CN114736183A - Preparation method of 3-methylflavone-8-carboxylic acid - Google Patents
Preparation method of 3-methylflavone-8-carboxylic acid Download PDFInfo
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- CN114736183A CN114736183A CN202210389366.7A CN202210389366A CN114736183A CN 114736183 A CN114736183 A CN 114736183A CN 202210389366 A CN202210389366 A CN 202210389366A CN 114736183 A CN114736183 A CN 114736183A
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- Prior art keywords
- methylflavone
- carboxylic acid
- reaction
- preparation
- methyl salicylate
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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 37
- 229960001047 methyl salicylate Drugs 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000002841 Lewis acid Substances 0.000 claims abstract description 6
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 238000006555 catalytic reaction Methods 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 238000010791 quenching Methods 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 7
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- 238000000967 suction filtration Methods 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
- 239000003513 alkali Substances 0.000 claims description 5
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 150000001875 compounds Chemical class 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
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 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
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 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
- 239000002253 acid Substances 0.000 claims 1
- 229940125782 compound 2 Drugs 0.000 claims 1
- 230000008707 rearrangement Effects 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 5
- 238000006462 rearrangement reaction Methods 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
- -1 propionyl methyl Chemical group 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229960001860 salicylate Drugs 0.000 description 4
- 239000012265 solid product Substances 0.000 description 4
- 238000001704 evaporation Methods 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
- 238000010992 reflux 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
- 239000007858 starting material Substances 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000015572 biosynthetic process Effects 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
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- XOEVKNFZUQEERE-UHFFFAOYSA-N flavoxate hydrochloride Chemical compound Cl.C1=CC=C2C(=O)C(C)=C(C=3C=CC=CC=3)OC2=C1C(=O)OCCN1CCCCC1 XOEVKNFZUQEERE-UHFFFAOYSA-N 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
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000003786 synthesis 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
- 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
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229960000855 flavoxate Drugs 0.000 description 1
- 229960003064 flavoxate hydrochloride Drugs 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- UFGVWANOISVHGQ-UHFFFAOYSA-N methyl 2-hydroxy-3-propanoylbenzoate Chemical compound CCC(=O)C1=CC=CC(C(=O)OC)=C1O UFGVWANOISVHGQ-UHFFFAOYSA-N 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
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 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
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 3-methylflavone-8-carboxylic acid, which comprises the steps of taking methyl salicylate as a starting raw material, generating propionyl methyl salicylate through rearrangement under the action of Lewis acid, and finally cyclizing and hydrolyzing to generate the 3-methylflavone-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 over 99.9 percent, and is a preparation method which has short process, small production risk and low process cost and is suitable for large-scale preparation of 3-methylflavone-8 carboxylic acid.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a flavoxate intermediate 3-methylflavone-8-carboxylic acid.
Background
3-methylflavone-8-carboxylic acid is a key intermediate for preparing smooth muscle relaxation medicine 'flavoxate hydrochloride'.
The synthesis research of 3-methylflavone-8-carboxylic acid is continuously improved and enhanced in recent decades, and the current main production methods comprise the following three methods:
patent US2921070 discloses that salicylic acid is used as a starting material, reacts with propionic anhydride to perform esterification, is rearranged under the catalysis of aluminum trichloride, and finally forms a ring with benzoic anhydride to generate 3-methylflavone 8-carboxylic acid, and the main disadvantages of the route are that salicylic acid forms a dimer itself, the content of rearrangement reaction isomers under the catalysis of aluminum trichloride is high, and the yield of the product is low;
in patent JP7953/1996, phenol is used as a raw material, a reaction product of the phenol and propionic anhydride is rearranged under the catalysis of aluminum trichloride, then reacts with propylene chloride to carry out secondary rearrangement, and is oxidized to generate 3-methylflavone-8 carboxylic acid after ring closure under the catalysis of sodium benzoate, the route undergoes two rearrangement reactions, and the purity and the yield of the product are very low;
in patent EP107804, methyl salicylate is used as a starting material, after bromination reaction, the product is reacted with propionyl chloride and then rearranged under the catalysis of aluminum trichloride, and then ring closure is carried out under the catalysis of sodium benzoate, and then 3-methylflavone-8 carboxylic acid is obtained through hydrogenolysis and hydrolysis.
Disclosure of Invention
The technical problem is as follows: the invention aims to provide a novel preparation method of 3-methylflavone-8-carboxylic acid, which synthesizes the 3-methylflavone-8-carboxylic acid through four steps of acylation, rearrangement, cyclization and hydrolysis.
The technical scheme adopted by the invention is as follows
The invention takes methyl salicylate as raw material, generates methyl salicylate phenolic ester through amidation, generates 3-propionyl methyl salicylate through Fries rearrangement under the catalysis of titanium tetrachloride, and finally generates 3-methylflavone-8-carboxylic acid through cyclization and hydrolysis, wherein the specific synthetic route is as follows:
the preparation method mainly comprises the following steps:
first, preparation of methyl 3-propionylsalicylate:
taking methyl salicylate shown in formula 5 and propionyl chloride as starting materials, generating a phenolic ester formula 4 in an organic solvent, concentrating after reaction, rearranging at high temperature under the catalysis of Lewis acid, and distilling under reduced pressure to obtain the 3-propionyl methyl salicylate formula 3.
Preferably, the organic solvent is dichloromethane, trichloromethane, toluene, carbon disulfide, tetrahydrofuran;
preferably, the lewis acid is titanium tetrachloride, aluminum trichloride, ferric chloride;
preferably, the reaction temperature is 120-180 ℃;
second step, preparation of methyl 3-methylflavone-8-carboxylate
Mixing 3-propionyl methyl salicylate and benzoyl chloride, preparing a compound 3-methylflavone-8-methyl carboxylate of a formula 2 under the catalysis of sodium benzoate, adding reaction liquid into alkaline water after the reaction is finished, quenching, and obtaining a product solid product through filtering and washing.
Preferably, the reaction temperature is 170-180 ℃;
preferably, the alkaline water can be selected from aqueous solution of sodium carbonate, potassium carbonate, sodium bicarbonate.
Third step, preparation of 3-methylflavone-8-carboxylic acid
3-methylflavone-8-carboxylic acid methyl ester is mixed with an alcoholic solution of alkali, and is hydrolyzed under the catalysis of the alkali to synthesize the compound 3-methylflavone-8-carboxylic acid shown in the formula 1.
Preferably, the alkaline reagent can be selected from inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, and the dosage of the alkaline reagent is 2.0 to 5.0 times, preferably 3.0 to 4.0 times of that of the 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 that the preparation method of the 3-methylflavone-8-carboxylic acid is provided, the problems of poor rearrangement reaction selectivity, more isomer impurities and difficult purification of intermediates are mainly solved, the use of bromine is avoided, the synthetic process is simplified, and the preparation method is a green and efficient synthetic process which is convenient for industrial production.
The technical advantages of the scheme are that (1) methyl salicylate is used as an initial material for acylation rearrangement, dimer impurities are avoided being generated, titanium tetrachloride is used as Lewis acid, isomer impurities are reduced in the rearrangement process, and (2) bromine which is expensive and high in toxicity is avoided being used in the process, so that the process is shortened, the risk of reaction is reduced, and three-waste pollution is reduced.
The specific embodiment is as follows:
for better understanding of the present invention, the following examples are given for illustration and not for limiting the scope of the present invention
Example 1
First, preparation of methyl 3-propionyl salicylate
Adding 30.4g (0.2 mol) of methyl salicylate and 200ml of carbon disulfide into a 500ml four-mouth bottle, starting stirring, slowly dropping 20.4g (0.24 mol) of propionyl chloride after all solids are dissolved, heating to 40 ℃, preserving heat for reaction for 4h, adding 38.0g (0.2 mol) of titanium tetrachloride, stirring for 0.5h, evaporating under reduced pressure to remove the solvent, heating to 120 ℃ for reaction for 4h, adding ice water for quenching reaction, and distilling oily matter under reduced pressure to obtain 33.6g of 3-propionyl methyl salicylate with the yield of 81%.
Second step, preparation of methyl 3-methylflavone-8-carboxylate
33.0g (0.16 mol) of methyl 3-propionyl salicylate and 63.9g (0.45 mol) of benzoyl chloride are added into a 1000ml reaction bottle in sequence, stirring is started, 64.8g (0.45 mol) of sodium benzoate is added, and the temperature is raised to 170 ℃ for reaction for 4 hours. Taking solution of dichloromethane and methanol with the volume ratio of 10:1 as developing solvent, adding reaction liquid into alkaline water to quench after TLC method detects that no residual 3-propionyl methyl salicylate exists, and obtaining product solid product 42.3g by filtering and washing, with the yield of 90%.
Third step, preparation of 3-methylflavone-8-carboxylic acid
400ml of ethanol and 22.4g (0.4 mol) of potassium hydroxide are sequentially added into a 1000ml reaction bottle and stirred at room temperature to be dissolved, 40g (0.136 mol) of 3-methylflavone-8-carboxylic acid methyl ester is added, the temperature is raised to reflux, the reaction is carried out for 10 hours, the pH value is adjusted to be =3 after the reaction is cooled, and 33.5g of 3-methylflavone-8-carboxylic acid is obtained through suction filtration and washing, and the yield is 88%.
Example 2
First, preparation of methyl 3-propionyl salicylate
Adding 30.4g (0.2 mol) of methyl salicylate and 300ml of dichloromethane into a 500ml four-mouth bottle, starting stirring, slowly dropping 20.4g (0.24 mol) of propionyl chloride after all solids are dissolved, heating to 40 ℃, preserving heat for reaction for 4h, adding 38.0g (0.2 mol) of titanium tetrachloride, stirring for 0.5h, evaporating the solvent under reduced pressure, heating to 150 ℃ for reaction for 4h, adding ice water for quenching reaction, and distilling oily substances under reduced pressure to obtain 31.1g of 3-propionyl methyl salicylate with the yield of 75%.
Second step, preparation of methyl 3-methylflavone-8-carboxylate
Adding 30.0g (0.15 mol) of 3-propionyl methyl salicylate and 59.9g (0.42 mol) of benzoyl chloride into a 1000ml reaction bottle in sequence, starting stirring, adding 60.8g (0.42 mol) of sodium benzoate, heating to 180 ℃ for reaction for 4 hours, taking a solution with a volume ratio of dichloromethane to methanol of 10:1 as a developing agent, adding a reaction solution into 400ml of sodium carbonate aqueous solution for quenching after detecting that no 3-propionyl methyl salicylate remains by a TLC method, stirring for 1 hour, carrying out suction filtration and washing to obtain 43.3g of a product solid product with the yield of 92%.
Third step, preparation of 3-methylflavone-8-carboxylic acid
400ml of methanol and 16.0g (0.4 mol) of sodium hydroxide are sequentially added into a 1000ml reaction bottle, stirred and dissolved at room temperature, 40g (0.136 mol) of 3-methylflavone-8-carboxylic acid methyl ester is added, the temperature is raised to reflux, the reaction is carried out for 10h, the pH is adjusted to be =2 by hydrochloric acid after cooling, and 32.3g of 3-methylflavone-8-carboxylic acid is obtained by suction filtration and washing with water, wherein the yield is 85%.
Example 3
First, preparation of methyl 3-propionyl salicylate
Adding 30.4g (0.2 mol) of methyl salicylate and 200ml of tetrahydrofuran into a 500ml four-mouth bottle, starting stirring, slowly dropping 20.4g (0.24 mol) of propionyl chloride after the solid is completely dissolved, heating to 40 ℃, preserving the temperature for reaction for 4h, adding 26.6g (0.2 mol) of aluminum trichloride, stirring for 0.5h, evaporating under reduced pressure to remove the solvent, heating to 180 ℃ for reaction for 4h, adding ice water for quenching reaction, and distilling oily matter under reduced pressure to obtain 26.9g of 3-propionyl methyl salicylate with the yield of 65%.
Second step, preparation of methyl 3-methylflavone-8-carboxylate
Adding 30.0g (0.15 mol) of 3-propionyl methyl salicylate and 59.9g (0.42 mol) of benzoyl chloride into a 1000ml reaction bottle in sequence, starting stirring, adding 60.8g (0.42 mol) of sodium benzoate, heating to 170 ℃ for reaction for 4h, taking a solution with a volume ratio of dichloromethane to methanol of 10:1 as a developing agent, adding a reaction solution into 600ml of sodium carbonate aqueous solution for quenching after detecting that no 3-propionyl methyl salicylate remains by a TLC method, stirring for 1h, carrying out suction filtration and washing to obtain 41.4g of a solid product with the yield of 88%.
Third step, preparation of 3-methylflavone-8-carboxylic acid
400ml of isopropanol and 9.6g (0.4 mol) of lithium hydroxide are sequentially added into a 1000ml reaction bottle and stirred at room temperature to be dissolved, 40g (0.136 mol) of 3-methylflavone-8-carboxylic acid methyl ester is added, the temperature is raised to reflux, the reaction is carried out for 10h, the pH is adjusted to be =3 by hydrochloric acid after cooling, and 30.8g of 3-methylflavone-8-carboxylic acid is obtained by suction filtration and washing with water, wherein the yield is 81%.
Claims (6)
1. A method for preparing 3-methylflavone-8-carboxylic acid is characterized by comprising the following steps:
the first step is as follows: adding methyl salicylate and propionyl chloride into an organic solvent, reacting, concentrating, and rearranging at high temperature under the catalysis of Lewis acid to obtain 3-propionyl methyl salicylate formula 3;
the second step is that: mixing the compound shown in the formula 2 with benzoyl chloride, stirring under the catalysis of sodium benzoate until the reaction is finished, quenching with alkaline water, stirring, and performing suction filtration to obtain 3-methylflavone-8-carboxylic acid methyl ester compound 2;
the third step: mixing the formula 2 with an alcoholic solution, hydrolyzing under the condition of alkali catalysis, and adjusting to acid to synthesize a compound 3-methylflavone-8-carboxylic acid type 1 after the reaction is finished.
2. The preparation method according to claim 1, wherein the organic solvent in the first step is one of dichloromethane, chloroform, toluene, carbon disulfide and tetrahydrofuran; the Lewis acid is one of titanium tetrachloride, aluminum trichloride and ferric chloride; the high temperature is 120-180 ℃.
3. The method as claimed in claim 1, wherein the alkaline water used in the second step is an aqueous solution of sodium carbonate, potassium carbonate or sodium bicarbonate, and the reaction temperature is 170-180 ℃.
4. The 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; adjust to acidity pH = 2-3.
5. The preparation method according to claim 1, wherein the feeding molar ratio of the methyl salicylate to the propionyl chloride is 1: 1.
6. the method according to claim 4, wherein the inorganic base is one of sodium hydroxide, potassium hydroxide and lithium hydroxide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210389366.7A CN114736183B (en) | 2022-04-14 | 2022-04-14 | Preparation method of 3-methyl flavone-8-carboxylic acid |
Applications Claiming Priority (1)
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| CN115960065A (en) * | 2023-01-06 | 2023-04-14 | 山东鲁西药业有限公司 | Preparation method of flavoxate hydrochloride |
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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 |