CN103896745A - Anticancer medicament Combretastatin A4 analogue and preparation method thereof - Google Patents
Anticancer medicament Combretastatin A4 analogue and preparation method thereof Download PDFInfo
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- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 Chemical class C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 title claims abstract description 27
- 239000003814 drug Substances 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 230000001093 anti-cancer Effects 0.000 title abstract 3
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 76
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 44
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 41
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 22
- 235000019253 formic acid Nutrition 0.000 claims abstract description 22
- -1 cis-1-(3 Chemical class 0.000 claims abstract description 8
- 150000002941 palladium compounds Chemical class 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 238000006722 reduction reaction Methods 0.000 claims abstract description 5
- CDZJQFRCCCDJLD-UHFFFAOYSA-N 5-ethynyl-1,2,3-trimethoxybenzene Chemical group COC1=CC(C#C)=CC(OC)=C1OC CDZJQFRCCCDJLD-UHFFFAOYSA-N 0.000 claims abstract description 4
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims abstract description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 88
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 76
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 44
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 43
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 42
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 claims description 42
- 229910052757 nitrogen Inorganic materials 0.000 claims description 38
- 239000002904 solvent Substances 0.000 claims description 27
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 22
- 101150003085 Pdcl gene Proteins 0.000 claims description 21
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 claims description 21
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 19
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 18
- 229940079593 drug Drugs 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 238000011275 oncology therapy Methods 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- SVDZDXBQOBWHLE-UHFFFAOYSA-N (4-fluorophenyl)phosphane Chemical compound FC1=CC=C(P)C=C1 SVDZDXBQOBWHLE-UHFFFAOYSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- VSIIHWOJPSSIDI-UHFFFAOYSA-N 1-ethoxy-4-iodobenzene Chemical compound CCOC1=CC=C(I)C=C1 VSIIHWOJPSSIDI-UHFFFAOYSA-N 0.000 abstract 1
- 239000005977 Ethylene Substances 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 239000003638 chemical reducing agent Substances 0.000 abstract 1
- 239000003446 ligand Substances 0.000 abstract 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 abstract 1
- 238000007039 two-step reaction Methods 0.000 abstract 1
- 150000001345 alkine derivatives Chemical class 0.000 description 102
- 229910052763 palladium Inorganic materials 0.000 description 34
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 17
- 229910052802 copper Inorganic materials 0.000 description 17
- 239000010949 copper Substances 0.000 description 17
- 230000005311 nuclear magnetism Effects 0.000 description 17
- 229960005537 combretastatin A-4 Drugs 0.000 description 11
- HVXBOLULGPECHP-UHFFFAOYSA-N combretastatin A4 Natural products C1=C(O)C(OC)=CC=C1C=CC1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-UHFFFAOYSA-N 0.000 description 11
- 238000012986 modification Methods 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- JVTZFYYHCGSXJV-UHFFFAOYSA-N isovanillin Chemical compound COC1=CC=C(C=O)C=C1O JVTZFYYHCGSXJV-UHFFFAOYSA-N 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- ILUSBJDVXKZYEP-UHFFFAOYSA-N 4-(aminomethyl)oxan-4-ol;hydrochloride Chemical compound Cl.NCC1(O)CCOCC1 ILUSBJDVXKZYEP-UHFFFAOYSA-N 0.000 description 1
- 241000375691 Combretum caffrum Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 241001299681 Salix herbacea Species 0.000 description 1
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- PJANXHGTPQOBST-QXMHVHEDSA-N cis-stilbene Chemical class C=1C=CC=CC=1/C=C\C1=CC=CC=C1 PJANXHGTPQOBST-QXMHVHEDSA-N 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- GEPJPYNDFSOARB-UHFFFAOYSA-N tris(4-fluorophenyl)phosphane Chemical compound C1=CC(F)=CC=C1P(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 GEPJPYNDFSOARB-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/215—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/20—Preparation of ethers by reactions not forming ether-oxygen bonds by hydrogenation of carbon-to-carbon double or triple bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to an anticancer medicament Combretastatin A4 analogue and a preparation method thereof. The Combretastatin A4 analogue, namely cis-1-(3,4,5-trimethoxy)-2-(4'-ethoxyphenyl) ethylene (B ring modified) is prepared by using 3,4,5-trimethoxy phenylacetylene, p-iodophenetole and the like as raw materials through two-step reaction. The key step is catalytic transfer hydrogenation reduction reaction using a palladium compound as a catalyst, using a phosphine-containing compound as a ligand and using formic acid as a reducer. The invention provides a new anticancer medicament Combretastatin A4 analogue CA4-OEt and a preparation method thereof. The analogue and the preparation method thereof disclosed by the invention have the advantages that the operation is simple, the raw materials and reagents are simple and readily available, the reaction is efficient, high stereoselectivity and atom economy are realized, the product is easily separated and purified and the like.
Description
Technical field:
The present invention relates to a kind of cancer therapy drug Combretastatin A4 analogue and preparation method thereof, relate in particular to a kind of synthetic cancer therapy drug Combretastatin A4 analogue (B encircles modification) and method thereof of highly-solid selectively.
Technical background:
A kind of compound with anti-tumor activity of Combretastatin A4 (CA4) for separating in African shrub dwarf willow tree (Combretum caffrum) bark plant.It is a kind of cis-stilbene class natural product, is the tubulin binding agent that a class acts on colchicine site.
At present, the complete synthesis route of the CA4 reporting both at home and abroad adopts the Wittig synthetic method (J.Med.Chem.1995,38,1666-1672) of the reports such as Pettit more.Gaukroger etc. have reported one, and condition is easy, step is short, CA4 synthetic route---the Perkin condensation strong to cis-product selectivity: take trimethoxy toluylic acid and Isovanillin as raw material, under triethylamine and aceticanhydride effect, be condensed into vinylbenzene acid, decarboxylize obtains cis CA4(J.Org.Chem.2001 again, 66,8135-8138).
In recent years, the research and development of CA4 structural modification and analogue are also subject to researchist's favor.CA4 structure is comparatively simple, mainly formed by three parts, and 3,4,5-2,4,5-trimethoxyphenyl (A ring), 3-hydroxyl-4-p-methoxy-phenyl (B ring) and connect the cis-double bonds (skeleton) of two phenyl ring.The research of CA4 analogue is mainly concentrated on the basis that keeps CA4 relation, to the structure of modification of these three parts.In the last few years, more to the research report of A ring and backbone modification, the B ring of CA4 is modified to report less.
The method that Gu Zhongyi etc. provide the B ring of a kind of CA4 to modify in " synthesizing of cancer therapy drug Combretastatin A4 and soluble derivative thereof ", take trimethoxy toluylic acid and Isovanillin as raw material, through condensation or further to connect the reaction such as side chain, decarboxylation synthetic, synthesize the soluble derivative with both sexes polymer small molecules polyoxyethylene glycol (PEG) side chain of CA4.But this synthetic method has just been carried out simple modifications to Perkin condensation, does not relate to the innovation of synthetic method.
Pettit etc. have also reported a kind of method (Bioorg.Med.Chem.2009,17,6606-6612) that B ring is modified, and the B in CA4 are encircled to the compounds replacing with nitro, and such also has anti-tumor activity.Its method departs from CA4 synthetic method with Perkin condensation of conventional Wittig in synthetic, and this cancer therapy drug Combretastatin A4 analogue synthetic had to certain inspiration meaning.
Summary of the invention:
Object of the present invention provides a kind of cancer therapy drug Combretastatin A4 analogue in order to improve the deficiencies in the prior art, another object of the present invention is to provide the preparation method of above-mentioned cancer therapy drug Combretastatin A4 analogue.
Technical scheme of the present invention is: a kind of cancer therapy drug Combretastatin A4 analogue, is characterized in that its molecular formula C
19h
22o
4, its structural formula is:
The present invention also provides the preparation method of above-mentioned cancer therapy drug Combretastatin A4 analogue, and concrete steps are as follows: A: under nitrogen protection, add 3,4,5-trimethoxy phenylacetylene, PdCl in reactor
2(PPh
3)
2and CuI, then add solvent that it is dissolved completely, then add alkali source to stir in reactor, in the most backward reactor, add iodobenzene ether, there is linked reaction in heating, obtains 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene; B: under nitrogen protection; to add that steps A makes in reactor 1-(3; 4; 5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, palladium compound and containing phosphine compound; add wherein again solvent that it is dissolved completely; in the most backward reactor, add formic acid; there is reduction reaction in heating; prepare cancer therapy drug CombretastatinCA4 analogue cis-1-(3; 4,5-trimethoxy)-2-(4`-phenelyl) ethene.
Its reaction equation is:
Preferably the alkali source described in above-mentioned steps A is ammoniacal liquor or triethylamine.PdCl in preferred steps A
2(PPh
3)
2account for respectively 3,4 with the molar weight of CuI, 1～5% and 2～10% of 5-trimethoxy phenylacetylene molar weight.
Reaction raw materials 3,4 in preferred steps A, 5-trimethoxy phenylacetylene, to hydroxide radical (OH in iodobenzene ether and alkali source
-) mol ratio be 1:(1～1.2): (1～10).
Solvent described in preferred steps A and B is tetrahydrofuran (THF) (THF), dioxane or 1,2-ethylene dichloride; In preferred steps A, in order to control 3,4,5-trimethoxy phenylacetylene, to add its concentration after solvent be 0.1～0.2M to the add-on of solvent.In step B, the add-on of solvent is 0.25M～1M for control 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene adds the concentration after solvent.
In preferred steps A, the temperature of linked reaction is 50～90 ℃; Reaction times is 8～12h.In preferred steps B, the temperature of reduction reaction is 60～100 ℃; Reaction times is 6～12h.
Palladium compound described in preferred steps B is PdCl
2, Pd (OAc)
2or Pd
2(dba)
3; Described is triphenylphosphine, three (4-p-methoxy-phenyl) phosphine or three (4-fluorophenyl) phosphine containing phosphine compound.
In preferred steps B, palladium compound and the molar weight containing phosphine compound account for respectively 2～5% and 8～20% of 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene molar weight; Formic acid and 1 in step B-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene molar ratio is (1～4): 1.
Beneficial effect:
The present invention is simple to operate, and raw material and reagent are simple and easy to get, and reaction is efficient, has stereoselectivity and the Atom economy of height, the advantages such as the easily separated purifying of product.
Embodiment:
Embodiment 1: under nitrogen protection, by 5mmol3,4,5-trimethoxy phenylacetylene, 0.25mmol PdCl
2(PPh
3)
2(n
palladium/ n
alkynes=5%) and 0.5mmol CuI(n
copper/ n
alkynes=10%) add in reactor, add 25mL THF(n
alkynes=0.2M), dissolve completely.Measure 10mmol NH
3h
2o
join in reactor, mix.Finally, take 5.5mmol iodobenzene ether is added to reactor, react 8h at 70 ℃.Make 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, productive rate 59%.
Under nitrogen protection, by 0.25mmol1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, 0.625%mmol Pd
2(dba)
3(n
palladium/ n
alkynes=5%) and 5%mmol tri-(4-p-methoxy-phenyl) phosphine (n
phosphine/ n
alkynes=20%) be dissolved into 0.25mL dioxane (n
alkynes=1M) in solvent, stirring at room temperature 15 minutes.Then, add 19 μ L formic acid.Reaction is heated to 100 ℃, after reaction 6h, and yield 99%, selectivity 58%.
Nuclear-magnetism and infrared analysis data are as follows:
1h NMR (400MHz, CDCl
3): δ 7.24 (d, 2H, J=8.0Hz), 6.79 (d, 2H, J=8.0Hz), 6.52 (d, 1H, J=12.0Hz), 6.52 (s, 2H), 6.44 (d, 1H, J=12.0Hz), 3.83 (q, 2H, J=6.8Hz), 3.77 (s, 3H), 3.68 (s, 6H), 3.83 (t, 3H, J=6.8Hz).
13c NMR (100MHz, CDCl
3) δ 158.1,153.2,137.3,133.1,130.5,129.8,129.7,128.8,113.9,106.2,61.4,56.0,55.3,14.9.IR (KBr): v2926,1509,1489,1206,1129,1051,757,691,667,611cm
-1.
Embodiment 2: under nitrogen protection, by 5mmol3,4,5-trimethoxy phenylacetylene, 0.125mmol PdCl
2(PPh
3)
2(n
palladium/ n
alkynes=2.5%) and 0.5mmol CuI(n
copper/ n
alkynes=5%) add in reactor, add 25mL THF(n
alkynes=0.2M), dissolve completely.Measure 10mmol NH
3h
2o
join in reactor, mix.Finally, take 5.5mmol iodobenzene ether is added to reactor, react 8h at 70 ℃.Make 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, productive rate 41%.
Under nitrogen protection, by 0.25mmol1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, 1.25%mmol PdCl
2(n
palladium/ n
alkynes=5%) and 5mmol% tri-(4-p-methoxy-phenyl) phosphine (n
phosphine/ n
alkynes=20%) be dissolved into 0.25mL dioxane (n
alkynes=1M) in solvent, stirring at room temperature 15 minutes.Then, add 19 μ L formic acid.Reaction is heated to 80 ℃, after reaction 6h, and yield 1%, selectivity 100%.
As follows through nuclear-magnetism and infrared analysis data:
1h NMR (400MHz, CDCl
3): δ 7.23 (d, 2H, J=8.0Hz), 6.79 (d, 2H, J=8.0Hz), 6.55 (d, 1H, J=12.0Hz), 6.53 (s, 2H), 6.48 (d, 1H, J=12.0Hz), 3.82 (q, 2H, J=6.8Hz), 3.77 (s, 3H), 3.68 (s, 6H), 3.82 (t, 3H, J=6.8Hz).
13c NMR (100MHz, CDCl
3) δ 158.3,153.2,137.3,133.3,130.5,129.5,129.7,128.8,113.8,106.1,61.4,56.0,54.9,14.9.IR (KBr): v2928,1506,1488,1206,1129,1050,755,690,667,610cm
-1.
Embodiment 3: under nitrogen protection, by 5mmol3,4,5-trimethoxy phenylacetylene, 0.05mmol PdCl
2(PPh
3)
2(n
palladium/ n
alkynes=1%) and 0.5mmol CuI(n
copper/ n
alkynes=2%) add in reactor, add 25mL THF(n
alkynes=0.2M), dissolve completely.Measure 10mmol NH
3h
2o
join in reactor, mix.Finally, take 5.5mmol iodobenzene ether is added to reactor, react 8h at 70 ℃.Make 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, productive rate 28%.
Under nitrogen protection, by 0.25mmol1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, 1.25%mmol Pd (OAc)
2(n
palladium/ n
alkynes=5%) and 5mmol% tri-(4-p-methoxy-phenyl) phosphine (n
phosphine/ n
alkynes=20%) be dissolved into 0.25mL dioxane (n
alkynes=1M) in solvent, stirring at room temperature 15 minutes.Then, add 19 μ L formic acid.Reaction is heated to 80 ℃, after reaction 6h, and yield 98%, selectivity 17%.
As follows through nuclear-magnetism and infrared analysis data:
1h NMR (400MHz, CDCl
3): δ 7.24 (d, 2H, J=8.0Hz), 6.79 (d, 2H, J=8.0Hz), 6.52 (d, 1H, J=12.0Hz), 6.52 (s, 2H), 6.44 (d, 1H, J=12.0Hz), 3.84 (q, 2H, J=6.8Hz), 3.78 (s, 3H), 3.66 (s, 6H), 3.81 (t, 3H, J=6.8Hz).
13c NMR (100MHz, CDCl
3) δ 158.2,153.1,137.3,133.1,130.4,129.6,129.5,128.5,113.7,106.1,61.4,56.0,55.2,14.9.IR (KBr): v2923,1508,1488,1206,1129,1050,755,692,667,611cm
-1.
Embodiment 4: under nitrogen protection, by 5mmol3,4,5-trimethoxy phenylacetylene, 0.25mmolPdCl
2(PPh
3)
2(n
palladium/ n
alkynes=5%) and 0.5mmol CuI(n
copper/ n
alkynes=10%) add in reactor, add 25mL THF(n
alkynes=0.2M), dissolve completely.Measure 3.3mmol Et
3n
join in reactor, mix.Finally, take 5.5mmol iodobenzene ether is added to reactor, react 8h at 70 ℃.Make 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, productive rate 15%.
Under nitrogen protection, by 0.25mmol1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, 0.625%mmol Pd
2(dba)
3(n
palladium/ n
alkynes=5%) and 5mmol% triphenylphosphine (n
phosphine/ n
alkynes=20%) be dissolved into 0.25mL dioxane (n
alkynes=1M) in solvent, stirring at room temperature 15 minutes.Then, add 19 μ L formic acid.Reaction is heated to 80 ℃, after reaction 6h, and yield 55%, selectivity 81%.
As follows through nuclear-magnetism and infrared analysis data:
1h NMR (400MHz, CDCl
3): δ 7.24 (d, 2H, J=8.0Hz), 6.79 (d, 2H, J=8.0Hz), 6.52 (d, 1H, J=12.0Hz), 6.52 (s, 2H), 6.44 (d, 1H, J=12.0Hz), 3.83 (q, 2H, J=6.8Hz), 3.75 (s, 3H), 3.66 (s, 6H), 3.83 (t, 3H, J=6.8Hz).
13c NMR (100MHz, CDCl
3) δ 158.0,153.2,137.3,133.3,130.5,129.8,129.5,128.9,113.9,106.0,61.4,56.0,54.9,14.9.IR (KBr): v2928,1513,1485,1203,1128,1054,757,694,667,611cm
-1.
Embodiment 5: under nitrogen protection, by 5mmol3,4,5-trimethoxy phenylacetylene, 0.25mmol PdCl
2(PPh
3)
2(n
palladium/ n
alkynes=5%) and 0.5mmol CuI(n
copper/ n
alkynes=10%) add in reactor, add 25mL THF(n
alkynes=0.2M), dissolve completely.Measure 10mmol NH
3h
2o
join in reactor, mix.Finally, take 5mmol iodobenzene ether is added to reactor, react 8h at 70 ℃.Make 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, productive rate 53%.
Under nitrogen protection, by 0.25mmol1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, 0.625%mmol Pd
2(dba)
3(n
palladium/ n
alkynes=5%) and 5mmol% tri-(4-fluorophenyl) phosphine (n
phosphine/ n
alkynes=20%) be dissolved into 0.25mL dioxane (n
alkynes=1M) in solvent, stirring at room temperature 15 minutes.Then, add 19 μ L formic acid.Reaction is heated to 80 ℃, after reaction 6h, and yield 32%, selectivity 84%.
As follows through nuclear-magnetism and infrared analysis data:
1h NMR (400MHz, CDCl
3): δ 7.24 (d, 2H, J=8.0Hz), 6.79 (d, 2H, J=8.0Hz), 6.52 (d, 1H, J=12.0Hz), 6.51 (s, 2H), 6.44 (d, 1H, J=12.0Hz), 3.83 (q, 2H, J=6.8Hz), 3.77 (s, 3H), 3.69 (s, 6H), 3.83 (t, 3H, J=6.8Hz).
13c NMR (100MHz, CDCl
3) δ 158.1,153.6,137.6,133.3,130.7,129.8,129.6,128.7,114.2,106.2,61.3,56.0,55.3,14.8.IR (KBr): v2930,1506,1485,1206,1133,1054,754,691,668,611cm
-1.
Embodiment 6: under nitrogen protection, by 5mmol3,4,5-trimethoxy phenylacetylene, 0.25mmol PdCl
2(PPh
3)
2(n
palladium/ n
alkynes=5%) and 0.5mmol CuI(n
copper/ n
alkynes=10%) add in reactor, add 25mL THF(n
alkynes=0.2M), dissolve completely.Measure 10mmol NH
3h
2o
join in reactor, mix.Finally, take 6mmol iodobenzene ether is added to reactor, react 8h at 70 ℃.Make 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, productive rate 58%.
Under nitrogen protection, by 0.25mmol1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, 0.250%mmol Pd
2(dba)
3(n
palladium/ n
alkynes=2%) and 2%mmol tri-(4-p-methoxy-phenyl) phosphine (n
phosphine/ n
alkynes=8%) be dissolved into 0.25mL dioxane (n
alkynes=1M) in solvent, stirring at room temperature 15 minutes.Then, add 19 μ L formic acid.Reaction is heated to 80 ℃, after reaction 6h, and yield 73%, selectivity 77%.
As follows through nuclear-magnetism and infrared analysis data:
1h NMR (400MHz, CDCl
3): δ 7.24 (d, 2H, J=8.0Hz), 6.79 (d, 2H, J=8.0Hz), 6.52 (d, 1H, J=12.0Hz), 6.56 (s, 2H), 6.44 (d, 1H, J=12.0Hz), 3.83 (q, 2H, J=6.8Hz), 3.75 (s, 3H), 3.68 (s, 6H), 3.81 (t, 3H, J=6.8Hz).
13c NMR (100MHz, CDCl3) δ 158.4,153.2,137.1,133.5,130.3,129.6,129.7,128.8,113.6,106.2,61.3,56.0,55.3,14.9.IR (KBr): v2922,1505,1484,1206,1129,1050,757,694,667,611cm
-1.
Embodiment 7: under nitrogen protection, by 5mmol3,4,5-trimethoxy phenylacetylene, 0.25mmolPdCl
2(PPh
3)
2(n
palladium/ n
alkynes=5%) and 0.5mmol CuI(n
copper/ n
alkynes=10%) add in reactor, add 25mL THF(n
alkynes=0.2M), dissolve completely.Measure 5mmol NH
3h
2o
join in reactor, mix.Finally, take 5.5mmol iodobenzene ether is added to reactor, react 8h at 70 ℃.Make 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, productive rate 41%.
Under nitrogen protection, by 0.25mmol1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, 0.375%mmol Pd
2(dba)
3(n
palladium/ n
alkynes=3%) and 3%mmol tri-(4-p-methoxy-phenyl) phosphine (n
phosphine/ n
alkynes=12%) be dissolved into 0.25mL dioxane (n
alkynes=1M) in solvent, stirring at room temperature 15 minutes.Then, add 19 μ L formic acid.Reaction is heated to 80 ℃, after reaction 6h, and yield 71%, selectivity 98%.
As follows through nuclear-magnetism and infrared analysis data:
1h NMR (400MHz, CDCl
3): δ 7.24 (d, 2H, J=8.0Hz), 6.79 (d, 2H, J=8.0Hz), 6.56 (d, 1H, J=12.0Hz), 6.52 (s, 2H), 6.44 (d, 1H, J=12.0Hz), 3.83 (q, 2H, J=6.8Hz), 3.75 (s, 3H), 3.68 (s, 6H), 3.81 (t, 3H, J=6.8Hz).
13c NMR (100MHz, CDCl
3) δ 158.1,153.5,137.3,133.1,130.3,129.8,129.5,128.8,113.6,106.2,61.4,56.2,55.3,14.9.IR (KBr): v2924,1509,1489,1204,1129,1051,755,691,667,611cm
-1.
Embodiment 8: under nitrogen protection, by 5mmol3,4,5-trimethoxy phenylacetylene, 0.25mmol PdCl
2(PPh
3)
2(n
palladium/ n
alkynes=5%) and 0.5mmol CuI(n
copper/ n
alkynes=10%) add in reactor, add 25mL THF(n
alkynes=0.2M), dissolve completely.Measure 50mmol NH
3h
2o
join in reactor, mix.Finally, take 5.5mmol iodobenzene ether is added to reactor, react 8h at 70 ℃.Make 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, productive rate 48%.
Under nitrogen protection, by 0.25mmol1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, 0.625%mmol Pd
2(dba)
3(n
palladium/ n
alkynes=5%) and 5%mmol tri-(4-p-methoxy-phenyl) phosphine (n
phosphine/ n
alkynes=20%) be dissolved into 0.25mL dioxane (n
alkynes=1M) in solvent, stirring at room temperature 15 minutes.Then, add 9.5 μ L formic acid.Reaction is heated to 80 ℃, after reaction 6h, and yield 59%, selectivity 96%.
As follows through nuclear-magnetism and infrared analysis data:
1h NMR (400MHz, CDCl
3): δ 7.24 (d, 2H, J=8.0Hz), 6.79 (d, 2H, J=8.0Hz), 6.52 (d, 1H, J=12.0Hz), 6.52 (s, 2H), 6.43 (d, 1H, J=12.0Hz), 3.83 (q, 2H, J=6.8Hz), 3.77 (s, 3H), 3.68 (s, 6H), 3.85 (t, 3H, J=6.8Hz).
13c NMR (100MHz, CDCl
3) δ 157.9,153.2,137.3,133.4,130.5,129.6,129.7,128.5,113.9,106.4,61.4,56.3,55.3,14.9.IR (KBr): v2925,1509,1488,1206,1127,1051,755,691,668,611cm
-1.
Embodiment 9: under nitrogen protection, by 5mmol3,4,5-trimethoxy phenylacetylene, 0.25mmol PdCl
2(PPh
3)
2(n
palladium/ n
alkynes=5%) and 0.5mmol CuI(n
copper/ n
alkynes=10%) add in reactor, add 25mL dioxane (n
alkynes=0.2M), dissolve completely.Measure 10mmol NH
3h
2o
join in reactor, mix.Finally, take 5.5mmol iodobenzene ether is added to reactor, react 8h at 70 ℃.Make 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, productive rate 52%.
Under nitrogen protection, by 0.25mmol1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, 0.625%mmol Pd
2(dba)
3(n
palladium/ n
alkynes=5%) and 5%mmol tri-(4-p-methoxy-phenyl) phosphine (n
phosphine/ n
alkynes=20%) be dissolved into 0.25mL dioxane (n
alkynes=1M) in solvent, stirring at room temperature 15 minutes.Then, add 38 μ L formic acid.Reaction is heated to 80 ℃, after reaction 6h, and yield 98%, selectivity 71%.
As follows through nuclear-magnetism and infrared analysis data:
1h NMR (400MHz, CDCl
3): δ 7.24 (d, 2H, J=8.0Hz), 6.79 (d, 2H, J=8.0Hz), 6.53 (d, 1H, J=12.0Hz), 6.52 (s, 2H), 6.44 (d, 1H, J=12.0Hz), 3.83 (q, 2H, J=6.8Hz), 3.75 (s, 3H), 3.68 (s, 6H), 3.83 (t, 3H, J=6.8Hz).
13c NMR (100MHz, CDCl
3) δ 158.5,153.2,137.5,133.3,130.5,129.9,129.7,128.8,113.9,106.1,61.4,56.2,55.3,14.9.IR (KBr): v2923,1506,1488,1206,1129,1051,755,691,667,611cm
-1.
Embodiment 10: under nitrogen protection, by 5mmol3,4,5-trimethoxy phenylacetylene, 0.25mmol PdCl
2(PPh
3)
2(n
palladium/ n
alkynes=5%) and 0.5mmol CuI(n
copper/ n
alkynes=10%) add in reactor, add 25mL1,2-ethylene dichloride
(n
alkynes=0.2M), dissolve completely.Measure 10mmol NH
3h
2o
join in reactor, mix.Finally, take 5.5mmol iodobenzene ether is added to reactor, react 8h at 70 ℃.Make 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, productive rate 45%.
Under nitrogen protection, by 0.25mmol1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, 0.625%mmol Pd
2(dba)
3(n
palladium/ n
alkynes=5%) and 5%mmol tri-(4-p-methoxy-phenyl) phosphine (n
phosphine/ n
alkynes=20%) be dissolved into 0.25mL tetrahydrofuran (THF) (n
alkynes=1M) in solvent, stirring at room temperature 15 minutes.Then, add 19 μ L formic acid.Reaction is heated to 80 ℃, after reaction 6h, and yield 89%, selectivity 91%.
As follows through nuclear-magnetism and infrared analysis data:
1h NMR (400MHz, CDCl
3): δ 7.24 (d, 2H, J=8.0Hz), 6.79 (d, 2H, J=8.0Hz), 6.52 (d, 1H, J=12.0Hz), 6.52 (s, 2H), 6.43 (d, 1H, J=12.0Hz), 3.83 (q, 2H, J=6.8Hz), 3.76 (s, 3H), 3.68 (s, 6H), 3.84 (t, 3H, J=6.8Hz).
13c NMR (100MHz, CDCl3) δ 158.3,153.4,137.3,133.1,130.5,129.8,129.7,128.6,113.9,106.1,61.4,56.0,55.3,14.9.IR (KBr): v2924,1508,1484,1206,1125,1051,757,690,667,611cm
-1.
Embodiment 11: under nitrogen protection, by 5mmol3,4,5-trimethoxy phenylacetylene, 0.25mmolPdCl
2(PPh
3)
2(n
palladium/ n
alkynes=5%) and 0.5mmol CuI(n
copper/ n
alkynes=10%) add in reactor, add 40 mL THF(n
alkynes=0.125M), dissolve completely.Measure 10mmol NH
3h
2o
join in reactor, mix.Finally, take 5.5mmol iodobenzene ether is added to reactor, react 8h at 70 ℃.Make 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, productive rate 48%.
Under nitrogen protection, by 0.25mmol1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, 0.625%mmol Pd
2(dba)
3(n
palladium/ n
alkynes=5%) and 5%mmol tri-(4-p-methoxy-phenyl) phosphine (n
phosphine/ n
alkynes=20%) be dissolved into 0.25mL1,2-ethylene dichloride (n
alkynes=1M) in solvent, stirring at room temperature 15 minutes.Then, add 19 μ L formic acid.Reaction is heated to 80 ℃, after reaction 6h, and yield 92%, selectivity 93%.
As follows through nuclear-magnetism and infrared analysis data:
1h NMR (400MHz, CDCl
3): δ 7.24 (d, 2H, J=8.0Hz), 6.78 (d, 2H, J=8.0Hz), 6.52 (d, 1H, J=12.0Hz), 6.52 (s, 2H), 6.44 (d, 1H, J=12.0Hz), 3.83 (q, 2H, J=6.8Hz), 3.75 (s, 3H), 3.68 (s, 6H), 3.83 (t, 3H, J=6.8Hz).
13c NMR (100MHz, CDCl
3) δ 158.5,153.3,137.3,133.0,130.5,129.8,129.7,128.6,113.9,106.5,61.4,56.0,55.2,14.9.IR (KBr): v2928,1508,1485,1206,1126,1051,754,691,664,611cm
-1.
Embodiment 12: under nitrogen protection, by 5mmol3,4,5-trimethoxy phenylacetylene, 0.25mmol PdCl
2(PPh
3)
2(n
palladium/ n
alkynes=5%) and 0.5mmol CuI(n
copper/ n
alkynes=10%) add in reactor, add 50mL THF(n
alkynes=0.1M), dissolve completely.Measure 10mmol NH
3h
2o
join in reactor, mix.Finally, take 5.5mmol iodobenzene ether is added to reactor, react 8h at 70 ℃.Make 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, productive rate 43%.
Under nitrogen protection, by 0.25mmol1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, 0.625%mmol Pd
2(dba)
3(n
palladium/ n
alkynes=5%) and 5%mmol tri-(4-p-methoxy-phenyl) phosphine (n
phosphine/ n
alkynes=20%) be dissolved into 0.50mL dioxane (n
alkynes=0.5M) in solvent, stirring at room temperature 15 minutes.Then, add 19 μ L formic acid.Reaction is heated to 80 ℃, after reaction 6h, and yield 74%, selectivity 92%.
As follows through nuclear-magnetism and infrared analysis data:
1h NMR (400MHz, CDCl
3): δ 7.24 (d, 2H, J=8.0Hz), 6.79 (d, 2H, J=8.0Hz), 6.52 (d, 1H, J=12.0Hz), 6.52 (s, 2H), 6.44 (d, 1H, J=12.0Hz), 3.83 (q, 2H, J=6.8Hz), 3.77 (s, 3H), 3.68 (s, 6H), 3.82 (t, 3H, J=6.8Hz).
13c NMR (100MHz, CDCl
3) δ 158.5,153.2,137.3,133.4,130.5,129.9,129.7,128.8,113.9,106.1,61.4,56.5,55.3,14.9.IR (KBr): v2929,1515,1494,1209,1133,1054,759,696,668,616cm
-1.
Embodiment 13: under nitrogen protection, by 5mmol3,4,5-trimethoxy phenylacetylene, 0.25mmol PdCl
2(PPh
3)
2(n
palladium/ n
alkynes=5%) and 0.5mmol CuI(n
copper/ n
alkynes=10%) add in reactor, add 25mL THF(n
alkynes=0.2M), dissolve completely.Measure 10mmol NH
3h
2o
join in reactor, mix.Finally, take 5.5mmol iodobenzene ether is added to reactor, react 8h at 50 ℃.Make 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, productive rate 38%.
Under nitrogen protection, by 0.25mmol1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, 0.625%mmol Pd
2(dba)
3(n
palladium/ n
alkynes=5%) and 5%mmol tri-(4-p-methoxy-phenyl) phosphine (n
phosphine/ n
alkynes=20%) be dissolved into 1.00mL dioxane (n
alkynes=0.25M) in solvent, stirring at room temperature 15 minutes.Then, add 19 μ L formic acid.Reaction is heated to 80 ℃, after reaction 6h, and yield 58%, selectivity 95%.
As follows through nuclear-magnetism and infrared analysis data:
1h NMR (400MHz, CDCl
3): δ 7.23 (d, 2H, J=8.0Hz), 6.79 (d, 2H, J=8.0Hz), 6.52 (d, 1H, J=12.0Hz), 6.53 (s, 2H), 6.44 (d, 1H, J=12.0Hz), 3.83 (q, 2H, J=6.8Hz), 3.75 (s, 3H), 3.68 (s, 6H), 3.83 (t, 3H, J=6.8Hz).
13c NMR (100MHz, CDCl
3) δ 158.4,153.2,137.3,133.5,130.3,129.8,129.7,128.5,113.7,106.2,61.3,56.0,55.2,14.9.IR (KBr): v2927,1508,1489,1208,1131,1054,757,691,670,611cm
-1.
Embodiment 14: under nitrogen protection, by 5mmol3,4,5-trimethoxy phenylacetylene, 0.25mmol PdCl
2(PPh
3)
2(n
palladium/ n
alkynes=5%) and 0.5mmol CuI(n
copper/ n
alkynes=10%) add in reactor, add 25mL THF(n
alkynes=0.2M), dissolve completely.Measure 10mmol NH
3h
2o
join in reactor, mix.Finally, take 5.5mm
ol adds reactor to iodobenzene ether, reacts 8h at 90 ℃.Make 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, productive rate 55%.
Under nitrogen protection, by 0.25mmol1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, 0.625%mmol Pd
2(dba)
3(n
palladium/ n
alkynes=5%) and 5%mmol tri-(4-p-methoxy-phenyl) phosphine (n
phosphine/ n
alkynes=20%) be dissolved into 0.25mL dioxane (n
alkynes=1M) in solvent, stirring at room temperature 15 minutes.Then, add 19 μ L formic acid.Reaction is heated to 60 ℃, after reaction 6h, and yield 68%, selectivity 92%.
As follows through nuclear-magnetism and infrared analysis data:
1h NMR (400MHz, CDCl
3): δ 7.24 (d, 2H, J=8.0Hz), 6.76 (d, 2H, J=8.0Hz), 6.52 (d, 1H, J=12.0Hz), 6.52 (s, 2H), 6.44 (d, 1H, J=12.0Hz), 3.83 (q, 2H, J=6.8Hz), 3.73 (s, 3H), 3.68 (s, 6H), 3.82 (t, 3H, J=6.8Hz).
13c NMR (100MHz, CDCl
3) δ 158.4,153.2,137.5,133.1,130.5,129.9,129.7,128.8,113.8,106.2,61.4,56.3,55.3,14.7.IR (KBr): v2928,1507,1486,1203,1129,1051,755,691,668,611cm
-1.
Embodiment 15: under nitrogen protection, by 5mmol3,4,5-trimethoxy phenylacetylene, 0.25mmol PdCl
2(PPh
3)
2(n
palladium/ n
alkynes=5%) and 0.5mmol CuI(n
copper/ n
alkynes=10%) add in reactor, add 25mL THF(n
alkynes=0.2M), dissolve completely.Measure 10mmol NH
3h
2o
join in reactor, mix.Finally, take 5.5mmol iodobenzene ether is added to reactor, react 10h at 70 ℃.Make 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, productive rate 61%.
Under nitrogen protection, by 0.25mmol1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, 0.625%mmol Pd
2(dba)
3(n
palladium/ n
alkynes=5%) and 5%mmol tri-(4-p-methoxy-phenyl) phosphine (n
phosphine/ n
alkynes=20%) be dissolved into 0.25mL dioxane (n
alkynes=1M) in solvent, stirring at room temperature 15 minutes.Then, add 19 μ L formic acid.Reaction is heated to 100 ℃, after reaction 6h, and yield 99%, selectivity 58%.
As follows through nuclear-magnetism and infrared analysis data:
1h NMR (400MHz, CDCl
3): δ 7.24 (d, 2H, J=8.0Hz), 6.79 (d, 2H, J=8.0Hz), 6.54 (d, 1H, J=12.0Hz), 6.52 (s, 2H), 6.44 (d, 1H, J=12.0Hz), 3.83 (q, 2H, J=6.8Hz), 3.76 (s, 3H), 3.68 (s, 6H), 3.81 (t, 3H, J=6.8Hz).
13c NMR (100MHz, CDCl
3) δ 158.2,153.2,137.2,133.1,130.4,129.8,129.5,128.8,113.7,106.2,61.2,56.0,55.1,14.9.IR (KBr): v2928,1509,1487,1206,1127,1051,755,691,665,611cm
-1.
Embodiment 16: under nitrogen protection, by 5mmol3,4,5-trimethoxy phenylacetylene, 0.25mmol PdCl
2(PPh
3)
2(n
palladium/ n
alkynes=5%) and 0.5mmol CuI(n
copper/ n
alkynes=10%) add in reactor, add 25mL THF(n
alkynes=0.2M), dissolve completely.Measure 10mmol NH
3h
2o
join in reactor, mix.Finally, take 5.5mmol iodobenzene ether is added to reactor, react 12h at 70 ℃.Make 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, productive rate 57%.
Under nitrogen protection, by 0.25mmol1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, 0.375%mmol Pd
2(dba)
3(n
palladium/ n
alkynes=3%) and 3%mmol tri-(4-p-methoxy-phenyl) phosphine (n
phosphine/ n
alkynes=12%) be dissolved into 0.25mL dioxane (n
alkynes=1M) in solvent, stirring at room temperature 15 minutes.Then, add 19 μ L formic acid.Reaction is heated to 80 ℃, after reaction 9h, and yield 98%, selectivity 84%.
As follows through nuclear-magnetism and infrared analysis data:
1h NMR (400MHz, CDCl
3): δ 7.23 (d, 2H, J=8.0Hz), 6.79 (d, 2H, J=8.0Hz), 6.52 (d, 1H, J=12.0Hz), 6.52 (s, 2H), 6.44 (d, 1H, J=12.0Hz), 3.83 (q, 2H, J=6.8Hz), 3.77 (s, 3H), 3.66 (s, 6H), 3.83 (t, 3H, J=6.8Hz).
13c NMR (100MHz, CDCl
3) δ 158.3,153.2,137.4,133.1,130.5,129.6,129.7,128.8,113.8,106.2,61.3,56.0,55.2,14.9.IR (KBr): v2926,1506,1488,1204,1129,1050,753,690,663,611cm
-1.
Embodiment 17: under nitrogen protection, by 5mmol3,4,5-trimethoxy phenylacetylene, 0.25mmol PdCl
2(PPh
3)
2(n
palladium/ n
alkynes=5%) and 0.5mmol CuI(n
copper/ n
alkynes=10%) add in reactor, add 25mL THF(n
alkynes=0.2M), dissolve completely.Measure 10mmol NH
3h
2o
join in reactor, mix.Finally, take 5.5mmol iodobenzene ether is added to reactor, react 8h at 70 ℃.Make 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, productive rate 59%.
Under nitrogen protection, by 0.25mmol1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, 0.375%mmol Pd
2(dba)
3(n
palladium/ n
alkynes=3%) and 3%mmol tri-(4-p-methoxy-phenyl) phosphine (n
phosphine/ n
alkynes=12%) be dissolved into 0.25mL dioxane (n
alkynes=1M) in solvent, stirring at room temperature 15 minutes.Then, add 19 μ L formic acid.Reaction is heated to 80 ℃, after reaction 12h, and yield 99%, selectivity 57%.
As follows through nuclear-magnetism and infrared analysis data:
1h NMR (400MHz, CDCl
3): δ 7.24 (d, 2H, J=8.0Hz), 6.79 (d, 2H, J=8.0Hz), 6.52 (d, 1H, J=12.0Hz), 6.49 (s, 2H), 6.44 (d, 1H, J=12.0Hz), 3.83 (q, 2H, J=6.8Hz), 3.76 (s, 3H), 3.65 (s, 6H), 3.83 (t, 3H, J=6.8Hz).
13c NMR (100MHz, CDCl
3) δ 158.1,153.0,137.3,133.1,130.4,129.8,129.5,128.8,113.9,106.2,61.3,56.0,55.3,14.7.IR (KBr): v2929,1509,1485,1205,1128,1050,756,691,667,610cm
-1.
Claims (10)
1. a cancer therapy drug Combretastatin A4 analogue, is characterized in that its molecular formula C
19h
22o
4, its structural formula is:
2. a method of preparing cancer therapy drug Combretastatin A4 analogue as claimed in claim 1, concrete steps are as follows: A: under nitrogen protection, add 3,4,5-trimethoxy phenylacetylene, PdCl in reactor
2(PPh
3)
2and CuI, then add solvent that it is dissolved completely, then add alkali source to stir in reactor, in the most backward reactor, add iodobenzene ether, there is linked reaction in heating, obtains 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene; B: under nitrogen protection; to add that steps A makes in reactor 1-(3; 4; 5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene, palladium compound and containing phosphine compound; add wherein again solvent that it is dissolved completely; in the most backward reactor, add formic acid; there is reduction reaction in heating; prepare cancer therapy drug CombretastatinCA4 analogue cis-1-(3; 4,5-trimethoxy)-2-(4`-phenelyl) ethene.
3. method as claimed in claim 2, is characterized in that the alkali source described in steps A is ammoniacal liquor or triethylamine.
4. method as claimed in claim 2, is characterized in that PdCl in steps A
2(PPh
3)
2account for respectively 3,4 with the molar weight of CuI, 1～5% and 2～10% of 5-trimethoxy phenylacetylene molar weight.
5. method as claimed in claim 2, is characterized in that reaction raw materials 3,4 in steps A, 5-trimethoxy phenylacetylene, is 1:(1～1.2 to mol ratio hydroxy in iodobenzene ether and alkali source): (1～10).
6. method as claimed in claim 2, is characterized in that the solvent described in steps A and B is tetrahydrofuran (THF), dioxane or 1,2-ethylene dichloride.
7. method as claimed in claim 2, the temperature that it is characterized in that linked reaction in steps A is 50～90 ℃; Reaction times is 8～12h.
8. method as claimed in claim 2, is characterized in that the palladium compound described in step B is PdCl
2, Pd (OAc)
2or Pd
2(dba)
3; Described is triphenylphosphine, three (4-p-methoxy-phenyl) phosphine or three (4-fluorophenyl) phosphine containing phosphine compound.
9. method as claimed in claim 2, it is characterized in that palladium compound in step B and the molar weight containing phosphine compound account for respectively 1-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene molar weights 2～5% and 8～20%; Formic acid and 1 in step B-(3,4,5-2,4,5-trimethoxyphenyl)-2-(4`-phenelyl) acetylene molar ratio is (1～4): 1.
10. method as claimed in claim 2, the temperature that it is characterized in that reduction reaction in step B is 60～100 ℃; Reaction times is 6～12h.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5430062A (en) * | 1992-05-21 | 1995-07-04 | Research Corporation Technologies, Inc. | Stilbene derivatives as anticancer agents |
| US20130244865A1 (en) * | 2010-11-25 | 2013-09-19 | National University Corporation Okayama University | Metal Complex Compound, Hydrogen Production Catalyst and Hydrogenation Reaction Catalyst Each Comprising the Metal Complex Compound, and Hydrogen Production Method and Hydrogenation Method Each Using the Catalyst |
-
2014
- 2014-03-25 CN CN201410114696.0A patent/CN103896745A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5430062A (en) * | 1992-05-21 | 1995-07-04 | Research Corporation Technologies, Inc. | Stilbene derivatives as anticancer agents |
| US20130244865A1 (en) * | 2010-11-25 | 2013-09-19 | National University Corporation Okayama University | Metal Complex Compound, Hydrogen Production Catalyst and Hydrogenation Reaction Catalyst Each Comprising the Metal Complex Compound, and Hydrogen Production Method and Hydrogenation Method Each Using the Catalyst |
Non-Patent Citations (2)
| Title |
|---|
| KENKICHI SONOGASHIRA等: "A CONVENIENT SYNTHESIS OF ACETYLENES : CATALYTIC SUBSTITUTIONS OF ACETYLEY HYDROGEN WITH BROMOALKENES, IODOARENES, AND BROMOPYRIDINES", 《TETRAHEDRON LETTER》 * |
| RUWEI SHEN等: "Facile Regio- and Stereoselective Hydrometallation of Alkynes with a Combination of Carboxylic Acids and Group 10 Transition Metal Complexes: Selective Hydrogenation of Alkynes with Formic Acid", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
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