CN115232074A - Synthesis method of 1-alkyl substituted-2-methyl-5-bromobenzimidazole - Google Patents
Synthesis method of 1-alkyl substituted-2-methyl-5-bromobenzimidazole Download PDFInfo
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- CN115232074A CN115232074A CN202211009550.0A CN202211009550A CN115232074A CN 115232074 A CN115232074 A CN 115232074A CN 202211009550 A CN202211009550 A CN 202211009550A CN 115232074 A CN115232074 A CN 115232074A
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 229940125904 compound 1 Drugs 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 29
- WRGKKASJBOREMB-UHFFFAOYSA-N 1,4-dibromo-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(Br)=CC=C1Br WRGKKASJBOREMB-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229940125782 compound 2 Drugs 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 239000012046 mixed solvent Substances 0.000 claims abstract description 10
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims abstract description 9
- 230000008569 process Effects 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 132
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 66
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 25
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 20
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 17
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 16
- 229940126214 compound 3 Drugs 0.000 claims description 15
- 230000002194 synthesizing effect Effects 0.000 claims description 13
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 12
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 12
- 239000007858 starting material Substances 0.000 claims description 11
- -1 amino compound Chemical class 0.000 claims description 9
- 238000006467 substitution reaction Methods 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 125000001246 bromo group Chemical group Br* 0.000 claims description 8
- 238000006555 catalytic reaction Methods 0.000 claims description 8
- 150000001924 cycloalkanes Chemical class 0.000 claims description 8
- 229910052759 nickel Inorganic materials 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 238000010189 synthetic method Methods 0.000 claims description 4
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 11
- 239000012535 impurity Substances 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 28
- 238000010992 reflux Methods 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 230000009471 action Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- WIHHVKUARKTSBU-UHFFFAOYSA-N 4-bromobenzene-1,2-diamine Chemical compound NC1=CC=C(Br)C=C1N WIHHVKUARKTSBU-UHFFFAOYSA-N 0.000 description 1
- FHDFUQGJYYGLHJ-UHFFFAOYSA-N 6-bromo-2-methyl-1h-benzimidazole Chemical compound C1=C(Br)C=C2NC(C)=NC2=C1 FHDFUQGJYYGLHJ-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
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- 229910052751 metal Inorganic materials 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
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- OYVXVLSZQHSNDK-UHFFFAOYSA-N n-methoxy-n-methylacetamide Chemical compound CON(C)C(C)=O OYVXVLSZQHSNDK-UHFFFAOYSA-N 0.000 description 1
- AHVQYHFYQWKUKB-UHFFFAOYSA-N oxan-4-amine Chemical compound NC1CCOCC1 AHVQYHFYQWKUKB-UHFFFAOYSA-N 0.000 description 1
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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
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
Abstract
The invention discloses a synthesis method of 1-alkyl substituted-2-methyl-5-bromobenzimidazoles, which comprises the following steps: the first step is as follows: all compounds of the general formula Compound 1 can be prepared by the process of the present invention (wherein R is 1 Alkyl), the second step: condensing the compound with the structure of the compound 2 with 1, 1-trimethylethane to obtain a compound 1. The invention takes cheap 2, 5-dibromo nitrobenzene as an initial material to successfully prepare 1-alkyl substituted-2-methyl-5-bromobenzimidazole through three-step reaction, and the reaction can be used for various R 1 The invention further improves the reaction rate and yield of the product and reduces the impurities of the product by adopting a mixed solvent for preparing the 1-alkyl substituted-2-methyl-5-bromobenzimidazole compound of the alkyl.
Description
Technical Field
The invention relates to the technical field of organic synthetic pharmacy, in particular to a synthetic method of 1-alkyl substituted-2-methyl-5-bromobenzimidazole.
Background
The benzimidazole compound has biological activities in HIV-1 resistance, tumor resistance, cell proliferation resistance, parasite resistance, inflammation resistance, oxidation resistance and epilepsy resistance. In addition to this, such compounds also act as metal ligands. The 2-methyl-5-bromobenzimidazole is an important medical intermediate, can be used for synthesizing various imidazole-containing medicaments, and is prepared by taking 4-bromo-o-phenylenediamine as a starting material and cyclizing the starting material with N-methoxy-N-methylacetamide.
The method has high price of starting materials, is difficult to control the cost, needs further reaction for introducing other alkyl at the 1 position, increases reaction steps, and causes the generation of impurities and the reduction of yield.
Disclosure of Invention
The invention aims to provide a synthesis method of 1-alkyl substituted-2-methyl-5-bromobenzimidazole, which aims to solve the synthesis problem of 1-alkyl substituted-2-methyl-5-bromobenzimidazole.
In order to achieve the purpose, the invention provides the following technical scheme: a synthetic method of 1-alkyl substituted-2-methyl-5-bromobenzimidazole comprises the following steps:
the first step is as follows: compound 1 all compounds of the general formula (wherein R is 1 Is an alkyl group):
the second step is that: condensing a compound having the structure of compound 2 with 1, 1-trimethylethane to obtain compound 1:
preferably, the compound 2, 1-trimethylethane, acetic acid and methanol are heated under reflux to give the compound 1.
Preferably, the 2, 5-dibromonitrobenzene is used as a starting material, and R is used 1 Substituting bromine at position 2 with amino compound to obtain compound 3, reducing nitro group to obtain compound 4, and cyclizing with 1, 1-trimethylethane to obtain compound 1:
preferably, the compound 3 is synthesized by taking N-butanol as a solvent, N, N-diisopropylethylamine, 2, 5-dibromonitrobenzene and R 1 The amino compounds of the group are reacted together.
Preferably, the compound 4 is synthesized by a method of adding hydrazine hydrate into a mixed solvent of methanol and THF under the catalysis of nickel.
Preferably, in the preparation of the compound 1, the ratio of acetic acid to methanol is 0.25-0.5.
Preferably, in the preparation of the compound 4, methanol and THF can be in any ratio, and according to the reaction rate and the condition of impurities, 0.5.
Preferably, R in the formula 1 Are alkanes, including alkanes, cycloalkanes, and possibly various substitutions thereof.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention successfully prepares the 1-alkyl substituted-2-methyl-5-bromobenzimidazole by using cheap 2, 5-dibromonitrobenzene as an initial material and performing three-step reaction.
2. The reaction of the present invention can be used for a variety of R 1 Preparation of 1-alkyl substituted-2-methyl-5-bromobenzimidazole compounds which are alkyl groups.
3. The invention further improves the reaction rate and yield of the product and reduces the impurities of the product by adopting the mixed solvent.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all 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.
Example I
A synthetic method of 1-alkyl substituted-2-methyl-5-bromobenzimidazole comprises the following steps:
the first step is as follows: compound 1 all compounds of the general formula (wherein R is 1 Is an alkyl group):
the second step is that: condensing a compound having the structure of compound 2 with 1, 1-trimethylethane to obtain compound 1:
compound 2, 1-trimethylethane, acetic acid and methanol are heated under reflux to give compound 1.
2, 5-dibromo nitrobenzene is used as a starting material, and R is used 1 Substituting bromine at position 2 with amino compound to obtain compound 3, reducing nitro group to obtain compound 4, and cyclizing with 1, 1-trimethylethane to obtain compound 1:
synthesis of Compound 3 fromButanol as solvent, N, N-diisopropylethylamine, 2, 5-dibromonitrobenzene and R 1 The amino compounds of the group are reacted together.
The compound 4 is synthesized by adding hydrazine hydrate into a mixed solvent of methanol and THF under the catalysis of nickel.
In the preparation of compound 1, the ratio of acetic acid to methanol is 0.25-0.5.
In the preparation of compound 4, methanol and THF may be in any ratio, and 0.5.
R in the structural formula 1 Are alkanes, including alkanes, cycloalkanes, and possibly various substitutions thereof.
The molecular formula is as follows:
synthesis of Compound 6: a mixture of compound 5 (3.00g, 10.68mmol), 2-methoxyethanolamine (2.40 g, 32.04 mmol), DIEA (6.90g, 53.40mmol) and n-butanol (30mL, 0.33mol) was heated at reflux overnight and the mixture was concentrated and purified on a silica gel column (PE) to give a yellow solid (2.50g, 85%).
Synthesis of compound 7: methanol (40mL, 0.98mol), THF (40 mL, 0.50 mol) were mixed well under nitrogen, compound 6 (2.50g, 9.10 mmol) was added and stirred well, a small amount of Ni (200mg, 0.56mmol) was added slowly, and then hydrazine hydrate (5mL, 0.10 mol) was added to the mixture. After the addition, the mixture was stirred at room temperature overnight, the mixture was filtered, and the filtrate was used directly in the next step (2.18g, 98%).
Synthesis of compound 8: a mixture of compound 7 (2.18g, 8.90mmol), 1-trimethoxyethane (5 g, 41.60 mmol), acetic acid (25 mL,0.44 mol), and methanol (50 mL,1.23 mol) was heated under reflux overnight, and the mixture was concentrated and purified on a silica gel column (PE: EA =1, 2) to give a solid (2.16g, 90%).
1HNMR(300MHzCDCl3)δ2.60(s,3H),3.25(s,3H),3.65(t,J＝5.4Hz,2H),4 .24(t,J＝5.4Hz,2H),7.15(d,J＝8.4Hz,1H),7.31(dd,J＝1.8,8.4Hz,1H),7.79( d,J＝1.5Hz,1H)；LC-MS270.0(M+H) + 。
Example II
This embodiment further illustrates, for example 1, a method of synthesizing 1-alkyl-substituted-2-methyl-5-bromobenzimidazoles, which is as follows:
the first step is as follows: all compounds of the general formula Compound 1 can be prepared by the process of the present invention (wherein R is 1 Is an alkyl group):
the second step is that: condensing a compound having the structure of compound 2 with 1, 1-trimethylethane to obtain compound 1:
compound 2, 1-trimethylethane, acetic acid and methanol are heated under reflux to give compound 1.
Using 2, 5-dibromonitrobenzene as a starting material and R 1 Substituting bromine at position 2 with amino compound to obtain compound 3, reducing nitro group to obtain compound 4, and cyclizing with 1, 1-trimethylethane to obtain compound 1:
the compound 3 is synthesized by taking N-butyl alcohol as a solvent, N, N-diisopropylethylamine, 2, 5-dibromonitrobenzene and R 1 The amino compounds of the group are reacted together.
The compound 4 is synthesized by adopting a method of adding hydrazine hydrate into a mixed solvent of methanol and THF under the catalysis of nickel.
In the preparation of compound 1, the ratio of acetic acid to methanol is 0.25 to 0.5.
In the preparation of compound 4, methanol and THF may be in any ratio, and 0.5.
R in the structural formula 1 Are alkanes, including alkanes, cycloalkanes, and possibly various substitutions thereof.
The molecular formula is as follows:
synthesis of compound 9: a mixture of compound 5 (3g, 10.68mmol), cyclohexylamine (3.53g, 32.60mmol), DIEA (2.76g, 21.36mmol) and n-butanol (30mL, 0.33mol) was heated to reflux overnight. The mixture was concentrated and purified on a silica gel column (PE) to give a yellow solid (1.84g, 86%).
Synthesis of compound 10: methanol (40mL, 0.98mol), THF (40 mL, 0.50 mol) were mixed well under nitrogen, compound 9 (1.84g, 6.15mmol) was added and stirred well, a small amount of Ni (200mg, 0.56mmol) was added slowly, then hydrazine hydrate (5mL, 0.10mol) was added to the mixture, after which the mixture was stirred overnight at room temperature, the mixture was filtered, and the filtrate was used directly in the next step (1.60g, 96%).
Synthesis of compound 11: a mixture of compound 10 (1.60g, 5.92mmol), 1-trimethoxyethane (5 g, 41.6 mmol), acetic acid (25ml, 0.44mol), and methanol (50ml, 1.23mol) was heated at reflux overnight, and the mixture was concentrated and purified on a silica gel column (PE: EA = 1) to give a solid (567 mg, 33%).
1HNMR(300MHzCDCl3)δ1.29～1.52(m,3H),1.80～2.00(m,5H),2.07～2.20( m,2H),2.60(s,3H),4.08～4.19(m,1H),7.26(d,J＝8.7Hz,1H),7.36(d,J＝1.8,8 .7Hz,1H),7.79(d,J＝1.5Hz,1H)；LC-MS294.0(M+H) + 。
Example III
This embodiment further illustrates, for example, a method for synthesizing 1-alkyl-substituted-2-methyl-5-bromobenzimidazoles, which comprises the following steps:
the first step is as follows: compound 1 all compounds of the general formula (wherein R is 1 As alkyl):
the second step is that: condensing a compound having the structure of compound 2 with 1, 1-trimethylethane to obtain compound 1:
compound 2, 1-trimethylethane, acetic acid and methanol are heated under reflux to give compound 1.
Using 2, 5-dibromonitrobenzene as a starting material and R 1 Substituting bromine at position 2 with amino compound to obtain compound 3, reducing nitro group to obtain compound 4, and cyclizing with 1, 1-trimethylethane to obtain compound 1:
the compound 3 is synthesized by taking N-butyl alcohol as a solvent, N, N-diisopropylethylamine, 2, 5-dibromonitrobenzene and R 1 The amino compounds of the group are reacted together.
The compound 4 is synthesized by adding hydrazine hydrate into a mixed solvent of methanol and THF under the catalysis of nickel.
In the preparation of compound 1, the ratio of acetic acid to methanol is 0.25-0.5.
In the preparation of compound 4, methanol and THF may be in any ratio, and 0.5.
R in the structural formula 1 Are alkanes, including alkanes, cycloalkanes, and possibly various substitutions thereof.
The molecular formula is as follows:
synthesis of compound 12: a mixture of compound 5 (2.00g, 7.12mmol), cyclopropylamine (2.03 g, 35.60 mmol), DIEA (2.76g, 21.36mmol) and n-butanol (30mL, 0.33mol) was heated under reflux overnight and the mixture was concentrated and purified on silica gel column (PE) to give a yellow solid (1.70g, 93%).
Synthesis of compound 13: methanol (40mL, 0.98mol), THF (40 mL, 0.50 mol) were mixed well under nitrogen, compound 12 (2.20g, 8.56mmol) was added and stirred well, a small amount of Ni (200mg, 0.56mmol) was slowly added, then hydrazine hydrate (5mL, 0.10mol) was added to the mixture, after addition, the mixture was stirred overnight at room temperature, the mixture was filtered, and the filtrate was used directly in the next step (1.17g, 60%).
Synthesis of compound 14: a mixture of compound 13 (1.17g, 5.13mmol), 1-trimethoxyethane (5 g, 41.6 mmol), acetic acid (25ml, 0.44mol) and methanol (50ml, 1.23mol) was heated under reflux overnight, and the mixture was concentrated and purified on a silica gel column (PE: EA =1, 2) to give a solid (1.16g, 90%).
1HNMR(300MHzCD3OD)δ1.03～1.09(m,2H),1.23～1.30(m,2H),2.65(s,3H) ,3.27～3.33(m,1H),7.15(d,J＝8.4Hz,1H),7.31(dd,J＝1.8,8.4Hz,1H),7.79(d ,J＝1.5Hz,1H)。
Example IV
This embodiment further illustrates, in another example, a method for synthesizing 1-alkyl-substituted-2-methyl-5-bromobenzimidazoles, which comprises the following steps:
the first step is as follows: all compounds of the general formula Compound 1 can be prepared by the process of the present invention (wherein R is 1 As alkyl):
the second step is that: condensing a compound having the structure of compound 2 with 1, 1-trimethylethane to obtain compound 1:
the compound 2, 1-trimethylethane, acetic acid and methanol are heated under reflux to give the compound 1.
Using 2, 5-dibromonitrobenzene as a starting material and R 1 Substituting bromine at position 2 with amino compound to obtain compound 3, reducing nitro group to obtain compound 4, and cyclizing with 1, 1-trimethylethane to obtain compound 1:
the compound 3 is synthesized by taking N-butyl alcohol as a solvent, N, N-diisopropylethylamine, 2, 5-dibromonitrobenzene and R 1 The amino compounds of the group are reacted together.
The compound 4 is synthesized by adopting a method of adding hydrazine hydrate into a mixed solvent of methanol and THF under the catalysis of nickel.
In the preparation of compound 1, the ratio of acetic acid to methanol is 0.25-0.5.
In the preparation of compound 4, methanol and THF may be in any ratio, and 0.5.
R in the structural formula 1 Are alkanes, including alkanes, cycloalkanes, and possibly various substitutions thereof.
The molecular formula is as follows:
synthesis of compound 15: a mixture of compound 5 (2.80g, 10.00mmol), tetrahydro-2H-pyran-4-amine (1.00g, 10.00mmol), DIEA (6.50g, 50.00mmol), and n-butanol (30mL, 0.33mol) was heated to reflux overnight, and the mixture was concentrated and purified on silica gel column (PE) to give a yellow solid (787 mg, 26%).
Synthesis of compound 16: methanol (40mL, 0.98mol), THF (40 mL, 0.50 mol) were mixed well under nitrogen, compound 15 (787 mg, 2.61mmol) was added and stirred well, a small amount of Ni (200mg, 0.56mmol) was added slowly, and then hydrazine hydrate (5mL, 0.10mol) was added to the mixture. After the addition, the mixture was stirred at room temperature overnight, the mixture was filtered, and the filtrate was used directly in the next step.
Synthesis of compound 17: a mixture of compound 16 (760mg, 2.79mmol), 1-trimethoxyethane (5 g, 41.6 mmol), acetic acid (25ml, 0.44mol), and methanol (50ml, 1.23mol) was heated at reflux overnight, and the mixture was concentrated and purified on a silica gel column (PE: EA = 1) to obtain a solid (561mg, 68%).
1HNMR(300MHzCDCl3)δ1.83～1.89(m,2H),2.45～2.59(m,2H),2.65(s,3H) ,3.59～3.68(m,2H),4.10～4.15(m,2H),4.57～4.68(m,1H),7.34(dd,J＝2.1,8.7 Hz,1H),7.62(d,J＝8.7Hz,1H),7.68(d,J＝1.8Hz,1H)。
Example V
This embodiment further illustrates, in another example, a method for synthesizing 1-alkyl-substituted-2-methyl-5-bromobenzimidazoles, which comprises the following steps:
the first step is as follows: all compounds of the general formula Compound 1 can be prepared by the process of the present invention (wherein R is 1 Is an alkyl group):
the second step is that: condensing a compound having the structure of compound 2 with 1, 1-trimethylethane to obtain compound 1:
compound 2, 1-trimethylethane, acetic acid and methanol are heated under reflux to give compound 1.
Using 2, 5-dibromonitrobenzene as a starting material and R 1 Substituting bromine at position 2 with amino compound to obtain compound 3, reducing nitro group to obtain compound 4, and cyclizing with 1, 1-trimethylethane to obtain compound 1:
the compound 3 is synthesized by taking N-butyl alcohol as a solvent, N, N-diisopropylethylamine, 2, 5-dibromonitrobenzene and R 1 The group amino compounds are reacted together.
The compound 4 is synthesized by adopting a method of adding hydrazine hydrate into a mixed solvent of methanol and THF under the catalysis of nickel.
In the preparation of compound 1, the ratio of acetic acid to methanol is 0.25 to 0.5.
In the preparation of compound 4, methanol and THF may be in any ratio, and 0.5.
R in the structural formula 1 Are alkanes, including alkanes, cycloalkanes, and possibly various substitutions thereof.
Effect of different ratios of acetic acid and methanol on synthesis of compound 8:
| the amount of acetic acid used | Amount of methanol | Ratio of | Reaction rate | Product harvestRate of change | Purity of the product |
| 25ml | 50ml | 0.5:1 | 12h | 90％ | 99.3％ |
| 50ml | 50ml | 1:1 | 10h | 87％ | 98.7％ |
| 25ml | 100ml | 0.25:1 | 15h | 84％ | 96.5％ |
Example VI
This embodiment further illustrates, in another example, a method for synthesizing 1-alkyl-substituted-2-methyl-5-bromobenzimidazoles, which comprises the following steps:
the first step is as follows: all compounds of the general formula Compound 1 can be prepared by the process of the present invention (wherein R is 1 Is an alkyl group):
the second step is that: condensing a compound having the structure of compound 2 with 1, 1-trimethylethane to obtain compound 1:
compound 2, 1-trimethylethane, acetic acid and methanol are heated under reflux to give compound 1.
Using 2, 5-dibromonitrobenzene as a starting material and R 1 Substituting bromine at position 2 with amino compound to obtain compound 3, reducing nitro group to obtain compound 4, and cyclizing with 1, 1-trimethylethane to obtain compound 1:
the compound 3 is synthesized by taking N-butyl alcohol as a solvent, N, N-diisopropylethylamine, 2, 5-dibromonitrobenzene and R 1 The amino compounds of the group are reacted together.
The compound 4 is synthesized by adopting a method of adding hydrazine hydrate into a mixed solvent of methanol and THF under the catalysis of nickel.
In the preparation of compound 1, the ratio of acetic acid to methanol is 0.25-0.5.
In the preparation of compound 4, methanol and THF may be in any ratio, and 0.5.
Effect of different ratios of methanol and THF on synthesis of compound 7:
| amount of methanol used | Amount of THF used | Ratio of | Reaction rate | Product yield | Purity of the product |
| 30ml | 60ml | 0.5:1 | 18h | 96％ | 98.7％ |
| 40ml | 40ml | 1:1 | 14h | 98％ | 99.2％ |
| 10ml | 70ml | 0.25:1 | 16h | 94％ | 97.4％ |
R in the structural formula 1 Are alkanes, including alkanes, cycloalkanes, and possibly various substitutions thereof.
It is noted that, herein, relational terms such as first and second, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (8)
1. A synthetic method of 1-alkyl substituted-2-methyl-5-bromobenzimidazole is characterized by comprising the following steps: the synthesis method of the 1-alkyl substituted-2-methyl-5-bromobenzimidazole comprises the following steps:
the first step is as follows: all compounds of the general formula Compound 1 can be prepared by the process of the present invention (wherein R is 1 Is an alkyl group):
the second step is that: condensing a compound having the structure of compound 2 with 1, 1-trimethylethane to obtain compound 1:
2. the method for synthesizing 1-alkyl substituted-2-methyl-5-bromobenzimidazole according to claim 1, which is characterized in that: the compound 2, 1-trimethylethane, acetic acid and methanol are heated and refluxed to obtain a compound 1.
3. A1-alkyl-substituted-2-methyl-5-bromobenzene as claimed in claim 1The method for synthesizing the benzimidazole is characterized by comprising the following steps: the 2, 5-dibromo nitrobenzene is used as a starting material, and R is used 1 Substituting bromine at position 2 with amino compound to obtain compound 3, reducing nitro group to obtain compound 4, and cyclizing with 1, 1-trimethylethane to obtain compound 1:
4. the method for synthesizing 1-alkyl substituted-2-methyl-5-bromobenzimidazole according to claim 1, which is characterized in that: the compound 3 is synthesized by taking N-butanol as a solvent, N, N-diisopropylethylamine, 2, 5-dibromonitrobenzene and R 1 The amino compounds of the group are reacted together.
5. The method for synthesizing 1-alkyl substituted-2-methyl-5-bromobenzimidazole according to claim 1, which is characterized in that: the compound 4 is synthesized by adopting a method of adding hydrazine hydrate into a mixed solvent of methanol and THF under the catalysis of nickel.
6. The method for synthesizing 1-alkyl substituted-2-methyl-5-bromobenzimidazole according to claim 1, which is characterized in that: in the preparation of the compound 1, the ratio of acetic acid to methanol is 0.25-0.5.
7. The method for synthesizing 1-alkyl substituted-2-methyl-5-bromobenzimidazole according to claim 1, which is characterized in that: in the preparation of the compound 4, methanol and THF may be in any ratio, and 0.5.
8. The method for synthesizing 1-alkyl substituted-2-methyl-5-bromobenzimidazole according to claim 1, which is characterized in that: r in the structural formula 1 Are alkanes, including alkanes, cycloalkanes, and possibly various substitutions thereof.
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