CN114736183B - Preparation method of 3-methyl flavone-8-carboxylic acid - Google Patents
Preparation method of 3-methyl flavone-8-carboxylic acid Download PDFInfo
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- CN114736183B CN114736183B CN202210389366.7A CN202210389366A CN114736183B CN 114736183 B CN114736183 B CN 114736183B CN 202210389366 A CN202210389366 A CN 202210389366A CN 114736183 B CN114736183 B CN 114736183B
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- KMMBBZOSQNLLMN-UHFFFAOYSA-N 3-methylflavone-8-carboxylic acid Chemical compound O1C2=C(C(O)=O)C=CC=C2C(=O)C(C)=C1C1=CC=CC=C1 KMMBBZOSQNLLMN-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 claims abstract description 34
- 229960001047 methyl salicylate Drugs 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000002841 Lewis acid Substances 0.000 claims abstract description 6
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 238000006555 catalytic reaction Methods 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- OSHFQLSUZICPRA-UHFFFAOYSA-N methyl 3-methyl-4-oxo-2-phenylchromene-8-carboxylate Chemical compound COC(=O)C1=CC=CC(C(C=2C)=O)=C1OC=2C1=CC=CC=C1 OSHFQLSUZICPRA-UHFFFAOYSA-N 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 claims description 7
- 238000010791 quenching Methods 0.000 claims description 7
- 230000000171 quenching effect Effects 0.000 claims description 7
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 7
- 235000010234 sodium benzoate Nutrition 0.000 claims description 7
- 239000004299 sodium benzoate Substances 0.000 claims description 7
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 6
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 claims 1
- 238000005815 base catalysis Methods 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 230000008707 rearrangement Effects 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 5
- -1 propionyl methyl Chemical group 0.000 abstract description 4
- 238000006462 rearrangement reaction Methods 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 4
- 230000010933 acylation Effects 0.000 abstract description 3
- 238000005917 acylation reaction Methods 0.000 abstract description 3
- 239000000539 dimer Substances 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 229960001860 salicylate Drugs 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000012265 solid product Substances 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 235000013824 polyphenols Nutrition 0.000 description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- KNKRKFALVUDBJE-UHFFFAOYSA-N 1,2-dichloropropane Chemical compound CC(Cl)CCl KNKRKFALVUDBJE-UHFFFAOYSA-N 0.000 description 1
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 1
- 238000005618 Fries rearrangement reaction Methods 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 231100000171 higher toxicity Toxicity 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960001344 methylphenidate Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000000050 smooth muscle relaxant Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Abstract
The invention discloses a preparation method of 3-methyl flavone-8-carboxylic acid, which uses methyl salicylate as a starting material, rearranges under the action of Lewis acid to generate propionyl methyl salicylate, and finally cyclizes and hydrolyzes to generate 3-methyl flavone-8-carboxylic acid. The process adopts methyl salicylate to carry out acylation rearrangement reaction, reduces the generation of dimer impurities and isomer impurities in the rearrangement process, has the purity of more than 99.9 percent, and is a preparation method with short process, low production risk and low process cost, and suitable for large-scale preparation of 3-methyl flavone-8 carboxylic acid.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a flavone methylphenidate intermediate 3-methyl flavone-8-carboxylic acid.
Background
3-methyl flavone-8-carboxylic acid is a key intermediate for preparing smooth muscle relaxant "flavoneperide hydrochloride".
The synthesis of 3-methylflavone-8-carboxylic acid has been continuously improved and enhanced in recent decades, and the main production methods at present are as follows:
patent US2921070 discloses that salicylic acid is used as a starting material, and is subjected to esterification reaction with propionic anhydride, rearrangement is carried out under the catalysis of aluminum trichloride, and finally 3-methylflavone 8-carboxylic acid is generated by ring closure with benzoic anhydride, and the main defects of the route are that salicylic acid forms a dimer, the content of rearrangement reaction isomers under the catalysis of aluminum trichloride is higher, so that the yield of a product is low;
phenol is taken as a raw material in patent JP7953/1996, a reaction product of phenol and propionic anhydride is rearranged under the catalysis of aluminum trichloride, then the reaction product of phenol and propylene chloride is subjected to secondary rearrangement, and 3-methylflavone-8 carboxylic acid is generated by oxidation after cyclization under the catalysis of sodium benzoate, wherein the course is subjected to two rearrangement reactions, and the purity and the yield of the product are very low;
in patent EP107804, methyl salicylate is taken as a starting material, the product is reacted with propionyl chloride through bromination reaction, then rearranged under the catalysis of aluminum trichloride, and then subjected to ring closure under the catalysis of sodium benzoate, and then subjected to hydrogenolysis and hydrolysis to obtain the 3-methylflavone-8 carboxylic acid, wherein the route has the advantages of avoiding the formation of rearranged isomers, and the disadvantages of longer synthetic route, bromine consumption in the route and higher toxicity and risk.
Disclosure of Invention
Technical problems: the invention aims to provide a novel preparation method of 3-methyl flavone-8-carboxylic acid, which synthesizes 3-methyl flavone-8-carboxylic acid through four steps of acylation, rearrangement, cyclization and hydrolysis.
The technical scheme adopted by the invention is as follows
Methyl salicylate is used as a raw material, methyl salicylate phenolic ester is generated through amidation, fries rearrangement is carried out under the catalysis of titanium tetrachloride to generate 3-propionyl methyl salicylate, and finally, 3-methylflavone-8-carboxylic acid is generated through cyclization and hydrolysis, wherein the specific synthetic route is as follows:
the preparation method mainly comprises the following steps:
in the first step, the preparation of 3-propionyl methyl salicylate:
methyl salicylate and propionyl chloride as shown in the formula 5 are used as starting materials, phenolic ester formula 4 is generated in an organic solvent, the reaction is carried out, the concentration is carried out, the reaction product is higher than Wen Chongpai under the catalysis of Lewis acid, and the 3-propionyl methyl salicylate formula 3 is obtained through reduced pressure distillation.
Preferably, the organic solvent is dichloromethane, chloroform, toluene, carbon disulfide, tetrahydrofuran;
preferably, the lewis acid is titanium tetrachloride, aluminum trichloride, ferric chloride;
preferably, the reaction temperature is 120-180 ℃;
in the second step, 3-methylflavone-8-carboxylic acid methyl ester preparation
Mixing 3-propionyl methyl salicylate with benzoyl chloride, preparing 3-methyl flavone-8-methyl carboxylate as compound in the formula 2 under the catalysis of sodium benzoate, adding the reaction solution into alkaline water for quenching after the reaction is finished, and carrying out filtering and washing to obtain a product solid product.
Preferably, the reaction temperature is 170-180 ℃;
preferably, the alkaline water is selected from sodium carbonate, potassium carbonate, and sodium bicarbonate.
Third step, preparation of 3-methylflavone-8-carboxylic acid
3-methylflavone-8-carboxylic acid methyl ester is mixed with alcohol solution of alkali, and is hydrolyzed under the catalysis of alkali to synthesize the compound 3-methylflavone-8-carboxylic acid of formula 1.
Preferably, the alkaline agent is selected from inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., and the dosage of the alkaline agent is 2.0-5.0 times, preferably 3.0-4.0 times, of 3-propionyl methyl salicylate;
preferably, the common alcohol solvent is methanol, ethanol, isopropanol, ethylene glycol and other solvents;
preferably, the reaction temperature is 60-120 ℃.
The invention has the beneficial effects of providing a preparation method of 3-methyl flavone-8 carboxylic acid, mainly solving the problems of poor rearrangement reaction selectivity, more isomer impurities and difficult purification of intermediates, avoiding the use of bromine, simplifying the synthesis process and being a green and efficient synthesis process convenient for industrial production.
The technical advantages of the scheme are that (1) methyl salicylate is used as an initial material for acylation rearrangement, generation of dimer impurities is avoided, titanium tetrachloride is used as Lewis acid, and generation of isomer impurities in the rearrangement process (2) bromine which is high in price and toxicity is avoided in the technical process, so that the process is shortened, the danger of reaction is reduced, and three-waste pollution is reduced.
Specific examples:
for a better understanding of the present invention, reference will be made to the following examples, but the summary of the invention is not limited thereto
Example 1
First step, preparation of methyl 3-propionyl salicylate
30.4g (0.2 mol) of methyl salicylate and 200ml of carbon disulfide are added into a 500ml four-necked flask, stirring is started, 20.4g (0.24 mol) of propionyl chloride is slowly dripped into the flask after the solid is completely dissolved, the temperature is raised to 40 ℃, the reaction is carried out for 4 hours under heat preservation, 38.0g (0.2 mol) of titanium tetrachloride is added, the mixture is stirred for 0.5 hour, the solvent is distilled off under reduced pressure, the temperature is raised to 120 ℃ for 4 hours, the reaction is quenched by adding ice water, and the oily matter is distilled under reduced pressure to obtain 33.6g of 3-propionyl methyl salicylate, and the yield is 81%.
In the second step, 3-methylflavone-8-carboxylic acid methyl ester preparation
To a 1000ml reaction flask were successively added 33.0g (0.16 mol) of methyl 3-propionyl salicylate, 63.9g (0.45 mol) of benzoyl chloride, and the mixture was stirred, 64.8g (0.45 mol) of sodium benzoate was added, and the mixture was heated to 170℃to react for 4 hours. The solution with the volume ratio of dichloromethane to methanol of 10:1 is taken as a developing agent, after detecting that the raw material 3-propionyl methyl salicylate is not remained by a TLC method, the reaction solution is added into alkaline water for quenching, and the solid product of 42.3g is obtained after the reaction solution is subjected to the filtration and washing, and the yield is 90%.
Third step, preparation of 3-methylflavone-8-carboxylic acid
400ml of ethanol, 22.4g (0.4 mol) of potassium hydroxide and 40g (0.136 mol) of 3-methylflavone-8-carboxylic acid methyl ester are added into a 1000ml reaction bottle, the mixture is stirred and dissolved at room temperature, the temperature is raised to reflux, the reaction is carried out for 10 hours, the mixture is cooled and then is adjusted to pH=3 by hydrochloric acid, and the 3-methylflavone-8-carboxylic acid is obtained by suction filtration and water washing, wherein the yield is 88%.
Example 2
First step, preparation of methyl 3-propionyl salicylate
30.4g (0.2 mol) of methyl salicylate and 300ml of methylene dichloride are added into a 500ml four-port bottle, stirring is started, 20.4g (0.24 mol) of propionyl chloride is slowly dripped into the bottle after the solid is completely dissolved, the temperature is raised to 40 ℃, the reaction is carried out for 4 hours under heat preservation, 38.0g (0.2 mol) of titanium tetrachloride is added, the mixture is stirred for 0.5 hour, the solvent is distilled off under reduced pressure, the temperature is raised to 150 ℃ for 4 hours, ice water is added for quenching reaction, the oily substance is distilled under reduced pressure to obtain 31.1g of 3-propionyl methyl salicylate, and the yield is 75%.
In the second step, 3-methylflavone-8-carboxylic acid methyl ester preparation
30.0g (0.15 mol) of methyl 3-propionyl salicylate, 59.9g (0.42 mol) of benzoyl chloride and 60.8g (0.42 mol) of sodium benzoate are sequentially added into a 1000ml reaction bottle, stirring is started, the temperature is raised to 180 ℃ for reaction for 4 hours, a solution with the volume ratio of dichloromethane to methanol being 10:1 is used as a developing agent, after the TLC method detects that the raw material methyl 3-propionyl salicylate is not remained, the reaction solution is added into 400ml of sodium carbonate aqueous solution for quenching, stirring is carried out for 1 hour, suction filtration and washing are carried out, 43.3g of a product solid product is obtained, and the yield is 92%.
Third step, preparation of 3-methylflavone-8-carboxylic acid
400ml of methanol, 16.0g (0.4 mol) of sodium hydroxide and 40g (0.136 mol) of 3-methylflavone-8-carboxylic acid methyl ester are added into a 1000ml reaction bottle, the mixture is stirred and dissolved at room temperature, the temperature is raised to reflux, the reaction is carried out for 10 hours, the mixture is cooled and then is adjusted to pH=2 by hydrochloric acid, and the mixture is filtered by suction and washed with water to obtain 32.3g of 3-methylflavone-8-carboxylic acid, wherein the yield is 85%.
Example 3
First step, preparation of methyl 3-propionyl salicylate
30.4g (0.2 mol) of methyl salicylate and 200ml of tetrahydrofuran are added into a 500ml four-necked flask, stirring is started, 20.4g (0.24 mol) of propionyl chloride is slowly dripped into the flask after the solid is completely dissolved, the temperature is raised to 40 ℃, the reaction is carried out for 4 hours under heat preservation, 26.6g (0.2 mol) of aluminum trichloride is added, the mixture is stirred for 0.5 hour, the solvent is distilled off under reduced pressure, the temperature is raised to 180 ℃ for reaction for 4 hours, ice water is added for quenching reaction, the oily matter is distilled under reduced pressure to obtain 26.9g of 3-propionyl methyl salicylate, and the yield is 65%.
In the second step, 3-methylflavone-8-carboxylic acid methyl ester preparation
30.0g (0.15 mol) of methyl 3-propionyl salicylate, 59.9g (0.42 mol) of benzoyl chloride and 60.8g (0.42 mol) of sodium benzoate are sequentially added into a 1000ml reaction bottle, stirring is started, the temperature is raised to 170 ℃ for reaction for 4 hours, after the solution of dichloromethane and methanol with the volume ratio of 10:1 is taken as a developing agent, the TLC method detects that the raw material methyl 3-propionyl salicylate is not remained, the reaction solution is added into 600ml of sodium carbonate aqueous solution for quenching, stirring is carried out for 1 hour, suction filtration and washing are carried out, and 41.4g of a product solid product is obtained, and the yield is 88%.
Third step, preparation of 3-methylflavone-8-carboxylic acid
400ml of isopropanol, 9.6g (0.4 mol) of lithium hydroxide and 40g (0.136 mol) of 3-methylflavone-8-carboxylic acid methyl ester are added into a 1000ml reaction bottle, the mixture is heated to reflux, the reaction is carried out for 10 hours, the mixture is cooled and then is adjusted to pH=3 by hydrochloric acid, and 30.8g of 3-methylflavone-8-carboxylic acid is obtained by suction filtration and water washing, wherein the yield is 81%.
Claims (5)
1. A process for preparing 3-methylflavone-8-carboxylic acid comprising the steps of:
the first step: adding methyl salicylate and propionyl chloride into an organic solvent, concentrating after reaction, and rearranging at high temperature under the catalysis of Lewis acid to obtain 3-propionyl methyl salicylate formula 3;
and a second step of: mixing formula 2 with benzoyl chloride, stirring under catalysis of sodium benzoate until reaction is completed, quenching with alkaline water, stirring, and suction filtering to obtain 3-methylflavone-8-carboxylic acid methyl ester formula 2;
and a third step of: mixing formula 2 with alcohol solution, hydrolyzing under base catalysis, and adjusting to acidic synthetic compound 3-methylflavone-8-carboxylic acid formula 1
Wherein the Lewis acid is titanium tetrachloride, and the organic solvent in the first step is one of dichloromethane, chloroform, toluene, carbon disulfide and tetrahydrofuran; high temperature of 120-180deg.C
。
2. The preparation method according to claim 1, wherein the alkaline water in the second step is one of sodium carbonate, potassium carbonate and sodium bicarbonate, and the reaction temperature is 170-180 ℃.
3. The preparation method according to claim 1, wherein the alcohol solution in the third step is one of methanol, ethanol, isopropanol, and ethylene glycol; the alkali is inorganic alkali; the acidity was adjusted to ph=2-3.
4. The preparation method according to claim 1, wherein the feeding molar ratio of the methyl salicylate to the propionyl chloride is 1:1.
5. the method according to claim 4, wherein the inorganic base is one of sodium hydroxide, potassium hydroxide and lithium hydroxide.
Priority Applications (1)
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Address after: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Applicant after: Dijia Pharmaceutical Group Co.,Ltd. Address before: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Applicant before: Dijia Pharmaceutical Group Co.,Ltd. |
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Denomination of invention: A preparation method of 3-methylflavone-8-carboxylic acid Granted publication date: 20231017 Pledgee: Weihai Branch of Shanghai Pudong Development Bank Co.,Ltd. Pledgor: Dijia Pharmaceutical Group Co.,Ltd. Registration number: Y2024980004733 |