CN111362878A - Preparation method of 4-amino-1, 3-dihydro-benzimidazole-2-ketone - Google Patents
Preparation method of 4-amino-1, 3-dihydro-benzimidazole-2-ketone Download PDFInfo
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- CN111362878A CN111362878A CN202010193064.3A CN202010193064A CN111362878A CN 111362878 A CN111362878 A CN 111362878A CN 202010193064 A CN202010193064 A CN 202010193064A CN 111362878 A CN111362878 A CN 111362878A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 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 32
- 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 abstract description 15
- BCUSTVNWMJXDSE-UHFFFAOYSA-N 4-amino-1,3-dihydrobenzimidazol-2-one Chemical compound NC1=CC=CC2=C1NC(=O)N2 BCUSTVNWMJXDSE-UHFFFAOYSA-N 0.000 claims abstract description 13
- 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 12
- 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 abstract description 6
- 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 17
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 17
- 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
- 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
- 238000001035 drying Methods 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000003054 catalyst Substances 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
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- 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
- 239000003513 alkali Substances 0.000 claims description 4
- 239000003153 chemical reaction reagent 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
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 3
- 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
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 3
- 230000000911 decarboxylating effect Effects 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
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 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
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 229940048181 sodium sulfide nonahydrate Drugs 0.000 claims description 2
- 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 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 239000005751 Copper oxide Substances 0.000 claims 1
- 229910000431 copper oxide Inorganic materials 0.000 claims 1
- 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 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 4
- 238000004176 ammonification Methods 0.000 abstract description 2
- 238000006114 decarboxylation reaction 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
- 229940108928 copper Drugs 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000000203 mixture Substances 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
- 230000000694 effects Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-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
- 229910001424 calcium ion Inorganic materials 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
- 238000001704 evaporation Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- 229940079101 sodium sulfide Drugs 0.000 description 2
- 229910052979 sodium sulfide Inorganic materials 0.000 description 2
- 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 2
- 238000003756 stirring Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 108091005462 Cation channels Proteins 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102000003563 TRPV Human genes 0.000 description 1
- 108060008564 TRPV Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000000202 analgesic effect Effects 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
- 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
- 239000012043 crude product Substances 0.000 description 1
- 229960003280 cupric chloride Drugs 0.000 description 1
- 229960004643 cupric oxide Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000000586 desensitisation Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000006870 function Effects 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
- 150000004690 nonahydrates Chemical class 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 230000008058 pain sensation Effects 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
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 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
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000003594 spinal ganglia Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 210000000427 trigeminal ganglion Anatomy 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 and 2, 6-dinitrochlorobenzene; preparing Q2 and 2, 6-dinitroaniline; preparing Q3 and 3-nitro o-phenylenediamine; q4, 4-nitro-1H-benzo [ d ] imidazol-2 (3H) -one preparation; q5 to give 4-amino-1, 3-dihydro-benzimidazol-2-one. The invention takes cheap 3, 5-dinitro-4-chlorobenzoic acid as raw material, and obtains the 4-amino-1, 3-dihydro-benzimidazole-2-ketone with high yield 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 vanilloid type1 (TRPV 1) is a non-selective cation channel, is mainly expressed in sensory neurons and fibers thereof, such as dorsal root ganglia and trigeminal ganglia, and participates in various physiological and pathological processes, and TRPV1 participates in the regulation of body temperature, mainly regulates the body temperature by regulating the temperature sensing region of the brain; TRPV1 is also involved in the treatment of certain central nervous system diseases. Modulation of TRPV1 activity may be effective in controlling neuronal excitability; TRPV1 proved to be the major sensor in pain channels, pain involving TRPV1 has inflammation-related pain, and pain due to tissue injury.
The main action mechanism of the TRPV1 agonist used for treating pain at present is to activate TRPV1 channel, enable calcium ion inflow, excite primary sensory neurons, cause desensitization of neurons after long-term use, and block pain transmission, but the side effect of the analgesic mechanism is large, for example, after capsaicin is combined with TRPV1, calcium ions in nerve cells are greatly accumulated, cell membranes are damaged, the intracellular capacitance is greatly reduced, and the mitochondrial membrane permeability can be changed, and finally the nerve cells are subjected to apoptosis.
Because the TRPV1 inhibitor has the function of blocking pain sensation, does not cause damage to nerve cells, and has extremely low side effect, the research on the TRPV1 inhibitor is more and more focused at present, and 4-amino-1, 3-dihydro-benzimidazole-2-ketone is an important intermediate for preparing the TRPV1 inhibitor, but in the prior art, the reaction process of the preparation method of the 4-amino-1, 3-dihydro-benzimidazole-2-ketone is slow, the final yield is low, and the preparation method is not suitable for industrial production.
Disclosure of Invention
In view of the above drawbacks and problems of the prior art, the present invention provides a method for preparing 4-amino-1, 3-dihydro-benzimidazol-2-one, which solves the following technical problems: provides a preparation method of 4-amino-1, 3-dihydro-benzimidazole-2-ketone suitable for large-scale industrialization.
In order to achieve the purpose, the invention provides the following technical scheme:
a method for preparing 4-amino-1, 3-dihydro-benzimidazole-2-ketone, wherein the reaction formula is as follows:
the preparation method comprises the following steps:
preparing Q1 and 2, 6-dinitrochlorobenzene, namely decarboxylating 3, 5-dinitro-4-chlorobenzoic acid serving as a raw material in a reaction solvent to form 2, 6-dinitrochlorobenzene at the reaction temperature of 180-200 ℃ for 1-3 hours at the reaction temperature;
preparing Q2 and 2, 6-dinitroaniline, reacting 2, 6-dinitrochlorobenzene with ammonia water at the temperature of 90-110 ℃ for 2-5 hours, extracting, drying, and separating by column chromatography to obtain 2, 6-dinitroaniline;
q3 and 3-nitro o-phenylenediamine are prepared, 2, 6-dinitroaniline is subjected to reduction reaction at the temperature of 50-80 ℃ for 1-3 hours to obtain 3-nitro-o-phenylenediamine;
preparing Q4 and 4-nitro-1H-benzo [ d ] imidazole-2 (3H) -ketone, namely preparing 4-nitro-1H-benzo [ d ] imidazole-2 (3H) -ketone from 3-nitro o-phenylenediamine and triphosgene at the reaction temperature of 70-80 ℃ for 1-2 hours;
q5, preparation of 4-amino-1, 3-dihydro-benzimidazole-2-ketone, and hydrogenation reduction reaction of 4-nitro-1H-benzo [ d ] imidazole-2 (3H) -ketone to obtain 4-amino-1, 3-dihydro-benzimidazole-2-ketone.
In the technical scheme, reagents used for drying in the Q1-Q5 are anhydrous magnesium sulfate or anhydrous sodium sulfate.
In the above technical scheme, in Q1, the reaction solvent is sulfolane or dimethyl sulfoxide.
In the technical scheme, in the reaction of the 2, 6-dinitrochlorobenzene of Q2 and 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 Q2 and 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 Q2 and ammonia water, the molar ratio of alkali to the 2, 6-dinitrochlorobenzene is 1-3: 1, and further 2: 1.
In the technical scheme, in the reaction of the 2, 6-dinitrochlorobenzene of Q2 and 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 Q2 and ammonia water, the molar ratio of polyamino carboxylic 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 Q2 and ammonia water, and the copper source catalyst is one of copper, cupric oxide, cupric 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 reagent nonahydrate is used for the reduction reaction in Q3.
In the 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 3-nitro o-phenylenediamine to triphosgene in Q4 is 1: 0.1 to 0.5, and further 1: 0.4.
The invention takes cheap 3, 5-dinitro-4-chlorobenzoic acid as raw material, and obtains the 4-amino-1, 3-dihydro-benzimidazole-2-ketone with high yield 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 large.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
As a preparation method of 4-amino-1, 3-dihydro-benzimidazole-2-ketone shown in the example, the reaction equation is as follows:
the preparation method comprises the following steps:
preparing Q1 and 2, 6-dinitrochlorobenzene, namely decarboxylating 3, 5-dinitro-4-chlorobenzoic acid serving as a raw material in a reaction solvent to form 2, 6-dinitrochlorobenzene at the reaction temperature of 180-200 ℃ for 1-3 hours at the reaction temperature;
preparing Q2 and 2, 6-dinitroaniline, reacting 2, 6-dinitrochlorobenzene with ammonia water at the temperature of 90-110 ℃ for 2-5 hours, extracting, drying, and separating by column chromatography to obtain 2, 6-dinitroaniline;
q3 and 3-nitro o-phenylenediamine are prepared, 2, 6-dinitroaniline is subjected to reduction reaction at the temperature of 50-80 ℃ for 1-3 hours to obtain 3-nitro-o-phenylenediamine;
preparing Q4 and 4-nitro-1H-benzo [ d ] imidazole-2 (3H) -ketone, namely preparing 4-nitro-1H-benzo [ d ] imidazole-2 (3H) -ketone from 3-nitro o-phenylenediamine and triphosgene at the reaction temperature of 70-80 ℃ for 1-2 hours;
q5, preparation of 4-amino-1, 3-dihydro-benzimidazole-2-ketone, and hydrogenation reduction reaction of 4-nitro-1H-benzo [ d ] imidazole-2 (3H) -ketone to obtain 4-amino-1, 3-dihydro-benzimidazole-2-ketone.
In the above step, the reagent used for drying is anhydrous magnesium sulfate or anhydrous sodium sulfate.
The technical solution of the present invention is illustrated by the following specific examples:
q1 and 2, 6-dinitrochlorobenzene are prepared by adding 800ml sulfolane as 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 2h, cooling to 130 ℃ after the reaction is finished, carrying out reduced pressure distillation, and rectifying to obtain 178.4g of the product 2, 6-dinitrochlorobenzene with the yield of 88.1%.
Q2 and 2, 6-dinitroaniline are prepared by adding 202.5g of 2, 6-dinitrochlorobenzene, 255ml of 25% ammonia water, 32g of Cu, 196.5g of diethylenetriaminepentaacetic acid and 80g of NaOH into a 1L flask, sealing, stirring for 3 hours at 100 ℃ under stirring, extracting with ethyl acetate after the reaction is finished, washing with saturated saline, drying with anhydrous sodium sulfate, and evaporating to obtain a crude product. Column chromatography (n-hexane: ethyl acetate: 4:1) to obtain 155.9g of 2, 6-dinitroaniline, the yield is 85.2%;
q3 and 3-nitrophthalenediamine were prepared by dissolving 91.5g of 2, 6-dinitroaniline in water in a 1L flask, heating to 55 ℃ for reaction for 30min, adding 360g of sodium sulfide and 126g of sodium bicarbonate to the flask, heating the mixture to 80 ℃ for reaction for 1h, filtering, washing with ice water, and separating and purifying by column chromatography (dichloromethane: methanol: 95:5) to obtain 68.1g of 3-nitrophthalenediamine with a yield of 89.0%.
Q4, 4-nitro-1H-benzo [ d ] imidazol-2 (3H) -one was prepared by dissolving 153g of 3-nitrophthalenediamine in 500ml of N, N-dimethylformamide in a 1L flask, then slowly adding 118.6g of triphosgene and 70ml of triethylamine to the solution, heating the mixture to 75 ℃, reacting for 1H, after the reaction was completed, evaporating the residual solvent, and then performing column chromatography (dichloromethane: N-hexane ═ 1:20) to obtain 145.2g of 4-nitro-1H-benzo [ d ] imidazol-2 (3H) -one in 81.1% yield.
Preparation of Q5, 4-amino-1, 3-dihydro-benzimidazol-2-one, 10% palladium on carbon was added to a solution of 179g of 4-nitro-1H-benzo [ d ] imidazol-2 (3H) -one in methanol (600ml) and acetic acid (100ml), the mixture was purged with argon, then hydrogen was bubbled through the solution for 10min, maintaining hydrogen pressure at balloon pressure overnight. The mixture was filtered and washed with methanol, the residual solvent was evaporated and the resulting solid was isolated 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 above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered 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 method for preparing 4-amino-1, 3-dihydro-benzimidazole-2-ketone is characterized in that:
the reaction equation is as follows:
the preparation method comprises the following steps:
preparing Q1 and 2, 6-dinitrochlorobenzene, namely decarboxylating 3, 5-dinitro-4-chlorobenzoic acid serving as a raw material in a reaction solvent to form 2, 6-dinitrochlorobenzene at the reaction temperature of 180-200 ℃ for 1-3 hours at the reaction temperature;
preparing Q2 and 2, 6-dinitroaniline, reacting 2, 6-dinitrochlorobenzene with ammonia water at the temperature of 90-110 ℃ for 2-5 hours, extracting, drying, and separating by column chromatography to obtain 2, 6-dinitroaniline;
q3 and 3-nitro o-phenylenediamine are prepared, 2, 6-dinitroaniline is subjected to reduction reaction at the temperature of 50-80 ℃ for 1-3 hours to obtain 3-nitro-o-phenylenediamine;
preparing Q4 and 4-nitro-1H-benzo [ d ] imidazole-2 (3H) -ketone, namely preparing 4-nitro-1H-benzo [ d ] imidazole-2 (3H) -ketone from 3-nitro o-phenylenediamine and triphosgene at the reaction temperature of 70-80 ℃ for 1-2 hours;
q5, preparation of 4-amino-1, 3-dihydro-benzimidazole-2-ketone, and hydrogenation reduction reaction of 4-nitro-1H-benzo [ d ] imidazole-2 (3H) -ketone to obtain 4-amino-1, 3-dihydro-benzimidazole-2-ketone.
2. The process for preparing 4-amino-1, 3-dihydro-benzimidazol-2-one according to claim 1, wherein: in the Q1-Q5, the reagent used for drying is anhydrous magnesium sulfate or anhydrous sodium sulfate.
3. The process for preparing 4-amino-1, 3-dihydro-benzimidazol-2-one according to claim 1 or 2, wherein: 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, wherein: in the reaction of the 2, 6-dinitrochlorobenzene of Q2 and ammonia water, the molar ratio of the 2, 6-dinitrochlorobenzene to the ammonia water is 1: 5-10.
5. The process for preparing 4-amino-1, 3-dihydro-benzimidazol-2-one according to claim 4, wherein: in the reaction of the 2, 6-dinitrochlorobenzene of Q2 and ammonia water, the alkali used in the reaction process is one of sodium hydroxide, potassium hydroxide and potassium phosphate.
6. The process according to claim 5 for the preparation of 4-amino-1, 3-dihydro-benzimidazol-2-one, wherein: in the reaction of the 2, 6-dinitrochlorobenzene of Q2 and ammonia water, the molar ratio of alkali to the 2, 6-dinitrochlorobenzene is 1-3: 1.
7. The process according to claim 6 for the preparation of 4-amino-1, 3-dihydro-benzimidazol-2-one, wherein: in the reaction of the 2, 6-dinitrochlorobenzene of Q2 and ammonia water, polyamino carboxylic acid used in the reaction process is diethylenetriamine pentaacetic acid or triethylenetetramine hexaacetic acid, and the molar ratio of the polyamino carboxylic acid to the 2, 6-dinitrochlorobenzene is 0.2-0.5: 1.
8. the process according to claim 7 for the preparation of 4-amino-1, 3-dihydro-benzimidazol-2-one, wherein: adding a copper source catalyst in the reaction of the 2, 6-dinitrochlorobenzene of Q2 and ammonia water, wherein the copper source catalyst is one of copper, copper oxide, copper chloride and cuprous chloride, and the molar ratio of the copper source catalyst to the 2, 6-dinitrochlorobenzene is 0.2-0.8: 1.
9. the process according to claim 8 for the preparation of 4-amino-1, 3-dihydro-benzimidazol-2-one, wherein: in the reduction reaction in the Q3, the molar ratio of the 2, 6-dinitroaniline to the sodium sulfide nonahydrate is 1: 2-4.
10. The process according to claim 9 for the preparation of 4-amino-1, 3-dihydro-benzimidazol-2-one, characterized in that: the molar ratio of 3-nitro o-phenylenediamine to triphosgene in 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 |