CN114716389A - Synthetic method of 3, 5-diethylisoxazole-4-carboxylic acid - Google Patents
Synthetic method of 3, 5-diethylisoxazole-4-carboxylic acid Download PDFInfo
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- CN114716389A CN114716389A CN202111673028.8A CN202111673028A CN114716389A CN 114716389 A CN114716389 A CN 114716389A CN 202111673028 A CN202111673028 A CN 202111673028A CN 114716389 A CN114716389 A CN 114716389A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members 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
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention relates to a synthesis method of 3, 5-diethylisoxazole-4-carboxylic acid, belonging to the technical field of organic synthesis, wherein the synthesis method takes 3-oxovaleric acid methyl ester and propionyl chloride as raw materials to react to generate the 3, 5-diethylisoxazole-4-carboxylic acid. The synthesis method of the 3, 5-diethylisoxazole-4-carboxylic acid has strong operability and high yield, saves solvent and time, and ensures that the purity of the final product reaches more than 99 percent.
Description
Technical Field
The invention relates to a synthesis method of 3, 5-diethylisoxazole-4-carboxylic acid, belonging to the technical field of organic synthesis.
Background
Actinic Keratosis (AK), also known as solar Keratosis. Is a skin precancerous lesion with high incidence rate in the elderly, and is better to be caused on the parts which can be directly irradiated by sunlight, such as the head, the neck, the forearm, the back of the hand and the like. Primary skin lesions of AK may appear as scaling erythema, pigmented erythema or hyperkeratosis. When the AK skin lesion develops nodules, ulcerations or rapidly increases in a short time, it indicates a tendency to develop into invasive Squamous Cell Carcinoma (SCC), and is sometimes indistinguishable from squamous cell carcinoma.
It has recently been discovered that rio in denmark, a new drug for treating photo-linear keratosis (Ingenol polyoxate, research and development code: LEO-43204), the chinese name: the structure of the novel giant ester is shown as the formula (I). Three clinics have begun. Ingenol is used as a mother nucleus, and 3, 5-diethylisoxazole-4-carboxylic acid is used instead of methylbutenoic acid (angelic acid) unlike the aforementioned ingenol gel. Presumably, the development of novel esters was aimed at solving the problem of side effects of ingenol mebutate.
Disclosure of Invention
The invention aims to solve the problem of difficulty in obtaining 3, 5-diethylisoxazole-4-carboxylic acid by using a compound with easily available sources and provide guarantee for the application of novel giant ester alcohol. The technical scheme of the invention is as follows:
a synthesis method of 3, 5-diethylisoxazole-4-carboxylic acid is characterized in that 3-oxovaleric acid methyl ester and propionyl chloride are used as raw materials to react to generate 3, 5-diethylisoxazole-4-carboxylic acid.
Further, the synthesis method of the 3, 5-diethylisoxazole-4-carboxylic acid comprises the following specific steps:
adding metal sodium into ethanol, performing reflux reaction, cooling a reaction system to 20-30 ℃ after the metal sodium is completely dissolved, then adding 3-oxo methyl valerate, stirring for 10 minutes, cooling to 0 ℃, slowly dropwise adding propionyl chloride, keeping the temperature of the reaction system at 10 +/-3 ℃, and slowly heating to room temperature for reaction for 12 hours after dropwise adding; cooling the reaction system to 10 +/-3 ℃, dropwise adding water, completely dissolving the reaction system and enabling the reaction system to be transparent, removing ethanol by rotation, extracting with ethyl acetate for 3 times, combining organic phases, drying with anhydrous sodium sulfate, and performing coarse purification to obtain a pure product.
Aiming at the problems that in the prior art, too much solvent and reagent are used, simultaneously the dosage of ethanol and magnesium is difficult to control and is slightly improper, magnesium powder cannot completely react, and the reaction fails, the invention further provides a synthesis method of the 3, 5-diethylisoxazole-4-carboxylic acid, which comprises the following specific steps:
adding 3-oxo-methyl valerate, magnesium chips/magnesium powder, ethanol and carbon tetrachloride into 30mL of toluene, stirring at room temperature for 30 minutes under the protection of nitrogen, heating a reaction system to reflux and stirring for 1 hour under the condition of strong stirring, then cooling the reaction system to 0-5 ℃, ensuring the low temperature of the reaction system, dripping propionyl chloride, heating the reaction system to room temperature after dripping, stirring and reacting for 1 hour, then cooling the reaction system to 0-5 ℃, then adding a hydrochloric acid aqueous solution, washing with a saturated sodium bicarbonate aqueous solution and a saturated saline solution, drying an organic phase with anhydrous sodium sulfate, and then spin-drying to obtain a light yellow oily product, and purifying by passing through a column to obtain a pure product. Preferably, the mass concentration of the aqueous hydrochloric acid solution is 5%.
Further, the synthesis method of the 3, 5-diethylisoxazole-4-carboxylic acid comprises the following specific steps:
adding 3-oxo methyl valerate into dichloromethane, adding magnesium chloride, cooling the reaction system to 0-5 ℃, ensuring the low temperature of the reaction system, adding pyridine, stirring for 15 minutes, ensuring the low temperature of the reaction system, dripping propionyl chloride, heating the reaction system to room temperature, stirring for reaction for 1 hour, cooling the reaction system to 0-5 ℃, adding a hydrochloric acid aqueous solution, separating an organic phase, washing with a saturated sodium bicarbonate aqueous solution and a saturated saline aqueous solution, drying the organic phase with anhydrous sodium sulfate, spin-drying to obtain a light yellow oily product, and purifying by a column to obtain a pure product. Preferably, the concentration of the aqueous hydrochloric acid solution is 2.0M.
Compared with the prior art, the invention has the following beneficial effects:
the synthesis method of the 3, 5-diethylisoxazole-4-carboxylic acid has strong operability and high yield, saves solvent and time, and ensures that the purity of the final product reaches more than 99 percent.
Drawings
FIG. 1 is a LC-MS diagram of 3, 5-diethylisoxazole-4-carboxylate in example 1;
FIG. 2 is a LC-MS diagram of 3, 5-diethylisoxazole-4-carboxylic acid in example 1;
FIG. 3 shows 3, 5-diethylisoxazole-4-carboxylic acid of example 11H-NMR chart;
FIG. 4 is a HPLC purity chart of 3, 5-diethylisoxazole-4-carboxylic acid in example 1.
Detailed Description
The present invention is further described below in conjunction with specific embodiments, and the advantages and features of the present invention will become more apparent as the description of the specific embodiments proceeds. The examples are illustrative only and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
Example 1: synthetic method of 3, 5-diethylisoxazole-4-carboxylic acid
Adding 1.0g of sodium metal into 25mL of ethanol, carrying out reflux reaction, cooling a reaction system to 20-30 ℃ after the sodium metal is completely dissolved, then adding 5.13g of methyl 3-oxopentanoate, stirring for 10 minutes, cooling to 0 ℃, slowly dropwise adding 4.01g of propionyl chloride, keeping the temperature of the reaction system at 10 +/-3 ℃, and slowly heating to room temperature for reaction for 12 hours after dropwise addition. The reaction system is cooled to 10 +/-3 ℃, 1.5mL of water is added dropwise, after the reaction system is completely dissolved and transparent, ethanol is removed by rotation, 5mL multiplied by 3 is extracted by ethyl acetate, organic phases are combined, anhydrous sodium sulfate is dried, and coarse purification is carried out to obtain 2.3g of a pure product, the purity can reach 99.6% through detection, and the total yield is 46%.
The LC-MS diagram of 3, 5-diethylisoxazole-4-carboxylic acid ester obtained in this example is shown in FIG. 1; the LC-MS diagram of 3, 5-diethylisoxazole-4-carboxylic acid is shown in FIG. 2; process for preparing 3, 5-diethylisoxazole-4-carboxylic acid1The H-NMR chart is shown in FIG. 3; the HPLC purity of 3, 5-diethylisoxazole-4-carboxylic acid is shown in FIG. 4.
Example 2: synthetic method of 3, 5-diethylisoxazole-4-carboxylic acid
Adding 1.56g of methyl 3-oxopentanoate, 0.29g of magnesium chips/magnesium powder, 1.84g of ethanol and 0.3mL of carbon tetrachloride into 30mL of toluene, stirring at room temperature for 30 minutes under the protection of nitrogen, heating the reaction system under the condition of strong stirring until reflux stirring for 1 hour, cooling the reaction system to 0-5 ℃, ensuring the low temperature of the reaction system, dripping 1.12g of propionyl chloride, heating the reaction system to room temperature after dripping is finished, stirring for reaction for 1 hour, cooling the reaction system to 0-5 ℃, adding 24mL of 5% hydrochloric acid aqueous solution, washing with 24mL of saturated sodium bicarbonate aqueous solution and 24mL of saturated saline aqueous solution, drying an organic phase by using anhydrous sodium sulfate, and then spin-drying to obtain a light yellow oily product, purifying by using a column to obtain 0.3g of a pure product, wherein the purity can reach 95.6% by detection, and the total yield is 19.6%.
Example 3: synthetic method of 3, 5-diethylisoxazole-4-carboxylic acid
Adding 5.0g of methyl 3-oxopentanoate into 50mL of dichloromethane, adding 3.7g of magnesium chloride, cooling the reaction system to 0-5 ℃ to ensure that the temperature of the reaction system is low, adding 6.2g of pyridine, stirring for 15 minutes to ensure that the temperature of the reaction system is low, dripping 3.6g of propionyl chloride into the reaction system, heating the reaction system to room temperature after dripping is finished, stirring for reaction for 1 hour, cooling the reaction system to 0-5 ℃, adding 50mL of 2.0M hydrochloric acid aqueous solution, separating an organic phase, washing the saturated sodium bicarbonate aqueous solution and the saturated salt aqueous solution, drying the organic phase by using anhydrous sodium sulfate, obtaining a light yellow oily product, purifying by passing through a column to obtain 1.2g of a pure product, wherein the purity can reach 96.1% by detection, and the total yield is 24.4%.
Comparative example 1:
dissolving 18.0g of hydroxylamine hydrochloride in 50mL of water, dripping into 100mL of absolute ethanol dissolved with 27.0g of 3-oxo-2-propionyl methyl valerate at room temperature, carrying out reflux reaction for 2 hours, removing ethanol in a reaction system, extracting 100mL of ethanol by multiplying the yield by 3, combining organic phases, drying with anhydrous sodium sulfate, and spin-drying to obtain a crude product of 30.2 g.
Dissolving 8.0g of sodium hydroxide in 35.0mL of water, dripping 75.0mL of absolute ethanol dissolved with 15.5g of methyl 3, 5-diethylisoxazole-4-carboxylate into the solution at room temperature, heating to 60 ℃, reacting for 1 hour, removing ethanol in the system, extracting by 75mL of ethyl acetate by 3, adjusting the pH of an aqueous phase to 2 by 6M hydrochloric acid, separating out solids, filtering, washing with water, and drying at 50 ℃ to obtain 13.1g of a product.
Claims (6)
1. A synthetic method of 3, 5-diethylisoxazole-4-carboxylic acid is characterized in that the synthetic method takes 3-oxovaleric acid methyl ester and propionyl chloride as raw materials to react to generate 3, 5-diethylisoxazole-4-carboxylic acid.
2. The method for synthesizing 3, 5-diethylisoxazole-4-carboxylic acid as claimed in claim 1, characterized by comprising the following steps:
adding metallic sodium into ethanol, performing reflux reaction, cooling a reaction system to 20-30 ℃ after the metallic sodium is completely dissolved, then adding methyl 3-oxopentanoate, stirring for 10 minutes, cooling to 0 ℃, slowly dropwise adding propionyl chloride, keeping the temperature of the reaction system at 10 +/-3 ℃, and slowly heating to room temperature for reaction for 12 hours after dropwise adding; cooling the reaction system to 10 +/-3 ℃, dropwise adding water, completely dissolving the reaction system, removing ethanol, extracting with ethyl acetate for 3 times, combining organic phases, drying with anhydrous sodium sulfate, and performing coarse purification to obtain a pure product.
3. The method for synthesizing 3, 5-diethylisoxazole-4-carboxylic acid as claimed in claim 1, characterized by comprising the following steps:
adding 3-oxo methyl valerate, magnesium chips/magnesium powder, ethanol and carbon tetrachloride into 30mL of toluene, stirring at room temperature for 30 minutes under the protection of nitrogen, heating a reaction system to reflux and stirring for 1 hour under the condition of strong stirring, then cooling the reaction system to 0-5 ℃, ensuring the low temperature of the reaction system, dripping propionyl chloride, heating the reaction system to room temperature and stirring for reaction for 1 hour after dripping, then cooling the reaction system to 0-5 ℃, then adding a hydrochloric acid aqueous solution, washing with a saturated sodium bicarbonate aqueous solution and a saturated salt aqueous solution, drying an organic phase with anhydrous sodium sulfate, and then spin-drying to obtain a light yellow oily product, and purifying by passing through a column to obtain a pure product.
4. The method for synthesizing 3, 5-diethylisoxazole-4-carboxylic acid as claimed in claim 3, wherein the method comprises the following steps: the mass concentration of the hydrochloric acid aqueous solution is 5%.
5. The method for synthesizing 3, 5-diethylisoxazole-4-carboxylic acid as claimed in claim 1, wherein the method comprises the following steps:
adding 3-oxo methyl valerate into dichloromethane, adding magnesium chloride, cooling the reaction system to 0-5 ℃, ensuring the low temperature of the reaction system, adding pyridine, stirring for 15 minutes, ensuring the low temperature of the reaction system, dripping propionyl chloride, heating the reaction system to room temperature, stirring for reaction for 1 hour, cooling the reaction system to 0-5 ℃, adding a hydrochloric acid aqueous solution, separating an organic phase, washing with a saturated sodium bicarbonate aqueous solution and a saturated saline aqueous solution, drying the organic phase with anhydrous sodium sulfate, spin-drying to obtain a light yellow oily product, and purifying by a column to obtain a pure product.
6. The method for synthesizing 3, 5-diethylisoxazole-4-carboxylic acid as claimed in claim 5, characterized by comprising the following steps: the concentration of the aqueous hydrochloric acid solution was 2.0M.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111673028.8A CN114716389A (en) | 2021-12-31 | 2021-12-31 | Synthetic method of 3, 5-diethylisoxazole-4-carboxylic acid |
| CN202211438577.1A CN115894397A (en) | 2021-12-31 | 2022-11-16 | Synthesis method of 3-oxo-2-propionyl methyl valerate |
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| CN202111673028.8A CN114716389A (en) | 2021-12-31 | 2021-12-31 | Synthetic method of 3, 5-diethylisoxazole-4-carboxylic acid |
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| CN114716389A true CN114716389A (en) | 2022-07-08 |
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| CN202111673028.8A Withdrawn CN114716389A (en) | 2021-12-31 | 2021-12-31 | Synthetic method of 3, 5-diethylisoxazole-4-carboxylic acid |
| CN202211438577.1A Pending CN115894397A (en) | 2021-12-31 | 2022-11-16 | Synthesis method of 3-oxo-2-propionyl methyl valerate |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103539753A (en) * | 2013-10-22 | 2014-01-29 | 天津药明康德新药开发有限公司 | Synthesis method of high-regioselectivity 3-substituted-4-isoxazole carboxylic acid |
| WO2017108927A1 (en) * | 2015-12-22 | 2017-06-29 | Leo Laboratories Limited | Process for preparation of ingenol 3-(3.5-diethylisoxazole-4-carboxylate) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU690079B2 (en) * | 1992-12-17 | 1998-04-23 | Pfizer Inc. | Substituted pyrazoles as CRF antagonists |
| CA2192208C (en) * | 1994-06-06 | 2002-09-10 | Pfizer Limited | Substituted pyrazoles |
| US7977358B2 (en) * | 2007-07-26 | 2011-07-12 | Hoffmann-La Roche Inc. | Pyrazol derivatives |
| US20140256740A1 (en) * | 2011-07-29 | 2014-09-11 | Tempero Pharmaceuticals, Inc. | Compounds and methods |
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2021
- 2021-12-31 CN CN202111673028.8A patent/CN114716389A/en not_active Withdrawn
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- 2022-11-16 CN CN202211438577.1A patent/CN115894397A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103539753A (en) * | 2013-10-22 | 2014-01-29 | 天津药明康德新药开发有限公司 | Synthesis method of high-regioselectivity 3-substituted-4-isoxazole carboxylic acid |
| WO2017108927A1 (en) * | 2015-12-22 | 2017-06-29 | Leo Laboratories Limited | Process for preparation of ingenol 3-(3.5-diethylisoxazole-4-carboxylate) |
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| CN115894397A (en) | 2023-04-04 |
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Application publication date: 20220708 |