CN103992212B - Synthesis method for cis-benvitimod, and applications of cis-benvitimod - Google Patents
Synthesis method for cis-benvitimod, and applications of cis-benvitimod Download PDFInfo
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- CN103992212B CN103992212B CN201410233095.1A CN201410233095A CN103992212B CN 103992212 B CN103992212 B CN 103992212B CN 201410233095 A CN201410233095 A CN 201410233095A CN 103992212 B CN103992212 B CN 103992212B
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- 238000001308 synthesis method Methods 0.000 title abstract 5
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 23
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000006722 reduction reaction Methods 0.000 claims abstract description 8
- 239000000126 substance Substances 0.000 claims abstract description 8
- 238000007069 methylation reaction Methods 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 164
- 238000006243 chemical reaction Methods 0.000 claims description 94
- -1 benzene alkene Chemical class 0.000 claims description 81
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 63
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 63
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 48
- 239000002253 acid Substances 0.000 claims description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 33
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 239000000047 product Substances 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000000605 extraction Methods 0.000 claims description 21
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 238000010189 synthetic method Methods 0.000 claims description 19
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 18
- 238000005406 washing Methods 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 10
- 230000001335 demethylating effect Effects 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 9
- 239000008346 aqueous phase Substances 0.000 claims description 9
- 238000006482 condensation reaction Methods 0.000 claims description 9
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000012071 phase Substances 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000001632 sodium acetate Substances 0.000 claims description 7
- 229960004249 sodium acetate Drugs 0.000 claims description 7
- 235000017281 sodium acetate Nutrition 0.000 claims description 7
- 239000010410 layer Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- 239000012044 organic layer Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 2
- 238000006114 decarboxylation reaction Methods 0.000 abstract description 16
- 230000017858 demethylation Effects 0.000 abstract description 15
- 238000010520 demethylation reaction Methods 0.000 abstract description 15
- 239000012535 impurity Substances 0.000 abstract description 12
- 230000008569 process Effects 0.000 abstract description 9
- 238000002360 preparation method Methods 0.000 abstract description 6
- 238000009833 condensation Methods 0.000 abstract description 3
- 230000005494 condensation Effects 0.000 abstract description 3
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- 230000009467 reduction Effects 0.000 abstract description 3
- XIIWDEPRIAPYOR-UHFFFAOYSA-N 3,5-dihydroxy-4-propan-2-ylbenzoic acid Chemical compound CC(C)C1=C(O)C=C(C(O)=O)C=C1O XIIWDEPRIAPYOR-UHFFFAOYSA-N 0.000 abstract 1
- 230000007547 defect Effects 0.000 abstract 1
- 230000011987 methylation Effects 0.000 abstract 1
- 239000003153 chemical reaction reagent Substances 0.000 description 31
- 239000003814 drug Substances 0.000 description 17
- 239000003054 catalyst Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 239000002699 waste material Substances 0.000 description 8
- 230000035484 reaction time Effects 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- ZLWLTDZLUVBSRJ-UHFFFAOYSA-K chembl2360149 Chemical compound [Na+].[Na+].[Na+].O=C1C(N=NC=2C=CC(=CC=2)S([O-])(=O)=O)=C(C(=O)[O-])NN1C1=CC=C(S([O-])(=O)=O)C=C1 ZLWLTDZLUVBSRJ-UHFFFAOYSA-K 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000006607 hypermethylation Effects 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical group C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 description 2
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 2
- 229940094989 trimethylsilane Drugs 0.000 description 2
- SWWQQSDRUYSMAR-UHFFFAOYSA-N 1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol;hydrochloride Chemical group Cl.C1=CC(O)=CC=C1CC1C2=CC(O)=C(O)C=C2CCN1 SWWQQSDRUYSMAR-UHFFFAOYSA-N 0.000 description 1
- ZISJNXNHJRQYJO-CMDGGOBGSA-N 5-[(e)-2-phenylethenyl]-2-propan-2-ylbenzene-1,3-diol Chemical compound C1=C(O)C(C(C)C)=C(O)C=C1\C=C\C1=CC=CC=C1 ZISJNXNHJRQYJO-CMDGGOBGSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 239000012027 Collins reagent Substances 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- GOPYZMJAIPBUGX-UHFFFAOYSA-N [O-2].[O-2].[Mn+4] Chemical class [O-2].[O-2].[Mn+4] GOPYZMJAIPBUGX-UHFFFAOYSA-N 0.000 description 1
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 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
- 206010009887 colitis Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- YLWCNZQVNYRELK-UHFFFAOYSA-N dodecane-1-thiol;sodium Chemical compound [Na].CCCCCCCCCCCCS YLWCNZQVNYRELK-UHFFFAOYSA-N 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 description 1
- NPRDHMWYZHSAHR-UHFFFAOYSA-N pyridine;trioxochromium Chemical compound O=[Cr](=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 NPRDHMWYZHSAHR-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
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- 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
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- 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
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
- C07C67/11—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond being mineral ester groups
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/36—Control of physical parameters of the fluid carrier in high pressure liquid systems
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
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Abstract
The invention discloses a synthesis method for cis-benvitimod, and applications of cis-benvitimod. The synthesis method comprises the following steps: by taking 3,5-dihydroxy-4-isopropylbenzoic acid as a raw material, sequentially performing methylation, reduction, oxidization, condensation, decarboxylation and demethylation to finally synthesize cis-benvitimod, the purity of the prepared high-purity product cis-benvitimod achieves 95-99%, and the cis-benvitimod can be used for detecting the content of cis-benvitimod as a standard substance in the synthesis of trans-benvitimod; according to the synthesis method, the defects that the cis-benvitimod is low in content, instable in properties and difficult to separate in the prior art can be overcome, a method for analyzing and detecting important impurities in the preparation process of the trans-benvitimod preparation process can be established. The synthesis method is applicable to synthesis of cis-benvitimod, the prepared product is used for detecting the content of cis-benvitimod as a standard substance in the synthesis process of trans-benvitimod.
Description
Technical field
The invention belongs to pharmacy field, relate to a kind of synthesis and application of diphenylethylene compounds, specifically the application of a kind of cis benzene alkene not synthetic method of moral and cis benzene alkene not moral.
Background technology
The toxicity of impurity in the former medicine of chemical synthetic drug and preparation, especially heredity toxicity is the important factor affecting drug safety.Impurity majority in medicine has potential biological activity, and the untoward reaction that medicine produces in Clinical practice, except outside the Pass having with the pharmacologically active of medicine itself, also has much relations with the impurity that exists in medicine.Some impurity can interact with medicine, directly affects drug safety and validity, even produces toxic action.The control of impurity of the drug is for the usefulness ensureing medicine, and the untoward reaction reducing medicine plays critical effect.Assorted Quality Research is the importance of drug research, and it through whole drug research all the time.Can the impurity in medicine obtain rationally, effectively controlling, and is directly connected to quality controllability and the security of medicine.
Benzene alkene not moral (Benvitimod) is anti-inflammation drugs of new generation, can be used for treating multiple great autoimmune disorder, as psoriasis, eczema, sends out property colitis and multiple anaphylactic disease dense.Benzene alkene not moral is diphenylethylene compounds, comprise cis-trans-isomer, trans benzene alkene not moral has stronger physiologically active, and physicochemical property are stablized, and cis benzene alkene not moral be mainly the by product of trans benzene alkene not in moral building-up process, method such as the cis-isomeride impurity in Wittig reaction of traditional synthesis benzene alkene not moral is inevitable.
As the major impurity in trans benzene alkene not moral synthesis, no matter be carry out drug testing, or the monitoring in reaction process, the establishment of the cis benzene alkene not synthesis and analyse method of moral has very important meaning.Traditional benzene alkene not in moral synthetic method the content of this impurity very low, and cis-compound character is extremely unstable, easily changes into transconfiguration, so according to synthetic method before, this cis-compound is difficult to separate.Its synthetic method was not reported in document before.Therefore, the route of synthesis finding cis benzene alkene not moral is most important.
The synthetic method of cis-stilbene compounds, in the prior art, has had a lot of report, but, the method reaction raw materials of synthesizing cis product and reagent source difficulty in prior art, costly, cost is higher for the catalyzer used, operational difficulty, is unfavorable for scale operation, such as:
1. Gaukroger K, John A. Hadfield. Novel syntheses of cis and trans isomers of combretastatin A-4 [J] .J. Org. Chem, 2001, (66): 8135-8138, with the styryl bromine replaced and the phenylo boric acid of replacement for raw material, Suzuki linked reaction under palladium chtalyst, obtains cis-compound, reaction process as shown in the formula:
The method productive rate is high and the selectivity of structure is good, but reaction raw materials source difficulty, catalyzer costly, limits the use of the method.
2. Felix N, Ngassa, Erick A, Lindsey, Brandon E, Haines.The first Cu-and amine-free Sonogashira-type cross-coupling in the C-6-alkynylation of protected 2 '-deoxyadenosine [J]. Tetrahedron Letters, 2009, (65) the phenylacetylene easily catalyzed dose of Pd/CaCO replaced: 4085-4091, is adopted
3, Fe
2(CO)
9, Pd (OAc)
2cis-compound is produced Deng catalytic reduction.Reaction process as shown in the formula:
The method advantage is alkynes stereospecificity reduction under catalyst action, overcomes the cis-trans isomerization in Wittig reaction, but because reaction needed is at-78 DEG C, be unfavorable for operation, and reagent source is difficult, price is higher, increase cost, be unfavorable for scale operation.
3. Belluci G, Chiappe C, Moro G Lo. Crown ether catalyzed stereospecific synthesis of Z-and E-stilbenes by Wittig reaction in a solid-liquid two-phases system [J] .Tetrahedron Letters, 1996, (37): 4225-4228, Pd (PPh is adopted
3)
4as catalyzer, organic zinc reagent and halogenide coupling generate cis-compound, reaction process as shown in the formula:
The advantage of the method is that selectivity is good, obtains cis yield high; Weak point is operational difficulty, and catalyzer is expensive.
4. Wang Zhi is new, Zhang Xuejing, all Yue, the synthesis of Zou Yongshun, trans-Resveratrol. Chinese pharmacy, 2005,14 (4); 204-208, reports and is dissolved in DMSO by trans-compound, is made into certain density solution, and react under 365nm uv irradiating, be converted to cis-compound, reaction process is shown in following formula:
But the method requires stricter to solution concentration preparation, reaction times.
Mostly adopt toluene to be solvent in prior art, add a small amount of acetic anhydride, back flow reaction at 110 DEG C, but employing toluene is solvent, yield is lower is 60-90%, and adopt acetic anhydride to be solvent in the present invention, yield can reach more than 94%.
The present invention adopts sodium acetate, anhydrous to be basic catalyst, and aftertreatment is simple, and yield is higher.
Present invention employs multiple basic catalyst to test, but when adopting triethylamine as basic catalyst, yield is lower; Adopt Anhydrous potassium carbonate and anhydrous potassium fluoride, in reaction process, sticky wall is serious, and reaction solution is that black sticks colloidal liquid, and aftertreatment is very difficult; When adopting Glacial acetic acid potassium to be basic catalyst, although aftertreatment is relatively simple, yield is lower; As can be seen here, be not that basic catalysts all in prior art can both be used in the present invention, and its consumption is also very large on reaction result impact, adopt 3,5-dimethoxy-4 '-propylbenzyl aldehyde and sodium-acetate mol ratio when be the weightmeasurement ratio of 1:2-4,3,5-dimethoxy-4 '-propylbenzyl aldehyde and acetic anhydride being 1g:20 ~ 30mL, react completely, yield is higher.Exceed ratio upper limit acetic anhydride excessive, be difficult to except clean, increase the difficulty of aftertreatment, waste reagent in last handling process; Exceed the reaction of ratio lower limit not exclusively, yield is lower.
(5) decarboxylic reaction
Be that the acid of 3,5-dimethoxy-4 's-isopropyl toluylene and the copper powder of 1:6 ~ 8 joins in quinoline by mol ratio, 180 DEG C react 3-5h after, be down to room temperature, add ethyl acetate and stir, filter, filtrate is colourless to water layer with dilute hydrochloric acid washing, and aqueous phase uses ethyl acetate reversed phase extraction again, merges organic layer, saturated common salt water washing is to neutral, be spin-dried for, obtain 3,5-dimethoxy-4 '-isopropyl toluylene, yield is 90-95%, and purity is 75-80%; Wherein:
3,5-dimethoxy-4 '-isopropyl toluylene acid is 1:15 ~ 20g/mL with the weight/volume of quinoline;
Cis-product of controlling well is not converted into stable trans product, and be the key of this step, the control of therefore reacting the factors such as mol ratio, temperature, reaction times and aftertreatment is extremely important.
Traditional decarboxylation method used be 210-230 DEG C of reaction, but high temperature easily aggravates the reversion of cis benzene alkene not moral, final based on trans benzene alkene not moral, therefore, the present invention is on the basis using preferably decarboxylation reagent copper powder and quinoline, strict control temperature of reaction, the content finally making cis benzene alkene not moral is 75-80%.
The present invention adopts copper powder and quinoline to be decarboxylation reagent, and aftertreatment is simple, and yield is higher.
Present invention employs multiple decarboxylation reagent to test, but adopt acetic acid and sulfuric acid back flow reaction at 110 DEG C, yield is lower; Adopt sodium-chlor and DMSO decarboxylation at 180 DEG C, or DMSO and water under reflux conditions decarboxylation time, during aftertreatment, DMSO is difficult to steam except clean, and yield is not high yet; Adopt decarboxylation under 60% sulfuric acid reflux conditions, yield is lower; Adopt concentrated hydrochloric acid decarboxylation at ambient temperature, mild conditions is difficult to decarboxylation, and yield is lower; Adopt tosic acid and water to react at 100 DEG C, toxicity is comparatively large, and yield is not high yet; Adopt lithium chloride, DMSO and water to react at 130 DEG C, lithium chloride is expensive, and cost is higher, and during aftertreatment, DMSO is difficult to removing; As can be seen here, be not that decarboxylation reagent all in prior art can both be used in the present invention, and its consumption is also very large on reaction result impact, adopt 3, the mol ratio of 5-dimethoxy-4 '-isopropyl toluylene acid and copper powder is 1:6-8,3,5-dimethoxy-4 '-isopropyl toluylene acid is 1g:15-20mL with the weight/volume of quinoline, exceed ratio upper limit copper powder and quinoline excessive, aftertreatment is difficult to be removed totally, increases the difficulty of aftertreatment, waste reagent, exceed ratio lower limit and then react incomplete, yield is lower.
(6) demethylating reaction
3,5-dimethoxy-4 '-isopropyl toluylene is placed in toluene, stirs in ice bath, be cooled to 0 DEG C, slowly add DMA after dissolving, add aluminum trichloride (anhydrous) in batches, after stirring 0.5h, rise to room temperature, after being heated to 100 DEG C of reaction 2-3h, be cooled to 60 DEG C, separate toluene layer while hot, in aqueous phase, add dilute hydrochloric acid stirring and adjusting pH value is 2-3, extraction into ethyl acetate, washing, concentrated, obtain target product cis benzene alkene not moral, yield is 92-98%, purity 70-80%, after being separated, yield is 65-75%, and purity is 95-99%; Wherein:
The weight/volume of 3,5-dimethoxy-4 '-isopropyl toluylene and toluene is for being 1:15 ~ 20g/mL;
The mol ratio of 3,5-dimethoxy-4 '-isopropyl toluylene and DMA, aluminum trichloride (anhydrous) is 1:5 ~ 7:5 ~ 7.
Common demethyl method is back flow reaction at 110 DEG C, temperature is too high, the reversion of easy aggravation cis benzene alkene not moral, final based on trans benzene alkene not moral, therefore, the present invention is selecting preferably demethylation reagent N, on the basis of accelerine and aluminum trichloride (anhydrous), proportioning between strict control reactant and temperature of reaction, the content finally making cis benzene alkene not moral is 70-80%, high purity 95-99% after being separated.
The present invention adopts DMA, aluminum trichloride (anhydrous) to be demethylation reagent, and simple to operate, yield is higher.
Present invention employs multiple demethylation reagent to test, but, employing must hydrochloride and pyridine hydrobromide salt as demethylation reagent, toxicity is comparatively large, harm environment and experimenter, and temperature of reaction is higher, and product configuration is transconfiguration substantially; Adopt BBr
3when/methylene dichloride is as demethylation reagent, due to BBr
3highly volatile, must in low temperature-70 ~ 80 DEG C dropping, severe reaction conditions, operational difficulty; When adopting trimethyl silane as demethylation reagent, because trimethyl silane easily volatilizees, not easily store, operate more difficult, and yield is lower; When adopting dense HI solution as demethylation reagent, increase cost, and yield is not high yet; When adopting 40%HBr/ acetic acid as demethylation reagent, yield is lower; When adopting lauryl mercaptan sodium/DMF as demethylation reagent, need 190 DEG C of reactions, temperature of reaction is higher, and product is transconfiguration substantially; As can be seen here, be not that demethylation reagents all in prior art can both be used in the present invention, and its consumption is also very large on reaction result impact, adopt the weight/volume of 3,5-dimethoxy-4 '-isopropyl toluylene and toluene for being 1g:15-20mL; The reaction mol ratio of 3,5-dimethoxy-4 '-isopropyl toluylene and DMA, aluminum trichloride (anhydrous) is 1:5 ~ 7:5 ~ 7.Exceed the difficulty that the ratio upper limit then increases aftertreatment, and waste reagent, exceed ratio lower limit and then react incomplete, yield is lower.
Present invention also offers the one application of above-mentioned synthetic method institute preparing cis benzene alkene not moral, it can as standard substance in the synthesis of trans benzene alkene not moral, for detecting the content of cis benzene alkene not moral.
Limit as one of the present invention, the content detecting cis benzene alkene not moral is the method adopting HPLC: chromatographic column is Nucleosil 5 C18; Column temperature is 20 DEG C; Determined wavelength is 318nm; Moving phase by volume ratio be 50: 50 acetonitrile and water form; Flow velocity is 0.6mL/min, and sample size is 5 μ L.
Owing to have employed above-mentioned technical scheme, compared with prior art, acquired technical progress is in the present invention:
The present invention is with 3,5-dihydroxyl-4-isopropyl acid for raw material, and successively through Hypermethylation, reduction, oxidation, condensation, decarboxylation and demethylating reaction final synthesizing cis benzene alkene not moral, prepared cis benzene alkene not moral purity reaches 95-99%; The high purity product prepared, can as standard substance in the synthesis of trans benzene alkene not moral, for detecting the content of cis benzene alkene not moral.Synthetic method of the present invention overcomes in prior art that moral content is not low, character is unstable and be difficult to the shortcoming that is separated because of cis benzene alkene, and establishes analysis and the detection method of a kind of important impurity of trans benzene alkene not in moral preparation process.
The present invention is applicable to the synthesis of cis benzene alkene not moral, and products made thereby is used for as standard substance in trans benzene alkene not moral building-up process, for the content detection of cis benzene alkene not moral.
The present invention is described in further detail below in conjunction with Figure of description and specific embodiment.
Summary of the invention
The technical problem to be solved in the present invention, be to provide the synthetic method of a kind of cis benzene alkene not moral, with 3,5-dihydroxyl-4-isopropyl acid is raw material, successively through Hypermethylation, reduction, oxidation, condensation, decarboxylation and demethylating reaction final synthesizing cis benzene alkene not moral, prepared cis benzene alkene not moral purity reaches 95-99%;
Another object of the present invention, is to provide the one application of aforesaid method institute preparing cis benzene alkene not moral, and it can as standard substance in the synthesis of trans benzene alkene not moral, for detecting the content of cis benzene alkene not moral; Overcome in prior art that moral content is not low, character is unstable and be difficult to the shortcoming that is separated because of cis benzene alkene, and establish analysis and the detection method of a kind of important impurity of trans benzene alkene not in moral preparation process.
For solving the problems of the technologies described above, the technical solution used in the present invention is:
The synthetic method of a kind of cis benzene alkene not moral, it is with 3,5-dihydroxyl-4-isopropyl acid is raw material, successively through methylation reaction synthesis 3,5-dimethoxy-4 '-isopropyl acid ester, reduction reaction synthesis 3,5-dimethoxy-4 '-isopropylbenzyl alcohol, oxidizing reaction synthesis 3,5-dimethoxy-4 '-propylbenzyl aldehyde, condensation reaction synthesis 3,5-dimethoxy-4 '-isopropyl toluylene acid, decarboxylic reaction synthesis 3,5-dimethoxy-4 '-isopropyl toluylene, eventually passes demethylating reaction synthesizing cis benzene alkene not moral.
Limit as one of the present invention, the reaction scheme of above-mentioned synthetic method is as follows:
。
As the further restriction of above-mentioned restriction, described synthetic method is carried out according to following steps order:
(1) methylation reaction
3,5-dihydroxyl-4-isopropyl acid, Anhydrous potassium carbonate are mixed with mol ratio 1:3 ~ 5, joins in DMF, at room temperature stir; Then, under the cooling of cryosel bath, slowly drip methyl iodide; Room temperature is risen to, reaction 2-3h after dropwising; Add water stirring after completion of the reaction, extraction into ethyl acetate, and concentrated, obtain 3,5-dimethoxy-4 '-isopropyl acid ester, yield is 90-95%, and purity is 95-99%; Wherein:
The mol ratio of 3,5-dihydroxyl-4-isopropyl acid and methyl iodide is 1:3 ~ 5;
The weightmeasurement ratio of 3,5-dihydroxyl-4-isopropyl acid and DMF is 1:20 ~ 30g/mL;
(2) reduction reaction
Be that 3,5-dimethoxy-4 's-isopropyl acid ester and the sodium borohydride mixed at room temperature of 1:4 ~ 6 stirs by tetrahydrofuran (THF), mol ratio, be heated to backflow, slow dropping methyl alcohol, after reaction 4 ~ 6h, the 3 ~ 5L that adds water stirs, extraction into ethyl acetate, washing, revolve and steam except desolventizing obtains white solid, i.e. 3,5-dimethoxy-4 's-isopropylbenzyl alcohol, yield is 94-98%, and purity is 95-99%; Wherein:
The amount ratio of 3,5-dimethoxy-4 '-isopropyl acid ester, methyl alcohol and tetrahydrofuran (THF) is 1:1 ~ 3:10 ~ 20g/mL/mL;
(3) oxidizing reaction
By 3,5-dimethoxy-4 '-isopropylbenzyl alcohol, DMSO and acetic anhydride mix and blend, after room temperature reaction 2-3h, add water stirring, extraction into ethyl acetate, washing, dry, concentrated 3,5-dimethoxy-4 '-propylbenzyl aldehyde, yield is 90-95%, and purity is 95-99%; Wherein:
The amount ratio of 3,5-dimethoxy-4 '-isopropylbenzyl alcohol, DMSO and acetic anhydride is 1:10 ~ 15:2 ~ 3g/mL/mL;
The present invention adopts DMSO to be oxygenant, and reaction conditions is gentle, and operational safety is simple, and yield is higher.
Present invention employs multiple oxygenant to test, but, adopt PCC, CrO3/ vitriol oil and Collins reagent, because toxicity is comparatively large, harm environment and experimenter, and in reaction process, sticky wall is serious, and not exclusively, aftertreatment is very difficult in reaction; When adopting potassium bichromate as oxygenant, because oxidisability is comparatively strong, the corresponding aldehyde product formed is less, is directly oxidized to acid; When adopting activated manganese dioxide, aluminum isopropylate as oxygenant, yield is lower, and aftertreatment is more difficult; As can be seen here, be not that the oxygenants that alcohol can be oxidized to aldehyde all in prior art can both be used in the present invention, and its consumption is also very large on reaction result impact, adopt 3, the weightmeasurement ratio of 5-dimethoxy-4 '-isopropylbenzyl alcohol, DMSO and acetic anhydride is 1:10 ~ 15:2 ~ 3g/mL/mL, exceed ratio upper limit DMSO and acetic anhydride excessive, be difficult to except clean in last handling process, increase the difficulty of aftertreatment, waste reagent, exceed ratio lower limit and can produce the incomplete phenomenon of reaction, and yield is lower.
(4) condensation reaction
Be 3 of 1:1 by mol ratio, 5-dimethoxy-4 '-propylbenzyl aldehyde and toluylic acid mixing, add in acetic anhydride, stirring and dissolving, add sodium-acetate, be heated to 135 DEG C, after reaction 6-8h, adding rare acid for adjusting pH after being down to room temperature is 2-3, extraction into ethyl acetate, concentrated, adding saturated sodium bicarbonate solution regulates pH to be 7 ~ 8, after stirring 2-3h, and dichloromethane extraction, aqueous phase adds dilute hydrochloric acid and adjusts pH to be 2 ~ 3, filter yellow solid, i.e. 3,5-dimethoxy-4 's-isopropyl toluylene acid, yield is 94-98%, and purity is 80-85%; Wherein:
The mol ratio of 3,5-dimethoxy-4 '-propylbenzyl aldehyde and sodium-acetate is 1:2 ~ 4;
The weight/volume of 3,5-dimethoxy-4 '-propylbenzyl aldehyde and acetic anhydride is 1:20 ~ 30g/mL;
This step is committed step of the present invention, and the ratio of cis-product controlled well is particularly crucial, and reaction conditions provided by the present invention makes the content of cis-product maximize, and ensures that yield is higher.
Accompanying drawing explanation
Fig. 1 is cis benzene alkene not moral in the embodiment of the present invention 1
1hNMR schemes;
Fig. 2 is trans benzene alkene not moral in the embodiment of the present invention 1
1hNMR schemes;
Fig. 3 be in the embodiment of the present invention 1 cis benzene alkene not moral HPLC figure;
Fig. 4 be in the embodiment of the present invention 1 trans benzene alkene not moral HPLC figure;
Fig. 5 be in the embodiment of the present invention 1 along anti-benzene alkene not moral mixture HPLC figure.
Embodiment
the application of the embodiment 1 one kinds of cis benzene alkene not synthetic method of moral and institute's preparing cis benzene alkene not moral
The synthetic method of this cis benzene alkene not moral, react according to following route:
Concrete preparation process is carried out according to following steps order:
(1) methylation reaction
By 195.12g(1mol) 3,5-dihydroxyl-4-isopropyl acid, 414.57g(3mol) add the DMF of 5000ml after Anhydrous potassium carbonate mixing, at room temperature stir, then under the cooling of cryosel bath, slow dropping 425.85g(3mol) methyl iodide, rise to room temperature after dropwising, reaction 2h, add water stirring after completion of the reaction, extraction into ethyl acetate, concentrated, obtain 3,5-dimethoxy-4 '-isopropyl acid ester; Yield is 93%, and purity is 99%.
(2) reduction reaction
By the tetrahydrofuran (THF) of 3000ml and 240g(1mol) 3,5-dimethoxy-4 '-isopropyl acid ester, 151.40g(4mol) sodium borohydride mixed at room temperature stir, be heated to backflow, slowly drip the methyl alcohol of 400ml, after reaction 4h, add 3L water to stir, extraction into ethyl acetate, washing, revolves and steams except desolventizing obtains white solid, obtain 3,5-dimethoxy-4 '-isopropylbenzyl alcohol; Yield is 96%, and purity is 99%.
(3) oxidizing reaction
By 212g(1mol) 3,5-dimethoxy-4 's-isopropylbenzyl alcohol, 800ml the acetic anhydride mix and blend of DMSO and 500ml, after room temperature reaction 2h, add water stirring, extraction into ethyl acetate, washing, drying, concentrates to obtain 3,5-dimethoxy-4 's-propylbenzyl aldehyde; Yield is 94%, and purity is 99%.
(4) condensation reaction
By 209.18g(1mol) 3,5-dimethoxy-4 '-propylbenzyl aldehyde and 136.15g(1mol) the mixture of toluylic acid add in the acetic anhydride of 5000ml, stirring and dissolving, add 246.09g sodium-acetate, be heated to 135 DEG C, after reaction 6h, adding rare acid for adjusting pH after being down to room temperature is 2, extraction into ethyl acetate, concentrated, adding saturated sodium bicarbonate solution regulates pH to be 7, after stirring 2h, and dichloromethane extraction, aqueous phase adds dilute hydrochloric acid and adjusts pH to be 2, filter yellow solid, obtain 3,5-dimethoxy-4 '-isopropyl toluylene acid; Yield is 96%, and purity is 80%.
(5) decarboxylic reaction
By 327g(1mol) 3, the acid of 5-dimethoxy-4 '-isopropyl toluylene and 384g(6mol) copper powder join in the quinoline of 5000ml, after 180 DEG C of reaction 3h, be down to room temperature, add ethyl acetate to stir, filter, filtrate is colourless to water layer with dilute hydrochloric acid washing, and aqueous phase uses ethyl acetate reversed phase extraction again, merge organic layer, saturated common salt water washing, to neutral, is spin-dried for and obtains 3,5-dimethoxy-4 '-isopropyl toluylene; Yield is 92%, and purity is 77%.
(6) demethylating reaction
By 282.32g(1mol) 3,5-dimethoxy-4 '-isopropyl toluylene is placed in the toluene of 4000ml, stir in ice bath, be cooled to 0 DEG C, slowly add 605.9g(5mol after dissolving) DMA, add 666.7g(5mol in batches) aluminum trichloride (anhydrous), after stirring 0.5h, rise to room temperature, after being heated to 100 DEG C of reaction 2h, be cooled to 60 DEG C, separate toluene layer while hot, in aqueous phase, add dilute hydrochloric acid stirring and adjusting pH value is 2, extraction into ethyl acetate, washing, concentrated, obtain cis benzene alkene not moral; Crude yield is 95%, and purity is 74%.After be separated through column chromatography, adopt 300-400 object silica gel, be separated to obtain cis benzene alkene not moral sterling, yield is 68%, and purity is 98.5%.Obtained cis benzene alkene not moral nuclear-magnetism figure as shown in Figure 1, nuclear magnetic data is as follows:
1H NMR (CDCl
3, 500 Hz, δ: ppm), 7.255 (m, 5H), 6.558 (d, 1H), 6.402 (d, 1H), 6.218 (s, 2H), 4.872 (s, 2H), 3.423 (m, 1H), 1.359 (q, 6H)。Coupling constant
j=12.
Trans benzene alkene not moral nuclear-magnetism figure as shown in Figure 2, nuclear magnetic data is as follows:
1H NMR (CDCl
3, 500 Hz, δ: ppm), 7.477 (d, 2H), 7.360 (t, 2H), 6.969 (q, 2H), 6.501 (s, 1H), 4.722 (s, 2H), 3.486 (m, 1H), 1.380 (t, 6H)。Coupling constant
j=16.
The HPLC condition of cis benzene alkene not moral sterling: chromatographic column is Nucleosil 5 C18; Column temperature is 20 DEG C; Determined wavelength is 318nm; Moving phase by volume ratio be 50: 50 acetonitrile and water form; Flow velocity is 0.6mL/min, and sample size is 5 μ L; Cis benzene alkene not moral is that 18.423min goes out peak in retention time, and content is 96.39%, sees accompanying drawing 3.Trans benzene alkene not moral is that 17.630min goes out peak in retention time, and content is 99.8%, sees accompanying drawing 4.After both mixing, trans benzene alkene not moral is that 17.664min goes out peak in retention time, and cis benzene alkene not moral is that 18.458min goes out peak in retention time, sees accompanying drawing 5.
Detect the cis benzene alkene prepared not moral stability and probe into its storage requirement, carried out following study on the stability experiment:
1, according to the stability experiment (Chinese Pharmacopoeia 2010 editions) that pharmacopeia is carried out
Note: the value in upper table is the content (%) of cis benzene alkene not moral.
2, illumination condition experiment
Note: the value in upper table is the content (%) of cis benzene alkene not moral.
3, temperature condition experiment
Note: the value in upper table is the content (%) of cis benzene alkene not moral, and stores under lucifuge condition.
4, permanent stability experiment
Note: the value in upper table is the content (%) of cis benzene alkene not moral, and stores under lucifuge condition.
According to above-mentioned test, the cis benzene alkene obtained by the present embodiment not moral has stability, and the storage requirement of obtained cis benzene alkene not moral should be: less than 0 DEG C, keep in Dark Place.
the synthetic method of embodiment 2-6 cis benzene alkene not moral
Embodiment 2-6 is respectively the synthetic method of a kind of cis benzene alkene not moral, and its building-up process is similar to embodiment 1, and difference is only wherein involved technical parameter, shown in table specific as follows:
embodiment 7 condition test
The present embodiment has carried out optionally screening to the technical parameter in embodiment 1-6, find the type of agents useful for same and consumption on react affect very large.
1, the oxygenant in reactions steps (3) and consumption thereof are selected, and be not the reaction that oxygenants all in prior art can both make its mild condition, and yield is higher, particular content sees the following form:
Finally determine that DMSO/ acetic anhydride is oxygenant, rear its consumption to be tested, the proportion relation of both discoveries and consumption comparatively large to the influence factor of reacting, shown in table specific as follows:
As can be seen from the above table, adopt 3, the weightmeasurement ratio of 5-dimethoxy-4 '-isopropylbenzyl alcohol, DMSO and acetic anhydride is 1:10 ~ 15:2 ~ 3g/mL/mL, exceed ratio upper limit DMSO and acetic anhydride excessive, be difficult to except clean, increase the difficulty of aftertreatment, waste reagent in last handling process, exceed ratio lower limit and can produce the incomplete phenomenon of reaction, and yield is lower.
2, select the basic catalyst that condensation reaction uses, be not the reaction that basic catalysts all in prior art can both make its mild condition, and yield is higher, particular content sees the following form:
As can be seen from the above table, select sodium acetate, anhydrous as the basic catalyst in condensation reaction, aftertreatment is relatively simple, and reaction yield is higher.
Finally determine that sodium acetate, anhydrous is basic catalyst, rear its consumption to be tested, the proportion relation of both discoveries and consumption comparatively large to the influence factor of reacting, shown in table specific as follows:
As can be seen from the above table, as can be seen from the above table, 3 are adopted, 5-dimethoxy-4 '-propylbenzyl aldehyde and sodium-acetate mol ratio when be the weightmeasurement ratio of 1:2-4,3,5-dimethoxy-4 '-propylbenzyl aldehyde and acetic anhydride being 1g:20 ~ 30mL, react completely, yield is higher.Exceed ratio upper limit acetic anhydride excessive, be difficult to except clean, increase the difficulty of aftertreatment, waste reagent in last handling process; Exceed the reaction of ratio lower limit not exclusively, yield is lower.
Also temperature of reaction and reaction times are selected, shown in table specific as follows simultaneously:
As can be seen from the above table, the temperature of reaction of condensation reaction selects 135 DEG C can arrive higher reaction yield, and the content of cis-product is also higher.
As can be seen from the above table, the reaction times of condensation reaction selects 6-8h can arrive higher reaction yield, and the content of cis-product is also higher.
3, select the decarboxylation reagent that decarboxylic reaction uses, be not the reaction that decarboxylation reagent all in prior art can both make its mild condition, and yield is higher, particular content sees the following form:
As can be seen from the above table, the reagent of decarboxylic reaction selects copper powder/quinoline can arrive higher reaction yield and aftertreatment is simple.
Finally determine that copper powder/quinoline is decarboxylation reagent, rear its consumption to be tested, the proportion relation of both discoveries and consumption comparatively large to the influence factor of reacting, shown in table specific as follows:
As can be seen from the above table, as can be seen from the above table, the mol ratio adopting 3,5-dimethoxy-4 '-isopropyl toluylene acid and copper powder is 1:6-8,3, the acid of 5-dimethoxy-4 '-isopropyl toluylene is 1g:15-20mL with the weight/volume of quinoline, exceed ratio upper limit copper powder and quinoline excessive, aftertreatment is difficult to remove totally, increase the difficulty of aftertreatment, waste reagent, exceed ratio lower limit and then react incomplete, yield is lower.
Also temperature of reaction and reaction times are selected, shown in table specific as follows simultaneously:
As can be seen from the above table, the temperature of reaction of decarboxylic reaction selects 180 DEG C can arrive higher reaction yield, and the content of cis-product is also higher.
As can be seen from the above table, the reaction times of decarboxylic reaction selects 3-5h can arrive higher reaction yield, and the content of cis-product is also higher.
4, select the demethylation reagent that demethylating reaction uses, be not the reaction that demethylation reagents all in prior art can both make its mild condition, and yield is higher, particular content sees the following form:
As can be seen from the above table, demethylation reagent selects DMA/anhydrous AlCl
3higher reaction yield can be arrived, simple to operate, and the content of cis-product is also higher.
Finally determine DMA/anhydrous AlCl
3for demethylation reagent, rear its consumption to be tested, the proportion relation of both discoveries and consumption comparatively large to the influence factor of reacting, shown in table specific as follows:
As can be seen from the above table, as can be seen from the above table, adopt the weight/volume of 3,5-dimethoxy-4 '-isopropyl toluylene and toluene for being 1g:15-20mL; The reaction mol ratio of 3,5-dimethoxy-4 '-isopropyl toluylene and DMA, aluminum trichloride (anhydrous) is 1:5 ~ 7:5 ~ 7.Exceed the difficulty that the ratio upper limit then increases aftertreatment, and waste reagent, exceed ratio lower limit and then react incomplete, yield is lower.
Also temperature of reaction and reaction times are selected, shown in table specific as follows simultaneously:
As can be seen from the above table, the temperature of reaction of demethylating reaction selects 100 DEG C can arrive higher reaction yield, and the content of cis-product is also higher.
As can be seen from the above table, the reaction times of demethylating reaction selects 6-8h can arrive higher reaction yield, and the content of cis-product is also higher.
5, condition test has been carried out to the HPLC method of cis benzene alkene not moral, finally determined: chromatographic column is Nucleosil 5 C18; Column temperature is 20 DEG C; Determined wavelength is 318nm; Moving phase by volume ratio be 50: 50 acetonitrile and water form; Flow velocity is 0.6mL/min, and sample size is 5 μ L.
When preparing detection solution, if adopt methyl alcohol sample, because cis-product is very unstable in methyl alcohol, trans product can be changed within very short time, if and during by acetonitrile/water sample, then cis-product is relatively stable, therefore selects acetonitrile/water to guarantee that the result detected is more accurately good as moving phase.
Concrete screening process is as follows:
As can be seen from the above table, cis-trans benzene alkene not moral HPLC separation condition select acetonitrile/water=50:50, flow velocity 0.6mL/min, can reach along anti-benzene alkene not moral be separated preferably.
Claims (3)
1. a synthetic method for cis benzene alkene not moral,
it is characterized in that:it is with 3,5-dihydroxyl-4-isopropyl acid is raw material, successively through methylation reaction synthesis 3,5-dimethoxy-4 '-isopropyl acid ester, reduction reaction synthesis 3,5-dimethoxy-4 '-isopropylbenzyl alcohol, oxidizing reaction synthesis 3,5-dimethoxy-4 '-propylbenzyl aldehyde, condensation reaction synthesis 3,5-dimethoxy-4 '-isopropyl toluylene acid, decarboxylic reaction synthesis 3,5-dimethoxy-4 '-isopropyl toluylene, eventually passes demethylating reaction synthesizing cis benzene alkene not moral;
Its synthetic method is reacted according to following route:
；
It carries out according to following steps order:
(1) methylation reaction
3,5-dihydroxyl-4-isopropyl acid, Anhydrous potassium carbonate are mixed with mol ratio 1:3 ~ 5, joins in DMF, at room temperature stir; Then, under the cooling of cryosel bath, slowly drip methyl iodide; Room temperature is risen to, reaction 2-3h after dropwising; Add water stirring after completion of the reaction, extraction into ethyl acetate, concentrated, obtains 3,5-dimethoxy-4 '-isopropyl acid ester; Wherein:
The mol ratio of 3,5-dihydroxyl-4-isopropyl acid and methyl iodide is 1:3 ~ 5;
The weightmeasurement ratio of 3,5-dihydroxyl-4-isopropyl acid and DMF is 1:20 ~ 30g/mL;
(2) reduction reaction
Be 3 of 1:4 ~ 6 by tetrahydrofuran (THF), mol ratio, 5-dimethoxy-4 '-isopropyl acid ester and sodium borohydride mixed at room temperature stir, be heated to backflow, slowly drip methyl alcohol, after reaction 4 ~ 6h, 3 ~ the 5L that adds water stirs, extraction into ethyl acetate, washing, revolves and steams except desolventizing obtains white solid, i.e. 3,5-dimethoxy-4 's-isopropylbenzyl alcohol; Wherein:
The amount ratio of 3,5-dimethoxy-4 '-isopropyl acid ester, methyl alcohol and tetrahydrofuran (THF) is 1:1 ~ 3:10 ~ 20g/mL/mL;
(3) oxidizing reaction
By 3,5-dimethoxy-4 '-isopropylbenzyl alcohol, DMSO and acetic anhydride mix and blend, after room temperature reaction 2-3h, add water stirring, extraction into ethyl acetate, washing, dry, concentrates to obtain 3,5-dimethoxy-4 's-propylbenzyl aldehyde; Wherein:
The amount ratio of 3,5-dimethoxy-4 '-isopropylbenzyl alcohol, DMSO and acetic anhydride is 1:10 ~ 15:2 ~ 3g/mL/mL;
(4) condensation reaction
Be 3,5-dimethoxy-4 's-propylbenzyl aldehyde and the toluylic acid mixing of 1:1 by mol ratio, add in acetic anhydride, stirring and dissolving, adds sodium-acetate, is heated to 135 DEG C, after reaction 6-8h, adding rare acid for adjusting pH after being down to room temperature is 2-3, extraction into ethyl acetate, concentrated, add saturated sodium bicarbonate solution and regulate pH to be 7 ~ 8, after stirring 2-3h, dichloromethane extraction, aqueous phase adds dilute hydrochloric acid and adjusts pH to be 2 ~ 3, filters yellow solid, i.e. 3,5-dimethoxy-4 's-isopropyl toluylene acid; Wherein:
The mol ratio of 3,5-dimethoxy-4 '-propylbenzyl aldehyde and sodium-acetate is 1:2 ~ 4;
The weight/volume of 3,5-dimethoxy-4 '-propylbenzyl aldehyde and acetic anhydride is 1:20 ~ 30g/mL;
(5) decarboxylic reaction
Be that the acid of 3,5-dimethoxy-4 's-isopropyl toluylene and the copper powder of 1:6 ~ 8 joins in quinoline by mol ratio, 180 DEG C react 3-5h after, be down to room temperature, add ethyl acetate to stir, filter, filtrate is colourless to water layer with dilute hydrochloric acid washing, aqueous phase uses ethyl acetate reversed phase extraction again, merge organic layer, saturated common salt water washing, to neutral, is spin-dried for, obtain 3,5-dimethoxy-4 '-isopropyl toluylene; Wherein:
3,5-dimethoxy-4 '-isopropyl toluylene acid is 1:15 ~ 20g/mL with the weight/volume of quinoline;
(6) demethylating reaction
3,5-dimethoxy-4 '-isopropyl toluylene is placed in toluene, stirs in ice bath, be cooled to 0 DEG C, after dissolving, slowly add DMA, add aluminum trichloride (anhydrous) in batches, after stirring 0.5h, rise to room temperature, after being heated to 100 DEG C of reaction 2-3h, being cooled to 60 DEG C, separating toluene layer while hot, in aqueous phase, add dilute hydrochloric acid stirring and adjusting pH value is 2-3, extraction into ethyl acetate, washing, concentrated, obtain target product cis benzene alkene not moral; Wherein:
The weight/volume of 3,5-dimethoxy-4 '-isopropyl toluylene and toluene is for being 1:15 ~ 20g/mL;
The mol ratio of 3,5-dimethoxy-4 '-isopropyl toluylene and DMA, aluminum trichloride (anhydrous) is 1:5 ~ 7:5 ~ 7.
2. an application for cis benzene alkene not moral,
it is characterized in that:use synthetic method described in claim 1 to prepare cis benzene alkene not moral, using described cis benzene alkene not moral in the synthesis of trans benzene alkene not moral as standard substance, for detecting the content of cis benzene alkene not moral.
3. the application of cis benzene alkene according to claim 2 not moral,
it is characterized in that:the content detecting cis benzene alkene not moral adopts the method for HPLC, and chromatographic column is Nucleosil 5 C18; Column temperature is 20 DEG C; Determined wavelength is 318nm; Moving phase by volume ratio be 50: 50 acetonitrile and water form; Flow velocity is 0.6mL/min, and sample size is 5 μ L.
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| CN104744243B (en) * | 2015-02-12 | 2016-04-06 | 河北科技大学 | (E)-2-phenyl-3-(3,5-dimethoxy-4 '-isopropyl benzene) purification method of propenoic acid |
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| CN105622603A (en) * | 2015-05-28 | 2016-06-01 | 广州牌牌生物科技有限公司 | Polynuclear compound and preparation method and application thereof |
| CN107058407A (en) * | 2017-05-22 | 2017-08-18 | 广西科学院 | A kind of method that utilization chemical-enzymatic prepares benzene alkene not moral |
| CN111148729A (en) * | 2017-09-30 | 2020-05-12 | 北京文丰天济医药科技有限公司 | Crystal form of benvitimod, application and preparation method thereof |
| CN112390707B (en) * | 2020-10-14 | 2023-04-28 | 中山大学 | Preparation and application of (Z) -3, 5-dihydroxy-4-isopropyl stilbene |
| CN112811985A (en) * | 2020-12-28 | 2021-05-18 | 江苏海岸药业有限公司 | Demethylation process for the preparation of this vismod |
| CN116003226A (en) * | 2022-12-28 | 2023-04-25 | 山东创新药物研发有限公司 | Synthesis method of present-vitamin mod impurity |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003086414A1 (en) * | 2002-04-10 | 2003-10-23 | Arizona Board Of Regents | Structural modification of resveratrol: sodium resverastatin phosphate |
| CN101648851A (en) * | 2009-09-03 | 2010-02-17 | 河北科技大学 | Clean preparation method of (E)-3,5-dyhydroxy-4-isopropyl toluylene |
-
2014
- 2014-05-29 CN CN201410233095.1A patent/CN103992212B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003086414A1 (en) * | 2002-04-10 | 2003-10-23 | Arizona Board Of Regents | Structural modification of resveratrol: sodium resverastatin phosphate |
| CN101648851A (en) * | 2009-09-03 | 2010-02-17 | 河北科技大学 | Clean preparation method of (E)-3,5-dyhydroxy-4-isopropyl toluylene |
Non-Patent Citations (8)
| Title |
|---|
| 刘鹏等.白藜芦醇的合成工艺改进.《中国药物化学杂志》.2008,第18卷(第6期), * |
| 利用Perkin反应制备香豆素的实验探析;高庆;《实验室科学》;201106;第14卷(第3期);75-78 * |
| 张成柱等.顺式_二苯乙烯类化合物合成方法研究进展.《精细化工》.2013,第45卷(第4期), * |
| 徐福培等.用二甲基亚砜氧化脂肪醇.《化学试剂》.1985, * |
| 楼纪东等.以二甲基亚砜在空气存在下氧化第一醇制备脂肪族醛的方法.《化学试剂》.1990,第12卷(第4期), * |
| 肉桂酸的Perkin合成工艺改进;任碧野等;《化学世界》;1996(第1期);21-23 * |
| 陈志涛等.肉桂酸的Perkin反应合成及其工艺优化.《重庆大学学报(自然科学版)》.2002,第25卷(第3期), * |
| 麻远.一类便捷的低毒氧化醇方法——DMSO_活化试剂氧化法.《大学化学》.2013,第28卷(第5期), * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019094934A1 (en) * | 2017-11-10 | 2019-05-16 | Dermavant Sciences GmbH | Process for preparing tapinarof |
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