHCFEPMCCT-UHFFFAOYSA-N diphenylcyanamide Chemical compound C=1C=CC=CC=1N(C#N)C1=CC=CC=C1 NWJGNHCFEPMCCT-UHFFFAOYSA-N 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 239000003480 eluent Substances 0.000 description 12
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
- 235000019341 magnesium sulphate Nutrition 0.000 description 12
- 229910052751 metal Inorganic materials 0.000 description 12
- 239000002184 metal Substances 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- 239000012071 phase Substances 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 238000001514 detection method Methods 0.000 description 10
- 230000005311 nuclear magnetism Effects 0.000 description 10
- XKAFKUGMXFMRCC-UHFFFAOYSA-N 1,1-diphenylurea Chemical compound C=1C=CC=CC=1N(C(=O)N)C1=CC=CC=C1 XKAFKUGMXFMRCC-UHFFFAOYSA-N 0.000 description 8
- GWEHVDNNLFDJLR-UHFFFAOYSA-N Carbanilide Natural products C=1C=CC=CC=1NC(=O)NC1=CC=CC=C1 GWEHVDNNLFDJLR-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000005303 weighing Methods 0.000 description 8
- 238000010812 external standard method Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- FHKPLLOSJHHKNU-INIZCTEOSA-N [(3S)-3-[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]oxypyrrolidin-1-yl]-(oxan-4-yl)methanone Chemical compound C(C)N1N=CC(=C1C)C=1N(C2=NC=NC(=C2N=1)O[C@@H]1CN(CC1)C(=O)C1CCOCC1)C FHKPLLOSJHHKNU-INIZCTEOSA-N 0.000 description 4
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- REDUQXCPUSNJOL-UHFFFAOYSA-N C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O Chemical compound C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O REDUQXCPUSNJOL-UHFFFAOYSA-N 0.000 description 3
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- HKOFCSYNFPLDFD-UHFFFAOYSA-N (2-fluorophenyl)cyanamide Chemical compound FC1=CC=CC=C1NC#N HKOFCSYNFPLDFD-UHFFFAOYSA-N 0.000 description 2
- WICJDHDKSYTQLS-UHFFFAOYSA-N (3-nitrophenyl)cyanamide Chemical compound [O-][N+](=O)C1=CC=CC(NC#N)=C1 WICJDHDKSYTQLS-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000806 fluorine-19 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- AXTPKYQMUDUCFW-UHFFFAOYSA-N 1,3-thiazole 1,1-dioxide Chemical compound O=S1(=O)C=CN=C1 AXTPKYQMUDUCFW-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
- AAPRNHKWNGDTOT-DVRVPOOOSA-N 2-[(3s)-3-(aminomethyl)piperidine-1-carbonyl]-n-[1-(cyclononen-1-ylmethyl)piperidin-4-yl]-9h-xanthene-9-carboxamide Chemical compound C1[C@H](CN)CCCN1C(=O)C1=CC=C(OC=2C(=CC=CC=2)C2C(=O)NC3CCN(CC=4CCCCCCCC=4)CC3)C2=C1 AAPRNHKWNGDTOT-DVRVPOOOSA-N 0.000 description 1
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 description 1
- 101001059929 Caenorhabditis elegans Forkhead box protein O Proteins 0.000 description 1
- BOQOJAKXNKUDLS-UHFFFAOYSA-N [4-(trifluoromethyl)phenyl]cyanamide Chemical compound FC(F)(F)C1=CC=C(NC#N)C=C1 BOQOJAKXNKUDLS-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 238000006400 oxidative hydrolysis reaction Methods 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of organic synthesis, and provides a green preparation method of N, N-disubstituted urea and derivatives, wherein N, N-disubstituted cyanamide is used as a raw material, and a series of N, N disubstituted urea derivatives are obtained by adding an oxidant and reacting under the mild conditions without noble metal and ligand. The method does not use noble metal and ligand, takes hydrogen peroxide as oxidant, has mild reaction conditions, accords with the environment-friendly chemical concept of safety and environment protection, can effectively reduce the production cost, improves the chemical selectivity and the yield, has great potential advantages in the aspect of industrialization, and can be conveniently applied to preparing N, N-disubstituted urea derivatives.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a green preparation method of N, N-disubstituted urea and derivatives.
Background
Hydrolysis of organic cyano groups R-c≡n (r=alkyl or aryl) is currently a process for preparing amides, but there are very few efficient catalytic systems for cyano hydrolysis. In fact, most of the examples cited in the literature have problems of using strong Brgnsted acids or bases as promoters, harsh reaction conditions, poor functional group compatibility, selective hydrolytic cleavage of functional groups, noble metal ligand catalysis, etc. In recent years, under mild conditions, tiO was used 2 The Ag, pd, ru, os and the ligand thereof selectively realize the hydrolysis of cyano groups, but the catalyst of the metal and the ligand thereof has extremely high cost, high synthesis difficulty and difficult industrialization.
N, N-disubstituted urea and derivatives can be used in high efficiency catalytic systems for the synthesis of primary and monosubstituted ureas (inaroo id, majnoi S, esmaeilpour m.europan Journal of Organic Chemistry,2018, 26:3481-3488.); can also be used for synthesizing a FOXO small molecule activator thiazole quinone (Cautain B, casttillo F, musso L, et al plos One,2016,11 (12): e 0167491) which shuttles between cytoplasm; phosphine-containing ligands of rhodium can also be formed as efficient aldehyde reduction catalysts (Meeuwissen J, sandee A J, de BruinB, et al organometallics,2010,29 (11): 2413-2421.).
In view of the above, it is necessary to develop a simple, convenient, safe and green method for synthesizing N, N-disubstituted ureas and derivatives.
Disclosure of Invention
The embodiment of the invention aims to provide a green preparation method of N, N-disubstituted urea and derivatives, which aims to solve the problems in the prior art.
The embodiment of the invention is realized in such a way that the green preparation method of N, N-disubstituted urea and derivatives comprises the following steps: under the condition of existence of a solvent, N, N-disubstituted cyanamide is taken as a raw material, and an oxidant is added to react under the mild conditions without noble metal and ligand to obtain the N, N disubstituted urea derivative. The reaction formula is as follows:
preferably R in said N, N-disubstituted cyanamide derivative and N, N-disubstituted urea derivative 1 、R 2 、R 3 、R 4 、R 5 Radicals are each independently selected from hydrogen, halogen, substituted or unsubstituted C 1-20 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 1-20 One or more of alkoxy, substituted or unsubstituted amino, carboxyl, ester, acyl, nitro.
Preferably, the reaction is carried out in a solvent which is one or more of water, acetonitrile, dimethyl sulfoxide, acetone, methanol, ethanol, ethylene glycol, polyethylene glycol, tetrahydrofuran, N, N-dimethylformamide, dichloromethane, dichloroethane, ethyl acetate; further preferably, the solvent is one or more of water, acetonitrile, dimethyl sulfoxide, acetone, N, N-dimethylformamide, methanol.
Preferably, the reaction is carried out under oxidizing conditions, the oxidizing agent being one or more of hydrogen peroxide, sodium peroxide, potassium permanganate, sodium perchlorate, potassium manganate, sodium chlorate, potassium chlorate, sodium hypochlorite, potassium hypochlorite, manganese dioxide. Further preferred oxidizing agent is one of hydrogen peroxide or sodium peroxide;
preferably, the reaction temperature is room temperature to 120 ℃, further preferably 20 to 100 ℃.
Preferably, the reaction time is 0.5 to 24 hours, and more preferably, the reaction time is 0.5 to 12 hours.
Preferably, the molar ratio of the N, N-disubstituted cyanamide to the oxidizing agent is 1: 1-10, wherein the molar ratio of the N, N-disubstituted cyanamide to the solvent is 1:20 to 200.
Preferably, the reaction is carried out under air or an inert atmosphere, which is a nitrogen atmosphere or an argon atmosphere. Further preferred reaction conditions are air.
Preferably, after the reaction is finished, ethyl acetate and water are added into the reaction solution for extraction, ethyl acetate is used for extracting water phase three times, organic phases are combined, anhydrous magnesium sulfate is used for drying the organic phases, and finally the organic phases are concentrated to obtain N, N-disubstituted urea and derivatives.
Preferably, the extract may also be an organic liquid insoluble in water, such as dichloromethane, dichloroethane, etc.
Preferably, the concentration is one of atmospheric distillation, vacuum distillation, rotary evaporation.
Preferably, the reaction solution is extracted by adding 20ml of ethyl acetate and saturated brine each, and the aqueous phase is extracted three times with 20ml of ethyl acetate, and finally the organic phases are combined and dried using anhydrous magnesium sulfate. The organic phase was concentrated to give N, N-disubstituted urea derivatives.
Preferably, the reaction solution can be purified by column chromatography, wherein 200-300 mesh silica gel is used as separation resin, and one or two or more of petroleum ether, n-hexane, dichloromethane, water, acetonitrile and ethyl acetate are selected as eluent.
Preferably, the N, N-disubstituted urea derivative has the structural formula shown below:
the invention has the technical effects that:
the invention provides a green preparation method of N, N-disubstituted urea and derivatives, which takes N, N-disubstituted cyanamide which is cheap and easy to obtain and green oxidant hydrogen peroxide as raw materials to react and synthesize a series of N, N-disubstituted urea and derivatives. The invention realizes cyano oxidative hydrolysis under the conditions of no noble metal, no ligand and mild condition, prepares 19N, N-disubstituted urea derivatives which are not reported, effectively reduces the production cost, improves the chemical selectivity and the yield, and has great potential advantages in the industrialized direction.
Drawings
FIG. 1 shows the nuclear magnetism of Compound 2a provided in example 1 of the present invention 1 H NMR spectrum;
FIG. 2 shows the nuclear magnetism of Compound 2a prepared in example 1 of the present invention 13 C NMR spectrum;
FIG. 3 is a high resolution mass spectrum of compound 2a provided in example 1 of the present invention;
FIG. 4 shows the nuclear magnetism of the compound 2b according to example 2 of the present invention 1 HNMR spectrogram;
FIG. 5 shows the nuclear magnetism of Compound 2b prepared in example 2 of the present invention 13 C NMR spectrum;
FIG. 6 shows the nuclear magnetism of Compound 2b prepared in example 2 of the present invention 19 F NMR spectrum;
FIG. 7 shows the nuclear magnetism of Compound 2h according to example 3 of the present invention 1 HNMR spectrogram;
FIG. 8 shows the nuclear magnetism of Compound 2h prepared in example 3 of the present invention 13 C NMR spectrum;
FIG. 9 shows the nuclear magnetism of Compound 2q provided in example 4 of the present invention 1 HNMR spectrogram;
FIG. 10 shows the nuclear magnetism of Compound 2q prepared in example 4 of the present invention 13 C NMR spectrum;
FIG. 11 shows the nuclear magnetism of Compound 2q prepared in example 4 of the present invention 19 F NMR spectrum.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
A green preparation method of N, N-disubstituted urea and derivatives comprises the following steps:
under the condition of existence of a solvent, N, N-disubstituted cyanamide is taken as a raw material, and an oxidant is added to react under the mild conditions without noble metal and ligand to obtain the N, N disubstituted urea derivative. The reaction formula is as follows:
wherein R in N, N-disubstituted cyanamide and N, N-disubstituted urea 1 、R 2 、R 3 、R 4 、R 5 Radicals are each independently selected from hydrogen, halogen, substituted or unsubstituted C 1-20 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 1-20 One or more of alkoxy, substituted or unsubstituted amino, carboxyl, ester, acyl, nitro.
According to the invention, the oxidant is one or more of hydrogen peroxide, sodium peroxide, potassium permanganate, sodium perchlorate, potassium manganate, sodium chlorate, potassium chlorate, sodium hypochlorite, potassium hypochlorite and manganese dioxide. It should be understood that in the reactions of the present invention, the above-described oxidizing agents may each create oxidizing reaction conditions in the reactions of the present invention. Thus, while specific examples of the invention are given as examples of the type of partial oxidizing agent used, and while it will be understood by those skilled in the art that examples are given solely to illustrate preferred embodiments of the invention and are not intended to limit the invention, other oxides may be used in accordance with the invention as set forth in the examples, as long as one or more of the above-described oxidizing agents are selected to effect the reactions described herein.
According to the invention, the reaction is carried out in the presence of a solvent, wherein the solvent is one or more of water, acetonitrile, tetrahydrofuran, acetone, methanol, ethanol, ethylene glycol, polyethylene glycol, dimethyl sulfoxide, N, N-dimethylformamide, dichloromethane, dichloroethane, benzene, toluene and ethyl acetate; it should be understood that in the reaction of the present invention, the above solvent is used only to dissolve N, N-disubstituted cyanamide, and the solvent itself does not participate in the reaction, so long as the solvent capable of dissolving N, N-disubstituted cyanamide is selected to realize the reaction of the present application, and in the specific examples of the present invention, although only examples of some solvents are given as the reaction solvents, it should be understood by those skilled in the art that examples are only given to illustrate preferred embodiments of the present invention and are not limiting, and that other solvents given by the examples may also be used to obtain the present invention.
According to the invention, the molar ratio of N, N-disubstituted cyanamide to oxidizing agent is 1:1 to 10. It should be understood that in the reaction of the present invention, the above reaction may occur as long as the oxidizing conditions of the oxidizing agent are present, and in the specific examples of the present invention, although only examples of the molar ratio of the part N, N-disubstituted cyanamide and the oxidizing agent are given, it should be understood by those skilled in the art that the examples are merely illustrative of the preferred embodiments given herein and are not limiting of the present invention, and that the present invention may be obtained according to other parameters given by those skilled in the art in light of the teaching given herein.
According to the invention, the molar ratio of N, N-disubstituted cyanamide to solvent is 1: 20-200, as long as the N, N-disubstituted cyanamide is slightly soluble in the solvent in the reaction of the present invention, the specific examples of the present invention only show the molar ratio of the part N, N-disubstituted cyanamide to the solvent, and it should be understood by those skilled in the art that the examples are only for explaining the preferred embodiments of the present invention and are not intended to limit the present invention, and the present invention can be obtained according to other parameters given by the present invention in the light of the examples given by the skilled person.
After the reaction is finished, the reaction liquid is added into the extraction liquid for extraction, ethyl acetate or dichloromethane is used for extracting water phase three times, the organic phases are combined, anhydrous magnesium sulfate is used for drying the organic phases, and finally the organic phases are concentrated to obtain N, N-disubstituted urea and derivatives.
The N, N-disubstituted cyanamide derivative prepared in the following examples has the following structural formula:
in order to further understand the present invention, the following examples are provided to illustrate the green preparation of N, N-disubstituted ureas and derivatives according to the present invention, and the scope of the present invention is not limited by the following examples.
Specific implementations of the invention are described in detail below in connection with specific embodiments.
Example 1
A green preparation method of N, N-disubstituted urea and derivatives thereof comprises the following steps:
the method comprises the following specific steps: weighing N, N-diphenyl cyanamide (1 mmol,222mg,1 a), dimethyl sulfoxide (10 mL), hydrogen peroxide (3 mmol,340mg,30% a.q.) into a 25mL round bottom flask, adding magnetons, plugging a rubber plug, transferring the rubber plug into a metal bath at room temperature (25-30 ℃) and stirring, reacting for 5 hours, detecting and tracking the reaction by TLC, cooling the flask to room temperature after the reaction is finished, adding 20mL of saturated saline and ethyl acetate into the system, extracting the water phase with ethyl acetate (20 mL of 3) for three times, merging organic phases, adding 1g of magnesium sulfate, and removing the solvent from the organic phase by a rotary evaporator after the complete drying to obtain a crude product; the crude product is loaded by silica gel, and the eluent adopts petroleum ether with the volume ratio: ethyl acetate = 2: after column chromatography purification of 1, pure N, N-diphenylurea was obtained as a white solid, 203mg of 2a product, yield 84.5% (N, N-diphenylcyanamide).
Structural identification of compound 2 a: compound 2a 1 H NMR、 13 C NMR and High Resolution Mass Spectrometry are shown in FIG. 1, FIG. 2 and FIG. 3, and the analysis results show that the obtained target products are correct, and specific data are shown in Table 1.
Example 2
A green preparation method of N, N-disubstituted urea and derivatives thereof comprises the following steps:
the method comprises the following specific steps: weighing N, N-bis (2-fluorophenyl) cyanamide (1 mmol,258mg,1 b), dimethyl sulfoxide (10 mL), hydrogen peroxide (3 mmol,340mg,30% a.q.) into a 25mL round bottom flask, adding magnetons, plugging a rubber plug, moving the rubber plug into a metal bath at room temperature (25-30 ℃) and stirring, reacting for 5 hours, detecting and tracking the reaction by TLC, cooling the flask to room temperature after the reaction is finished, adding 20mL of saturated saline solution and ethyl acetate into the system, extracting the water phase by ethyl acetate for three times, merging organic phases, adding 1g of magnesium sulfate, and removing the solvent from the organic phase by a rotary evaporator after the complete drying to obtain a crude product; the crude product is loaded by silica gel, and the eluent adopts petroleum ether with the volume ratio: ethyl acetate = 2: after column chromatography purification of 1, pure N, N-bis (2-fluorophenyl) urea was obtained as a white solid, 2b product 199mg, yield 72.1% (N, N-bis (2-fluorophenyl) cyanamide).
Structural identification of compound 2 b: compound 2b 1 H NMR、 13 C NMR、 19 F NMR is shown in FIG. 4, FIG. 5 and FIG. 6, and the analysis results show that the obtained target product is correct, and specific data are shown in Table 1.
Example 3
A green preparation method of N, N-disubstituted urea and derivatives thereof comprises the following steps:
the method comprises the following specific steps: n, N-bis (3-nitrophenyl) cyanamide (1 mmol,312.3mg,1 h), dimethyl sulfoxide (10 mL), hydrogen peroxide (3 mmol,340mg,30% a.q.) are weighed into a 25mL round bottom flask, magnetons are added, rubber plugs are plugged, the rubber plugs are moved into a metal bath at room temperature (25-30 ℃) and stirred, reaction is carried out for 5h, TLC detection and tracking reaction are carried out, after the reaction is finished, the flask is cooled to room temperature, 20mL of saturated saline solution and ethyl acetate are added into the system and extracted, the aqueous phase is extracted three times with ethyl acetate, the organic phases are combined, 1g of magnesium sulfate is added, and after full drying, the solvent is removed from the organic phase by a rotary evaporator, so as to obtain a crude product; the crude product is loaded by silica gel, and the eluent adopts petroleum ether with the volume ratio: ethyl acetate = 2: after column chromatography purification of 1, pure N, N-bis (3-nitrophenyl) urea was obtained as pale yellow solid, 225mg of product was obtained in 2 hours, and the yield was 68.1% (N, N-bis (3-nitrophenyl) cyanamide).
Structural identification of compound 2 h: compound 2h 1 H NMR、 13 The C NMR is shown in FIG. 7 and FIG. 8, and the analysis results show that the obtained target product is correct, and the specific data are shown in Table 1.
Example 4
A green preparation method of N, N-disubstituted urea and derivatives thereof comprises the following steps:
the method comprises the following specific steps: n, N-bis (4-trifluoromethylphenyl) cyanamide (1 mmol,358mg,1 q), dimethyl sulfoxide (10 mL), hydrogen peroxide (3 mmol,340mg,30% a.q.) are weighed into a 25mL round bottom flask, magnetons are added, rubber plugs are plugged, the rubber plugs are moved into a metal bath at room temperature (25-30 ℃) and stirred, reaction is carried out for 5h, TLC detection and tracking reaction are carried out, after the reaction is finished, the flask is cooled to room temperature, 20mL of saturated saline solution and ethyl acetate are added into the system and extracted, the aqueous phase is extracted three times with ethyl acetate, the organic phases are combined, 1g of magnesium sulfate is added, and after full drying, the solvent is removed from the organic phase by a rotary evaporator, so as to obtain a crude product; the crude product is loaded by silica gel, and the eluent adopts petroleum ether with the volume ratio: ethyl acetate = 2: after purification by column chromatography, pure N, N-bis (2-fluorophenyl) urea was obtained as a white solid, 2q product was 310mg, and the yield was 82.3% (N, N-bis (4-trifluoromethylphenyl)).
Structural identification of compound 2 q: compound 2q 1 H NMR、 13 C NMR、 19 F NMR is shown in FIG. 9, FIG. 10,The analysis results shown in fig. 11 indicate that the obtained target product is correct, and specific data are shown in a chart 1.
Example 5
A green preparation method of N, N-disubstituted urea and derivatives thereof comprises the following steps: the method comprises the following specific steps: weighing N, N-diphenyl cyanamide (1 mmol,222mg,1 a), dimethyl sulfoxide (10 mL), hydrogen peroxide (1 mmol,111mg,30% a.q.) into a 25mL round bottom flask, adding magnetons, plugging a rubber plug, transferring the rubber plug into a metal bath at room temperature (25-30 ℃) and stirring, reacting for 5 hours, detecting and tracking the reaction by TLC, cooling the flask to room temperature after the reaction is finished, adding 20mL of saturated saline and ethyl acetate into the system, extracting the water phase with ethyl acetate for three times, merging organic phases, adding 1g of magnesium sulfate, fully drying, and removing the solvent from the organic phase by using a rotary evaporator to obtain a crude product; the crude product is loaded by silica gel, and the eluent adopts petroleum ether with the volume ratio: ethyl acetate = 2: after the column chromatography purification is carried out on the 1, the pure N, N-diphenyl urea is obtained as white solid, the 2a product is 86mg, and the yield is 35.8 percent (N, N-diphenyl cyanamide meter, high performance liquid chromatography external standard method detection).
Example 6
A green preparation method of N, N-disubstituted urea and derivatives thereof comprises the following steps: the method comprises the following specific steps: weighing N, N-diphenyl cyanamide (1 mmol,222mg,1 a), dimethyl sulfoxide (10 mL), hydrogen peroxide (10 mmol,1113mg,30% a.q.) into a 25mL round bottom flask, adding a magneton, plugging a rubber plug, transferring the rubber plug into a metal bath at room temperature (25-30 ℃) and stirring, reacting for 5 hours, detecting and tracking the reaction by TLC, cooling the flask to room temperature after the reaction is finished, adding 20mL of saturated saline and ethyl acetate into the system, extracting the water phase with ethyl acetate for three times, merging organic phases, adding 1g of magnesium sulfate, fully drying, and removing the solvent from the organic phase by using a rotary evaporator to obtain a crude product; the crude product is loaded by silica gel, and the eluent adopts petroleum ether with the volume ratio: ethyl acetate = 2: after the column chromatography purification is carried out on the 1, the pure N, N-diphenyl urea is obtained as white solid, the 2a product is 205mg, and the yield is 85.4 percent (N, N-diphenyl cyanamide meter, high performance liquid chromatography external standard method detection).
Example 7
A green preparation method of N, N-disubstituted urea and derivatives thereof comprises the following steps: the method comprises the following specific steps: n, N-diphenylcyanamide (1 mmol,222mg,1 a), dimethyl sulfoxide (10 mL), hydrogen peroxide (3 mmol,334mg,30% a.q.) are weighed into a 25mL round bottom flask, magnetons are added, rubber plugs are plugged, the mixture is moved into a metal bath at room temperature (100 ℃) and stirred, the reaction is carried out for 0.5h, TLC detection and tracking reaction are carried out, after the reaction is finished, the flask is cooled to room temperature, 20mL of saturated saline water and ethyl acetate are added into the system and are extracted, the water phase is extracted three times by ethyl acetate, the organic phases are combined, 1g of magnesium sulfate is added, and after the mixture is sufficiently dried, the solvent is removed from the organic phases by a rotary evaporator, so that a crude product is obtained; the crude product is loaded by silica gel, and the eluent adopts petroleum ether with the volume ratio: ethyl acetate = 2: after the column chromatography purification is carried out on the 1, the pure N, N-diphenyl urea is obtained as white solid, the 2a product is 173mg, and the yield is 72.1 percent (N, N-diphenyl cyanamide meter, high performance liquid chromatography external standard method detection).
Example 8
A green preparation method of N, N-disubstituted urea and derivatives thereof comprises the following steps: the method comprises the following specific steps: weighing N, N-diphenyl cyanamide (1 mmol,222mg,1 a), tetrahydrofuran (10 mL), hydrogen peroxide (3 mmol,334mg,30% a.q.) into a 25mL round bottom flask, adding a magneton, plugging a rubber plug, transferring the rubber plug into a metal bath at room temperature (25-30 ℃) and stirring, reacting for 5 hours, detecting and tracking the reaction by TLC, cooling the flask to room temperature after the reaction is finished, adding 20mL of saturated saline and ethyl acetate into the system, extracting the water phase with ethyl acetate for three times, merging organic phases, adding 1g of magnesium sulfate, fully drying, and removing the solvent from the organic phase by using a rotary evaporator to obtain a crude product; the crude product is loaded by silica gel, and the eluent adopts petroleum ether with the volume ratio: ethyl acetate = 2: after the column chromatography purification is carried out on the 1, the pure N, N-diphenyl urea is obtained as white solid, the 2a product is 188mg, and the yield is 78.3 percent (N, N-diphenyl cyanamide meter, high performance liquid chromatography external standard method detection).
Example 9
A green preparation method of N, N-disubstituted urea and derivatives thereof comprises the following steps: weighing N, N-diphenyl cyanamide (1 mmol,222mg,1 a), dimethyl sulfoxide (1.42 mL), hydrogen peroxide (3 mmol,340mg,30% a.q.) into a 25mL round bottom flask, adding magnetons, plugging a rubber plug, transferring the rubber plug into a metal bath at room temperature (25-30 ℃) and stirring, reacting for 5 hours, detecting and tracking the reaction by TLC, cooling the flask to room temperature after the reaction is finished, adding 20mL of saturated saline and ethyl acetate into the system, extracting the water phase with ethyl acetate for three times, merging organic phases, adding 1g of magnesium sulfate, and removing the solvent from the organic phase by using a rotary evaporator after the sufficient drying to obtain a crude product; the crude product is loaded by silica gel, and the eluent adopts petroleum ether with the volume ratio: ethyl acetate = 2: after the column chromatography purification of 1, the pure N, N-diphenyl urea is obtained as white solid, the 2a product is 189mg, and the yield is 78.6% (N, N-diphenyl cyanamide meter, high performance liquid chromatography external standard method detection).
Example 10
A green preparation method of N, N-disubstituted urea and derivatives thereof comprises the following steps: weighing N, N-diphenyl cyanamide (1 mmol,222mg,1 a), dimethyl sulfoxide (14.2 mL), hydrogen peroxide (3 mmol,340mg,30% a.q.) into a 25mL round bottom flask, adding a magneton, plugging a rubber plug, transferring the rubber plug into a metal bath at room temperature (25-30 ℃) and stirring, reacting for 5 hours, detecting and tracking the reaction by TLC, cooling the flask to room temperature after the reaction is finished, adding saturated saline and ethyl acetate into the system, respectively 20mL and extracting, extracting the water phase with ethyl acetate for three times, merging organic phases, adding 1g of magnesium sulfate, and removing the solvent from the organic phase by using a rotary evaporator after the magnesium sulfate is fully dried to obtain a crude product; the crude product is loaded by silica gel, and the eluent adopts petroleum ether with the volume ratio: ethyl acetate = 2: after the column chromatography purification is carried out on the 1, the pure N, N-diphenyl urea is obtained as white solid, the 2a product is 199mg, and the yield is 83.0 percent (N, N-diphenyl cyanamide meter, high performance liquid chromatography external standard method detection).
Example 11
A green preparation method of N, N-disubstituted urea and derivatives thereof comprises the following steps: weighing N, N-diphenyl cyanamide (1 mmol,222mg,1 a), dimethyl sulfoxide (10 mL), sodium hypochlorite (3 mmol,1488mg,15% a.q.) in a 25mL round bottom flask, adding a magneton, plugging a rubber plug, transferring the rubber plug into a metal bath at room temperature (25-30 ℃) and stirring, reacting for 5 hours, detecting and tracking the reaction by TLC, cooling the flask to room temperature after the reaction is finished, adding 20mL of saturated saline and ethyl acetate into the system, extracting the water phase with ethyl acetate for three times, merging the organic phases, adding 1g of magnesium sulfate, fully drying, and removing the solvent from the organic phase by using a rotary evaporator to obtain a crude product; the crude product is loaded by silica gel, and the eluent adopts petroleum ether with the volume ratio: ethyl acetate = 2: after the column chromatography purification is carried out on the 1, the pure N, N-diphenyl urea is obtained as white solid, the 2a product is 144mg, and the yield is 59.9% (N, N-diphenyl cyanamide meter, high performance liquid chromatography external standard method detection).
The present invention also synthesizes the compounds 2a to 3u shown in Table 1 by the similar method as in examples 1 to 4 above, and the method for synthesizing the compounds 2a to 3u is the same as the principle of examples 1 to 4, except for the difference of the raw materials, wherein the synthetic reaction raw materials, the structural formulae, the product yields, and the nuclear magnetic resonance data of the compounds 2a to 3r are given in Table 1.
TABLE 1N, N reaction raw materials, products, yields and Nuclear magnetic resonance/Mass Spectrometry data for disubstituted cyanamide derivatives
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced with equivalents; such modifications and substitutions do not depart from the spirit of the technical solutions according to the embodiments of the present invention.
Claims (9)
1. A green preparation method of N, N-disubstituted urea and derivatives, which is characterized by comprising the following steps: under the condition of existence of a solvent, N, N-disubstituted cyanamide is taken as a raw material, and an oxidant is added to react under the mild conditions without noble metal and ligand to obtain the N, N disubstituted urea derivative. The reaction formula is as follows:
2. a green process for the preparation of N, N-disubstituted ureas and derivatives according to claim 1 wherein R in said N, N-disubstituted cyanamides and N, N-disubstituted ureas 1 、R 2 、R 3 、R 4 、R 5 Radicals are each independently selected from hydrogen, halogen, substituted or unsubstituted C 1-20 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 1-20 One or more of alkoxy, substituted or unsubstituted amino, carboxyl, ester, acyl, nitro.
3. The green preparation method of N, N-disubstituted urea and derivatives according to claim 1, wherein the solvent is one or more of water, acetonitrile, tetrahydrofuran, acetone, methanol, ethanol, ethylene glycol, polyethylene glycol, dimethyl sulfoxide, N, N-dimethylformamide, dichloromethane, dichloroethane, benzene, toluene, and ethyl acetate.
4. The method for preparing N, N-disubstituted urea and derivatives according to claim 1, wherein the oxidizing agent is one or more of hydrogen peroxide, sodium peroxide, potassium permanganate, sodium perchlorate, potassium manganate, sodium chlorate, potassium chlorate, sodium hypochlorite, potassium hypochlorite, and manganese dioxide.
5. The green process for the preparation of N, N-disubstituted ureas and derivatives according to claim 1 wherein said reaction temperature is from room temperature to 120 ℃.
6. The green process for the preparation of N, N-disubstituted ureas and derivatives according to claim 1 wherein said reaction time is from 0.5 to 24 hours.
7. The green process for the preparation of N, N-disubstituted ureas and derivatives according to claim 1 wherein the molar ratio of N, N-disubstituted cyanamide to oxidizing agent is 1: 1-10, wherein the molar ratio of the N, N-disubstituted cyanamide to the solvent is 1:20 to 200.
8. A green process for the preparation of N, N-disubstituted ureas and derivatives according to claim 1 wherein said reaction is carried out under air or an inert atmosphere which is nitrogen or argon.
9. The green process for preparing N, N-disubstituted urea and derivatives according to claim 1, wherein after the reaction is completed, the reaction solution is added into the extraction solution for extraction, the aqueous phase is extracted three times with ethyl acetate or dichloromethane, the organic phases are combined, the organic phases are dried with anhydrous magnesium sulfate, and finally the organic phases are concentrated to obtain N, N-disubstituted urea and derivatives.
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