CN102977044A - Method for preparing 3-(4-methoxyphenyl)-isoxazole-5-carboxylic acid - Google Patents
Method for preparing 3-(4-methoxyphenyl)-isoxazole-5-carboxylic acid Download PDFInfo
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- CN102977044A CN102977044A CN2012104841420A CN201210484142A CN102977044A CN 102977044 A CN102977044 A CN 102977044A CN 2012104841420 A CN2012104841420 A CN 2012104841420A CN 201210484142 A CN201210484142 A CN 201210484142A CN 102977044 A CN102977044 A CN 102977044A
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- methoxy
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Abstract
The invention discloses a method for preparing 3-(4-methoxyphenyl)-isoxazole-5-carboxylic acid. Hydroxylamine hydrochloride is freed under the alkaline condition, is reacted with 4-methoxybenzaldehyde to form oxime, is added with TSN(Cl)Na, copper sulfate pentahydrate and copper powder, is dripped with methyl acrylate and is cyclized to obtain methyl 3-(4-methoxyphenyl)-isoxazole-5-formate, and finally, a target compound of 3-(4-methoxyphenyl)-isoxazole-5-carboxylic acid is obtained after hydrolyzation.
Description
Technical field
The synthesis technology that the present invention relates to a kind of 3-(4-anisole)-isoxazole-5-base carboxylic acids improves, and belongs to the medicine bioengineering chemical technology field.Also relate to some intermediate that obtains by this method.
Background technology
3-(4-anisole)-isoxazole-5-base carboxylic acids are white solid, are a kind of important biology,drug and chemical industry intermediates.
The preparation of 3-(4-anisole)-isoxazole-5-base carboxylic acids, free under alkaline condition by oxammonium hydrochloride, be reacted into oxime with 4-methoxybenzaldehyde, add TSN (Cl) Na, Salzburg vitriol and copper powder, drip methyl acrylate, Guan Huan gets 3-(4-p-methoxy-phenyl)-isoxazole-5-methyl-formiate, is hydrolyzed at last to get target compound 3-(4-p-methoxy-phenyl)-isoxazole-5-carboxylic acid.
Summary of the invention
The present invention mainly improves former operational path, makes per step operation controlled easy to operate, is beneficial to amplify to produce, and improves yield.
The invention provides formula (4) compound
The present invention also provides by formula (3) compound
The method of ammonification preparation formula (4) compound
The method is that used alkali includes but not limited to potassium hydroxide, sodium hydroxide and lithium hydroxide by-(4-p-methoxy-phenyl)-isoxazoles-5-methyl formate hydrolysis, preferred potassium hydroxide; Temperature of reaction 20 ~ 100 degree, preferred 95 ~ 100 degree; 2 ~ 12 hours reaction times, preferred 3 ~ 4 hours.
The invention provides by formula (2) compound
The method of preparation formula (3) compound
The 4-methoxybenzaldehyde oxime is added TSN (Cl) Na, Salzburg vitriol and copper powder, drip methyl acrylate, time for adding 5 ~ 60 minutes, preferred 20 ~ 30 minutes; Used naoh concentration 1 ~ 10N, preferred 1N.
The invention provides by formula (1) compound
The method of preparation formula (2) compound
The oxammonium hydrochloride oxammonium hydrochloride solvent for use that dissociates, include but not limited to the mixed solvent of methyl alcohol, ethanol, water, the trimethyl carbinol and methyl alcohol, ethanol, the trimethyl carbinol and water, the mixed solvent of preferred tertiary fourth alcohol and water; Used alkali includes but not limited to sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, triethylamine, pyridine, preferred sodium hydroxide; Temperature of reaction-10 ~ 50 degree is about preferred 20 degree; 30 minutes ~ 2 hours reaction times, preferred 30 minutes.Free oxammonium hydrochloride and 4-methoxybenzaldehyde reaction out, temperature of reaction-5 ~ 30 degree is about preferred 20 degree; 1 ~ 16 hour reaction times, preferred 1 hour.
Embodiment
Embodiment 1
146 gram oxammonium hydrochlorides are dissolved in 4 liters of trimethyl carbinols: in water (1:1) mixed solvent, add 84 gram sodium hydroxide, stirring at room 30 minutes in batches, drip 260 gram 4-methoxybenzaldehydes, dropwise stirring at room 1 hour, TLC shows the aldehyde completely dissolve, does not process, and directly enters next step.
Embodiment 2
Take by weighing 500 gram TSN (Cl) Na, be added in the mentioned solution in batches, the time is more than 30 minutes, then add 15 gram Salzburg vitriols and 0.5 gram copper powder, stir the lower 223 gram methyl acrylates that drip, carefully drip an amount of 1N sodium hydroxide to pH=6, stirring is spent the night.Reaction mixture is poured in the frozen water, adds 5 liters of ammoniacal liquor and removes all mantoquitas, filters, and filter cake gets 303 by column chromatography and digests compound 3.
Embodiment 3
200 gram potassium hydroxide are dissolved in 2 premium on currency, add 350 gram 3-(4-p-methoxy-phenyl) ,-isoxazoles-5-methyl-formiate, reflux 3 ~ 4 hours, be cooled to room temperature, the ice-water bath cooling is transferred pH=3 with concentrated hydrochloric acid, filters, drying obtains 152 gram white solid 3-(4-p-methoxy-phenyl) ,-isoxazoles-5-carboxylic acid.
Claims (5)
1. the preparation method of a 3-(4-p-methoxy-phenyl)-isoxazole-5-carboxylic acid, oxammonium hydrochloride is dissolved in the mixed solvent of the trimethyl carbinol and water, use alkaline purification, 4-methoxybenzaldehyde is added, stir, TLC shows that 4-methoxybenzaldehyde reacts completely, divide short run to add TSN (Cl) Na, add again Salzburg vitriol and copper powder, drip methyl acrylate, then drip sodium hydroxide and regulate pH=6, stir, reaction mixture is poured into water, and adds ammoniacal liquor and removes mantoquita, filter, filter cake is crossed post, gets compound 3-(4-p-methoxy-phenyl)-isoxazoles-5-methyl-formiate, and potassium hydroxide is water-soluble, add 3-(4-p-methoxy-phenyl)-isoxazoles-5-methyl-formiate, reflux is chilled to room temperature, regulates pH=3 with hydrochloric acid, filter, get target compound 3-(4-p-methoxy-phenyl)-isoxazoles-5-carboxylic acid.
2. the preparation method of 3-(4-p-methoxy-phenyl)-isoxazoles-5-carboxylic acid as claimed in claim 1, it is characterized in that: oxammonium hydrochloride alkalization solvent for use includes but not limited to the mixed solvent of methyl alcohol, ethanol, water, the trimethyl carbinol and methyl alcohol, ethanol, the trimethyl carbinol and water; Used alkali includes but not limited to sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, triethylamine, pyridine; Temperature of reaction-10 ~ 50 degree; 1 ~ 5 hour reaction times.
3. the preparation method of 3-(4-p-methoxy-phenyl)-isoxazoles-5-carboxylic acid as claimed in claim 1, it is characterized in that: free oxammonium hydrochloride out and 4-methoxybenzaldehyde reaction, temperature of reaction-5 ~ 30 is spent, 1 ~ 16 hour reaction times.
4. the preparation method of 3-(4-p-methoxy-phenyl)-isoxazoles-5-carboxylic acid as claimed in claim 1, it is characterized in that: the 4-methoxybenzaldehyde oxime adds TSN (Cl) Na, cupric sulfate pentahydrate and copper powder, drip methyl acrylate, time for adding 5 ~ 60 minutes, used naoh concentration 1 ~ 10N.
5. the preparation method of 3-(4-p-methoxy-phenyl)-isoxazoles-5-carboxylic acid as claimed in claim 1, it is characterized in that: the hydrolysis of 3-(4-p-methoxy-phenyl)-isoxazoles-5-methyl-formiate, used alkali includes but not limited to potassium hydroxide, sodium hydroxide and lithium hydroxide, temperature of reaction 20 ~ 100 degree, 2 ~ 12 hours reaction times.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012104841420A CN102977044A (en) | 2012-11-26 | 2012-11-26 | Method for preparing 3-(4-methoxyphenyl)-isoxazole-5-carboxylic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012104841420A CN102977044A (en) | 2012-11-26 | 2012-11-26 | Method for preparing 3-(4-methoxyphenyl)-isoxazole-5-carboxylic acid |
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| CN102977044A true CN102977044A (en) | 2013-03-20 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2012104841420A Pending CN102977044A (en) | 2012-11-26 | 2012-11-26 | Method for preparing 3-(4-methoxyphenyl)-isoxazole-5-carboxylic acid |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1687075A (en) * | 2005-03-24 | 2005-10-26 | 天津药物研究院 | 3-phenyl iso-oxazole-5-aminocarbonyl substituted beta-lactam derivative and application |
| WO2012058187A1 (en) * | 2010-10-29 | 2012-05-03 | Merck Sharp & Dohme Corp. | Cyclic amine substituted oxazolidinone cetp inhibitor |
-
2012
- 2012-11-26 CN CN2012104841420A patent/CN102977044A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1687075A (en) * | 2005-03-24 | 2005-10-26 | 天津药物研究院 | 3-phenyl iso-oxazole-5-aminocarbonyl substituted beta-lactam derivative and application |
| WO2012058187A1 (en) * | 2010-10-29 | 2012-05-03 | Merck Sharp & Dohme Corp. | Cyclic amine substituted oxazolidinone cetp inhibitor |
Non-Patent Citations (6)
| Title |
|---|
| FAHMI HIMO 等: "Copper(I)-Catalyzed Synthesis of Azoles. DFT Study Predicts Unprecedented Reactivity and Intermediates", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| SCOTT GRECIAN 等: "Ruthenium-Catalyzed Cycloaddition of Nitrile Oxides and Alkynes:Practical Synthesis of Isoxazoles", 《ANGEWANDTE CHEMIE》 * |
| SHIBING TANG 等: "Efficient and Regioselective One-Pot Synthesis of 3-Substituted and 3,5-Disubstituted Isoxazoles", 《ORGANIC LETTERS》 * |
| SHOU-RI SHENG 等: "Methyl 3-substituted-isoxazole-5- carboxylates syntheses on solid supports via wang resin-bound 2,3-dibromopropionate", 《HETEROATOM CHEMISTRY》 * |
| SURESHBABU DADIBOYENA 等: "Isoxazoles from 1,1-disubstituted bromoalkenes", 《TETRAHEDRON LETTERS》 * |
| TROND V.HANSEN 等: "one-pot copper(I)-catalyzed synthesis of 3,5-disubstituted isoxazoles", 《JOURNAL OF THE ORGANIC CHEMISTRY》 * |
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Application publication date: 20130320 |