CN110330427B - Synthesis method of fenbufen - Google Patents
Synthesis method of fenbufen Download PDFInfo
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- CN110330427B CN110330427B CN201910681369.6A CN201910681369A CN110330427B CN 110330427 B CN110330427 B CN 110330427B CN 201910681369 A CN201910681369 A CN 201910681369A CN 110330427 B CN110330427 B CN 110330427B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C07C67/00—Preparation of carboxylic acid esters
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- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D215/40—Nitrogen atoms attached in position 8
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Abstract
The invention discloses a synthetic method of fenbufen. In the method, raw materials such as N- (octaaminoquinoline) butyl-3-enamide, 4-bromobiphenyl and the like and anhydrous 2, 3-butanediol are mixed uniformly in an inert atmosphere and then stirred vigorously in an oil bath at 125-135 ℃ for reaction for 12 hours to obtain a compound with a guide group; adding the compound into an ethanol solvent containing sodium hydroxide, heating and refluxing to obtain biphenyl butyric acid; mixing biphenyl butyric acid, p-toluenesulfonic acid and methanol, and heating and refluxing to obtain biphenyl methyl butyrate; adding biphenyl methyl butyrate and potassium peroxymonosulfonate into nitromethane, adding potassium bromide, reacting at 50 ℃, adding sodium hydroxide, refluxing and acidifying to obtain fenbufen. The method effectively solves the problem of excessive steps in the existing fenbufen synthesis process, and has the characteristics of high reaction regioselectivity and yield, mild reaction conditions and simple reaction and post-treatment purification processes.
Description
Technical Field
The invention belongs to the technical field of organic chemistry, and particularly relates to a synthetic method of fenbufen.
Background
Fenbufen (fenbufen) is chemically 3- (4-biphenylcarbonyl) propionic acid, white or off-white needle crystals. Long-acting non-steroidal anti-inflammatory analgesic drugs. The mechanism of action is the inhibition of prostaglandin synthesis. Can be used for treating rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gout, etc.
However, the existing synthesis method of fenbufen generally has the problems of more synthesis steps, poor reaction regioselectivity, low product yield, mild reaction conditions, complex reaction and post-treatment purification processes and the like.
Disclosure of Invention
The invention aims to provide a method for synthesizing fenbufen, which aims to solve the problems in the prior art in the background art.
The invention is realized in such a way that a method for synthesizing fenbufen comprises the following steps:
(1) under an inert atmosphere, mixing the material and anhydrous 2, 3-butanediol according to a molar volume ratio of 0.1 mmol: adding 1mL of the mixture into a reaction container, uniformly mixing, placing the reaction container in an oil bath at 125-135 ℃, violently stirring for reacting for 12 hours, and purifying a reaction product through a silica gel column to obtain a compound with a guide group; wherein the related materials comprise a molar ratio of 1: (1-3): (0.01-0.1): (0.02-0.2): (1-5): (1-3): (1-100) N- (octaaminoquinoline) but-3-enamide, 4-bromobiphenyl, allylpalladium (II) chloride dimer, 2- (dicyclohexylphosphono) -1-phenyl-1H-pyrrole, lithium acetate, cyanoacetic acid, and water;
(2) adding the compound into an ethanol solvent containing sodium hydroxide, heating the mixture to 130-140 ℃, refluxing for 12 hours, removing the solvent from the reaction product through reduced pressure distillation, extracting and collecting a water layer to obtain biphenyl butyric acid; wherein the molar ratio of the compound to the sodium hydroxide to the ethanol is 1: (1.5-4): (5-50);
(3) adding p-toluenesulfonic acid and methanol into the biphenyl butyric acid, heating to 100-120 ℃, carrying out reflux reaction for 6 hours, removing a reaction solvent in a reaction product, and purifying to obtain biphenyl methyl butyrate; wherein the molar ratio of the biphenyl methyl butyrate to the p-toluenesulfonic acid to the methanol is 1: 0.03: (50-100);
(4) adding the methyl biphenylbutyrate and the potassium peroxymonosulfonate into nitromethane, adding potassium bromide, reacting at 50 ℃ for 24 hours, removing a reaction solvent in a reaction product, purifying, and adding sodium hydroxide for reflux acidification to obtain fenbufen; wherein the molar ratio of the biphenyl methyl butyrate to the potassium peroxymonosulfonate to the nitromethane to the potassium bromide is 1: (2-5): 3: 0.5.
preferably, in step (1), the inert gas used in the inert atmosphere is argon;
in step (1), the silica gel column purification is performed by washing a chromatographic silica gel column with petroleum ether and ethyl acetate in a ratio of 1: 20.
Preferably, in the step (2), the pressure of the reduced pressure distillation is within 100mbar, and the temperature is more than 80 ℃; the extraction was by addition of dichloromethane.
Preferably, in the step (3) and the step (4), the reaction solvent in the reaction product is removed by a reduced pressure distillation method, wherein the pressure of the reduced pressure distillation is within 100mbar, and the temperature is more than 80 ℃; in step (3), the purification is by column chromatography on silica gel.
In order to overcome the defects and steps in the prior art, the invention discloses a synthesis method of fenbufen. In the method, raw materials such as N- (octaaminoquinoline) butyl-3-enamide, 4-bromobiphenyl and the like and anhydrous 2, 3-butanediol are mixed uniformly in an inert atmosphere and then stirred vigorously in an oil bath at 125-135 ℃ for reaction for 12 hours to obtain a compound with a guide group; adding the compound into an ethanol solvent containing sodium hydroxide, heating and refluxing to obtain biphenyl butyric acid; mixing biphenyl butyric acid, p-toluenesulfonic acid and methanol, and heating and refluxing to obtain biphenyl methyl butyrate; adding biphenyl methyl butyrate and potassium peroxymonosulfonate into nitromethane, adding potassium bromide, reacting at 50 ℃, adding sodium hydroxide, refluxing and acidifying to obtain fenbufen. Wherein, the synthetic reaction process of the fenbufen is as follows:
compared with the defects and shortcomings of the prior art, the invention has the following beneficial effects:
(1) according to the invention, through reduction HECK reaction, the octaaminoquinoline is designed as a compound of a guide group to control the region and chemical selectivity in the reaction, so that the problem of excessive steps in the existing fenbufen synthesis process is effectively solved; in addition, the method has the characteristics of high reaction area selectivity and yield, mild reaction conditions and simple reaction and post-treatment purification processes;
(2) the anti-inflammatory and analgesic effects of the fenbufen are weaker than that of indometacin but stronger than that of aspirin.
Drawings
Figure 1 is a hydrogen spectrum of fenbufen of the present invention;
fig. 2 is a carbon spectrum of fenbufen of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
(1) Under inert atmosphere, 0.01mmol of allyl palladium (II) chloride dimer, 0.2mmol of 2- (dicyclohexyl phosphonyl) -1-phenyl-1H-pyrrole, 1mmol of N- (octa-aminoquinoline) but-3-enamide, 5mmol of lithium acetate, 3mmol of 4-bromobiphenyl, 3mmol of cyanoacetic acid and 100mmol of water are mixed, 0.1mmol of mixed material and 1mL of anhydrous 2, 3-butanediol are added into a reaction vessel for uniform mixing, the reaction vessel is placed in an oil bath at 125 ℃ for vigorous stirring reaction for 12 hours, and a reaction product is subjected to silica gel column purification (washing a chromatographic silica gel column with ethyl acetate 1:20 compared with petroleum ether) to obtain a compound with a guide group;
(2) adding 1mmol of the compound into 50mmol of ethanol solvent containing 1.5mmol of sodium hydroxide, heating the mixture to 130 ℃ for refluxing for 12 hours, removing the solvent from the reaction product by reduced pressure distillation (the pressure of the reduced pressure distillation is less than 100mbar, and the temperature is more than 80 ℃), extracting (extracting for 3 times by using dichloromethane), and collecting a water layer to obtain biphenyl butyric acid;
(3) adding 0.03mmol of p-toluenesulfonic acid and 50mmol of methanol into 1mmol of biphenyl butyric acid, heating to 100 ℃, refluxing and reacting for 6 hours, removing the solvent of the reaction product by reduced pressure distillation (the pressure of the reduced pressure distillation is within 100mbar and the temperature is more than 80 ℃), and purifying by silica gel column (washing the silica gel column by ethyl acetate 1:20 in petroleum ether ratio) to obtain biphenyl methyl butyrate;
(4) adding 1mmol of methyl biphenylbutyrate and 2mmol of potassium peroxymonosulfonate into 3mmol of nitromethane, adding 0.5mmol of potassium bromide, reacting at 50 ℃ for 24 hours, removing the solvent of the reaction product by reduced pressure distillation (the pressure of the reduced pressure distillation is less than 100mbar, and the temperature is more than 80 ℃), purifying by a silica gel column (washing the silica gel column by ethyl acetate 1:20 according to the ratio of petroleum ether), adding solid sodium hydroxide into the purified product, refluxing and acidifying to obtain the fenbufen. The hydrogen spectrum and the carbon spectrum of the fenbufen are shown in figure 1 and figure 2 respectively.
Example 2
(1) Under an inert atmosphere, 0.1mmol of allylpalladium (II) chloride dimer, 0.02mmol of 2- (dicyclohexylphosphono) -1-phenyl-1H-pyrrole, 1mmol of N- (octaaminoquinoline) but-3-enamide, 1mmol of lithium acetate, 1) mmol of 4-bromobiphenyl, 1mmol of cyanoacetic acid and 1mmol of water are mixed, 0.1mmol of the mixture and 1mL of anhydrous 2, 3-butanediol are added into a reaction vessel and mixed uniformly, the reaction vessel is placed in an oil bath at 125 ℃ and stirred vigorously for reaction for 12 hours, and the reaction product is purified by a silica gel column (using petroleum ether to react with ethyl acetate 1:20 washing a chromatographic silica gel column) to obtain a compound with a guide group;
(2) adding 1mmol of the compound into 5mmol of ethanol solvent containing 4mmol of sodium hydroxide, heating the mixture to 140 ℃, refluxing for 12 hours, removing the solvent from the reaction product by reduced pressure distillation (the pressure of the reduced pressure distillation is within 100mbar and the temperature is more than 80 ℃), extracting (extracting for 3 times by using dichloromethane), and collecting a water layer to obtain biphenyl butyric acid;
(3) adding 0.03mmol of p-toluenesulfonic acid and 100mmol of methanol into 1mmol of biphenyl butyric acid, heating to 120 ℃, refluxing and reacting for 6 hours, removing the solvent of the reaction product by reduced pressure distillation (the pressure of the reduced pressure distillation is within 100mbar and the temperature is more than 80 ℃), and purifying by silica gel column (washing the silica gel column by ethyl acetate 1:20 in petroleum ether ratio) to obtain biphenyl methyl butyrate;
(4) adding 1mmol of methyl biphenylbutyrate and 5mmol of potassium peroxymonosulfonate into 3mmol of nitromethane, adding 0.5mmol of potassium bromide, reacting at 50 ℃ for 24 hours, removing the solvent of the reaction product by reduced pressure distillation (the pressure of the reduced pressure distillation is less than 100mbar, and the temperature is more than 80 ℃), purifying by a silica gel column (washing the silica gel column by ethyl acetate 1:20 according to the ratio of petroleum ether), adding solid sodium hydroxide into the purified product, refluxing and acidifying to obtain the fenbufen.
Example 3
(1) Under inert atmosphere, 0.05mmol of allyl palladium (II) chloride dimer, 0.1mmol of 2- (dicyclohexyl phosphonyl) -1-phenyl-1H-pyrrole, 1mmol of N- (octa-aminoquinoline) but-3-enamide, 3mmol of lithium acetate, 2mmol of 4-bromobiphenyl, 2mmol of cyanoacetic acid and 50mmol of water are mixed, 0.1mmol of mixed material and 1mL of anhydrous 2, 3-butanediol are added into a reaction vessel for uniform mixing, the reaction vessel is placed in an oil bath at 125 ℃ for vigorous stirring reaction for 12 hours, and a reaction product is subjected to silica gel column purification (washing a chromatographic silica gel column by ethyl acetate 1:20 compared with petroleum ether) to obtain a compound with a guide group;
(2) adding 1mmol of the compound into 30mmol of ethanol solvent containing 2.5mmol of sodium hydroxide, heating the mixture to 135 ℃ for refluxing for 12 hours, removing the solvent from the reaction product by reduced pressure distillation (the pressure of the reduced pressure distillation is less than 100mbar and the temperature is more than 80 ℃), extracting (extracting for 3 times by using dichloromethane), and collecting a water layer to obtain biphenyl butyric acid;
(3) adding 0.03mmol of p-toluenesulfonic acid and 75mmol of methanol into 1mmol of biphenyl butyric acid, heating to 110 ℃, refluxing and reacting for 6 hours, removing the solvent of the reaction product by reduced pressure distillation (the pressure of the reduced pressure distillation is within 100mbar and the temperature is more than 80 ℃), and purifying by silica gel column (washing the silica gel column by ethyl acetate 1:20 in petroleum ether ratio) to obtain biphenyl methyl butyrate;
(4) adding 1mmol of biphenyl methyl butyrate and 3.5mmol of potassium peroxymonosulfonate into 3mmol of nitromethane, adding 0.5mmol of potassium bromide, reacting at 50 ℃ for 24 hours, removing the solvent of the reaction product through reduced pressure distillation (the pressure of the reduced pressure distillation is less than 100mbar, and the temperature is more than 80 ℃), purifying through a silica gel column (washing the silica gel column with ethyl acetate 1:20 in a petroleum ether ratio), and adding solid sodium hydroxide into the purified product for reflux acidification to obtain the fenbufen.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (4)
1. A synthetic method of fenbufen, which is characterized by comprising the following steps:
(1) under an inert atmosphere, mixing the material and anhydrous 2, 3-butanediol according to a molar volume ratio of 0.1 mmol: adding 1mL of the mixture into a reaction container, uniformly mixing, placing the reaction container in an oil bath at 125-135 ℃, violently stirring for reacting for 12 hours, and purifying a reaction product through a silica gel column to obtain a compound with a guide group; wherein the material comprises a molar ratio of 1: (1-3): (0.01-0.1): (0.02-0.2): (1-5): (1-3): (1-100) N- (octaaminoquinoline) but-3-enamide, 4-bromobiphenyl, allylpalladium (II) chloride dimer, 2- (dicyclohexylphosphono) -1-phenyl-1H-pyrrole, lithium acetate, cyanoacetic acid, and water;
(2) adding the compound into an ethanol solvent containing sodium hydroxide, heating the mixture to 130-140 ℃, refluxing for 12 hours, removing the solvent from the reaction product through reduced pressure distillation, extracting and collecting a water layer to obtain biphenyl butyric acid; wherein the molar ratio of the compound to the sodium hydroxide to the ethanol is 1: (1.5-4): (5-50);
(3) adding p-toluenesulfonic acid and methanol into the biphenyl butyric acid, heating to 100-120 ℃, carrying out reflux reaction for 6 hours, removing a reaction solvent in a reaction product, and purifying to obtain biphenyl methyl butyrate; wherein the molar ratio of the biphenyl methyl butyrate to the p-toluenesulfonic acid to the methanol is 1: 0.03: (50-100);
(4) adding the methyl biphenylbutyrate and the potassium peroxymonosulfonate into nitromethane, adding potassium bromide, reacting at 50 ℃ for 24 hours, removing a reaction solvent in a reaction product, purifying, and adding sodium hydroxide for reflux acidification to obtain fenbufen; wherein the molar ratio of the biphenyl methyl butyrate to the potassium peroxymonosulfonate to the nitromethane to the potassium bromide is 1: (2-5): 3: 0.5.
2. the method for synthesizing fenbufen according to claim 1, wherein in step (1), the inert gas used in the inert atmosphere is argon;
in step (1), the silica gel column purification is performed by washing a chromatographic silica gel column with petroleum ether and ethyl acetate in a ratio of 1: 20.
3. The method for synthesizing fenbufen according to claim 1, wherein in step (2), the pressure of the reduced pressure distillation is within 100mbar, and the temperature is 80 ℃ or higher; the extraction was by addition of dichloromethane.
4. The method for synthesizing fenbufen according to claim 1, wherein in the steps (3) and (4), the reaction solvent in the reaction product is removed by a reduced pressure distillation method, wherein the reduced pressure distillation is performed at a pressure of 100mbar or less and at a temperature of 80 ℃ or higher; in step (3), the purification is by column chromatography on silica gel.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1052301A (en) * | 1990-11-28 | 1991-06-19 | 湖北师范学院 | The improvement of synthesis method for " fenbufen " |
| CN1791606A (en) * | 2003-05-16 | 2006-06-21 | 德古萨股份公司 | Nitrogen-containing monodentate phosphines and their use in catalysis |
| CN108658857A (en) * | 2018-06-14 | 2018-10-16 | 南京工业大学 | A kind of method of synthesis of carboxylic acid derivative |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1052301A (en) * | 1990-11-28 | 1991-06-19 | 湖北师范学院 | The improvement of synthesis method for " fenbufen " |
| CN1791606A (en) * | 2003-05-16 | 2006-06-21 | 德古萨股份公司 | Nitrogen-containing monodentate phosphines and their use in catalysis |
| CN108658857A (en) * | 2018-06-14 | 2018-10-16 | 南京工业大学 | A kind of method of synthesis of carboxylic acid derivative |
Non-Patent Citations (5)
| Title |
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| Direct and Selective Benzylic Oxidation of Alkylarenes via C-H Abstraction Using Alkali Metal Bromides;Katsuhiko Moriyama et al.;《Org. Lett.》;20120418;第14卷(第9期);第2414-2417页 * |
| Nickel(0)-catalyzed linear-selective hydroarylation of unactivated alkenes and styrenes with aryl boronic acids;Honggui Lv et al.;《Chem. Sci.》;20180718;第9卷;第6839-6843页 * |
| Nickel-Catalyzed β,γ-Dicarbofunctionalization of Alkenyl Carbonyl Compounds via Conjunctive Cross-Coupling;Joseph Derosa et al.;《J. Am. Chem. Soc.》;20170724;第139卷;第10657-10660页 * |
| Palladium-Catalyzed Regiocontrollable Reductive Heck Reaction of Unactivated Aliphatic Alkenes;Chengdong Wang et al.;《J. Am. Chem. Soc.》;20180620;第140卷;第9332-9336页 * |
| Three-component vicinal-diarylation of alkenes via direct transmetalation of arylboronic acids;Yun Zhang et al.;《Chem. Sci.》;20190703;第10卷;第7952-7957页 * |
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