CN103980212A - One-pot synthesis method for heterocyclic derivatives of dibenzodiazepine - Google Patents
One-pot synthesis method for heterocyclic derivatives of dibenzodiazepine Download PDFInfo
- Publication number
- CN103980212A CN103980212A CN201410206756.1A CN201410206756A CN103980212A CN 103980212 A CN103980212 A CN 103980212A CN 201410206756 A CN201410206756 A CN 201410206756A CN 103980212 A CN103980212 A CN 103980212A
- Authority
- CN
- China
- Prior art keywords
- reaction
- ammoniacal liquor
- hexichol
- synthesis method
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 25
- 125000000623 heterocyclic group Chemical group 0.000 title abstract description 4
- 238000005580 one pot reaction Methods 0.000 title abstract 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 57
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 33
- 238000003756 stirring Methods 0.000 claims abstract description 14
- 239000000126 substance Substances 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 60
- -1 hexichol acid amides Chemical class 0.000 claims description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 23
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 229940049706 benzodiazepine Drugs 0.000 claims description 12
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 150000004880 oxines Chemical group 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 15
- 239000003054 catalyst Substances 0.000 abstract description 5
- 239000000758 substrate Substances 0.000 abstract description 4
- 230000003197 catalytic effect Effects 0.000 abstract description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 abstract 2
- 239000003446 ligand Substances 0.000 abstract 2
- 238000001035 drying Methods 0.000 abstract 1
- 239000010970 precious metal Substances 0.000 abstract 1
- 238000007086 side reaction Methods 0.000 abstract 1
- 238000000967 suction filtration Methods 0.000 abstract 1
- 150000001408 amides Chemical class 0.000 description 23
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 23
- 239000000047 product Substances 0.000 description 14
- 238000004821 distillation Methods 0.000 description 12
- 238000000605 extraction Methods 0.000 description 12
- 238000001953 recrystallisation Methods 0.000 description 12
- 238000004587 chromatography analysis Methods 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- 238000005406 washing Methods 0.000 description 11
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 description 10
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical class ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 125000001207 fluorophenyl group Chemical group 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 238000000926 separation method Methods 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 229960001866 silicon dioxide Drugs 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000001228 spectrum Methods 0.000 description 10
- 239000010949 copper Substances 0.000 description 9
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical group C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 8
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 6
- 125000000068 chlorophenyl group Chemical group 0.000 description 6
- 125000004799 bromophenyl group Chemical group 0.000 description 5
- 125000006303 iodophenyl group Chemical group 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 2
- JNWFVQVADGTBHZ-UHFFFAOYSA-N 2-(2-iodophenyl)benzamide Chemical compound NC(=O)C1=CC=CC=C1C1=CC=CC=C1I JNWFVQVADGTBHZ-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- HRVRWIBVVHOHNN-UHFFFAOYSA-N 2-bromo-3-nitrophenol Chemical class OC1=CC=CC([N+]([O-])=O)=C1Br HRVRWIBVVHOHNN-UHFFFAOYSA-N 0.000 description 1
- RBGDLYUEXLWQBZ-UHFFFAOYSA-N 2-chlorobenzamide Chemical compound NC(=O)C1=CC=CC=C1Cl RBGDLYUEXLWQBZ-UHFFFAOYSA-N 0.000 description 1
- QPGGEKPRGVJKQB-UHFFFAOYSA-N 5-[2-(dimethylamino)ethyl]-11-methyl-6-benzo[b][1,4]benzodiazepinone Chemical compound O=C1N(CCN(C)C)C2=CC=CC=C2N(C)C2=CC=CC=C21 QPGGEKPRGVJKQB-UHFFFAOYSA-N 0.000 description 1
- 0 C=C(C=C1)C=CC(I)=C1*(Nc1ccccc1Br)=O Chemical compound C=C(C=C1)C=CC(I)=C1*(Nc1ccccc1Br)=O 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 1
- 102000003964 Histone deacetylase Human genes 0.000 description 1
- 108090000353 Histone deacetylase Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- BBWMBEPXGBXRON-UHFFFAOYSA-N O=C1NC2C=CC=CC2Nc2c1cccc2 Chemical compound O=C1NC2C=CC=CC2Nc2c1cccc2 BBWMBEPXGBXRON-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000034337 acetylcholine receptors Human genes 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000005266 diarylamine group Chemical group 0.000 description 1
- 229960003075 dibenzepin Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- ZHDORMMHAKXTPT-UHFFFAOYSA-N n-benzoylbenzamide Chemical group C=1C=CC=CC=1C(=O)NC(=O)C1=CC=CC=C1 ZHDORMMHAKXTPT-UHFFFAOYSA-N 0.000 description 1
- 150000005181 nitrobenzenes Chemical class 0.000 description 1
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 1
- 229960005017 olanzapine Drugs 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229940075993 receptor modulator Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001519 thymoleptic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to a one-pot synthesis method for heterocyclic derivatives of dibenzodiazepine. The one-pot synthesis method comprises the steps of with dibenzamides and ammonia water as raw materials, dissolving dibenzamides and ammonia water into an organic solvent according to the substance amount ratio of (0.5-1):2; adding an alkaline medium; adding a catalyst and a ligand; reacting at the temperature of 10-30 DEG C for 5-10h while stirring, and then, reacting at the temperature of 100-130 DEG C for 20-24h; carrying out suction filtration, extracting, drying and separating by using a chromatographic column to obtain a pure product. The one-pot synthesis method has the advantages of simplicity and convenience in reaction operation, relatively mild in condition, high in catalytic activity, little in side reaction, convenience for product after-treatment, high product selectivity and wide substrate expansion range; in addition, a catalytic system is capable of omitting precious metal chemical complexes and reducing economic costs generated by complex ligand application and high reaction temperature, and is safe, convenient and little to environment pollution.
Description
Technical field
The present invention relates to organic synthesis field, be specifically related to a kind of method of synthetic two Benzodiazepine Hete rocyclic derivatives.
Background technology
Many have a heterocycle structure that bioactive compound all contains two Benzodiazepines, and the compound with hexichol diazepine structure plays an important role at medicine and pesticide industry at biologically active drug or agency.Comprising clinical thymoleptic dibenzepin (A), non-peptide endothelin-receptor antagonists (B), inhibitors of histone deacetylase (C), M acetylcholine receptor modulator (D).
The method of synthetic these compounds of tradition is to general structure 1, the selective alkylation of unsubstituted 11-oxygen two these tricyclic structures of Benzodiazepine of 6-.But reactions steps is long owing to being subject to the impact of commercially available available starting raw material, and in the alkylated reaction of diarylamine, the low productive rate that causes of reactive behavior due to amine is not high.
In recent years, the method for synthetic two Benzodiazepine Hete rocyclic derivatives that had bibliographical information, the people such as such as Murugesan have reported for work and have used K
2cO
3the bromo-3-nitrophenols of catalysis 4-and 1-brooethyl naphthalene are under the existence of dimethyl formamide (DMF), room temperature reaction synthetic compound, again at copper catalyst, under alkaline matter, reflux 6 hours through synthetic two Benzodiazepine Hete rocyclic derivatives (the Murugesan et al.Bioorg.Med.Chem.Lett.1995 of 3,4 steps, 5,253); Wang in 2007, the people such as L have reported for work by the back flow reaction and then obtain two Benzodiazepine heterocycle structures (Wang, L et al.J.Med.Chem.2007,50,4162.) in chlorobenzene solution of 0-chloro-benzoic acid and O-Phenylene Diamine under copper catalysis; Binaschi in 2010, the people such as M have reported 1, the selective alkylation of unsubstituted 11-oxygen two these tricyclic structures of Benzodiazepine of 6-, and then synthetic two Benzodiazepine Hete rocyclic derivatives (Binaschi, M et al.Med.Chem.Lett.2010, Isosorbide-5-Nitrae 11.).
But, aforesaid method exists some defects, these tricyclic heterocyclics react with 2-halogenated nitrobenzene and conventionally need several steps with the anthranilic acid of copper catalytic coupling its preparation, beginning, these method sequence length are loaded down with trivial details, expensive raw material price, productive rate is on the low side, aftertreatment is more difficult, whether can under the condition that changes catalyst system, prepare that structure for activity hexichol acid amides on the low side, and then prepare medicine olanzapine, leoponex and still have very much researching value.System is immature, productive rate is on the low side and the dependence of complex substrate has seriously been restricted to its industrial applications in a lot of fields.
Summary of the invention
The object of the present invention is to provide the method for the synthetic two Benzodiazepine Hete rocyclic derivatives of one kettle way.The feature such as the method has that cost is low, the operability of mild condition, raw material is large, productive rate is high, substrate suitability is wide.
The technical solution used in the present invention is: the method for the synthetic two Benzodiazepine Hete rocyclic derivatives of one kettle way, its concrete steps are as follows: getting hexichol acid amides is that 0.5~1:2 is dissolved in organic solvent with ammoniacal liquor by amount of substance ratio, add alkaline medium, add catalyzer and part, first stirring reaction 5~10h at 10~30 DEG C of temperature, then at 100~130 DEG C of temperature, react 20~24h acquisition hexichol diazepine analog derivative.
Reaction process is as follows:
Preferably dibenzoyl amine structure is as follows:
wherein X is selected from the one in iodine, chlorine or bromine, and Y is selected from the one in iodine, chlorine or bromine, and R is selected from chlorine, fluorine or methyl a kind of.
Hexichol acid amides is selected from: the iodo-N-of 2-(the iodo-phenyl of 2-)-benzamide
n-(the iodo-phenyl of the fluoro-2-of 4-)-2-iodobenzene methane amide
n-(the bromo-phenyl of 2-)-2-iodobenzene methane amide
n-(the fluoro-phenyl of the bromo-4-of 2-)-2-iodobenzene methane amide
n-(the fluoro-phenyl of the chloro-4-of 2-)-2-iodobenzene methane amide
n-(the chloro-phenyl of 2-)-2-iodobenzene methane amide
bromo-N-(the bromo-phenyl of 2-)-benzamide
the bromo-N-of 2-(the fluoro-phenyl of the bromo-4-of 2-)-benzamide
The bromo-N-of 2-(the iodo-phenyl of the fluoro-2-of 4-)-benzamide
the bromo-N-of 2-(the iodo-phenyl of 2-)-benzamide
the bromo-N-of 2-(the chloro-phenyl of 2-)-benzamide
the bromo-N-of 2-(the chloro-phenyl of the fluoro-2-of 4-)-benzamide
the chloro-N-of 2-(the chloro-phenyl of 2-)-benzamide
the chloro-N-of 2-(the fluoro-phenyl of the chloro-4-of 2-)-benzamide
the chloro-N-of 2-(the fluoro-phenyl of the iodo-4-of 2-)-benzamide
the chloro-N-of 2-(the fluoro-phenyl of the bromo-4-of 2-)-benzamide
n-(the bromo-phenyl of 2-) the chloro-benzamide of-2-
the chloro-N-of 2-(the iodo-phenyl of 2-)-benzamide
in one.
Described alkaline medium is phosphate radical metal-salt, carbonate metal-salt or hydroxide radical metal-salt, and molecular formula is (M)
3pO
4, (M)
2cO
3or M (OH), wherein metal M is selected from the one of caesium (Cs), sodium (Na) or potassium (K); Preferably alkaline medium is KOH, NaOH, K
3pO
4or K
2cO
3; Preferably alkaline medium is 1~1.5:1 with the amount of substance ratio of ammoniacal liquor.
In technique scheme, the one in the preferred dimethyl sulfoxide (DMSO) of solvent (DMSO), dimethyl formamide (DMF), methyl alcohol or toluene.The add-on of solvent is solubilizing reaction raw material.
Preferably above-mentioned catalyzer is CuI, CuBr, Cu
2o or Cu
2cl.The amount of substance ratio of preferred catalyst and ammoniacal liquor is 0.05~0.1:1.
Preferably above-mentioned part is oxine and 1,10-phenanthroline or L-PROLINE.Preferably part is 0.05~0.1:1 with the amount of substance ratio of ammoniacal liquor.
The mass concentration of preferred above-mentioned ammoniacal liquor is 25%~28%.
In technique scheme, reaction is first at 10~30 DEG C of stirring reaction 5~10h, the reaction 20-24 hour in temperature to 100~130 DEG C again, system through cooling, extraction, dry, chromatography column separates, underpressure distillation obtains product, after recrystallization, can obtain highly purified product.
Due to the utilization of technique scheme, the present invention compared with prior art has following advantages:
1. due to alkaline medium, and the application of reactant hexichol acid amides and ammoniacal liquor, this reaction can be carried out at lower temperature, and reaction conditions is simple, gentleness, and reaction yield is high, can reach 95% productive rate.
2. taking phosphate radical metal-salt as alkaline medium, ammoniacal liquor is cheap and easy to get, and reaction system adds cheap part can obtain target product, has solved the increase problem of final product Financial cost, has reduced the pollution to environment; Product can complete aftertreatment through overcooling, extraction, dry, underpressure distillation, washing, recrystallization, and aftertreatment is simple, convenient.
3. above-mentioned set up catalyst system, suitability is extensive, and the transformation efficiency of substrate and the productive rate of product are all higher, have expanded the industrial applications in a lot of fields.
Embodiment
Below in conjunction with embodiment, the invention will be further described, but embodiment does not limit the present invention in any way: embodiment 1:
The present embodiment is the synthetic of hexichol Diazepines, with N-(the fluoro-phenyl of the bromo-4-of 2-)-2-iodobenzene methane amide, ammoniacal liquor (25%~28%), K
3pO
4, CuI, dimethyl formamide, 1,10 phenanthroline be raw material, reaction formula is as follows:
Preparation method: add N-(the fluoro-phenyl of the bromo-4-of 2-)-2-iodobenzene methane amide of 0.5mmol in 25ml eggplant-shape bottle, the ammoniacal liquor of 1mmol, the CuI of 0.05mmol, the K of 1.5mmol
3pO
4, 1,10 phenanthroline of 0.05mmol, then add 2ml dimethyl formamide, first stirring reaction 5 hours at 10 DEG C, the reaction of some silica-gel plate finishes, and shifts eggplant-shape bottle to oil bath pan, and 110 DEG C are stirred 24 hours, and solution becomes Vandyke brown, has product generation.
Reaction solution is filtered and obtains white solid after cooling, extraction, dry, chromatography column separation, underpressure distillation, washing, recrystallization.
Productive rate is 89%, and the fusing point of this hexichol diazepine is: 240-265 DEG C; Nucleus magnetic hydrogen spectrum
1h NMR (500MHz, CDCl
3) :=7.99-8.01 (d, J=7.85Hz, 1H), 7.59-7.62 (dd, J=8.575Hz, 1H), 7.24-7.27 (t, 3H), 7.04-7.07 (t, 1H), 6.76-6.79 (t, 2H).
Embodiment 2:
The present embodiment is the synthetic of hexichol Diazepines, with N-(the bromo-phenyl of 2-)-2-iodobenzene methane amide, ammoniacal liquor (25%~28%), KOH, Cu
2o, dimethyl formamide, 1,10 phenanthroline are raw material, and reaction formula is as follows:
Preparation method: add N-(the bromo-phenyl of 2-)-2-iodobenzene methane amide of 0.25mmol in 25ml eggplant-shape bottle, the ammoniacal liquor of 1mmol, the Cu of 0.05mmol
2o, the KOH of 1.5mmol, 1,10 phenanthroline of 0.05mmol, add again 2ml dimethyl sulfoxide (DMSO) (DMSO), first stirring reaction 10 hours at 15 DEG C, the reaction of some silica-gel plate finishes, and shifts eggplant-shape bottle to oil bath pan, 110 DEG C are stirred 24 hours, and solution becomes Vandyke brown, have product to generate.
Reaction solution is filtered and obtains white solid after cooling, extraction, dry, chromatography column separation, underpressure distillation, washing, recrystallization.
Productive rate is 89%, and the fusing point of this hexichol diazepine is: 259-261 DEG C; Nucleus magnetic hydrogen spectrum
1h NMR (300MHz, CDCl
3) :=9.79 (s, 1H), 7.79 (s, 1H), 7.61-7.64 (d, J=8.0Hz, 1H), 7.27-7.32 (dd, J=8.0Hz, 1.6Hz, 1H), 6.82-6.95 (m, 6H).
Embodiment 3:
The present embodiment is the synthetic of hexichol Diazepines, taking N-(the bromo-5-chloro-phenyl-of 2-)-2-iodobenzene methane amide, ammoniacal liquor (25%~28%), NaOH, CuBr, dimethyl formamide, oxine as raw material, reaction formula is as follows:
Preparation method: N-(the bromo-5-chloro-phenyl-of the 2-)-2-iodobenzene methane amide that adds 0.25mmol in 25ml eggplant-shape bottle, the ammoniacal liquor of 1mmol, the CuBr of 0.05mmol, the NaOH of 1.5mmol, the oxine of 0.05mmol, add again 2ml dimethyl formamide, first stirring reaction 5 hours at 30 DEG C, the reaction of some silica-gel plate finishes, shift eggplant-shape bottle to oil bath pan, 100 DEG C are stirred 20 hours, and solution becomes dark color, have product to generate.
Reaction solution is filtered and obtains white solid after cooling, extraction, dry, chromatography column separation, underpressure distillation, washing, recrystallization.
Productive rate is 81%, and the fusing point of this hexichol diazepine is: 230-250 DEG C; Nucleus magnetic hydrogen spectrum:
1h NMR (300 MHz, CDCl
3) :=7.92 – 7.95 (dd, J=2.1,8.4Hz, 1H), 7.87 – 7.90 (dd, J=1.5,8.1Hz, 1H), 7.73 – 7.77 (d, J=8.4Hz, 1H), 7.42 – 7.46 (dd, J=2.1,8.4Hz, 1H), 7.26 – 7.34 (m, 1H), 7.14 (s, 2H), 6.90 – 6.93 (dd, J=0.6,8.4Hz, 1H), 6.68 – 6.73 (m, 1H).
Embodiment 4:
The present embodiment is the synthetic of hexichol Diazepines, with N-(the chloro-phenyl of 2-)-2-iodobenzene methane amide, ammoniacal liquor (25%~28%), K
3cO
3, CuI, dimethyl formamide, oxine be raw material, reaction formula is as follows:
Preparation method: add N-(the chloro-phenyl of 2-)-2-iodobenzene methane amide of 0.5mmol in 25ml eggplant-shape bottle, the ammoniacal liquor of 1mmol, the CuI of 0.1mmol, the K of 1mmol
3cO
3, the oxine of 0.1mmol, then add 2ml dimethyl formamide, first stirring reaction 5 hours at 30 DEG C, the reaction of some silica-gel plate finishes, and shifts eggplant-shape bottle to oil bath pan, and 130 DEG C are stirred 24 hours, and solution becomes dark color, has product generation.
Reaction solution is filtered and obtains white solid after cooling, extraction, dry, chromatography column separation, underpressure distillation, washing, recrystallization.
Productive rate is 79%, and the fusing point of this hexichol diazepine is: 250-260 DEG C; Nucleus magnetic hydrogen spectrum
1h NMR (300MHz, CDCl
3) :=9.79 (s, 1H), 7.79 (s, 1H), 7.61-7.a64 (d, J=8.0Hz, 1H), 7.27-7.32 (dd, J=8.0Hz, 1.6Hz, 1H), 6.82-6.95 (m, 6H).
Embodiment 5:
The present embodiment is the synthetic of hexichol Diazepines, with N-(the bromo-3-chloro-phenyl-of 2-)-2-iodobenzene methane amide, ammoniacal liquor (25%~28%), K
3pO
4, Cu
2cl, dimethyl formamide, 1,10 phenanthroline are raw material, and reaction formula is as follows:
Preparation method: add N-(the bromo-3-chloro-phenyl-of the 2-)-2-iodobenzene methane amide of 0.5mmol in 25ml eggplant-shape bottle, the ammoniacal liquor of 1mmol, the Cu of 0.05mmol
2cl, the K of 1.5mmol
3pO
4, 1,10 phenanthroline of 0.05mmol, then add 2ml dimethyl formamide, first stirring reaction 8 hours at 20 DEG C, the reaction of some silica-gel plate finishes, and shifts eggplant-shape bottle to oil bath pan, and 110 DEG C are stirred 24 hours, and solution becomes dark color, has product generation.
Reaction solution is filtered and obtains white solid after cooling, extraction, dry, chromatography column separation, underpressure distillation, washing, recrystallization.
Productive rate is 83%, and the fusing point of this hexichol diazepine is: 220-240 DEG C; Nucleus magnetic hydrogen spectrum:
1h NMR (300MHz, DMSO-d
6) :=7.90 – 7.95 (dd, J=1.5,8.1Hz, 1H), 7.74 – 7.79 (dd, J=0.9,8.1Hz, 1H), 7.44 – 7.51 (dd, J=0.9,8.1Hz, 1H), 7.40 – 7.43 (d, J=7.8Hz, 1H), 7.28 – 7.39 (m, 1H), 7.16 (s, 2H), 6.90 – 6.94 (d, J=7.5Hz, 1H), 6.67 – 6.72 (m, 1H).
Embodiment 6:
The present embodiment is the synthetic of hexichol Diazepines, with N-(the bromo-3-aminomethyl phenyl of 2-)-2-iodobenzene methane amide, ammoniacal liquor (25%~28%), K
3pO
4, CuI, dimethyl formamide, 1,10 phenanthroline be raw material, reaction formula is as follows:
Preparation method: add N-(the bromo-3-aminomethyl phenyl of the 2-)-2-iodobenzene methane amide of 0.5mmol in 25ml eggplant-shape bottle, the ammoniacal liquor of 1mmol, the CuI of 0.05mmol, the K of 1.5mmol
3pO
4, 1,10 phenanthroline of 0.05mmol, then add 2ml dimethyl formamide, first, 15 times stirring reactions 8 hours, the reaction of some silica-gel plate finishes, and shifts eggplant-shape bottle to oil bath pan, and 100 DEG C are stirred 20 hours, and solution becomes Vandyke brown, has product generation.
Reaction solution is filtered and obtains white solid after cooling, extraction, dry, chromatography column separation, underpressure distillation, washing, recrystallization.
Productive rate is 85%, and the fusing point of this hexichol diazepine is: 230-260 DEG C; Nucleus magnetic hydrogen spectrum
1h NMR (300MHz, DMSO-d
6): δ=11.26 (s, 1H), 8.72 (s, 1H), 8.16 – 8.20 (d, J=8.7Hz, 1H), 7.63-7.66 (d, J=8.1Hz, 1H), 7.26 – 7.37 (dd, J=7.5,15.6Hz, 1H), 6.97 – 7.03 (d, J=8.4Hz, 1H), 6.70 – 6.79 (dd, J=7.5,11.7Hz, 2H), 5.78 (s, 1H), 2.48 (s, 3H).
Embodiment 7:
The present embodiment is the synthetic of hexichol Diazepines, with N-(the fluoro-phenyl of the bromo-5-of 2-)-2-iodobenzene methane amide, ammoniacal liquor (25%~28%), K
3pO
4, CuI, toluene, 1,10 phenanthroline be raw material, reaction formula is as follows:
Preparation method: add N-(the fluoro-phenyl of the bromo-5-of 2-)-2-iodobenzene methane amide of 0.5mmol in 25ml eggplant-shape bottle, the ammoniacal liquor of 1mmol, the CuI of 0.05mmol, the K of 1.5mmol
3pO
4, 1,10 phenanthroline of 0.05mmol, then add 2ml toluene, first stirring reaction 5 hours at 10 DEG C, the reaction of some silica-gel plate finishes, and shifts eggplant-shape bottle to oil bath pan, and 110 DEG C are stirred 24 hours, and solution becomes Vandyke brown, has product generation.
Reaction solution is filtered and obtains white solid after cooling, extraction, dry, chromatography column separation, underpressure distillation, washing, recrystallization.
Productive rate is 83%, and the fusing point of this hexichol diazepine is: 235-260 DEG C; Nucleus magnetic hydrogen spectrum
1h NMR (400MHz, CDCl
3) δ=8.39 (s, 1H), 7.92-7.90 (d, J=7.6Hz, 1H), 7.35-7.31 (t, J=3.6Hz, 1H), 7.00-7.97 (t, J=3.6Hz, 1H), 6.76-6.74 (m, 4H), 5.33 (s, 1H).
Embodiment 8:
The present embodiment is the synthetic of hexichol Diazepines, with N-(the bromo-4-aminomethyl phenyl of 2-)-2-iodobenzene methane amide, ammoniacal liquor (25%~28%), K
3pO
4, CuBr, dimethyl sulfoxide (DMSO), oxine be raw material, reaction formula is as follows:
Preparation method: add N-(the bromo-4-aminomethyl phenyl of the 2-)-2-iodobenzene methane amide of 0.5mmol in 25ml eggplant-shape bottle, the ammoniacal liquor of 1mmol, the CuBr of 0.05mmol, the K of 1.5mmol
3pO
4, the oxine of 0.05mmol, then add 2ml dimethyl sulfoxide (DMSO), first stirring reaction 5 hours at 20 DEG C, the reaction of some silica-gel plate finishes, and shifts eggplant-shape bottle to oil bath pan, and 110 DEG C are stirred 24 hours, and solution becomes Vandyke brown, has product generation.
Reaction solution is filtered and obtains white solid after cooling, extraction, dry, chromatography column separation, underpressure distillation, washing, recrystallization.
Productive rate is 81%, and the fusing point of this hexichol diazepine is: 225-255 DEG C; Nucleus magnetic hydrogen spectrum
1h NMR (500MHz, CDCl
3): δ=8.05 (d, J=3.9Hz, 1H), 7.58 (d, J=4.0Hz, 1H), 7.37 (s, 1H), 7.29-7.26 (m, 1H), 7.6-7.14 (m, 1H), 6.83-6.79 (m, 2H), 6.32 (s, 2H), 2.51 (s, 3H).
Embodiment 9:
The present embodiment is the synthetic of hexichol Diazepines, with the iodo-N-of 2-(2-iodophenyl) benzamide, ammoniacal liquor (25%~28%), K
3pO
4, CuI, dimethyl formamide, 1,10 phenanthroline be raw material, reaction formula is as follows:
Preparation method: add the iodo-N-of 2-(2-iodophenyl) benzamide of 0.5mmol in 25ml eggplant-shape bottle, the ammoniacal liquor of 1mmol, the CuI of 0.05mmol, the K of 1.5mmol
3pO
4, 1,10 phenanthroline of 0.05mmol, then add 2ml dimethyl formamide, first stirring reaction 5 hours at 15 DEG C, the reaction of some silica-gel plate finishes, and shifts eggplant-shape bottle to oil bath pan, and 110 DEG C are stirred 24 hours, and solution becomes Vandyke brown, has product generation.
Reaction solution is filtered and obtains white solid after cooling, extraction, dry, chromatography column separation, underpressure distillation, washing, recrystallization.
Productive rate is 74%, and the fusing point of this hexichol diazepine is: 245-260 DEG C; Nucleus magnetic hydrogen spectrum
1h NMR (300MHz, CDCl
3) :=9.79 (s, 1H), 7.79 (s, 1H), 7.61-7.a64 (d, J=8.0Hz, 1H), 7.27-7.32 (dd, J=8.0Hz, 1.6Hz, 1H), 6.82-6.95 (m, 6H).
Embodiment 10:
The present embodiment is the synthetic of hexichol Diazepines, with N-(the chloro-5-fluorophenyl of 2-)-2-iodobenzene methane amide, ammoniacal liquor (25%~28%), K
3pO
4, CuI, dimethyl formamide, 1,10 phenanthroline be raw material, reaction formula is as follows:
Preparation method: add N-(the chloro-5-fluorophenyl of the 2-)-2-iodobenzene methane amide of 0.5mmol in 25ml eggplant-shape bottle, the ammoniacal liquor of 1mmol, the CuI of 0.05mmol, the K of 1.5mmol
3pO
4, the oxine of 0.05mmol, then add 2ml dimethyl formamide, first stirring reaction 5 hours at 25 DEG C, the reaction of some silica-gel plate finishes, and shifts eggplant-shape bottle to oil bath pan, and 110 DEG C are stirred 24 hours, and solution becomes Vandyke brown, has product generation.
Reaction solution is filtered and obtains white solid after cooling, extraction, dry, chromatography column separation, underpressure distillation, washing, recrystallization.
Productive rate is 75%, and the fusing point of this hexichol diazepine is: 235-260 DEG C; Nucleus magnetic hydrogen spectrum
1h NMR (400MHz, CDCl
3) δ=8.39 (s, 1H), 7.92-7.90 (d, J=7.6Hz, 1H), 7.35-7.31 (t, J=3.6Hz, 1H), 7.00-7.97 (t, J=3.6Hz, 1H), 6.76-6.74 (m, 4H), 5.33 (s, 1H).
Claims (9)
1. the method for the synthetic two Benzodiazepine Hete rocyclic derivatives of one kettle way, its concrete steps are as follows: getting hexichol acid amides is that 0.5~1:2 is dissolved in organic solvent with ammoniacal liquor by amount of substance ratio, add alkaline medium, add catalyzer and part, first stirring reaction 5~10h at 10~30 DEG C of temperature, then at 100~130 DEG C of temperature, react 20~24h acquisition hexichol diazepine analog derivative.
2. method according to claim 1, is characterized in that described alkaline medium is KOH, NaOH, K
3pO
4or K
2cO
3.
3. method according to claim 1, is characterized in that described organic solvent is dimethyl sulfoxide (DMSO), dimethyl formamide, methyl alcohol or toluene.
4. method according to claim 1, is characterized in that described catalyzer is CuI, CuBr, Cu
2o or Cu
2cl.
5. method according to claim 1, is characterized in that described part is oxine and 1,10-phenanthroline or L-PROLINE.
6. method according to claim 1, is characterized in that: the amount of substance ratio of catalyzer and ammoniacal liquor is 0.05~0.1:1.
7. the method for closing according to claim 1, is characterized in that: alkaline medium is 1~1.5:1 with the amount of substance ratio of ammoniacal liquor.
8. method according to claim 1, is characterized in that: part is 0.05~0.1:1 with the amount of substance ratio of ammoniacal liquor.
9. method according to claim 1, is characterized in that: the structure of described hexichol acid amides is as follows:
wherein X is selected from the one in iodine, chlorine or bromine, and Y is selected from the one in iodine, chlorine or bromine, and R is selected from chlorine, fluorine or methyl a kind of.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410206756.1A CN103980212A (en) | 2014-05-15 | 2014-05-15 | One-pot synthesis method for heterocyclic derivatives of dibenzodiazepine |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410206756.1A CN103980212A (en) | 2014-05-15 | 2014-05-15 | One-pot synthesis method for heterocyclic derivatives of dibenzodiazepine |
Publications (1)
Publication Number | Publication Date |
---|---|
CN103980212A true CN103980212A (en) | 2014-08-13 |
Family
ID=51272408
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410206756.1A Pending CN103980212A (en) | 2014-05-15 | 2014-05-15 | One-pot synthesis method for heterocyclic derivatives of dibenzodiazepine |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN103980212A (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104892532A (en) * | 2015-05-20 | 2015-09-09 | 成都理工大学 | Synthetic process of chiral 3-substituted 1,3,4,5-tetrahydro-1,4-benzodiazepine-2-ketone |
CN106220576A (en) * | 2016-07-28 | 2016-12-14 | 常州大学 | A kind of synthetic method of clozapine key intermediate |
CN106279048A (en) * | 2016-07-28 | 2017-01-04 | 常州大学 | A kind of method preparing clozapine key intermediate |
CN108586364A (en) * | 2017-12-28 | 2018-09-28 | 新乡医学院 | A kind of Dibenzazepines compound and the preparation method and application thereof |
CN110773144A (en) * | 2019-10-28 | 2020-02-11 | 湖南科技学院 | Catalytic system for preparing amide by hydrolyzing cyano and application thereof |
CN114276304A (en) * | 2021-10-09 | 2022-04-05 | 南京苏亦欣医药科技有限公司 | A method for preparing 1, 5-benzodiazepine derivative as medicinal intermediate containing fused ring |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR900005278B1 (en) * | 1982-02-06 | 1990-07-27 | 닥터 칼 토매 게젤샤프트 미트 베슈랭크터 하프퉁 | Process for preparing substituted dibenzodiazepinones |
US20100228023A1 (en) * | 2009-01-12 | 2010-09-09 | Council Of Scientific And Industrial Research | ONE STEP PROCESS FOR THE PREPARATION OF SUBSTITUTED 5, 10-DIHYDRODIBENZO [b,e][1, 4]DIAZEPINE-11-ONES |
CN102199162A (en) * | 2011-03-30 | 2011-09-28 | 安徽美诺华药物化学有限公司 | Preparation method for olanzapine intermediate compound |
-
2014
- 2014-05-15 CN CN201410206756.1A patent/CN103980212A/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR900005278B1 (en) * | 1982-02-06 | 1990-07-27 | 닥터 칼 토매 게젤샤프트 미트 베슈랭크터 하프퉁 | Process for preparing substituted dibenzodiazepinones |
US20100228023A1 (en) * | 2009-01-12 | 2010-09-09 | Council Of Scientific And Industrial Research | ONE STEP PROCESS FOR THE PREPARATION OF SUBSTITUTED 5, 10-DIHYDRODIBENZO [b,e][1, 4]DIAZEPINE-11-ONES |
CN102199162A (en) * | 2011-03-30 | 2011-09-28 | 安徽美诺华药物化学有限公司 | Preparation method for olanzapine intermediate compound |
Non-Patent Citations (3)
Title |
---|
VEERABABURAO KAVALA等: "One-Pot Tandem Synthesis of 2-Arylbenzoxazole Derivatives via Copper-Catalyzed C_N and C_O Bond Formation", 《ADV. SYNTH. CATAL》, vol. 354, 6 July 2012 (2012-07-06), pages 2229 - 2240 * |
XIAOQIONG DIAO等: "The N-Aryl Aminocarbonyl ortho-Substituent Effect in Cu-Catalyzed Aryl Amination and Its Application in the Synthesis of 5-Substituted 11-Oxo-dibenzodiazepines", 《ORGANIC LETTERS》, vol. 13, no. 24, 16 November 2011 (2011-11-16), pages 6422 - 6425 * |
刁小琼: "Cu(I)催化的碳氮键偶联及其在合成杂环化合物中的应用研究", 《复旦大学博士学位论文》, 31 August 2012 (2012-08-31) * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104892532A (en) * | 2015-05-20 | 2015-09-09 | 成都理工大学 | Synthetic process of chiral 3-substituted 1,3,4,5-tetrahydro-1,4-benzodiazepine-2-ketone |
CN104892532B (en) * | 2015-05-20 | 2017-09-08 | 成都理工大学 | Chirality 3 replaces the synthesis technique of the ketone of 1,3,4,5 tetrahydrochysene, 1,4 benzene phenodiazine * 2 |
CN106220576A (en) * | 2016-07-28 | 2016-12-14 | 常州大学 | A kind of synthetic method of clozapine key intermediate |
CN106279048A (en) * | 2016-07-28 | 2017-01-04 | 常州大学 | A kind of method preparing clozapine key intermediate |
CN106279048B (en) * | 2016-07-28 | 2018-10-16 | 常州大学 | A method of preparing Clozapine key intermediate |
CN106220576B (en) * | 2016-07-28 | 2018-10-16 | 常州大学 | A kind of synthetic method of Clozapine key intermediate |
CN108586364A (en) * | 2017-12-28 | 2018-09-28 | 新乡医学院 | A kind of Dibenzazepines compound and the preparation method and application thereof |
CN110773144A (en) * | 2019-10-28 | 2020-02-11 | 湖南科技学院 | Catalytic system for preparing amide by hydrolyzing cyano and application thereof |
CN114276304A (en) * | 2021-10-09 | 2022-04-05 | 南京苏亦欣医药科技有限公司 | A method for preparing 1, 5-benzodiazepine derivative as medicinal intermediate containing fused ring |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103980212A (en) | One-pot synthesis method for heterocyclic derivatives of dibenzodiazepine | |
Bachhav et al. | Efficient protocol for the synthesis of quinoxaline, benzoxazole and benzimidazole derivatives using glycerol as green solvent | |
Bhosale et al. | An efficient protocol for the synthesis of quinoxaline derivatives at room temperature using molecular iodine as the catalyst | |
Trivedi et al. | A convenient one-pot synthesis of 2-substituted benzimidazoles | |
Davoodnia et al. | Highly efficient solvent-free synthesis of quinazolin-4 (3H)-ones and 2, 3-dihydroquinazolin-4 (1H)-ones using tetrabutylammonium bromide as novel ionic liquid catalyst | |
Aridoss et al. | Building Heterocyclic Systems with RC (OR) 2+ Carbocations in Recyclable Brønsted Acidic Ionic Liquids: Facile Synthesis of 1‐Substituted 1H‐1, 2, 3, 4‐Tetrazoles, Benzazoles and Other Ring Systems with CH (OEt) 3 and EtC (OEt) 3 in [EtNH3][NO3] and [PMIM (SO3H)][OTf] | |
Gan et al. | Imidazolium chloride-catalyzed synthesis of benzimidazoles and 2-substituted benzimidazoles from o-phenylenediamines and DMF derivatives | |
Azizi et al. | Eco-efficiency and scalable synthesis of bisamides in deep eutectic solvent | |
Ding et al. | Rhodium-catalyzed ortho-selective C–H halogenation of 2-arylbenzo [d] thiazoles using N-halosuccinimides as halogen sources | |
CN103788013B (en) | Synthetic method of 2-aryl benzothiazole compounds | |
Brown et al. | Bromination of isoquinoline, quinoline, quinazoline and quinoxaline in strong acid | |
CN107892654B (en) | Isolongifolane-based fluorescent acid-base indicator and synthetic method and application thereof | |
KR20100101315A (en) | Process for preparing phenanthridine derivatives using trifluoroacetic acid | |
CN107602570B (en) | Method for synthesizing nitrogen-containing multi-membered heterocyclic compound | |
CN103130810B (en) | Synthesis method of pyrrolo[1,5-c] quinazoline compounds | |
Dabiri et al. | Water-Accelerated Selective Synthesis of 1, 2-Disubstituted Benzimidazoles at Room Temperature Catalyzed by Br⊘ nsted Acidic Ionic Liquid | |
CN102584860A (en) | Spiro-heterocyclic compound containing indole structures and preparation method of spiro-heterocyclic compound | |
CN107200705A (en) | A kind of preparation method of the indolone derivatives of 3 nitro 2 | |
CN109535140A (en) | A method of double indoles substituted-dihydro pyrrolones derivatives are constructed based on oxime ester and indoles | |
CN103304520B (en) | Preparation method of multi-substituted furan compound | |
CN102153433B (en) | N-monosubstituted-alpha-carbonylamide compound and preparation method thereof | |
CN109651367A (en) | A method of preparing 1,4- dihydroquinoline and pyrrolo- [1,2-a] quinolines | |
CN106905234B (en) | A method of the synthesis chloro- 6- amino -7- ethoxyquinoline of linatinib intermediate 3- cyano -4- | |
Nordmann et al. | Anilines as Substrates in Consecutive Four-Component Synthesis of Novel 1-Aryl-5-benzoyl-6-phenyl-3, 4-dihydropyridin-2 (1H)-ones | |
Almansour et al. | A simple, rapid, expedient and sustainable green strategy for the synthesis of benz-/naphthimidazoles |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C12 | Rejection of a patent application after its publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20140813 |