CN116924993A - Preparation method of 1-cyclopentyl-3- (2, 4-dimethoxy phenyl) -2-oxo ethyl) imidazolidine-2, 4, 5-trione - Google Patents
Preparation method of 1-cyclopentyl-3- (2, 4-dimethoxy phenyl) -2-oxo ethyl) imidazolidine-2, 4, 5-trione Download PDFInfo
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- CN116924993A CN116924993A CN202310747667.7A CN202310747667A CN116924993A CN 116924993 A CN116924993 A CN 116924993A CN 202310747667 A CN202310747667 A CN 202310747667A CN 116924993 A CN116924993 A CN 116924993A
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- ZFLIKDUSUDBGCD-UHFFFAOYSA-N parabanic acid Chemical compound O=C1NC(=O)C(=O)N1 ZFLIKDUSUDBGCD-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims abstract description 38
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims abstract description 18
- RVMONZOKUDHZTA-UHFFFAOYSA-N 1-cyclopentylimidazolidine-2,4,5-trione Chemical compound O=C1NC(=O)C(=O)N1C1CCCC1 RVMONZOKUDHZTA-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 11
- VQTDPCRSXHFMOL-UHFFFAOYSA-N 2,4-Dimethoxyacetophenone Chemical compound COC1=CC=C(C(C)=O)C(OC)=C1 VQTDPCRSXHFMOL-UHFFFAOYSA-N 0.000 claims abstract description 10
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 claims abstract description 10
- NIZHERJWXFHGGU-UHFFFAOYSA-N isocyanato(trimethyl)silane Chemical compound C[Si](C)(C)N=C=O NIZHERJWXFHGGU-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 43
- 239000002904 solvent Substances 0.000 claims description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 8
- CBEYJGNJOCTQGW-UHFFFAOYSA-N cyclopentylurea Chemical compound NC(=O)NC1CCCC1 CBEYJGNJOCTQGW-UHFFFAOYSA-N 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- MARXMDRWROUXMD-UHFFFAOYSA-N 2-bromoisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(Br)C(=O)C2=C1 MARXMDRWROUXMD-UHFFFAOYSA-N 0.000 claims description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 2
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims 2
- 239000002585 base Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 238000001914 filtration Methods 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 8
- 239000012043 crude product Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- VELKDFZESRLQKO-UHFFFAOYSA-N 4-cyclopentylpyrazol-3-one Chemical compound C1(CCCC1)C=1C(N=NC=1)=O VELKDFZESRLQKO-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-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
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- 101001035951 Homo sapiens Hyaluronan-binding protein 2 Proteins 0.000 description 1
- 102100039238 Hyaluronan-binding protein 2 Human genes 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D233/30—Oxygen or sulfur atoms
- C07D233/40—Two or more oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of organic synthesis, and provides a preparation method of 1-cyclopentyl-3- (2, 4-dimethoxy phenyl) -2-oxo ethyl) imidazolidine-2, 4, 5-trione, which comprises the following steps: (1) Preparing 1-cyclopentyl imidazolidine-2, 4, 5-trione by using cyclopentylamine, trimethylsilyl isocyanate and oxalyl chloride; (2) Preparing 2-bromo-1- (2, 4-dimethoxy) acetophenone by using 2, 4-dimethoxy acetophenone; (3) Preparing 1-cyclopentyl-3- (2, 4-dimethoxy phenyl) -2-oxo ethyl) imidazolidine-2, 4, 5-trione by using the 1-cyclopentyl-imidazolidine-2, 4, 5-trione prepared in the step (1) and the 2-bromo-1- (2, 4-dimethoxy) acetophenone prepared in the step (2); the preparation method fills the blank of the preparation method of the compound; and the method is easy to operate, environment-friendly, low in cost and high in yield, can realize commercial large-scale preparation and production, and meets the current continuously-growing market demands.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of 1-cyclopentyl-3- (2, 4-dimethoxy phenyl) -2-oxo ethyl) imidazolidine-2, 4, 5-trione.
Background
1-cyclopentyl-3- (2, 4-dimethoxy phenyl) -2-oxo ethyl) imidazolidine-2, 4, 5-trione is an important chemical raw material, is an important key intermediate for producing medicines, and is also a common monomer in high polymer materials. It has wide application in organic material, small molecule medicine, pesticide, etc. At present, no professional literature report exists on the synthesis of 1-cyclopentyl-3- (2, 4-dimethoxyphenyl) -2-oxoethyl) imidazolidine-2, 4, 5-trione.
Disclosure of Invention
The invention aims to provide a preparation method of 1-cyclopentyl-3- (2, 4-dimethoxy phenyl) -2-oxo-ethyl) imidazolidine-2, 4, 5-trione, which fills the blank of the preparation method of the compound; and the method is easy to operate, environment-friendly, low in cost and high in yield, can realize commercial large-scale preparation and production, and meets the current continuously-growing market demands.
The invention provides a preparation method of 1-cyclopentyl-3- (2, 4-dimethoxy phenyl) -2-oxo ethyl) imidazolidine-2, 4, 5-trione, which has the following synthetic route:
the invention takes cyclopentylamine, trimethylsilyl isocyanate and 2, 4-dimethoxy acetophenone as initial raw materials to prepare a target product. Cyclopentylamine and trimethylsilyl isocyanate are subjected to nucleophilic addition reaction and cycloaddition reaction to efficiently and safely prepare cyclopentyl pyrazolone; the target product is prepared by nucleophilic substitution reaction of cyclopentyl pyrazolone and 2-bromo-1- (2, 4-dimethoxy) acetophenone prepared by substitution reaction of 2, 4-dimethoxy acetophenone.
Specifically, the synthesis steps of the invention include:
step (1)
Taking cyclopentylamine as a raw material, adding a) solvent, adding trimethyl silicon-based isocyanate under stirring to react for 12-24 hours at 0-40 ℃, then adding b) solvent to continue to react for 1-2 hours, evaporating the solvent to obtain a white solid intermediate, adding c) solvent into the white solid intermediate, slowly adding oxalyl chloride under the protection of inert gas at-10-5 ℃, heating to 0-40 ℃ to react for 2-4 hours, adding water to quench, adding ethyl acetate to extract for three times, merging organic phases, drying with anhydrous magnesium sulfate, filtering, evaporating the solvent under reduced pressure to obtain a white crude product, and recrystallizing the crude product with a recrystallization solvent to obtain a pure product.
In the step (1), the solvent a) can be one or a mixture of a plurality of tetrahydrofuran, 1, 4-dioxane, diethyl ether, toluene, methylene dichloride and chloroform;
in the step (1), the molar ratio of the trimethylsilyl isocyanate to the cyclopentylamine is 0.8:1-2:1;
in the step (1), the solvent b) can be one or a mixture of several of methanol, ethanol, 2-propanol and tertiary butanol;
step (1), c) the solvent can be one or more of tetrahydrofuran, 1, 4-dioxane, acetonitrile, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methanol and ethanol;
in the step (1), the molar ratio of the cyclopentylurea to the oxalyl chloride is 1:0.8-1:1.3;
in the step (1), the recrystallization solvent can be one or more of ethyl acetate, butyl acetate, toluene, ethylbenzene, benzene, methylene dichloride and 1, 2-dichloroethane.
Step (2)
2, 4-dimethoxy acetophenone is taken as a raw material, d) solvent is added, bromine source is added, the reaction is carried out for 8 to 24 hours at the temperature of 75 to 100 ℃, then the filtration and the reduced pressure distillation are carried out to remove the solvent, and the 2-bromo-1- (2, 4-dimethoxy) acetophenone is prepared by column chromatography purification.
In step (2), the bromine source used may be copper bromide (CuBr) 2 ) N-bromosuccinimide (NBS), pyridine perbromide (PHBP), elemental bromine, 1, 3-dibromo-5, 5-Dimethylhydantoin (DBH), carbon tetrabromide (CBr) 4 ) One or a mixture of a plurality of N-bromophthalimide (NBP);
in the step (2), the molar ratio of the 2, 4-dimethoxy acetophenone to the bromine source is 1:0.8-1:3;
in the step (2), the solvent d) can be one or a mixture of more of n-pentane, tetrahydrofuran, chloroform, dichloromethane, 1, 4-dioxane, acetonitrile, DMF, DMSO and ethyl acetate;
in the step (2), the stripping agent used in the column chromatography elution can be one or a mixture of more of ethyl acetate, dichloromethane, petroleum ether, diethyl ether and methanol.
Step (3)
Adding e) solvent into 1-cyclopentyl imidazolidine-2, 4, 5-trione and 2-bromo-1- (2, 4-dimethoxy) acetophenone, reacting at 0-50 ℃ for 8-24h under the condition of adding alkali, extracting, drying, filtering, distilling under reduced pressure, and re-crystallizing to obtain 1-cyclopentyl-3- (2, 4-dimethoxy phenyl) -2-oxo ethyl) imidazolidine-2, 4, 5-trione.
In the step (3), the alkali can be one or a mixture of a plurality of triethylamine, diisopropylethylamine, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium phosphate, sodium hydroxide and potassium hydroxide;
in the step (3), the solvent e) can be one or a mixture of more of tetrahydrofuran, chloroform, dichloromethane, ethyl acetate and DMF;
in the step (3), the molar ratio of the alkali to the 1-cyclopentyl imidazolidine-2, 4, 5-trione is 0.5:1-3:1;
in the step (3), the molar ratio of the 1-cyclopentyl imidazolidine-2, 4, 5-trione to the 2-bromo-1- (2, 4-dimethoxy) acetophenone is 1:1-3:1;
in the step (3), the solvent used in the extraction can be one or more of n-pentane, diethyl ether and n-hexane;
in the step (3), the solvent used in the recrystallization can be one or more of dichloromethane, ethyl acetate, tetrahydrofuran, petroleum ether, n-pentane, diethyl ether and n-hexane.
The technical scheme of the embodiment of the invention has at least the following advantages and beneficial effects:
the synthesis process for preparing the 1-cyclopentyl-3- (2, 4-dimethoxy phenyl) -2-oxo-ethyl) imidazolidine-2, 4, 5-trione has the advantages of simple equipment requirement, easy operation, environmental friendliness, low cost and high yield, can realize commercial large-scale preparation and production, and meets the current continuously-growing market demand.
Drawings
FIG. 1 is a hydrogen spectrum of 1-cyclopentyl-3- (2, 4-dimethoxyphenyl) -2-oxoethyl) imidazolidine-2, 4, 5-trione provided in example 6 of the present invention;
FIG. 2 is a carbon spectrum of 1-cyclopentyl-3- (2, 4-dimethoxyphenyl) -2-oxoethyl) imidazolidine-2, 4, 5-trione provided in example 6 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
EXAMPLE 1 preparation of 1-cyclopentylimidazolidine-2, 4, 5-trione
Sequentially adding 30kg of cyclopentylamine and 500L of dichloromethane into a reaction kettle, cooling to 0 ℃, adding 13kg of trimethylsilyl isocyanate, reacting for 12 hours, adding 100L of methanol under stirring to react for 1 hour at 10-35 ℃, and then evaporating the solvent under reduced pressure to obtain 40.1kg of white solid cyclopentylurea with the yield of 89%; adding 40Kg of cyclopentylurea and 600L of tetrahydrofuran into a reaction kettle at one time, slowly adding 47.5Kg of oxalyl chloride under the protection of inert gas, heating to 10 ℃ for reaction for 3 hours, adding water for quenching, adding ethyl acetate for extraction for three times, combining organic phases, drying over anhydrous magnesium sulfate, filtering, decompressing and evaporating the solvent to obtain a white crude product, and recrystallizing the crude product by ethyl acetate to obtain 52.3Kg of pure 1-cyclopentylimidazole-2, 4, 5-trione with the yield of 92%.
EXAMPLE 2 preparation of 1-cyclopentylimidazolidine-2, 4, 5-trione
Sequentially adding 40kg of cyclopentylamine and 500L of ethyl acetate into a reaction kettle, cooling to 15 ℃, adding 17.5kg of trimethylsilyl isocyanate, reacting for 12 hours, adding 100L of methanol under stirring, reacting for 2 hours at 15 ℃, and then evaporating the solvent under reduced pressure to obtain 41.3kg of white solid cyclopentylurea with the yield of 68%; adding 40Kg of cyclopentylurea and 600L of dichloromethane into a reaction kettle at one time, slowly adding 47.5Kg of oxalyl chloride under the protection of inert gas, heating to 30 ℃ for reaction for 3 hours, adding water for quenching, adding dichloromethane for extraction for three times, combining organic phases, drying anhydrous magnesium sulfate, filtering, decompressing and evaporating solvent to obtain a white crude product, and recrystallizing the crude product by dichloromethane to obtain a pure product of 44.3Kg of 1-cyclopentylimidazole-2, 4, 5-trione with the yield of 78%.
EXAMPLE 3 preparation of 2-bromo-1- (2, 4-dimethoxy) acetophenone
72kg of 2, 4-dimethoxy acetophenone, 800L of chloroform and 205kg of copper bromide are sequentially added into a reaction kettle, and stirred and reacted for 10 hours at 80 ℃; then filtering, decompressing and evaporating the solvent, and purifying by adopting ethyl acetate column chromatography to prepare 65kg of 2-bromo-1- (2, 4-dimethoxy) acetophenone with the yield of 63%.
EXAMPLE 4 preparation of 2-bromo-1- (2, 4-dimethoxy) acetophenone
56kg of 2, 4-dimethoxy acetophenone and 800L of dichloromethane are sequentially added into the reaction kettle, then 60.8kg of N-bromosuccinimide (NBS), 5.6kg of p-toluenesulfonic acid are stirred and reacted for 15 hours at 75 ℃; then filtering, decompressing and evaporating the solvent, purifying by adopting dichloromethane column chromatography to prepare 30.2kg of 2-bromo-1- (2, 4-dimethoxy) acetophenone with the yield of 37%.
EXAMPLE 5 preparation of 1-cyclopentyl-3- (2, 4-dimethoxyphenyl) -2-oxoethyl) imidazolidine-2, 4, 5-trione
25Kg of 2-bromo-1- (2, 4-dimethoxy) acetophenone, 37.7Kg of potassium carbonate and 300L of DMF are sequentially added into a reaction kettle, the temperature is reduced to 10 ℃, 16.0Kg of 2-bromo-1- (2, 4-dimethoxy) acetophenone is added for reaction for 10 hours, then 10% citric acid solution 500L is added under stirring for quenching reaction, ethyl acetate is used for extraction, anhydrous magnesium sulfate is used for drying, filtration is carried out, the solvent is distilled off under reduced pressure, ethyl acetate solution is added for recrystallization to obtain 35Kg of 1-cyclopentyl-3- (2, 4-dimethoxy phenyl) -2-oxo-ethyl) imidazolidine-2, 4, 5-trione, and the yield is 78%.
EXAMPLE 6 preparation of 1-cyclopentyl-3- (2, 4-dimethoxyphenyl) -2-oxoethyl) imidazolidine-2, 4, 5-trione
20Kg of 2-bromo-1- (2, 4-dimethoxy) acetophenone, 21.1Kg of sodium carbonate and 300L of DMF are sequentially added into a reaction kettle, the temperature is reduced to 10 ℃, 12.8Kg of 2-bromo-1- (2, 4-dimethoxy) acetophenone is added for reaction for 15 hours, then 500L of water is added under stirring for quenching reaction, ethyl acetate is used for extraction, anhydrous magnesium sulfate is used for drying, filtration, the solvent is distilled off under reduced pressure, ethyl acetate solution is added for recrystallization, and 24.6Kg of 1-cyclopentyl-3- (2, 4-dimethoxy phenyl) -2-oxo-ethyl) imidazolidine-2, 4, 5-trione is obtained with the yield of 68%.
1H NMR(400MHz,Chloroform-d)δ7.96(d,J＝8.8Hz,1H),6.57(dd,J＝8.9,2.3Hz,1H),6.48(d,J＝2.2Hz,1H),4.96(s,2H),4.57(p,J＝8.3Hz,1H),3.96(s,3H),3.88(s,3H),2.14–1.84(m,6H),1.63(dq,J＝9.8,4.9,4.4Hz,2H).
13C NMR(101MHz,CDCl3)δ188.3,166.0,161.8,156.9,156.8,153.8,133.5,117.0,106.2,98.1,55.7,55.6,52.6,49.1,29.5,24.8.
The hydrogen spectrum of 1-cyclopentyl-3- (2, 4-dimethoxy phenyl) -2-oxo ethyl) imidazolidine-2, 4, 5-trione is shown in figure 1, and the carbon spectrum is shown in figure 2.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A process for the preparation of 1-cyclopentyl-3- (2, 4-dimethoxyphenyl) -2-oxoethyl) imidazolidine-2, 4, 5-trione, comprising the steps of:
(1) Preparing 1-cyclopentyl imidazolidine-2, 4, 5-trione by using cyclopentylamine, trimethylsilyl isocyanate and oxalyl chloride;
(2) Preparing 2-bromo-1- (2, 4-dimethoxy) acetophenone by using 2, 4-dimethoxy acetophenone;
(3) Preparing 1-cyclopentyl-3- (2, 4-dimethoxy phenyl) -2-oxo ethyl) imidazolidine-2, 4, 5-trione by using the 1-cyclopentyl-imidazolidine-2, 4, 5-trione prepared in the step (1) and the 2-bromo-1- (2, 4-dimethoxy) acetophenone prepared in the step (2).
2. The process for the preparation of 1-cyclopentyl-3- (2, 4-dimethoxyphenyl) -2-oxoethyl) imidazolidine-2, 4, 5-trione according to claim 1, wherein step (1) comprises:
adding a solvent a) into cyclopentylamine serving as a raw material, adding trimethylsilyl isocyanate, reacting for a period of time at a certain temperature, and then adding a solvent b) for continuous reaction for a period of time to obtain an intermediate cyclopentylurea;
(1.2) adding the solvent in the intermediate cyclopentylurea, slowly adding oxalyl chloride under the protection of inert gas at a certain temperature, heating, and reacting for a period of time to obtain the 1-cyclopentylimidazole-2, 4, 5-trione.
3. The process for the preparation of 1-cyclopentyl-3- (2, 4-dimethoxyphenyl) -2-oxoethyl) imidazolidine-2, 4, 5-trione according to claim 2, characterized in that in step (1.1), the molar ratio of trimethylsilyl isocyanate to cyclopentylamine is between 0.8:1 and 2:1; in the step (1.2), the molar ratio of the cyclopentylurea to the oxalyl chloride is 1:0.8-1:1.3.
4. The process for the preparation of 1-cyclopentyl-3- (2, 4-dimethoxyphenyl) -2-oxoethyl) imidazolidine-2, 4, 5-trione according to claim 2,
in step (1.1), a) the solvent includes, but is not limited to, one or more of tetrahydrofuran, 1, 4-dioxane, diethyl ether, toluene, methylene chloride or chloroform; b) Solvents include, but are not limited to, one or more of methanol, ethanol, 2-propanol, tert-butanol;
in step (1.2), the solvent c) includes, but is not limited to, one or more of tetrahydrofuran, 1, 4-dioxane, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, methanol, and ethanol;
in step (1.1), after adding a) the solvent: the reaction temperature is 0-40 ℃ and the reaction time is 12-24h; adding the solvent b) and then reacting for 1-2h;
in the step (1.2), the temperature of the oxalyl chloride is-10-5 ℃; then heating to 0-40 ℃ and reacting for 2-4h.
5. The process for the preparation of 1-cyclopentyl-3- (2, 4-dimethoxyphenyl) -2-oxoethyl) imidazolidine-2, 4, 5-trione according to claim 1, wherein step (2) comprises:
2, 4-dimethoxy acetophenone is taken as a raw material, d) solvent and bromine source are added, and the mixture reacts for a period of time at a certain temperature to prepare 2-bromo-1- (2, 4-dimethoxy) acetophenone.
6. The method for producing 1-cyclopentyl-3- (2, 4-dimethoxyphenyl) -2-oxoethyl) imidazolidine-2, 4, 5-trione according to claim 5, wherein the molar ratio of 2, 4-dimethoxyacetophenone to bromine source is from 1:0.8 to 1:3.
7. The method of preparing 1-cyclopentyl-3- (2, 4-dimethoxyphenyl) -2-oxoethyl) imidazolidine-2, 4, 5-trione according to claim 5, wherein the bromine source comprises, but is not limited to, one or a mixture of copper bromide, N-bromosuccinimide, pyridine perbromide, elemental bromine, 1, 3-dibromo-5, 5-dimethylhydantoin, carbon tetrabromide, N-bromophthalimide; the solvent d) comprises one or a mixture of more than one of n-pentane, tetrahydrofuran, chloroform, dichloromethane, 1, 4-dioxane, acetonitrile, DMF, DMSO and ethyl acetate;
in the step (2): the reaction temperature is 70-100 ℃ and the reaction time is 8-24h.
8. The process for the preparation of 1-cyclopentyl-3- (2, 4-dimethoxyphenyl) -2-oxoethyl) imidazolidine-2, 4, 5-trione according to claim 1, wherein step (3) comprises:
and e) solvent is added into the 1-cyclopentyl imidazolidine-2, 4, 5-trione and 2-bromo-1- (2, 4-dimethoxy) acetophenone, and substitution reaction is carried out under the condition of adding alkali, thus obtaining the 1-cyclopentyl-3- (2, 4-dimethoxy phenyl) -2-oxo ethyl) imidazolidine-2, 4, 5-trione.
9. The process for the preparation of 1-cyclopentyl-3- (2, 4-dimethoxyphenyl) -2-oxoethyl) imidazolidine-2, 4, 5-trione according to claim 8, characterized in that the molar ratio of 1-cyclopentylimidazole-2, 4, 5-trione to 2-bromo-1- (2, 4-dimethoxy) acetophenone is from 1:1 to 3:1; the molar ratio of the alkali to the 1-cyclopentyl imidazolidine-2, 4, 5-trione is 0.5:1-3:1.
10. The method for preparing 1-cyclopentyl-3- (2, 4-dimethoxyphenyl) -2-oxoethyl) imidazolidine-2, 4, 5-trione according to claim 8, wherein the e) solvent comprises, but is not limited to, one or a mixture of several of tetrahydrofuran, chloroform, dichloromethane, ethyl acetate, DMF; the base comprises, but is not limited to, triethylamine, diisopropylethylamine, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide or a mixture of several of them;
in the step (3): the reaction temperature is 0-50 ℃ and the reaction time is 8-24h.
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