CN105481812B - Preparation method of 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid - Google Patents
Preparation method of 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid Download PDFInfo
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- CN105481812B CN105481812B CN201510860246.0A CN201510860246A CN105481812B CN 105481812 B CN105481812 B CN 105481812B CN 201510860246 A CN201510860246 A CN 201510860246A CN 105481812 B CN105481812 B CN 105481812B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
- C07D309/40—Oxygen atoms attached in positions 3 and 4, e.g. maltol
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Abstract
The invention discloses a preparation method of 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid, which comprises the following steps: adding kojic acid, benzyl chloride and methanol benzyl chloride into a reaction container, and heating and carrying out reflux reaction for 16-18 hours; then carrying out reduced pressure distillation, evaporating the solvent to dryness, and cooling to normal temperature; adding methanol and water, stirring, washing, filtering and drying to obtain an intermediate; adding the intermediate and water into a reactor, reducing the temperature to 0-minus 10 ℃, adding sodium periodate, controlling the temperature to be not higher than 5 ℃, dropwise adding a proper amount of water, stirring for 5-15 minutes, heating to 12-22 ℃, stirring for reacting for 2.5-3.5 hours, extracting with ethyl acetate, layering, drying, filtering and drying to obtain a white solid which is 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid. The invention provides a new method for preparing 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid, does not produce a large amount of waste water containing chromium, prevents serious pollution to the environment and can realize industrial production.
Description
Technical Field
The invention relates to a preparation method of 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid.
Background
At present, 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid is an important intermediate for chemical synthesis and medical synthesis, and the method for producing 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid is mainly characterized in that a benzyl group is connected to an oxygen double bond of kojic acid, oxidizing with Jones reagent to obtain 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid, the method adopts the Jones reagent as the oxidant, the Jones reagent contains chromium trioxide, a large amount of wastewater is generated finally in the whole reaction, the wastewater contains chromium which is a heavy metal, the chromium not only can seriously pollute the environmental soil, but also is a strong mutagenic substance and can induce cancers and cause deformity.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a preparation method of 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid, and solves the technical problems of high wastewater content, high cost of separated products and low purity of the 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid prepared by the prior art.
The chemical reaction formula of the invention is as follows:
the technical scheme of the invention is as follows: a preparation method of 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid comprises the following steps:
step 1, adding kojic acid into a reactor, adding methanol to dissolve the kojic acid, adding benzyl chloride and a proper amount of 40% alkali solution, and heating and refluxing for reaction for 16-18 hours to obtain a reaction solution;
step 2, carrying out reduced pressure distillation on the reaction solution until the solvent is evaporated to dryness, stopping distillation, and cooling to normal temperature;
step 3, adding methanol and water into the substances left after distillation in the step 2, stirring, washing, filtering, and drying the obtained solid to obtain a light yellow solid as an intermediate;
step 4, adding the intermediate into a reactor, then adding a proper amount of water, reducing the temperature to 0-minus 10 ℃, adding sodium periodate, controlling the temperature to be not higher than 5 ℃, dropwise adding a proper amount of water after finishing adding, stirring for 5-15 minutes, heating to 12-22 ℃, and stirring for 2.5-3.5 hours to react to obtain a reaction solution;
and 5, filtering the reaction liquid obtained in the step 4, adjusting the pH value of the filtrate to 5-6 by using hydrochloric acid, extracting by using ethyl acetate, layering, drying, filtering, and drying the obtained solid to obtain a white solid, namely 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid.
Preferably, the molar ratio of kojic acid to benzyl chloride in step 1 is 1: 1-1: 1.2.
preferably, the volume ratio of the methanol to the water added after the reaction in the step 3 is 1: 3-1: 5.
Preferably, the molar ratio of the intermediate to the sodium periodate in the step 4 is 1: 3-1: 4.
compared with the prior art, the invention has the beneficial effects that:
the invention provides a new method for preparing 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid, the invention adopts sodium periodate to replace Jones reagent, on one hand, a large amount of waste water is generated after the Jones reagent is oxidized, the waste water is large, the process for separating the 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid product is complex, the separation cost is high, and the purity of the obtained 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid product is low, which causes the production cost of the 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid to be increased; chromium trioxide is contained in the Jones reagent, and the waste water generated by the reaction contains chromium element; the sodium periodate is adopted, the water generated by the reaction is less, the 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid is convenient to separate, the separation purity is higher, the separation cost of the 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid is saved, and the wastewater does not contain heavy metal elements causing serious pollution to the environment, so that the standard of environmental protection is better met.
Detailed Description
The technical solution of the present invention is further illustrated by the following examples.
Example one
A preparation method of 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid, add 90g kojic acid into 2000ml single-neck flask at first, add 660ml methanol to dissolve kojic acid, add 80g benzyl chloride and 63ml 40% alkali solution, heat up the reflux reaction for 16 hours and get the reaction solution; distilling the reaction solution under reduced pressure until the solvent is evaporated to dryness, and cooling to normal temperature; adding 60ml of methanol and 180ml of water into the substances left after distillation, stirring, washing, filtering, and drying the obtained solid to obtain 103g of light yellow solid serving as an intermediate; adding 103g of intermediate into a reactor, then adding 2000ml of water, reducing the temperature to 0 ℃, adding sodium periodate, controlling the temperature to be not higher than 5 ℃, after the addition is finished, dropwise adding 40ml of water, stirring for 5 minutes, heating to 12 ℃, and stirring for reacting for 2.5 hours to obtain a reaction solution; and filtering the obtained reaction solution, adjusting the pH value of the filtrate to 5-6 by using hydrochloric acid, extracting by using 500g of ethyl acetate, layering, drying, filtering, and drying the obtained solid to obtain 56g of white solid 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid.
Example two
A preparation method of 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid, add 90g kojic acid into 2000ml single-neck flask at first, add 660ml methanol to dissolve kojic acid, add 88g benzyl chloride and 63ml 40% alkali solution, heat up the reflux reaction for 17 hours and get the reaction solution; distilling the reaction solution under reduced pressure until the solvent is evaporated to dryness, and cooling to normal temperature; adding 60ml of methanol and 240ml of water into the substances left after distillation, stirring, washing, filtering, and drying the obtained solid to obtain 116g of light yellow solid as an intermediate; adding 116g of intermediate into a reactor, then adding 2000ml of water, reducing the temperature to-5 ℃, adding sodium periodate, controlling the temperature to be not higher than 5 ℃, after the addition is finished, dropwise adding 40ml of water, stirring for 10 minutes, heating to 17 ℃, and stirring for reacting for 3 hours to obtain reaction liquid; and filtering the obtained reaction solution, adjusting the pH value of the filtrate to 5-6 by using hydrochloric acid, extracting by using 500g of ethyl acetate, layering, drying, filtering, and drying the obtained solid to obtain 80g of white solid 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid.
EXAMPLE III
A preparation method of 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid, add 90g kojic acid into 2000ml single-neck flask at first, add 660ml methanol to dissolve kojic acid, add 96g benzyl chloride and 63ml 40% alkali solution, heat up reflux reaction for 18 hours and get the reaction solution; distilling the reaction solution under reduced pressure until the solvent is evaporated to dryness, and cooling to normal temperature; adding 60ml of methanol and 300ml of water into the substances left after distillation, stirring, washing, filtering, and drying the obtained solid to obtain 116g of light yellow solid as an intermediate; adding 116g of intermediate into a reactor, then adding 2000ml of water, reducing the temperature to-10 ℃, adding sodium periodate, controlling the temperature to be not higher than 5 ℃, after the addition is finished, dropwise adding 40ml of water, stirring for 15 minutes, heating to 22 ℃, and stirring for reacting for 3.5 hours to obtain a reaction solution; and filtering the obtained reaction solution, adjusting the pH value of the filtrate to 5-6 by using hydrochloric acid, extracting by using 500g of ethyl acetate, layering, drying, filtering, and drying the obtained solid to obtain 80g of white solid 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid.
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, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (3)
1. A preparation method of 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid is characterized by comprising the following steps:
step 1, adding kojic acid into a reaction container, adding methanol to dissolve the kojic acid, adding benzyl chloride and a proper amount of 40% alkali solution, and heating and carrying out reflux reaction for 16-18 hours to obtain a reaction solution;
step 2, carrying out reduced pressure distillation on the reaction solution until the solvent is evaporated to dryness, stopping distillation, and cooling to normal temperature;
step 3, adding methanol and water into the substances left after distillation in the step 2, stirring, washing, filtering, and drying the obtained solid to obtain a light yellow solid as an intermediate;
step 4, adding the intermediate into a reactor, then adding a proper amount of water, reducing the temperature to 0-minus 10 ℃, adding sodium periodate, controlling the temperature to be not higher than 5 ℃, dropwise adding a proper amount of water after finishing adding, stirring for 5-15 minutes, heating to 12-22 ℃, and stirring for 2.5-3.5 hours to react to obtain a reaction solution;
step 5, filtering the reaction liquid obtained in the step 4, adjusting the pH value of the filtrate to 5-6 by using hydrochloric acid, extracting by using ethyl acetate, layering, drying, filtering, and drying the obtained solid to obtain a white solid which is 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid;
in the step 1, the molar ratio of kojic acid to benzyl chloride is 1: 1-1: 1.2.
2. The process for preparing 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid as claimed in claim 1, wherein: the volume ratio of the methanol to the water added after the reaction in the step 3 is 1: 3-1: 5.
3. The process for preparing 5-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid as claimed in claim 1, wherein: in the step 4, the molar ratio of the intermediate to the sodium periodate is 1: 3-1: 4.
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| WO2020132820A1 (en) * | 2018-12-24 | 2020-07-02 | 广东莱佛士制药技术有限公司 | Synthesis method for 3-(benzyloxy)-4-oxo-4h-pyran-2-carboxylic acid |
Citations (4)
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| US5891892A (en) * | 1996-10-29 | 1999-04-06 | Warner-Lambert Company | Small molecule biaryl compounds as inhibitors of endothelin converting enzyme |
| CN102325769A (en) * | 2008-12-19 | 2012-01-18 | 美国辉瑞有限公司 | Monocarbams |
| CN102869256A (en) * | 2010-03-04 | 2013-01-09 | 默沙东公司 | Inhibitors of catechol O-methyl transferase and their use in the treatment of psychotic disorders |
| CN103228652A (en) * | 2010-11-29 | 2013-07-31 | 辉瑞大药厂 | Monobactams |
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- 2015-11-30 CN CN201510860246.0A patent/CN105481812B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5891892A (en) * | 1996-10-29 | 1999-04-06 | Warner-Lambert Company | Small molecule biaryl compounds as inhibitors of endothelin converting enzyme |
| CN102325769A (en) * | 2008-12-19 | 2012-01-18 | 美国辉瑞有限公司 | Monocarbams |
| CN102869256A (en) * | 2010-03-04 | 2013-01-09 | 默沙东公司 | Inhibitors of catechol O-methyl transferase and their use in the treatment of psychotic disorders |
| CN103228652A (en) * | 2010-11-29 | 2013-07-31 | 辉瑞大药厂 | Monobactams |
Non-Patent Citations (2)
| Title |
|---|
| Preparation, Gram-Negative Antibacterial Activity, and Hydrolytic Stability of Novel Siderophore-Conjugated Monocarbam Diols;Mark E. Flanagan等;《ACS Medicinal Chemistry Letters》;20110302;第2卷;第388页scheme 1 * |
| Synthesis of 4(1H)-pyridinone derivatives and investigation of analgesic and antiinflammatory activities;Gulcan Ozturk等;《Farmaco》;20011231;第56卷;第254页左栏第3.1-3.2节 * |
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