CN104230689B - 6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds and preparation method thereof - Google Patents
6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds and preparation method thereof Download PDFInfo
- Publication number
- CN104230689B CN104230689B CN201410264592.8A CN201410264592A CN104230689B CN 104230689 B CN104230689 B CN 104230689B CN 201410264592 A CN201410264592 A CN 201410264592A CN 104230689 B CN104230689 B CN 104230689B
- Authority
- CN
- China
- Prior art keywords
- hexichol
- dihydro
- cod
- ketone
- ring heptan
- 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.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
- C07C2603/32—Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to 6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds and preparation method thereof, the general formula of this compound is:. Get adjacent bromine aryl methyl alcohol, aryl methyl ketone, [Ir (cod) Cl]2, palladium salt, silver salt, 1,1 ˊ-dinaphthalene-2,2 ˊ-bis-diphenyl phosphines and alkali join in organic solvent, at N2Under gas protection, add hot reflux, reaction finishes rear filtration, evaporate to dryness, recrystallization and obtains 6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds. The method one-step synthesis 6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds, reaction substrate scope is wide, productive rate is high, and economical in reaction is efficient, has a extensive future.
Description
Technical field
The present invention relates to technical field of organic synthesis, be specifically related to 6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketoneCompound and preparation method thereof.
Background technology
Allocolchicine () compounds is important cancer therapy drug, has unique effectMechanism, efficiently active and to advantages such as solid tumor are evident in efficacy, enjoys people's concern, and developing this type of medicine has wideMarket prospects. Allocolchicine is that separation obtains from the spending of liliaceous plant colchicum, and its product category and output are limited,Can not meet the need of market. The synthetic method of allocolchicine derivative has a great development now, and it is synthetic most importantIntermediate be 6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds (). Existing bibliographical informationSynthesizing of this intermediate, but reactions steps is more, condition is harsh, complex operation, yield is lower. Be somebody's turn to do so that metal catalytic is synthetic at presentClass intermediate is most study and a kind of the most promising method, for improving Atom economy and the combined coefficient of reaction, one potMethod cascade reaction can with succinct, high selectivity and efficiently advantage synthesize complicated molecule, become chemist and endeavour to grindStudy carefully an important directions of development. In recent years, metal catalytic alcohol reacts with the alpha-alkyl of aryl methyl ketone and carbon-hydrogen bond activation reaction,Become carbon-carbon bond generate important method and organic synthesis in indispensable means. As far as we know, with how goldenBelong to the adjacent bromine aryl methyl alcohol of catalysis and aryl methyl ketone (or adjacent bromine aryl methyl ketone and aryl methyl alcohol) by alpha-alkylization reaction and hydrocarbonBond activation reaction one-step synthesis 6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds is not also reported. We pass throughThe cascade reaction of the adjacent bromine aryl methyl alcohol of iridium, palladium and silver-colored co-catalysis and aryl methyl ketone (or adjacent bromine aryl methyl ketone and aryl methyl alcohol),One kettle way prepares 6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds, and used catalyst commodity can obtain, substrateScope is wide, productive rate is high, and economical and efficient has a extensive future.
Summary of the invention
The object of the invention is the deficiency for solving the problems of the technologies described above, provide 6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds and preparation method thereof.
The present invention is the deficiency solving the problems of the technologies described above, and the technical scheme adopting is: 6,7-dihydro-5H-hexichol [a,C] ring heptan-5-ketone compounds, the general formula of this compound is:
，
Wherein, R1、R2For-H ,-CH3、-OCH3、-C2H5、-CN、-NO2、-COOCH3,-CHO ,-F ,-Cl or-Br; R1、R2Be positioned at the upper arbitrary position of aromatic ring 1-4 and 8-11.
Described 6, the preparation method of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds, gets adjacent bromine aryl firstAlcohol, aryl methyl ketone, [Ir (cod) Cl]2(cod=1,5-cyclo-octadiene), palladium salt, silver salt, 1,1'-dinaphthalene-2, the two hexichol of 2'-Phosphine and alkali join in organic solvent, at N2Under gas protection, add hot reflux, reaction finishes rear filtration, evaporate to dryness, recrystallization and obtains 6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds. Adjacent bromine aryl methyl alcohol, aryl methyl ketone, [Ir (cod) Cl]2（cod=1,5-cyclo-octadiene), palladium salt, silver salt, 1,1'-dinaphthalene-2, the mol ratio of the two diphenyl phosphines of 2'-and alkali be 1:1～2:0.01～0.1：0.05～0.2：1～3：0.05～0.2：1～3。
Described 6, the preparation method of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds, gets adjacent bromine aryl secondKetone, aryl methyl alcohol, [Ir (cod) Cl]2(cod=1,5-cyclo-octadiene), palladium salt, silver salt, 1,1'-dinaphthalene-2, the two hexichol of 2'-Phosphine and alkali join in organic solvent, at N2Under gas protection, add hot reflux, reaction finishes rear filtration, evaporate to dryness, recrystallization and obtains 6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds. Adjacent bromine aryl methyl ketone, aryl methyl alcohol, [Ir (cod) Cl]2（cod=1,5-cyclo-octadiene), palladium salt, silver salt, 1,1'-dinaphthalene-2, the mol ratio of the two diphenyl phosphines of 2'-and alkali be 1:1～2:0.005～0.1：0.02～0.2：1～3：0.05～0.2：1～5。
Above-mentioned palladium salt is that palladium salt is palladium bichloride, palladium or palladium trifluoroacetate; Silver salt is silver carbonate, silver acetate or trifluoroSilver acetate.
Above-mentioned alkali is NaOH, potassium hydroxide, cesium hydroxide, sodium carbonate, potash, cesium carbonate, sodium phosphate or phosphorusAcid potassium.
Above-mentioned organic solvent is dioxane, benzene, toluene, DMF or dimethyl sulfoxide (DMSO).
The above-mentioned condition of stating back flow reaction is: reaction temperature 100-160 DEG C, reaction time 6-48h.
Beneficial effect
The present invention utilizes the available slaine of commodity, the adjacent bromine aryl methyl alcohol of co-catalysis and aryl methyl ketone (or adjacent bromine arylEthyl ketone and aryl methyl alcohol), react and carbon-hydrogen bond activation reaction one kettle way system with the alpha-alkyl of aryl methyl ketone by aryl methyl alcoholStandby 6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds, for synthetic replace 6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone derivatives provides a practical method, and the method is simple to operate, and substrate scope is wide, productive rate is high, has important answeringBy value.
Detailed description of the invention
Embodiment 1:6, the preparation of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone (1)
Under inert gas (as high pure nitrogen) protection, (conventional when anhydrous and oxygen-free operation to the Schlek reaction tube of 10mlA kind of glass apparatus) add the adjacent bromoacetophenone of 1.0mmol phenmethylol, 2.0mmol, 0.01mmol[Ir (cod) Cl]2、0.1mmol palladium, 1.0mmol silver carbonate, 0.1mmol1,1'-dinaphthalene-2, the two diphenyl phosphines of 2'-and 1.0mmol cesium hydroxideWith 5ml dioxane, use nitrogen replacement reaction tube 3 times, then under magnetic agitation, be heated to 110 DEG C with oil bath, reaction refluxes24 hours. Remove oil bath, water-bath drops to room temperature; Add 3ml water to reactant liquor, the dichloromethane extraction of use 5ml three times, merges organicAlso use mutually anhydrous MgSO4Dry 30 minutes, filter; Filtrate is concentrated with rotary evaporator, the solid after concentrated taking carrene asSolvent, recrystallization obtains net product 1, productive rate 85%. The nmr analysis data of this product are as follows:1HNMR.(400MHz,CDCl3):7.58-7.67 (m, 2H), 7.27-7.46 (m, 6H), 2.99 (s, 4H), molecular formula is as follows:
。
Embodiment 2:9-methyl-6, the preparation of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone (2)
Under inert gas (as high pure nitrogen) protection, (conventional when anhydrous and oxygen-free operation to the Schlek reaction tube of 10mlA kind of glass apparatus) add the bromo-5-methylbenzyl alcohol of 2.0mmol2-, 1.0mmol acetophenone, 0.05mmol[Ir (cod)Cl]2, 0.1mmol palladium bichloride, 3.0mmol silver acetate, 0.12mmol1,1'-dinaphthalene-2, the two diphenyl phosphines of 2'-and 2.0mmol hydrogenPotassium oxide and 5ml toluene, use nitrogen replacement reaction tube 3 times, then under magnetic agitation, is heated to 110 DEG C with oil bath, reacts backFlow 6 hours. Remove oil bath, water-bath drops to room temperature; Add 3ml water to reactant liquor, the dichloromethane extraction of use 5ml three times, is associated withMachine is also used anhydrous MgSO mutually4Dry 30 minutes, filter; Filtrate is concentrated with rotary evaporator, and the solid after concentrating is with carreneFor solvent, recrystallization obtains net product 2, productive rate 89%. The nmr analysis data of this product are as follows:1HNMR.(400MHz,CDCl3):7.55-7.64(m,2H),7.25-7.43(m,3H),7.09(s,1H),7.03(d,1H),2.97 (s, 4H), 2.34 (s, 3H), molecular formula is as follows:
。
Embodiment 3:10-methoxyl group-6, the preparation of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone (5)
Under inert gas (as high pure nitrogen) protection, (conventional when anhydrous and oxygen-free operation to the Schlek reaction tube of 10mlA kind of glass apparatus) add the adjacent bromoacetophenone of 1.0mmol P-methoxybenzyl alcohol, 1.6mmol, 0.08mmol[Ir (cod)Cl]2, 0.2mmol palladium trifluoroacetate, 3.0mmol trifluoroacetic acid silver, 0.2mmol1,1'-dinaphthalene-2, the two diphenyl phosphines of 2'-and3mmol potash and 5ml benzene, use nitrogen replacement reaction tube 3 times, then under magnetic agitation, is heated to 60 DEG C with oil bath, reactionReflux 48 hours. Remove oil bath, water-bath drops to room temperature; Add 3ml water to reactant liquor, the dichloromethane extraction of use 5ml three times, mergesOrganic phase is also used anhydrous MgSO4Dry 30 minutes, filter; Filtrate is concentrated with rotary evaporator, and the solid after concentrating is with dichloromethaneAlkane is solvent, and recrystallization obtains net product 5, productive rate 90%. The nmr analysis data of this product are as follows:1HNMR.(400MHz,CDCl3):7.52-7.61(m,2H),7.21-7.40(m,3H),7.07(s,1H),6.82(d,1H),3.84 (s, 3H), 2.96 (s, 4H), molecular formula is as follows:
。
Embodiment 4:10-is bromo-6, the preparation of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone (7)
Under inert gas (as high pure nitrogen) protection, (conventional when anhydrous and oxygen-free operation to the Schlek reaction tube of 10mlA kind of glass apparatus) add 1.0mmol to the adjacent bromoacetophenone of bromobenzene methyl alcohol, 1.2mmol, 0.08mmol[Ir (cod) Cl]2、0.07mmol palladium, 2.0mmol silver acetate, 0.16mmol1,1'-dinaphthalene-2, the two diphenyl phosphines of 2'-and 2.5mmol potassium phosphateAnd 5mlN, dinethylformamide, uses nitrogen replacement reaction tube 3 times, then under magnetic agitation, is heated to 160 DEG C with oil bath,Reaction refluxes 36 hours. Remove oil bath, water-bath drops to room temperature; Add 3ml water to reactant liquor, the dichloromethane extraction of use 5ml three times,Merge organic phase and use anhydrous MgSO4Dry 30 minutes, filter; Filtrate is concentrated with rotary evaporator, and the solid after concentrating is with twoChloromethanes is solvent, and recrystallization obtains net product 7, productive rate 78%. The nmr analysis data of this product are as follows:1HNMR.(400MHz,CDCl3):7.86(s,1H),7.59-7.67(m,2H),7.33-7.52(m,4H),3.02(s,4H), molecular formula is as follows:
。
Embodiment 5:10-ethyl-6, the preparation of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone (8)
Under inert gas (as high pure nitrogen) protection, (conventional when anhydrous and oxygen-free operation to the Schlek reaction tube of 10mlA kind of glass apparatus) add 1.0mmol to the adjacent bromoacetophenone of ethylo benzene methyl alcohol, 1.4mmol, 0.06mmol[Ir (cod)Cl]2, 0.08mmol palladium, 2.5mmol silver carbonate, 0.12mmol1,1'-dinaphthalene-2, the two diphenyl phosphines of 2'-and 3.0mmol carbonAcid caesium and 5ml dioxane, use nitrogen replacement reaction tube 3 times, then under magnetic agitation, is heated to 130 DEG C with oil bath, reactionReflux 30 hours. Remove oil bath, water-bath drops to room temperature; Add 3ml water to reactant liquor, the dichloromethane extraction of use 5ml three times, mergesOrganic phase is also used anhydrous MgSO4Dry 30 minutes, filter; Filtrate is concentrated with rotary evaporator, and the solid after concentrating is with dichloromethaneAlkane is solvent, and recrystallization obtains net product 8, productive rate 87%. The nmr analysis data of this product are as follows:1HNMR.(400MHz,CDCl3):7.53-7.64(m,3H),7.25-7.43(m,2H),7.23(m,1H),7.12(d,1H),2.97 (s, 4H), 2.53 (q, 2H), 1.25 (t, 3H), molecular formula is as follows:
。
Embodiment 6:9-is chloro-6, the preparation of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone (10)
Under inert gas (as high pure nitrogen) protection, (conventional when anhydrous and oxygen-free operation to the Schlek reaction tube of 10mlA kind of glass apparatus) add the adjacent bromoacetophenone of chlorobenzene methanol between 1.0mmol, 1.9mmol, 0.04mmol[Ir (cod) Cl]2、0.06mmol palladium, 3.6mmol silver carbonate, 0.15mmol1,1'-dinaphthalene-2, the two diphenyl phosphines of 2'-and 3.0mmol hydroxideSodium and 5ml dimethyl sulfoxide (DMSO), use nitrogen replacement reaction tube 3 times, then under magnetic agitation, is heated to 150 DEG C with oil bath, reactionReflux 40 hours. Remove oil bath, water-bath drops to room temperature; Add 3ml water to reactant liquor, the dichloromethane extraction of use 5ml three times, mergesOrganic phase is also used anhydrous MgSO4Dry 30 minutes, filter; Filtrate is concentrated with rotary evaporator, and the solid after concentrating is with dichloromethaneAlkane is solvent, and recrystallization obtains net product 10, productive rate 78%. The nmr analysis data of this product are as follows:1HNMR.(400MHz,CDCl3):7.63-7.72(m,2H),7.34-7.49(m,3H),7.29(s,1H),7.07(d,1H), 3.05 (s, 4H), molecular formula is as follows:
。
Embodiment 7:3-methyl-6, the preparation of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone (12)
Under inert gas (as high pure nitrogen) protection, (conventional when anhydrous and oxygen-free operation to the Schlek reaction tube of 10mlA kind of glass apparatus) add methyl acetophenone, 0.07mmol[Ir (cod) between the adjacent bromobenzene methyl alcohol of 1.7mmol, 1.0mmolCl]2, 0.13mmol palladium bichloride, 3.0mmol silver carbonate, 0.2mmol1,1'-dinaphthalene-2, the two diphenyl phosphines of 2'-and 2.2mmol hydrogenCesium oxide and 5ml toluene, use nitrogen replacement reaction tube 3 times, then under magnetic agitation, is heated to 100 DEG C with oil bath, reacts backFlow 28 hours. Remove oil bath, water-bath drops to room temperature; Add 3ml water to reactant liquor, the dichloromethane extraction of use 5ml three times, is associated withMachine is also used anhydrous MgSO mutually4Dry 30 minutes, filter; Filtrate is concentrated with rotary evaporator, and the solid after concentrating is with carreneFor solvent, recrystallization obtains net product 12, productive rate 84%. The nmr analysis data of this product are as follows:1HNMR.(400MHz,CDCl3):7.56-7.65(m,2H),7.52(s,1H),7.25-7.44(m,4H),2.98(s,4H),2.34 (s, 3H), molecular formula is as follows:
。
Embodiment 8:2-cyano group-6, the preparation of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone (14)
Under inert gas (as high pure nitrogen) protection, (conventional when anhydrous and oxygen-free operation to the Schlek reaction tube of 10mlA kind of glass apparatus) add the adjacent bromobenzene methyl alcohol of 1.8mmol, 1.0mmol 4-Acetylbenzonitrile, 0.05mmol[Ir (cod)Cl]2, 0.16mmol palladium, 2.7mmol trifluoroacetic acid silver, 0.17mmol1,1'-dinaphthalene-2, the two diphenyl phosphines of 2'-and2.0mmol potassium hydroxide and 5ml benzene, use nitrogen replacement reaction tube 3 times, then under magnetic agitation, is heated to 130 DEG C with oil bath,Reaction refluxes 28 hours. Remove oil bath, water-bath drops to room temperature; Add 3ml water to reactant liquor, the dichloromethane extraction of use 5ml three times,Merge organic phase and use anhydrous MgSO4Dry 30 minutes, filter; Filtrate is concentrated with rotary evaporator, and the solid after concentrating is with twoChloromethanes is solvent, and recrystallization obtains net product 14, productive rate 72%. The nmr analysis data of this product are as follows:1HNMR.(400MHz,CDCl3):7.95(s,1H),7.79-7.83(d,2H),7.26-7.51(m,4H),3.01(s,4H), molecular formula is as follows:
。
Embodiment 9:2-aldehyde radical-6, the preparation of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone (16)
Under inert gas (as high pure nitrogen) protection, (conventional when anhydrous and oxygen-free operation to the Schlek reaction tube of 10mlA kind of glass apparatus) add the adjacent bromobenzene methyl alcohol of 1.0mmol, 2.0mmol to aldehyde radical acetophenone, 0.1mmol[Ir (cod) Cl]2, 0.2mmol palladium trifluoroacetate, 2.6mmol silver carbonate, 0.2mmol1,1'-dinaphthalene-2, the two diphenyl phosphines of 2'-and 2.2mmol hydrogenCesium oxide and 5ml dioxane, use nitrogen replacement reaction tube 3 times, then under magnetic agitation, is heated to 110 DEG C with oil bath, anti-Should reflux 18 hours. Remove oil bath, water-bath drops to room temperature; Add 3ml water to reactant liquor, the dichloromethane extraction of use 5ml three times, closesAnd organic phase is also used anhydrous MgSO4Dry 30 minutes, filter; Filtrate is concentrated with rotary evaporator, and the solid after concentrating is with dichloroMethane is solvent, and recrystallization obtains net product 16, productive rate 71%. The nmr analysis data of this product are as follows:1HNMR.(400MHz,CDCl3):9.92(s,1H),7.93(s,1H),7.76-7.80(d,2H),7.24-7.46(m,4H), 3.00 (s, 4H), molecular formula is as follows:
。
Embodiment 10:4-methyl-6, the preparation of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone (19)
Under inert gas (as high pure nitrogen) protection, (conventional when anhydrous and oxygen-free operation to the Schlek reaction tube of 10mlA kind of glass apparatus) add the adjacent bromobenzene methyl alcohol of 1.3mmol, 1.0mmol o-methyl-benzene ethyl ketone, 0.09mmol[Ir (cod)Cl]2, 0.16mmol palladium, 2.3mmol trifluoroacetic acid silver, 0.15mmol1,1'-dinaphthalene-2, the two diphenyl phosphines of 2'-and2.3mmol sodium phosphate and 5ml benzene, use nitrogen replacement reaction tube 3 times, then under magnetic agitation, is heated to 120 DEG C with oil bath, anti-Should reflux 30 hours. Remove oil bath, water-bath drops to room temperature; Add 3ml water to reactant liquor, the dichloromethane extraction of use 5ml three times, closesAnd organic phase is also used anhydrous MgSO4Dry 30 minutes, filter; Filtrate is concentrated with rotary evaporator, and the solid after concentrating is with dichloroMethane is solvent, and recrystallization obtains net product 19, productive rate 86%. The nmr analysis data of this product are as follows:1HNMR.(400MHz,CDCl3):7.55-7.63(m,2H),7.32-7.56(m,5H),3.00(s,4H),2.39(s,3H), molecular formula is as follows:
。
Embodiment 11:3-is chloro-6, the preparation of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone (21)
Under inert gas (as high pure nitrogen) protection, (conventional when anhydrous and oxygen-free operation to the Schlek reaction tube of 10mlA kind of glass apparatus) add bromoacetophenone, 0.07mmol[Ir (cod) Cl between the adjacent bromobenzene methyl alcohol of 1.6mmol, 1.0mmol]2、0.12mmol palladium, 1.7mmol silver carbonate, 0.17mmol1,1'-dinaphthalene-2, the two diphenyl phosphines of 2'-and 2.5mmol hydroxideSodium and 5ml dioxane, use nitrogen replacement reaction tube 3 times, then under magnetic agitation, is heated to 110 DEG C with oil bath, reacts backFlow 26 hours. Remove oil bath, water-bath drops to room temperature; Add 3ml water to reactant liquor, the dichloromethane extraction of use 5ml three times, is associated withMachine is also used anhydrous MgSO mutually4Dry 30 minutes, filter; Filtrate is concentrated with rotary evaporator, and the solid after concentrating is with carreneFor solvent, recrystallization obtains net product 21, productive rate 87%. The nmr analysis data of this product are as follows:1HNMR.(400MHz,CDCl3):7.87 (s, 1H), 7.59-7.73 (m, 2H), 7.23-7.42 (m, 4H), 3.02 (s, 4H), pointMinor is as follows:
。
Embodiment 12:3-methoxyl group-6, the preparation of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone (23)
Under inert gas (as high pure nitrogen) protection, (conventional when anhydrous and oxygen-free operation to the Schlek reaction tube of 10mlA kind of glass apparatus) add the adjacent bromobenzene methyl alcohol of 1.2mmol, 1.0mmol meta-methoxy acetophenone, 0.07mmol[Ir (cod)Cl]2, 0.18mmol palladium trifluoroacetate, 1.8mmol silver acetate, 0.18mmol1,1'-dinaphthalene-2, the two diphenyl phosphines of 2'-and3.0mmol potash and 5ml toluene, use nitrogen replacement reaction tube 3 times, then under magnetic agitation, is heated to 110 DEG C with oil bath,Reaction refluxes 12 hours. Remove oil bath, water-bath drops to room temperature; Add 3ml water to reactant liquor, the dichloromethane extraction of use 5ml three times,Merge organic phase and use anhydrous MgSO4Dry 30 minutes, filter; Filtrate is concentrated with rotary evaporator, and the solid after concentrating is with twoChloromethanes is solvent, and recrystallization obtains net product 23, productive rate 88%. The nmr analysis data of this product are as follows:1HNMR.(400MHz,CDCl3):7.53-7.62(m,2H),7.49(s,1H),7.23-7.41(m,4H),3.83(s,3H), 2.97 (s, 4H), molecular formula is as follows:
。
The bromo-10-of embodiment 13:2-methyl-6, the preparation of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone (25)
Under inert gas (as high pure nitrogen) protection, (conventional when anhydrous and oxygen-free operation to the Schlek reaction tube of 10mlA kind of glass apparatus) add 1.5mmol2-bromobenzene methyl alcohol, 1.0mmol parabromoacetophenone, 0.08mmol[Ir (cod) Cl]2, 0.16mmol palladium bichloride, 2.5mmol silver carbonate, 0.15mmol1,1'-dinaphthalene-2, the two diphenyl phosphines of 2'-and 3.0mmol hydrogen-oxygenChange potassium and 5ml dioxane, use nitrogen replacement reaction tube 3 times, then under magnetic agitation, be heated to 110 DEG C with oil bath, reactionReflux 16 hours. Remove oil bath, water-bath drops to room temperature; Add 3ml water to reactant liquor, the dichloromethane extraction of use 5ml three times, mergesOrganic phase is also used anhydrous MgSO4Dry 30 minutes, filter; Filtrate is concentrated with rotary evaporator, and the solid after concentrating is with dichloromethaneAlkane is solvent, and recrystallization obtains net product 25, productive rate 89%. The nmr analysis data of this product are as follows:1HNMR.(400MHz,CDCl3):7.85(s,1H),7.57-7.71(m,2H),7.43(s,1H),7.14-7.36(m,2H), 2.98 (s, 4H), 2.36 (s, 3H), molecular formula is as follows:
。
Embodiment 14:3-methyl acetate base-10-is bromo-6, the preparation of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone (28)
Under inert gas (as high pure nitrogen) protection, (conventional when anhydrous and oxygen-free operation to the Schlek reaction tube of 10mlA kind of glass apparatus) add 2.0mmol to bromobenzene methyl alcohol, the bromo-5-methyl acetate of 1.0mmol2-benzoylformaldoxime, 0.07mmol[Ir(cod)Cl]2, 0.15mmol palladium, 1.5mmol trifluoroacetic acid silver, 0.18mmol1,1'-dinaphthalene-2, the two hexichol of 2'-Phosphine and 1.5mmol cesium hydroxide and 5ml toluene, use nitrogen replacement reaction tube 3 times, then under magnetic agitation, is heated to oil bath110 DEG C, reaction refluxes 15 hours. Remove oil bath, water-bath drops to room temperature; Add 3ml water to reactant liquor, by the carrene extraction of 5mlGet three times, merge organic phase and use anhydrous MgSO4Dry 30 minutes, filter; Filtrate is concentrated with rotary evaporator, consolidating after concentratingBody is taking carrene as solvent, and recrystallization obtains net product 28, productive rate 75%. The nmr analysis data of this product are as follows:1HNMR.(400MHz,CDCl3):8.25(s,1H),7.76-7.81(m,2H),7.72(s,1H),7.21-7.47 (m, 2H), 3.89 (s, 3H), 3.01 (s, 4H), molecular formula is as follows:
。
Embodiment 16:3-methyl-9-is bromo-6, the preparation of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone (30)
Under inert gas (as high pure nitrogen) protection, (conventional when anhydrous and oxygen-free operation to the Schlek reaction tube of 10mlA kind of glass apparatus) add bromobenzene methyl alcohol between 1.5mmol, the bromo-5-methyl acetophenone of 1.0mmol2-, 0.1mmol[Ir(cod)Cl]2, 0.2mmol palladium, 3.0mmol silver carbonate, 0.2mmol1,1'-dinaphthalene-2, the two diphenyl phosphines of 2'-and3.0mmol cesium hydroxide and 5ml dioxane, use nitrogen replacement reaction tube 3 times, then under magnetic agitation, is heated to oil bath110 DEG C, reaction refluxes 48 hours. Remove oil bath, water-bath drops to room temperature; Add 3ml water to reactant liquor, by the carrene extraction of 5mlGet three times, merge organic phase and use anhydrous MgSO4Dry 30 minutes, filter; Filtrate is concentrated with rotary evaporator, consolidating after concentratingBody is taking carrene as solvent, and recrystallization obtains net product 30, productive rate 87%. The nmr analysis data of this product are as follows:1HNMR.(400MHz,CDCl3):7.81(s,1H),7.59-7.73(m,2H),7.39(s,1H),7.12-7.30 (m, 2H), 3.02 (s, 4H), 2.34 (s, 3H), molecular formula is as follows:
。
Claims (5)
- The preparation method of 1.6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds, the general formula of this compound is:, wherein, R1、R2For-H ,-CH3、-OCH3、-C2H5、-CN、-NO2、-COOCH3,-CHO ,-F ,-Cl or-Br; R1、R2Be positioned at the upper arbitrary position of aromatic ring 1-4 and 8-11, it is characterized in that:Preparation method is: get adjacent bromine aryl methyl alcohol, aryl methyl ketone, [Ir (cod) Cl]2(cod=1,5-cyclo-octadiene), palladium salt,Silver salt, 1,1'-dinaphthalene-2, the two diphenyl phosphines of 2'-and alkali join in organic solvent, at N2Under gas protection, add hot reflux, reaction knotFiltration after bundle, evaporate to dryness, recrystallization obtain 6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds;Or get adjacent bromine aryl methyl ketone, aryl methyl alcohol, [Ir (cod) Cl]2(cod=1,5-cyclo-octadiene), palladium salt, silver salt, 1,1'-Dinaphthalene-2, the two diphenyl phosphines of 2'-and alkali join in organic solvent, at N2Under gas protection, add hot reflux, reaction finishes rear filtration, steamingDo, be recrystallized and obtain 6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds;Described palladium salt is palladium bichloride, palladium or palladium trifluoroacetate; Silver salt is silver carbonate, silver acetate or trifluoroacetic acid silver; InstituteThe alkali of stating is NaOH, potassium hydroxide, cesium hydroxide, sodium carbonate, potash, cesium carbonate, sodium phosphate or potassium phosphate.
- 2. as claimed in claim 16, the preparation method of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds, its spyLevy and be: described organic solvent is dioxane, benzene, toluene, DMF or dimethyl sulfoxide (DMSO).
- 3. as claimed in claim 16, the preparation method of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds, its spyLevy and be: the condition of described back flow reaction is: reaction temperature 100-160 DEG C, reaction time 6-48h.
- 4. as claimed in claim 16, the preparation method of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds, its spyLevy and be: adjacent bromine aryl methyl alcohol, aryl methyl ketone, [Ir (cod) Cl]2(cod=1,5-cyclo-octadiene), palladium salt, silver salt, 1,1'-Dinaphthalene-2, the mol ratio of the two diphenyl phosphines of 2'-and alkali be 1:1～2:0.01～0.1:0.05～0.2:1～3:0.05～0.2:1～3。
- 5. as claimed in claim 16, the preparation method of 7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds, its spyLevy and be: adjacent bromine aryl methyl ketone, aryl methyl alcohol, [Ir (cod) Cl]2(cod=1,5-cyclo-octadiene), palladium salt, silver salt, 1,1'-Dinaphthalene-2, the mol ratio of the two diphenyl phosphines of 2'-and alkali is 1:1～2:0.005～0.1:0.02～0.2:1～3:0.05～0.2:1～5。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410264592.8A CN104230689B (en) | 2014-06-16 | 2014-06-16 | 6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410264592.8A CN104230689B (en) | 2014-06-16 | 2014-06-16 | 6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104230689A CN104230689A (en) | 2014-12-24 |
| CN104230689B true CN104230689B (en) | 2016-06-08 |
Family
ID=52219704
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410264592.8A Expired - Fee Related CN104230689B (en) | 2014-06-16 | 2014-06-16 | 6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104230689B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108586342A (en) * | 2017-12-27 | 2018-09-28 | 连云港笃翔化工有限公司 | Condensed biaryl azatropylidene -5- ketone compounds and its synthetic method |
| CN113214157A (en) * | 2021-04-25 | 2021-08-06 | 广西壮族自治区花红药业集团股份公司 | Application of pyrrolidone compound in preparation of medicine for treating inflammatory diseases |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101602686A (en) * | 2009-05-26 | 2009-12-16 | 苏州派腾生物医药科技有限公司 | A kind of preparation method of colchicine |
| CN102603556A (en) * | 2012-02-29 | 2012-07-25 | 浙江大学 | Method for preparing intermediate of colchicine derivatives |
-
2014
- 2014-06-16 CN CN201410264592.8A patent/CN104230689B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101602686A (en) * | 2009-05-26 | 2009-12-16 | 苏州派腾生物医药科技有限公司 | A kind of preparation method of colchicine |
| CN102603556A (en) * | 2012-02-29 | 2012-07-25 | 浙江大学 | Method for preparing intermediate of colchicine derivatives |
Non-Patent Citations (3)
| Title |
|---|
| Application of Aryl Siloxane Cross-Coupling to the Synthesis of Allocolchicinoids;W.Michael Seganish et al.,;《Organic Letters》;20060810;第8卷(第18期);第3951-3954页 * |
| Excited state carbon acid dissociation and competing photorearrangements of 5H-dibenzo[a,c]cycloheptene derivatives;David Budac et al.,;《Can.J.Chem.》;19961231;第74卷;第1447-1464页 * |
| 多取代联苯衍生物的合成研究;任周阳等;《云南大学学报（自然科学版）》;20061231;第28卷(第5期);第425-431页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104230689A (en) | 2014-12-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112679420B (en) | Preparation method of 2,5-dibromopyridine | |
| CN103772278A (en) | Important tetrahydroisoquinoline derivative midbody and synthesis method thereof | |
| CN104230689B (en) | 6,7-dihydro-5H-hexichol [a, c] ring heptan-5-ketone compounds and preparation method thereof | |
| CN105566215A (en) | Preparation method of Stivarga | |
| CN103880822B (en) | Containing 2,4,6-trisubstituted pyrimidine compounds of 1,2,3-triazole, preparation method and application thereof | |
| KR20100101315A (en) | Process for preparing phenanthridine derivatives using trifluoroacetic acid | |
| Chouguiat et al. | A new and efficient one-pot synthesis of 2-hydroxy-1, 4-dihydrobenzoxazines via a three-component Petasis reaction | |
| CN104529895A (en) | Synthetic method of nitrogen-containing heterocyclic compound | |
| CN102850337B (en) | Multi-azole linked spirorenone compound and preparation method and application thereof | |
| CN103242371B (en) | Biaryl pyridine ring palladium N-heterocyclic carbine compound and its production and use | |
| CN104016917B (en) | 5,6-dihydro coffee pyridine compounds and preparation method thereof | |
| CN103408525B (en) | A kind of synthetic method of flavonoid compound and application thereof | |
| CN102659708A (en) | Structure and preparation method for heterocyclic aryl acetylene compounds containing benzoxazole and benzothiazole groups | |
| CN103242379B (en) | 2-ferrocenyl-aryl quinoline and preparation method thereof | |
| CN104119319B (en) | Containing the pyrimidine derivatives and its production and use of 1,2,3-triazole and urea structure uint | |
| CN108047258A (en) | A kind of method of synthesizing amino pyridine boronic acid ester | |
| CN109369772B (en) | Synthetic method and anti-tumor application of phenanthridine nitidine derivatives | |
| CN103450078B (en) | 2-aryl-6-(2-aryl acetylenyl) cinolineand and preparation method thereof | |
| CN104926723B (en) | Synthetic method of phenanthridine ketone compounds | |
| CN103242223A (en) | Preparation method of 2-pyridineoxydiaryl ketone derivative | |
| CN103524556B (en) | SF-277 aminophosphonate ester derivatives and synthetic method thereof and application | |
| CN101284779B (en) | Preparation method of (E)-4-(beta-bromovinyl)phenol ester | |
| CN109232366A (en) | The preparation method and applications of 2- acyl group -3- amino indole class compound | |
| CN105949143A (en) | Synthesis method of diaryloxazepine ketone compound | |
| CN106083728B (en) | The synthetic method of diaryl and Diazepines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information |
Inventor after: Wang Zhiqiang Inventor after: Xu Chunying Inventor after: Lou Xinhua Inventor after: Fu Weijun Inventor after: Xu Chen Inventor before: Lou Xinhua Inventor before: Li Hongmei Inventor before: Wang Zhiqiang Inventor before: Fu Weijun Inventor before: Xu Chen |
|
| COR | Change of bibliographic data | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160608 Termination date: 20170616 |