CN101665419B - Method for preparing (Z)-3'-hydroxy-3,4',5-trimethoxy diphenylethene - Google Patents
Method for preparing (Z)-3'-hydroxy-3,4',5-trimethoxy diphenylethene Download PDFInfo
- Publication number
- CN101665419B CN101665419B CN200910041790A CN200910041790A CN101665419B CN 101665419 B CN101665419 B CN 101665419B CN 200910041790 A CN200910041790 A CN 200910041790A CN 200910041790 A CN200910041790 A CN 200910041790A CN 101665419 B CN101665419 B CN 101665419B
- Authority
- CN
- China
- Prior art keywords
- hydroxyl
- reaction
- acid
- preparation
- trimethoxy
- 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
- 238000000034 method Methods 0.000 title abstract description 6
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical compound C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 title abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 88
- JVTZFYYHCGSXJV-UHFFFAOYSA-N isovanillin Chemical compound COC1=CC=C(C=O)C=C1O JVTZFYYHCGSXJV-UHFFFAOYSA-N 0.000 claims abstract description 18
- FFPAFDDLAGTGPQ-UHFFFAOYSA-N 2-(3,5-dimethoxyphenyl)acetic acid Chemical compound COC1=CC(CC(O)=O)=CC(OC)=C1 FFPAFDDLAGTGPQ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000003684 Perkin reaction Methods 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- 238000003756 stirring Methods 0.000 claims description 34
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 32
- PJANXHGTPQOBST-VAWYXSNFSA-N trans-stilbene Chemical group C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 18
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 17
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 17
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 16
- YJKHOUIVWKQRSL-UHFFFAOYSA-N 1-(3,5-dimethoxyphenyl)ethanone Chemical compound COC1=CC(OC)=CC(C(C)=O)=C1 YJKHOUIVWKQRSL-UHFFFAOYSA-N 0.000 claims description 12
- 150000007530 organic bases Chemical class 0.000 claims description 12
- -1 thiomorpholine acid amides Chemical class 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- 239000005864 Sulphur Substances 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 150000008065 acid anhydrides Chemical class 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000010949 copper Substances 0.000 claims description 6
- 229910052802 copper Inorganic materials 0.000 claims description 6
- 230000001035 methylating effect Effects 0.000 claims description 6
- 239000003444 phase transfer catalyst Substances 0.000 claims description 6
- 235000017550 sodium carbonate Nutrition 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 150000002460 imidazoles Chemical class 0.000 claims description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical group [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- LQOBMKYCRQDMTN-UHFFFAOYSA-N 3-(2-ethylphenyl)pentan-3-amine;hydrochloride Chemical compound Cl.CCC1=CC=CC=C1C(N)(CC)CC LQOBMKYCRQDMTN-UHFFFAOYSA-N 0.000 claims description 3
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 3
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 claims description 3
- MBXNQZHITVCSLJ-UHFFFAOYSA-N methyl fluorosulfonate Chemical compound COS(F)(=O)=O MBXNQZHITVCSLJ-UHFFFAOYSA-N 0.000 claims description 3
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical group COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 2
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 claims description 2
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 claims description 2
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 claims description 2
- HNJXPTMEWIVQQM-UHFFFAOYSA-M triethyl(hexadecyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](CC)(CC)CC HNJXPTMEWIVQQM-UHFFFAOYSA-M 0.000 claims description 2
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 claims 1
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N methylimidazole Natural products CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract description 7
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 238000005672 Willgerodt-Kindler rearrangement reaction Methods 0.000 abstract description 2
- 238000007069 methylation reaction Methods 0.000 abstract description 2
- WQXWIKCZNIGMAP-UHFFFAOYSA-N 3',5'-Dihydroxyacetophenone Chemical compound CC(=O)C1=CC(O)=CC(O)=C1 WQXWIKCZNIGMAP-UHFFFAOYSA-N 0.000 abstract 2
- 239000002994 raw material Substances 0.000 abstract 2
- 239000000243 solution Substances 0.000 description 34
- 239000007787 solid Substances 0.000 description 26
- 238000000967 suction filtration Methods 0.000 description 26
- 238000001816 cooling Methods 0.000 description 21
- 238000004809 thin layer chromatography Methods 0.000 description 12
- 238000001514 detection method Methods 0.000 description 9
- 239000013078 crystal Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 238000004611 spectroscopical analysis Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- ZPOLNCDBPYJDSE-UHFFFAOYSA-N 3-[4-[bis(2-chloroethyl)amino]phenyl]-2-formamidopropanoic acid Chemical compound O=CNC(C(=O)O)CC1=CC=C(N(CCCl)CCCl)C=C1 ZPOLNCDBPYJDSE-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000007239 Wittig reaction Methods 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- PJANXHGTPQOBST-QXMHVHEDSA-N cis-stilbene Chemical group C=1C=CC=CC=1/C=C\C1=CC=CC=C1 PJANXHGTPQOBST-QXMHVHEDSA-N 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- NRPFNQUDKRYCNX-UHFFFAOYSA-N 4-methoxyphenylacetic acid Chemical compound COC1=CC=C(CC(O)=O)C=C1 NRPFNQUDKRYCNX-UHFFFAOYSA-N 0.000 description 1
- KHKMVPFNBZHBRI-UHFFFAOYSA-N COc1cc(CCC(N2CCOCC2)=S)cc(OC)c1 Chemical compound COc1cc(CCC(N2CCOCC2)=S)cc(OC)c1 KHKMVPFNBZHBRI-UHFFFAOYSA-N 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 125000001453 quaternary ammonium group Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing (Z)-3'-hydroxy-3,4',5-trimethoxy diphenylethene, comprising the following steps: taking 3,5-dihydroxyacetophenone as raw material, and then obtaining 3,5-dimethoxy hypnone by methylation reaction under the alkaline condition; then obtaining 3,5-dimethoxyphenylacetic acid by Willgerodt-Kindler rearrangement and hydrolysis reaction; enabling the 3,5-dimethoxyphenylacetic acid and isovanillin to carry out Perkin reaction to obtain (E)-2-(3',5'-dimethoxyphenyl)-3-(3'-hydroxy-4'-methoxyphenyl)crylic acid, and then obtaining the target compound, i.e. the (Z)-3'-oxhydryl-3,4',5-trimethoxy diphenylethene, by decarboxylic reaction. The raw materials of 3,5-dihydroxyacetophenone and isovanillin adopted by the invention have low price and are easy to obtain. The technical process has the advantages of simple operation, good cis-selectivity and high yield.
Description
Technical field
The present invention relates to field of medicine and chemical technology, particularly a kind of (Z)-3 '-hydroxyl-3,4 ', the preparation method of 5-trimethoxy toluylene.
Background technology
People such as M.Roberti (J.Med.Chem, 2003,46,3546) are in the research about Verakanol derivative, and (Z)-3 '-hydroxyl-3 has been synthesized in design, and 4 ', 5-trimethoxy toluylene, this compound has the cis-stilbene skeleton structure.Related activity data presentation, this compound have very strong inhibition HL-60 cell-proliferation activity (IC
50Be 0.03 μ M) and induce the active (AC of HL-60 apoptosis
50Be 0.04 μ M), and the HL-60R cell with multidrug resistance also had the active (IC of very strong inhibition
50Be 0.025 μ M, AC
50Be 0.03 μ M).Therefore, this compound has very high research and development and is worth, and is expected in tumour and other associated treatment fields, to be applied.
The disclosed synthetic route of people such as M.Roberti is: earlier hydroxyl is protected; Make up the diphenylethylene compounds skeleton through the Wittig reaction; Obtain mixture along anti-toluylene analog derivative; Obtain cis-stilbene derivative through separating to purify, obtain target compound through the deprotection base again.But the overall yield of this method is merely 24%, and complex operation; Severe reaction conditions, reagent costliness and instability etc. are included in and need use the silica-based protection base as hydroxyl of tertiary butyl dimethyl-in the reaction process; The Wittig reaction needs is reacted structure toluylene skeleton in THF under highly basic n-Butyl Lithium and-70 ℃ of conditions; The product that generates is along the back mixing compound, separates purification difficult, in deprotection reaction, need carry out waterless operation with aluminum chloride; And it is very low respectively to go on foot reaction yield, causes to be difficult to large-scale production.
Patent ZL 200610033788.1 disclosed synthetic routes are: the homoanisic acid bromination reaction; With 3, the reaction of 5-dimethoxy benzaldehyde makes up the toluylene skeleton again, and decarboxylation got target compound (Z)-3 '-hydroxyl-3 after bromine became hydroxyl; 4 ', 5-trimethoxy toluylene.Problems such as but this method still exists operating process loaded down with trivial details, and the bromine change hydroxyl step reaction time is long, cis-selective is relatively low, yield is lower are difficult to realize scale preparation.
Summary of the invention
The objective of the invention is to overcome the shortcoming that exists in the prior art, a kind of simple to operate, cost is low, yield is high (Z)-3 '-hydroxyl-3 is provided, 4 ', the preparation method of 5-trimethoxy toluylene.
The object of the invention is realized through following technical proposals:
A kind of (Z)-3 '-hydroxyl-3,4 ', the preparation method of 5-trimethoxy toluylene (structural formula 1) comprises the steps:
(1) under alkaline condition, 3,5-resacetophenone (structural formula 2) reacts with methylating reagent in water, and aftertreatment obtains 3,5-dimethoxy-acetophenone (structural formula 3);
(2) said 3; The 5-dimethoxy-acetophenone obtains midbody thiomorpholine acid amides (structural formula 4) through the Willgerodt-Kindler rearrangement reaction; Obtain 3 through hydrolysis again, 5-dimethoxyphenylacetic acid (structural formula 5), that is: 3; The tosic acid of 5-dimethoxy-acetophenone and sulphur, morpholine and catalytic amount obtains midbody thiomorpholine acid amides (structural formula 4) 80～150 ℃ of following stirring reactions 3～8 hours; Under the condition of alkalescence and phase-transfer catalyst existence, obtained 3 in 3～8 hours in 60～130 ℃ of hydrolysis reaction, 5-dimethoxyphenylacetic acid (structural formula 5) again;
(3) said 3,5-dimethoxyphenylacetic acid and Isovanillin (structural formula 6) obtain (E)-2-(3 ', 5 '-Dimethoxyphenyl)-3-(3 '-hydroxyl-4 '-p-methoxy-phenyl) vinylformic acid (structural formula 7) through the Perkin reaction under acid anhydrides and organic bases condition;
(4) said (E)-2-(3 ', 5 '-Dimethoxyphenyl)-3-(3 '-hydroxyl-4 '-p-methoxy-phenyl) vinylformic acid is under the catalysis of organic bases and copper containing catalyst, through decarboxylic reaction; After the separation and purification; Obtain (Z)-3 '-hydroxyl-3,4 ', 5-trimethoxy toluylene.
Formula (1) formula (2) formula (3)
Formula (4) formula (5)
Formula (6) formula (7)
In the step 1, the methylation reaction temperature is 0～60 ℃, preferred 25 ℃; Reaction times is 2～10 hours, preferred 5 hours.Said methylating reagent is trifluoromethane sulfonic acid methyl esters, methyl fluorosulfonate, Me
2SO
4, Me
2CO
3, CH
3I or CH
2N
2, preferred Me
2SO
4The alkali that said alkaline condition adopts is NaOH, KOH, Na
2CO
3Or K
2CO
3, preferred NaOH.
In the step 1,3,5-resacetophenone: methylating reagent: the mol ratio of alkali is 1: 2～5: 2～6, is preferably 1: 2.5: 3.Said aftertreatment is that reaction solution is directly poured in the frozen water, leaves standstill, and cooling, suction filtration obtains 3, the 5-dimethoxy-acetophenone.
In the step 2,3, preferred 120 ℃ of the temperature of reaction of 5-dimethoxy-acetophenone and sulphur, morpholine and tosic acid, preferred 5 hours of reaction times.Preferred 100 ℃ of the hydrolysising reacting temperature of midbody thiomorpholine acid amides, preferred 5 hours of reaction times.
In the step 2,3,5-dimethoxy-acetophenone: sulphur: the mol ratio of morpholine is 1: 1～5: 1～10; The consumption of tosic acid is 3,1/25～1/15, preferred 1/20 of 5-dimethoxy-acetophenone mole number.
In the step 2; Said phase-transfer catalyst is a quaternary ammonium salt-type phase transfer catalyst; Be specially Tetrabutyl amonium bromide, tetraethylammonium bromide, triethyl butyl brometo de amonio, 3,5-dimethylphenyl benzyl brometo de amonio, dimethyl ethyl phenyl brometo de amonio, triethyl benzyl ammonia chloride, cetyltriethylammonium bromide, tetramethyl ammonium chloride or tetrabutylammonium chloride, preferred Tetrabutyl amonium bromide.Said alkali is sodium hydroxide, Pottasium Hydroxide, sodium hydrogencarbonate, saleratus, yellow soda ash or salt of wormwood, preferred sodium hydroxide.The consumption of said phase-transfer catalyst is 1/25～1/15, preferred 1/20 of a thiomorpholine acid amides mole number; The consumption of alkali is 3～6 times of thiomorpholine acid amides mole number, and preferred 4 times, the concentration of alkaline solution is 20% quality.
In the step 3, temperature of reaction is 80～140 ℃, preferred 110 ℃; Reaction times is 3～9 hours, preferred 6 hours.Said acid anhydrides is diacetyl oxide, propionic anhydride or butyryl oxide, preferred diacetyl oxide; Organic bases is DMF, ethamine, quadrol, triethylamine, quinoline, pyridine or piperidines, preferred triethylamine.Said 3,5-dimethoxyphenylacetic acid: Isovanillin: organic bases: the mol ratio of acid anhydrides is 1: 1: 2～5: 3～7, is preferably 1: 1: 2: 3.
In the step 4, said copper containing catalyst is mixture, quinoline and the CuCrO of mixture, quinoline and the Red copper oxide of quinoline and copper powder
2Mixture or quinoline and CuCrO
2-BaCrO
4Mixture, the mixture of preferred quinoline and copper powder; Temperature of reaction is 170～230 ℃, preferred 210 ℃; Reaction times is 1～4 hour, preferred 2.5 hours.Said organic bases is quinoline, imidazoles, n-formyl sarcolysine base imidazoles or diazabicylo (DBU), preferred quinoline.(E)-and 2-(3 ', 5 '-Dimethoxyphenyl)-3-(3 '-hydroxyl-4 '-p-methoxy-phenyl) vinylformic acid: copper containing catalyst: the mol ratio of organic bases is 1: 2～10: 5～20, preferred 1: 8: 15.
Above-mentioned reaction synthetic route is following:
Formula (2) formula (3)
Formula (4) formula (5)
Formula (5) formula (6) formula (7)
Formula (1)
The present invention compared with prior art has following advantage and effect:
(1) cost of material of the present invention's employing is cheap, and cost is low, and reaction conditions is gentle, and experimental implementation is easy.
(2) methylate in the step, need not adopt SX, directly pour in the frozen water reaction solution into cooling and leave standstill and promptly get product, spectrogram confirmation product has reached required purity, and yield can be up to 96%.
(3) the present invention adopts the Perkin reaction to make up the toluylene skeleton; Phenyl ring is midbody formula (the E)-2-(3 ' of cis-configuration; 5 '-Dimethoxyphenyl)-and 3-(3 '-hydroxyl-4 '-p-methoxy-phenyl) vinylformic acid accounts for more than 90%, and the title product cis-selective is high, yield is high, purity good.
Embodiment
Below in conjunction with embodiment the present invention is done further detailed description, but embodiment of the present invention is not limited thereto.
Embodiment 1
With 1.52g (0.010mol) 3,5-resacetophenone and 10ml water join in the reaction flask, and room temperature (25 ℃) stirs the sodium hydroxide that drips 1.2g (0.030mol) down simultaneously and (is mixed with the aqueous solution; Concentration is about 20% quality) and the methyl-sulfate solution of 2.36ml (0.025mol); About 1.5h dropwises continued stirring reaction 1h, reaction solution is poured in the frozen water of 20ml to leave standstill cooling, and suction filtration gets brown solid 3; 5-dimethoxy-acetophenone 1.73g, yield 96.11%.
Embodiment 2
With 1.52g (0.010mol) 3; 5-resacetophenone and 10ml water join in the reaction flask, and ice-water bath (0 ℃) stirs down and drips the aqueous sodium hydroxide solution of about 20% mass percent of 0.80g (0.020mol) and the methyl-sulfate solution of 1.89ml (0.020mol) simultaneously, and about 1h dropwises continued stirring reaction 1.5h; Reaction solution is poured in the frozen water of 20ml and left standstill cooling; Suction filtration gets brown solid 3,5-dimethoxy-acetophenone 1.21g, yield 67.22%.
Embodiment 3
With 1.52g (0.010mol) 3; 5-resacetophenone and 10ml water join in the reaction flask, and 60 ℃ of constant temperature stir down and drip the aqueous sodium hydroxide solution of about 20% mass percent of 2.40g (0.060mol) and the methyl-sulfate solution of 4.72ml (0.050mol) simultaneously, and about 3h dropwises continued stirring reaction 6h; Reaction solution is poured in the frozen water of 20ml and left standstill cooling; Suction filtration gets brown solid 3,5-dimethoxy-acetophenone 1.37g, yield 76.11%.
Embodiment 4
With 1.52g (0.010mol) 3; 5-resacetophenone and 10ml water join in the reaction flask, and 45 ℃ of constant temperature stir down and drip the potassium hydroxide aqueous solution of about 20% quality of 1.68g (0.030mol) and the methylcarbonate solution of 2.10ml (0.025mol) simultaneously, and about 2h dropwises continued stirring reaction 2h; Reaction solution is poured in the frozen water of 20ml and left standstill cooling; Suction filtration gets brown solid 3,5-dimethoxy-acetophenone 1.41g, yield 78.33%.
Embodiment 5
With 1.52g (0.010mol) 3; 5-resacetophenone and 10ml water join in the reaction flask, drip the aqueous sodium carbonate of about 20% quality of 3.18g (0.030mol) and the methyl iodide of 3.55g (0.025mol) under the stirring at room simultaneously, and about 3h dropwises continued stirring reaction 2h; Reaction solution is poured in the frozen water of 20ml and left standstill cooling; Suction filtration gets brown solid 3,5-dimethoxy-acetophenone 1.57g, yield 87.22%.
Embodiment 6
With 1.52g (0.010mol) 3; 5-resacetophenone and 10ml water join in the reaction flask, drip the wet chemical of about 20% quality of 4.14g (0.030mol) and the diazomethane of 1.05g (0.025mol) under the stirring at room simultaneously, and about 2h dropwises continued stirring reaction 2h; Reaction solution is poured in the frozen water of 20ml and left standstill cooling; Suction filtration gets brown solid 3,5-dimethoxy-acetophenone 1.37g, yield 76.11%.
Embodiment 7
With 1.52g (0.010mol) 3; 5-resacetophenone and 10ml water join in the reaction flask, drip the aqueous sodium hydroxide solution of about 20% quality of 1.20g (0.030mol) and the trifluoromethane sulfonic acid methyl esters of 4.10g (0.025mol) under the stirring at room simultaneously, and about 2h dropwises continued stirring reaction 2h; Reaction solution is poured in the frozen water of 20ml and left standstill cooling; Suction filtration gets brown solid 3,5-dimethoxy-acetophenone 1.45g, yield 80.55%.
Embodiment 8
With 1.52g (0.010mol) 3; 5-resacetophenone and 10ml water join in the reaction flask, and 45 ℃ of constant temperature stir down and drip the aqueous sodium hydroxide solution of about 20% quality of 1.20g (0.030mol) and the methyl fluorosulfonate of 2.85g (0.025mol) simultaneously, and about 2h dropwises continued stirring reaction 2h; Reaction solution is poured in the frozen water of 20ml and left standstill cooling; Suction filtration gets brown solid 3,5-dimethoxy-acetophenone 1.41g, yield 78.33%.
Embodiment 9
With 1.52g (0.010mol) 3; 5-resacetophenone and 10ml water join in the reaction flask, and 0 ℃ of constant temperature stirs down and drips the aqueous sodium carbonate of about 20% quality of 6.36g (0.060mol) and the methylcarbonate solution of 1.68ml (0.020mol) simultaneously, and about 3h dropwises continued stirring reaction 2h; Reaction solution is poured in the frozen water of 20ml and left standstill cooling; Suction filtration gets brown solid 3,5-dimethoxy-acetophenone 1.16g, yield 64.44%.
Embodiment 10
With 1.52g (0.010mol) 3; 5-resacetophenone and 10ml water join in the reaction flask, and 60 ℃ of constant temperature stir down and drip the potassium hydroxide aqueous solution of about 20% quality of 1.12g (0.020mol) and the methyl iodide of 7.10g (0.050mol) simultaneously, and about 2h dropwises continued stirring reaction 4h; Reaction solution is poured in the frozen water of 20ml and left standstill cooling; Suction filtration gets brown solid 3,5-dimethoxy-acetophenone 1.29g, yield 71.66%.
Embodiment 11
With 1.80g (0.010mol) 3; 5-dimethoxy-acetophenone, 0.40g (0.015mol) sulphur, 0.095g (0.50mmol) tosic acid and 1.74ml (0.02mol) morpholine join in the reaction flask, are heated to 120 ℃, constant temperature stirring reaction 5h; Reaction finishes, and is cooled to room temperature.In reaction solution, add the aqueous sodium hydroxide solution and 0.161g (0.5mmol) Tetrabutyl amonium bromide of 20% quality of 1.60g (0.040mol), be heated to 100 ℃, isothermal reaction 5h, TLC thin-layer chromatography detection reaction is to complete.
Reaction solution is poured in the water, added acid and be acidified to PH=7, suction filtration is removed oily impurity; Filtrating adds acid and continues to be acidified to PH=2, has this moment a large amount of white solids to generate, and leaves standstill the cooling suction filtration; Get bullion 3, the 5-dimethoxyphenylacetic acid, bullion gets white needle-like crystals 3 through the water recrystallization; 5-dimethoxyphenylacetic acid 1.59g, yield 81.12%.
Embodiment 12
With 1.80g (0.010mol) 3; 5-dimethoxy-acetophenone, 0.32g (0.010mol) sulphur, 0.095g (0.50mmol) tosic acid and 0.87ml (0.01mol) morpholine join in the reaction flask, are heated to 80 ℃, constant temperature stirring reaction 3h; Reaction finishes, and is cooled to room temperature.In reaction solution, add the potassium bicarbonate aqueous solution and 0.114g (0.5mmol) triethyl benzyl ammonia chloride of 20% quality of 4.0g (0.040mol), be heated to 60 ℃, isothermal reaction 3h, TLC thin-layer chromatography detection reaction is to complete.
Reaction solution is poured in the water, added acid and be acidified to PH=7, suction filtration is removed oily impurity; Filtrating adds acid and continues to be acidified to PH=2, has this moment a large amount of white solids to generate, and leaves standstill the cooling suction filtration; Get bullion 3, the 5-dimethoxyphenylacetic acid, bullion gets white needle-like crystals 3 through the water recrystallization; 5-dimethoxyphenylacetic acid 1.27g, yield 64.79%.
Embodiment 13
With 1.80g (0.010mol) 3; 5-dimethoxy-acetophenone, 1.60g (0.050mol) S, 0.095g (0.50mmol) tosic acid and 8.70ml (0.10mol) morpholine join in the reaction flask, are heated to 150 ℃, constant temperature stirring reaction 8h; Reaction finishes, and is cooled to room temperature.In reaction solution, add the aqueous sodium carbonate and 0.182g (0.5mmol) cetyl trimethylammonium bromide of 20% quality of 4.24g (0.040mol), be heated to 130 ℃, isothermal reaction 8h, TLC thin-layer chromatography detection reaction is to complete.
Reaction solution is poured in the water, added acid and be acidified to PH=7, suction filtration is removed oily impurity; Filtrating adds acid and continues to be acidified to PH=2, has this moment a large amount of white solids to generate, and leaves standstill the cooling suction filtration; Get bullion 3, the 5-dimethoxyphenylacetic acid, bullion gets white needle-like crystals 3 through the water recrystallization; 5-dimethoxyphenylacetic acid 1.38g, yield 70.41%.
Embodiment 14
With 1.96g (0.010mol) 3; 5-dimethoxyphenylacetic acid, 1.52g (0.010mol) Isovanillin, 2.78ml (0.020mol) triethylamine and 2.82ml (0.030mol) diacetyl oxide join in the reaction flask; Be warming up to 110 ℃ of constant temperature stirring reaction 6h, the TLC detection reaction is to complete.Reaction solution is poured in the frozen water, be acidified to PH=3 under stirring, leave standstill the cooling suction filtration and get yellow solid.Yellow solid adds an amount of 10% aqueous sodium hydroxide solution dissolving; The ETHYLE ACETATE washing, water layer is acidified to PH=2 again, has a large amount of solids to generate; Leave standstill the cooling suction filtration and get little yellow solid bullion (E)-2-(3 ', 5 '-Dimethoxyphenyl)-3-(3 '-hydroxyl-4 '-p-methoxy-phenyl) vinylformic acid.
Bullion gets little yellow needle-like crystal (E)-2-(3 ', 5 '-Dimethoxyphenyl)-3-(3 '-hydroxyl-4 '-p-methoxy-phenyl) vinylformic acid 2.89g, yield 87.57% with ethyl alcohol recrystallization.
Embodiment 15
With 1.96g (0.010mol) 3; 5-dimethoxyphenylacetic acid, 1.52g (0.010mol) Isovanillin, 2.78ml (0.020mol) triethylamine and 2.82ml (0.030mol) diacetyl oxide join in the reaction flask; Be warming up to 80 ℃ of constant temperature stirring reaction 3h, the TLC detection reaction is to complete.Reaction solution is poured in the frozen water, be acidified to PH=3 under stirring, leave standstill the cooling suction filtration and get yellow solid.Yellow solid adds an amount of 10% aqueous sodium hydroxide solution dissolving; The ETHYLE ACETATE washing, water layer is acidified to PH=2 again, has a large amount of solids to generate; Leave standstill the cooling suction filtration and get little yellow bullion (E)-2-(3 ', 5 '-Dimethoxyphenyl)-3-(3 '-hydroxyl-4 '-p-methoxy-phenyl) vinylformic acid.
Bullion gets little yellow needle-like crystal (E)-2-(3 ', 5 '-Dimethoxyphenyl)-3-(3 '-hydroxyl-4 '-p-methoxy-phenyl) vinylformic acid 2.47g, yield 74.85% with ethyl alcohol recrystallization.
Embodiment 16
With 1.96g (0.010mol) 3; 5-dimethoxyphenylacetic acid, 1.52g (0.010mol) Isovanillin, 2.78ml (0.020mol) triethylamine and 2.82ml (0.030mol) diacetyl oxide join in the reaction flask; Be warming up to 140 ℃ of constant temperature stirring reaction 9h, the TLC detection reaction is to complete.Reaction solution is poured in the frozen water, be acidified to PH=3 under stirring, leave standstill the cooling suction filtration and get yellow solid.Yellow solid adds an amount of 10% aqueous sodium hydroxide solution dissolving; The ETHYLE ACETATE washing, water layer is acidified to PH=2 again, has a large amount of solids to generate; Leave standstill the cooling suction filtration and get little yellow bullion (E)-2-(3 ', 5 '-Dimethoxyphenyl)-3-(3 '-hydroxyl-4 '-p-methoxy-phenyl) vinylformic acid.
Bullion gets little yellow needle-like crystal (E)-2-(3 ', 5 '-Dimethoxyphenyl)-3-(3 '-hydroxyl-4 '-p-methoxy-phenyl) vinylformic acid 2.53g, yield 76.67% with alcohol crystal.
Embodiment 17
With 3.30g (0.010mol) (E)-2-(3 '; 5 '-Dimethoxyphenyl)-3-(3 '-hydroxyl-4 '-p-methoxy-phenyl) vinylformic acid, 5.12g (0.080mol) copper powder and 17ml (0.15mol) quinoline join in the reaction flask; Be warming up to 210 ℃ of constant temperature stirring reaction 2.5h, the TLC detection reaction is to complete.Suction filtration is removed copper powder, washs copper powder with ETHYLE ACETATE, and filtrating uses Hydrogen chloride (1: 1), water washing, organic layer to revolve dried the thick solid of Vandyke brown successively.Get white rhomboidan (Z)-3 '-hydroxyl-3 with the sherwood oil extracting, 4 ', 5-trimethoxy toluylene 2.35g, yield 82.17%.
Embodiment 18
With 3.30g (0.010mol) (E)-2-(3 '; 5 '-Dimethoxyphenyl)-3-(3 '-hydroxyl-4 '-p-methoxy-phenyl) vinylformic acid, 4.29g (0.030mol) Red copper oxide and 9ml (0.080mol) quinoline join in the reaction flask; Be warming up to 210 ℃ of constant temperature stirring reaction 2.5h, the TLC detection reaction is to complete.Suction filtration is removed copper powder, washs copper powder with ETHYLE ACETATE, and filtrating uses Hydrogen chloride (1: 1), water washing, organic layer to revolve dried the thick solid of Vandyke brown successively.Get white rhomboidan (Z)-3 '-hydroxyl-3 with the sherwood oil extracting, 4 ', 5-trimethoxy toluylene 1.83g, yield 63.99%.
Embodiment 19
With 3.30g (0.010mol) (E)-2-(3 '; 5 '-Dimethoxyphenyl)-3-(3 '-hydroxyl-4 '-p-methoxy-phenyl) vinylformic acid, 2.56g (0.040mol) copper powder and 6.5ml (0.080mol) n-formyl sarcolysine base imidazoles join in the reaction flask; Be warming up to 210 ℃ of constant temperature stirring reaction 2.5h, the TLC detection reaction is to complete.Suction filtration is removed copper powder, washs copper powder with ETHYLE ACETATE, and filtrating uses Hydrogen chloride (1: 1), water washing, organic layer to revolve dried the thick solid of Vandyke brown successively.Get white rhomboidan (Z)-3 '-hydroxyl-3 with the sherwood oil extracting, 4 ', 5-trimethoxy toluylene 2.01g, yield 70.28%.
Test case 1
3 of the foregoing description preparation, the fusing point and the spectroscopic data of 5-dimethoxy-acetophenone are following: mp:33～35 ℃;
1H-NMR (400MHz, CDCl
3, δ/ppm, J/Hz): 2.551 (s, 3H), 3.813 (s, 6H), 6.623～6.635 (t, 1H, J=2.4), 7.066～7.071 (d, 2H, J=2.0).
Test case 2
3 of the foregoing description preparation, the 5-dimethoxyphenylacetic acid fusing point and spectroscopic data following: mp:92～94 ℃;
1H-NMR (400MHz, CDCl
3, δ/ppm, J/Hz): 3.566 (s, 2H), 3.762 (s, 6H), 6.362～6.373 (t, 1H, J=2.0), 6.417～6.422 (d, 2H, J=2.0); MS (m/z): [M]
+196, [M-CO
2-H]
+151, [M-CO
2-H-OCH
3]
+121, [M-CO
2-H-2OCH
3]
+91.
Test case 3
(E)-2-(3 ', 5 '-Dimethoxyphenyl)-3-(3 '-hydroxyl-4 '-p-methoxy-phenyl) the vinylformic acid fusing point and the spectroscopic data of the foregoing description preparation are following: mp:183～185 ℃;
1H-NMR (400MHz, CDCl
3, δ/ppm, J/Hz): 3.741 (s, 6H), 3.840 (s, 3H), 6.378～6.384 (d, 2H, J=2.4), 6.458～6.470 (t, 1H, J=2.4), 6.649～6.704 (m, 3H), 7.785 (s, 1H); IR (KBr, cm
-1): 3359,3012,2933,2840,2628,2364,1826,1764,1673,1598,1508,1461; 1446,1423,1388,1364,1297,1267,1201,1149,1060,1025,968,927; 887,854,800,763,728,686,653,624,566,528,439; MS (m/z): [M]
+330.
Test case 4
(Z)-3 '-hydroxyl-3 of the foregoing description preparation, 4 ', 5-trimethoxy toluylene fusing point and spectroscopic data are following: mp:91～93 ℃;
1H-NMR (400MHz, CDCl
3, δ/ppm, J/Hz): 3.660 (s, 6H), 3.836 (s, 3H), 5.499 (s; 1H ,-OH), 6.299～6.310 (t, 1H, J=2.2), 6.43 (d, 2H; J=2.2), 6.406～6.486 (dd, 2H, J=12.4), 6.683～6.703 (d, 1H, J=8.0); 6.754～6.780 (dd, 1H, J=8.4), 6.869～6.874 (d, 1H, J=2.0); MS (m/z): [M]
+286.
Claims (9)
1. (Z)-3 '-hydroxyl-3,4 ', the preparation method of 5-trimethoxy toluylene is characterized in that comprising the steps:
(1) under alkaline condition, 3, the 5-resacetophenone reacts with methylating reagent in water, and aftertreatment obtains 3, the 5-dimethoxy-acetophenone;
(2) 3,5-dimethoxy-acetophenones and sulphur, morpholine, tosic acid obtain midbody thiomorpholine acid amides 80～150 ℃ of following stirring reactions 3～8 hours; Under the condition of alkalescence and phase-transfer catalyst existence, obtained 3 in 3～8 hours in 60～130 ℃ of hydrolysis reaction, the 5-dimethoxyphenylacetic acid again; Said phase-transfer catalyst is Tetrabutyl amonium bromide, tetraethylammonium bromide, triethyl butyl brometo de amonio, 3,5-dimethylphenyl benzyl brometo de amonio, dimethyl ethyl phenyl brometo de amonio, triethyl benzyl ammonia chloride, cetyltriethylammonium bromide, tetramethyl ammonium chloride or tetrabutylammonium chloride;
(3) said 3,5-dimethoxyphenylacetic acid and Isovanillin obtain (E)-2-(3 ', 5 '-Dimethoxyphenyl)-3-(3 '-hydroxyl-4 '-p-methoxy-phenyl) vinylformic acid through the Perkin reaction under acid anhydrides and organic bases condition;
(4) said (E)-2-(3 '; 5 '-Dimethoxyphenyl)-and 3-(3 '-hydroxyl-4 '-p-methoxy-phenyl) vinylformic acid is under the catalysis of organic bases and copper containing catalyst, and said copper containing catalyst is mixture, quinoline and the CuCrO of mixture, quinoline and the Red copper oxide of quinoline and copper powder
2Mixture or quinoline and CuCrO
2-BaCrO
4Mixture; Through decarboxylic reaction, after the separation and purification, obtain (Z)-3 '-hydroxyl-3,4 ', 5-trimethoxy toluylene.
2. (Z) according to claim 1-3 '-hydroxyl-3,4 ', the preparation method of 5-trimethoxy toluylene is characterized in that: in the step (1), said methylating reagent is trifluoromethane sulfonic acid methyl esters, methyl fluorosulfonate, Me
2SO
4, Me
2CO
3, CH
3I or CH
2N
2The alkali that said alkaline condition adopts is NaOH, KOH, Na
2CO
3Or K
2CO
3
3. (Z) according to claim 2-3 '-hydroxyl-3,4 ', the preparation method of 5-trimethoxy toluylene is characterized in that: in the step (1), 3,5-resacetophenone: methylating reagent: the mol ratio of alkali is 1: 2～5: 2～6.
4. (Z) according to claim 1-3 '-hydroxyl-3,4 ', the preparation method of 5-trimethoxy toluylene is characterized in that: in the step (2), 3,5-dimethoxy-acetophenone: sulphur: the mol ratio of morpholine is 1: 1～5: 1～10.
5. (Z) according to claim 1-3 '-hydroxyl-3; 4 '; The preparation method of 5-trimethoxy toluylene is characterized in that: in the step (2), the alkali that said alkalescence adopts is sodium hydroxide, Pottasium Hydroxide, sodium hydrogencarbonate, saleratus, yellow soda ash or salt of wormwood.
6. (Z) according to claim 1-3 '-hydroxyl-3,4 ', the preparation method of 5-trimethoxy toluylene is characterized in that: in the step (3), said acid anhydrides is diacetyl oxide, propionic anhydride or butyryl oxide; Organic bases is ethamine, quadrol, triethylamine, quinoline, pyridine or piperidines.
7. (Z) according to claim 1-3 '-hydroxyl-3; 4 ', the preparation method of 5-trimethoxy toluylene is characterized in that: in the step (3); Said 3,5-dimethoxyphenylacetic acid: Isovanillin: organic bases: the mol ratio of acid anhydrides is 1: 1: 2～5: 3～7.
8. (Z) according to claim 1-3 '-hydroxyl-3,4 ', the preparation method of 5-trimethoxy toluylene is characterized in that: in the step (4), said organic bases is quinoline, imidazoles, Methylimidazole or diazabicylo.
9. (Z) according to claim 1-3 '-hydroxyl-3; 4 '; The preparation method of 5-trimethoxy toluylene; It is characterized in that: in the step (4), said (E)-2-(3 ', 5 '-Dimethoxyphenyl)-3-(3 '-hydroxyl-4 '-p-methoxy-phenyl) vinylformic acid: copper containing catalyst: the mol ratio of organic bases is 1: 2～10: 5～20.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910041790A CN101665419B (en) | 2009-08-11 | 2009-08-11 | Method for preparing (Z)-3'-hydroxy-3,4',5-trimethoxy diphenylethene |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910041790A CN101665419B (en) | 2009-08-11 | 2009-08-11 | Method for preparing (Z)-3'-hydroxy-3,4',5-trimethoxy diphenylethene |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101665419A CN101665419A (en) | 2010-03-10 |
| CN101665419B true CN101665419B (en) | 2012-10-03 |
Family
ID=41802226
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910041790A Expired - Fee Related CN101665419B (en) | 2009-08-11 | 2009-08-11 | Method for preparing (Z)-3'-hydroxy-3,4',5-trimethoxy diphenylethene |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101665419B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108586211B (en) * | 2018-06-08 | 2021-03-19 | 郑州德瑞医药科技有限公司 | Synthesis method of 1, 1-diarylethene derivatives |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101402555A (en) * | 2008-09-02 | 2009-04-08 | 中国科学院广州化学研究所 | Method of preparing (Z)-3'-hydroxyl-3,4,4',5-tetramethoxy toluylene |
-
2009
- 2009-08-11 CN CN200910041790A patent/CN101665419B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101402555A (en) * | 2008-09-02 | 2009-04-08 | 中国科学院广州化学研究所 | Method of preparing (Z)-3'-hydroxyl-3,4,4',5-tetramethoxy toluylene |
Non-Patent Citations (4)
| Title |
|---|
| Marinella Roberti et al..Synthesis and Biological Evaluation of Resveratrol and Analogues as Apoptosis-Inducing Agents.《J. Med. Chem.》.2003,第46卷第3546-3554页. * |
| Mingzhang Gao et al..Synthesis of radiolabeled stilbene derivatives as new potential PET probes for aryl hydrocarbon receptor in cancers.《Bioorganic & Medicinal Chemistry Letters》.2006,第16卷第5767–5772页. * |
| Yong Zou et al..Synthesis of combretastatin A-4 and erianin.《JOURNAL OF CHEMICAL RESEARCH》.2008,第354–356页. * |
| 郑丽玲等.Willgerodt-Kindler法合成系列芳基乙酸化合物.《化学试剂》.2006,第28卷(第9期),第553-554页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101665419A (en) | 2010-03-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102531856B (en) | Method for synthesizing asymmetric diaryl ether derivative | |
| CN106365986B (en) | Compound and preparation method thereof and the purposes in synthesis Bu Waxitan | |
| CN108264469A (en) | It is a kind of to prepare 2-（Cyclohexadienylidene）The method and its application of malonate derivative | |
| CN103601645A (en) | Preparation method of 1-(phenethylamino) propane-2-alcoholic compounds or salts thereof | |
| CN104356012A (en) | Preparation method of sarpogrelate hydrochloride photodegradation impurities | |
| US9771317B2 (en) | Process for preparing lacosamide and related compounds | |
| CN101665419B (en) | Method for preparing (Z)-3'-hydroxy-3,4',5-trimethoxy diphenylethene | |
| CN101704796B (en) | Preparation method of 3-morpholone | |
| CN104829465A (en) | Method for preparing 4-isopropamide group-1-butanol | |
| CN101665418B (en) | Methods for preparing E-3,5-dimethoxy-4'-oxhydryl diphenylethene and derivative thereof | |
| CN105541786B (en) | A kind of Montelukast side-chain intermediate and preparation method thereof | |
| CN102127014B (en) | Azaphenanthrone compound and preparation method thereof | |
| CN112174823B (en) | Intermediate for synthesizing 2, 2-dimethyl-3-oxetanone and preparation method and application thereof | |
| CN102993088A (en) | 4-hydroxy-2-pyridone preparation method | |
| CN104774183A (en) | Preparation method of formoxyl rosuvastatin calcium intermediate | |
| CN102675294A (en) | Method of synthesizing losartan and losartan intermediates | |
| CN109096098B (en) | Preparation method of trans-1, 3-dihydroxycyclobutane-1-carboxylic acid | |
| CN102675064B (en) | Preparation method and application of Z-3,4,4',5-tetramethoxy-2',3'-dihydroxy diphenylethylene | |
| CN103288605B (en) | Synthetic method of combretastatin | |
| CN104030923B (en) | A kind of synthetic method of DL tanshinol borneol ester | |
| Ishihara et al. | A hydrogen-bonded supramolecular hexagonal columnar liquid crystal composed of a tricarboxylic triphenylene and monopyridyl dendrons | |
| CN103044274B (en) | Method for synthesizing tolterodine tartrate without solvent | |
| CN115108926B (en) | Intermediate compound for preparing erdasatinib and preparation method | |
| CN108250008A (en) | 3,3,3`, 3`- tetramethyl -1,1`- spiro indan -6,6`- diol, derivatives chiral separation methods | |
| CN102070427B (en) | Synthesis methods of flocumafen and flocumafen intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: GUANGZHOU CAS TEST TECHNICAL SERVICES CO., LTD. Free format text: FORMER OWNER: GUANGZHOU INST. OF CHEMISTRY, CHINESE ACADEMY OF SCIENCES Effective date: 20141224 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20141224 Address after: 510650 Guangdong city of Guangzhou province Tianhe District Xing Ke Lu 368 experiments building room A Patentee after: GUANGZHOU CAS TESTING TECHNOLOGY SERVICE CO.,LTD. Address before: 510650 No. 368 Xing family street, Guangzhou, Guangdong, Tianhe District Patentee before: Guangzhou Institute of Chemistry, Chinese Academy of Sciences |
|
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: Room a, No.368, Xingke Road, Tianhe District, Guangzhou City, Guangdong Province Patentee after: Zhongke Testing Technology Service (Guangzhou) Co.,Ltd. Address before: Room a, No.368, Xingke Road, Tianhe District, Guangzhou City, Guangdong Province Patentee before: GUANGZHOU CAS TESTING TECHNOLOGY SERVICE Co.,Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20121003 Termination date: 20210811 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |