CN111362878B - Preparation method of 4-amino-1, 3-dihydro-benzimidazol-2-one - Google Patents
Preparation method of 4-amino-1, 3-dihydro-benzimidazol-2-one Download PDFInfo
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- CN111362878B CN111362878B CN202010193064.3A CN202010193064A CN111362878B CN 111362878 B CN111362878 B CN 111362878B CN 202010193064 A CN202010193064 A CN 202010193064A CN 111362878 B CN111362878 B CN 111362878B
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- dinitrochlorobenzene
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- BCUSTVNWMJXDSE-UHFFFAOYSA-N 4-amino-1,3-dihydrobenzimidazol-2-one Chemical compound NC1=CC=CC2=C1NC(=O)N2 BCUSTVNWMJXDSE-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- BPPMIQPXQVIZNJ-UHFFFAOYSA-N 2-chloro-1,3-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC([N+]([O-])=O)=C1Cl BPPMIQPXQVIZNJ-UHFFFAOYSA-N 0.000 claims abstract description 31
- IOCXBXZBNOYTLQ-UHFFFAOYSA-N 3-nitrobenzene-1,2-diamine Chemical compound NC1=CC=CC([N+]([O-])=O)=C1N IOCXBXZBNOYTLQ-UHFFFAOYSA-N 0.000 claims abstract description 15
- NEXYNHXFBYYIHI-UHFFFAOYSA-N 4-nitro-1,3-dihydrobenzimidazol-2-one Chemical compound [O-][N+](=O)C1=CC=CC2=C1NC(=O)N2 NEXYNHXFBYYIHI-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 16
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 16
- QFUSCYRJMXLNRB-UHFFFAOYSA-N 2,6-dinitroaniline Chemical compound NC1=C([N+]([O-])=O)C=CC=C1[N+]([O-])=O QFUSCYRJMXLNRB-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000010949 copper Substances 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
- 238000006722 reduction reaction Methods 0.000 claims description 9
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 8
- 229910052802 copper Inorganic materials 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- PCTFIHOVQYYAMH-UHFFFAOYSA-N 3,5-dinitro-4-chlorobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=C(Cl)C([N+]([O-])=O)=C1 PCTFIHOVQYYAMH-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 229940048181 sodium sulfide nonahydrate Drugs 0.000 claims description 4
- WMDLZMCDBSJMTM-UHFFFAOYSA-M sodium;sulfanide;nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[SH-] WMDLZMCDBSJMTM-UHFFFAOYSA-M 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
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 229960003330 pentetic acid Drugs 0.000 claims description 3
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical group O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 3
- RUSUZAGBORAKPY-UHFFFAOYSA-N acetic acid;n'-[2-(2-aminoethylamino)ethyl]ethane-1,2-diamine Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.NCCNCCNCCN RUSUZAGBORAKPY-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
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 230000008901 benefit Effects 0.000 abstract description 4
- 238000004176 ammonification Methods 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 102000003566 TRPV1 Human genes 0.000 description 11
- 101150016206 Trpv1 gene Proteins 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 108091006146 Channels Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 108091005462 Cation channels Proteins 0.000 description 1
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 1
- 239000005751 Copper oxide Substances 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 102000003563 TRPV Human genes 0.000 description 1
- 108060008564 TRPV Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 229960002504 capsaicin Drugs 0.000 description 1
- 235000017663 capsaicin Nutrition 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910000431 copper oxide Inorganic materials 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000001700 mitochondrial membrane Anatomy 0.000 description 1
- 230000008587 neuronal excitability Effects 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 210000002248 primary sensory neuron Anatomy 0.000 description 1
- YQUVCSBJEUQKSH-UHFFFAOYSA-N protochatechuic acid Natural products OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000001044 sensory neuron Anatomy 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229940079101 sodium sulfide Drugs 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- ZGHLCBJZQLNUAZ-UHFFFAOYSA-N sodium sulfide nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[Na+].[S-2] ZGHLCBJZQLNUAZ-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000003594 spinal ganglia Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 210000000427 trigeminal ganglion Anatomy 0.000 description 1
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 1
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/26—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of 4-amino-1, 3-dihydro-benzimidazole-2-ketone, which comprises the following steps: preparing Q1, 2, 6-dinitrochlorobenzene; preparing Q2, 6-dinitroaniline; preparing Q3, 3-nitro-o-phenylenediamine; preparation of Q4, 4-nitro-1H-benzo [ d ] imidazol-2 (3H) -one; q5, 4-amino-1, 3-dihydro-benzimidazol-2-one. The invention takes cheap 3, 5-binitro-4-chlorobenzoic acid as raw material, and obtains high-yield 4-amino-1, 3-dihydro-benzimidazole-2-ketone through decarboxylation, ammonification and other reactions. The whole reaction process is easy to control, the product yield is high, good social benefit and economic benefit can be brought, and the economic value potential is large.
Description
Technical Field
The invention relates to the technical field of organic matter synthesis pharmacy, in particular to a preparation method of 4-amino-1, 3-dihydro-benzimidazole-2-ketone.
Background
Transient receptor potential vanillic acid subtype 1 (transient receptor potential vanilloid type, TRPV 1) is a non-selective cation channel, is mainly expressed in sensory neurons and fibers thereof, such as dorsal root ganglion and trigeminal ganglion, and participates in various physiological and pathological processes, TRPV1 participates in regulation of body temperature, and mainly regulates body temperature by regulating the temperature sensing area of the brain; TRPV1 is also involved in the treatment of certain central nervous system disorders. Modulating TRPV1 activity can be effective in controlling neuronal excitability; TRPV1 has been shown to be the primary sensor in pain channels, and pain involving TRPV1 has pain associated with inflammation, pain resulting from tissue injury.
The main action mechanism of the traditional TRPV1 agonist for pain treatment is to activate TRPV1 channel, excite primary sensory neurons, desensitize the neurons after long-term use, and block pain transmission, but the pain relieving mechanism has great side effects, such as that after capsaicin is combined with TRPV1, calcium ions in nerve cells are gathered in a large amount, cell membranes are destroyed, intracellular capacitance is greatly reduced, mitochondrial membrane permeability is possibly changed, and nerve cell apoptosis is finally caused.
Because the TRPV1 inhibitor has the effect of blocking pain sense, does not cause damage to nerve cells and has extremely low side effect, the current research on the TRPV1 inhibitor is more and more important, 4-amino-1, 3-dihydro-benzimidazol-2-one is an important intermediate for preparing the TRPV1 inhibitor, but the preparation method of 4-amino-1, 3-dihydro-benzimidazol-2-one in the prior art has slow reaction process and low final yield, and is not suitable for industrial production.
Disclosure of Invention
Aiming at the defects and problems in the prior art, the invention provides a preparation method of 4-amino-1, 3-dihydro-benzimidazole-2-ketone, which aims to solve the technical problems: provides a preparation method of 4-amino-1, 3-dihydro-benzimidazole-2-ketone, which is suitable for large-scale industrialization.
In order to achieve the above purpose, the present invention provides the following technical solutions:
a preparation method of 4-amino-1, 3-dihydro-benzimidazol-2-one comprises the following steps:
the preparation method comprises the following steps:
q1, 2, 6-dinitrochlorobenzene is prepared, 3, 5-dinitro-4-chlorobenzoic acid is taken as a raw material at the reaction temperature, 2, 6-dinitrochlorobenzene is formed by decarboxylation in a reaction solvent, the reaction temperature is 180-200 ℃, and the reaction time is 1-3 hours;
preparing Q2, 6-dinitroaniline, reacting 2, 6-dinitrochlorobenzene with ammonia water at 90-110 ℃ for 2-5 hours, extracting, drying, and separating by column chromatography to obtain 2, 6-dinitroaniline;
q3, 3-nitro-o-phenylenediamine is prepared, the reduction reaction is carried out on 2, 6-dinitroaniline, the reaction temperature is 50-80 ℃, and the reaction time is 1-3 hours, so that 3-nitro-o-phenylenediamine is obtained;
q4, 4-nitro-1H-benzo [ d ] imidazole-2 (3H) -ketone is prepared, 3-nitro-o-phenylenediamine and triphosgene are reacted to generate 4-nitro-1H-benzo [ d ] imidazole-2 (3H) -ketone, the reaction temperature is 70-80 ℃, and the reaction time is 1-2 hours;
q5, 4-amino-1, 3-dihydro-benzimidazol-2-one, 4-nitro-1H-benzo [ d ] imidazol-2 (3H) -one completes hydrogenation reduction reaction to obtain 4-amino-1, 3-dihydro-benzimidazol-2-one.
In the technical scheme, in the Q1-Q5, the reagent used for drying is anhydrous magnesium sulfate or anhydrous sodium sulfate.
In the above technical scheme, in the Q1, the reaction solvent is sulfolane or dimethyl sulfoxide.
In the technical scheme, in the reaction of the 2, 6-dinitrochlorobenzene of the Q2 and the ammonia water, the molar ratio of the 2, 6-dinitrochlorobenzene to the ammonia water is 1:5-10, and further 1:8.
In the technical scheme, in the reaction of the 2, 6-dinitrochlorobenzene of the Q2 and the ammonia water, the alkali used in the reaction process is one of sodium hydroxide, potassium hydroxide and potassium phosphate.
In the technical scheme, in the reaction of the 2, 6-dinitrochlorobenzene of the Q2 and the ammonia water, the molar ratio of the alkali to the 2, 6-dinitrochlorobenzene is 1-3:1, and is further 2:1.
In the technical scheme, in the reaction of the 2, 6-dinitrochlorobenzene of the Q2 and the ammonia water, the polyaminocarboxylic acid used in the reaction process is diethylenetriamine pentaacetic acid or triethylenetetramine hexaacetic acid.
In the technical scheme, in the reaction of the 2, 6-dinitrochlorobenzene of the Q2 and the ammonia water, the molar ratio of the polyaminocarboxylic acid to the 2, 6-dinitrochlorobenzene is 0.2-0.5: 1, further 0.5:1.
In the technical scheme, a copper source catalyst is added in the reaction of the 2, 6-dinitrochlorobenzene of the Q2 and ammonia water, and the copper source catalyst is one of copper, copper oxide, copper chloride and cuprous chloride.
In the technical scheme, the molar ratio of the copper source catalyst to the 2, 6-dinitrochlorobenzene is 0.2-0.8: 1, further 0.5:1.
In the above technical scheme, sodium sulfide nonahydrate reagent is used for the reduction reaction in Q3.
In the above technical scheme, in the reduction reaction in Q3, the molar ratio of 2, 6-dinitroaniline to sodium sulfide nonahydrate is 1:2-4, and further 1:3.
In the technical scheme, the molar ratio of the 3-nitroo-phenylenediamine to the triphosgene in the Q4 is 1:0.1 to 0.5, and further 1:0.4.
The invention takes cheap 3, 5-binitro-4-chlorobenzoic acid as raw material, and obtains high-yield 4-amino-1, 3-dihydro-benzimidazole-2-ketone through decarboxylation, ammonification and other reactions. The whole reaction process is easy to control, the product yield is high, the method is suitable for industrial production, good social benefit and economic benefit can be brought, and the economic value potential is high.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
As a preparation method of 4-amino-1, 3-dihydro-benzimidazol-2-one shown in the example, the reaction equation is as follows:
the preparation method comprises the following steps:
q1, 2, 6-dinitrochlorobenzene is prepared, 3, 5-dinitro-4-chlorobenzoic acid is taken as a raw material at the reaction temperature, 2, 6-dinitrochlorobenzene is formed by decarboxylation in a reaction solvent, the reaction temperature is 180-200 ℃, and the reaction time is 1-3 hours;
preparing Q2, 6-dinitroaniline, reacting 2, 6-dinitrochlorobenzene with ammonia water at 90-110 ℃ for 2-5 hours, extracting, drying, and separating by column chromatography to obtain 2, 6-dinitroaniline;
q3, 3-nitro-o-phenylenediamine is prepared, the reduction reaction is carried out on 2, 6-dinitroaniline, the reaction temperature is 50-80 ℃, and the reaction time is 1-3 hours, so that 3-nitro-o-phenylenediamine is obtained;
q4, 4-nitro-1H-benzo [ d ] imidazole-2 (3H) -ketone is prepared, 3-nitro-o-phenylenediamine and triphosgene are reacted to generate 4-nitro-1H-benzo [ d ] imidazole-2 (3H) -ketone, the reaction temperature is 70-80 ℃, and the reaction time is 1-2 hours;
q5, 4-amino-1, 3-dihydro-benzimidazol-2-one, 4-nitro-1H-benzo [ d ] imidazol-2 (3H) -one completes hydrogenation reduction reaction to obtain 4-amino-1, 3-dihydro-benzimidazol-2-one.
In the above steps, the reagent used for drying is anhydrous magnesium sulfate or anhydrous sodium sulfate.
The following specific embodiments illustrate the technical scheme of the present invention:
preparation of Q1, 2, 6-dinitrochlorobenzene, adding 800ml of sulfolane as a solvent into a 2L flask, adding 246.5g of 3, 5-dinitro-4-chlorobenzoic acid and 168g of sodium bicarbonate, heating to 195 ℃ for reaction for 2 hours, cooling to 130 ℃ after the reaction is completed, distilling under reduced pressure, rectifying to obtain 178.4g of 2, 6-dinitrochlorobenzene, and obtaining the product with 88.1 percent of yield.
Preparation of Q2, 6-dinitroaniline to a 1L flask were added 202.5g of 2, 6-dinitrochlorobenzene, 255ml of 25% aqueous ammonia, 32g of Cu, 196.5g of diethylenetriamine pentaacetic acid and 80g of NaOH, and after sealing, the mixture was stirred at 100℃for 3 hours, after completion of the reaction, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to give a crude product. Column chromatography (n-hexane: ethyl acetate=4:1) gives 155.9g of the product 2, 6-dinitroaniline in 85.2% yield;
preparation of Q3, 3-nitroo-phenylenediamine 91.5g of 2, 6-dinitroaniline is dissolved in water in a 1L flask, heated to 55 ℃ for reaction for 30min, then 360g of sodium sulfide and 126g of sodium bicarbonate are added into the flask, the mixture is heated to 80 ℃ for reaction for 1h, filtered, washed with ice water, and separated and purified by column chromatography (dichloromethane: methanol=95:5), thus obtaining 68.1g of 3-nitroo-phenylenediamine with a yield of 89.0%.
Preparation of Q4, 4-nitro-1H-benzo [ d ] imidazol-2 (3H) -one 153g of 3-nitroo-phenylenediamine was dissolved in 500ml of N, N-dimethylformamide in a 1L flask, 118.6g of triphosgene and 70ml of triethylamine were slowly added to the solution, the mixture was heated to 75℃and reacted for 1H, after the reaction was completed, the residual solvent was evaporated, and then separated by column chromatography (dichloromethane: n-hexane=1:20) to give 145.2g of 4-nitro-1H-benzo [ d ] imidazol-2 (3H) -one in a yield of 81.1%.
Preparation of Q5, 4-amino-1, 3-dihydro-benzimidazol-2-one 10% Palladium on carbon was added to a solution of 178 g of 4-nitro-1H-benzo [ d ] imidazol-2 (3H) -one in methanol (600 ml) and acetic acid (100 ml), the mixture was purged with argon, and then hydrogen gas was bubbled into the solution for 10min, maintaining the hydrogen gas pressure at the balloon pressure overnight. The mixture was filtered and washed with methanol, the residual solvent was evaporated and the resulting solid was separated by column chromatography (methanol: dichloromethane=1:10) to give 128.4g of 4-amino-1, 3-dihydro-benzimidazol-2-one in 86.2% yield.
The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and any person skilled in the art will readily recognize that variations or substitutions are within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (10)
1. A preparation method of 4-amino-1, 3-dihydro-benzimidazol-2-one is characterized by comprising the following steps:
the reaction equation is shown below:
the preparation method comprises the following steps:
q1, 2, 6-dinitrochlorobenzene is prepared, 3, 5-dinitro-4-chlorobenzoic acid is taken as a raw material at the reaction temperature, 2, 6-dinitrochlorobenzene is formed by decarboxylation in a reaction solvent, the reaction temperature is 180-200 ℃, and the reaction time is 1-3 hours;
preparing Q2, 6-dinitroaniline, reacting 2, 6-dinitrochlorobenzene with ammonia water in the presence of alkali and polyaminocarboxylic acid under the catalysis of a copper source catalyst at the reaction temperature of 90-110 ℃ for 2-5 hours, extracting, drying and separating by column chromatography to obtain 2, 6-dinitroaniline; the copper source catalyst is copper;
q3, 3-nitro-o-phenylenediamine is prepared, the reduction reaction is carried out on 2, 6-dinitroaniline, the reaction temperature is 50-80 ℃, and the reaction time is 1-3 hours, so that 3-nitro-o-phenylenediamine is obtained;
q4, 4-nitro-1H-benzo [ d ] imidazole-2 (3H) -ketone is prepared, 3-nitro-o-phenylenediamine and triphosgene are reacted to generate 4-nitro-1H-benzo [ d ] imidazole-2 (3H) -ketone, the reaction temperature is 70-80 ℃, and the reaction time is 1-2 hours;
q5, 4-amino-1, 3-dihydro-benzimidazol-2-one, 4-nitro-1H-benzo [ d ] imidazol-2 (3H) -one completes hydrogenation reduction reaction to obtain 4-amino-1, 3-dihydro-benzimidazol-2-one.
2. The method for preparing 4-amino-1, 3-dihydro-benzimidazol-2-one according to claim 1, wherein:
in Q2, the reagent used for drying is anhydrous magnesium sulfate or anhydrous sodium sulfate.
3. A process for the preparation of 4-amino-1, 3-dihydro-benzimidazol-2-one according to claim 1 or 2, characterized in that: in the Q1, the reaction solvent is sulfolane or dimethyl sulfoxide.
4. A process for the preparation of 4-amino-1, 3-dihydro-benzimidazol-2-one according to claim 3, characterized in that:
in the reaction of the 2, 6-dinitrochlorobenzene of the Q2 and the ammonia water, the mol ratio of the 2, 6-dinitrochlorobenzene to the ammonia water is 1:5-10.
5. The method for preparing 4-amino-1, 3-dihydro-benzimidazol-2-one according to claim 1, wherein:
and alkali is used in the reaction process of the 2, 6-dinitrochlorobenzene of the Q2 and ammonia water, and the alkali is one of sodium hydroxide, potassium hydroxide and potassium phosphate.
6. The method for preparing 4-amino-1, 3-dihydro-benzimidazol-2-one according to claim 5, wherein:
in the reaction of the 2, 6-dinitrochlorobenzene of the Q2 and the ammonia water, the mol ratio of the alkali to the 2, 6-dinitrochlorobenzene is 1-3:1.
7. The method for preparing 4-amino-1, 3-dihydro-benzimidazol-2-one according to claim 1, wherein: in the reaction process of the 2, 6-dinitrochlorobenzene of the Q2 and ammonia water, polyaminocarboxylic acid is diethylenetriamine pentaacetic acid or triethylenetetramine hexaacetic acid, and the molar ratio of the polyaminocarboxylic acid to the 2, 6-dinitrochlorobenzene is 0.2-0.5: 1.
8. the method for preparing 4-amino-1, 3-dihydro-benzimidazol-2-one according to claim 7, wherein:
the molar ratio of the copper source catalyst to the 2, 6-dinitrochlorobenzene is 0.2-0.8: 1.
9. the method for preparing 4-amino-1, 3-dihydro-benzimidazol-2-one according to claim 8, wherein:
sodium sulfide nonahydrate is used in the reduction reaction of Q3, and the molar ratio of 2, 6-dinitroaniline to sodium sulfide nonahydrate is 1:2-4.
10. The method for preparing 4-amino-1, 3-dihydro-benzimidazol-2-one according to claim 9, wherein: the molar ratio of the 3-nitroo-phenylenediamine to the triphosgene in the Q4 is 1:0.1 to 0.5.
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Denomination of invention: A preparation method of 4-amino-1,3-dihydro-benzimidazole-2-one Granted publication date: 20230919 Pledgee: Agricultural Bank of China Xiangtan County Branch Pledgor: Hunan Furui Biomedical Technology Co.,Ltd. Registration number: Y2024980000042 |