CN103787872A - New method for synthesizing 4-methoxymandelic acid - Google Patents
New method for synthesizing 4-methoxymandelic acid Download PDFInfo
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- CN103787872A CN103787872A CN201210431239.5A CN201210431239A CN103787872A CN 103787872 A CN103787872 A CN 103787872A CN 201210431239 A CN201210431239 A CN 201210431239A CN 103787872 A CN103787872 A CN 103787872A
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- ITECRQOOEQWFPE-UHFFFAOYSA-N COc1ccc(C(C(O)=O)O)cc1 Chemical compound COc1ccc(C(C(O)=O)O)cc1 ITECRQOOEQWFPE-UHFFFAOYSA-N 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N COc1ccc(C=O)cc1 Chemical compound COc1ccc(C=O)cc1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N COc1ccccc1 Chemical compound COc1ccccc1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
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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
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
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Abstract
A method for preparing 4-methoxymandelic acid is characterized in that anisole and an aqueous solution of glyoxalic acid undergo a reaction under the catalysis of a protonic acid as raw materials, and a certain amount of a secondary solvent is added to improve the selectivity and the yield. The method avoids the use of toxic, severely-environmentally-hazardous or precious raw materials in present methods, and has the advantages of simplicity, safety and low cost.
Description
Technical field:
The invention belongs to organic compound synthesis technical field, relate to a kind of preparation method to the acid of methoxyl group tonsilla.
Technical background:
Amygdalic acid and derivative thereof are important fine-chemical intermediates, are all widely used in multiple fields such as medicine production, asymmetric synthesis, optical resolution.Such as amygdalic acid and derivative thereof are easily converted into important medicine and the fine-chemical intermediates such as fragrant alcohol amine compound, Alpha-hydroxy fragrance acetamides, phenylglycine derivatives.Wherein to methoxyl group tonsilla, acid is the important intermediate of synthetic homoanisic acid, and homoanisic acid is the intermediate of synthetic thymoleptic Wen Falaxin of new generation (Venlafaxine), it is also the key intermediate of the multiple cardiovascular agentes such as synthetic maincenter cough medicine Dextromethorphane Hbr, puerarin, osajin.So to synthetic the having great importance of methoxyl group tonsilla acid.
It is synthetic at present that to methoxyl group tonsilla, acid mainly contains following several method:
1), the cyanidization agent such as aubepine and prussiate reacts and obtains mandelonitrile, then hydrolysis obtains amygdalic acid product;
Owing to having used hypertoxic prussiate, the requirement of production operation and waste disposal is all higher, and environmental pollution is serious, and aubepine easily carries out st-yrax reaction, has affected the yield of reaction and the purity of product, and yield is low, is eliminated gradually.Also has raw material aubepine costliness.
2), aubepine is prepared through Cabbeen with trichloromethane under Catalyzed By Phase-transfer Catalyst;
It is synthetic to the acid of methoxyl group tonsilla that Chinese patent CN10135296A, CN101298416A and CN100554235C have reported this route.Although these processing condition are gentle, but produce a large amount of acid-base waste fluids, and inevitably can partly there is Cannizzaro reaction (cannizzaro reaction) and produce by product anisic acid in aubepine, affect purity and the yield of product.
Same aubepine is expensive, and cost is high.
3), p-methoxy-acetophenone dichloride, alkaline hydrolysis preparation (sweet Yongping etc., chemical reagent, 2007,29 (8), 496-498).
The method, take p-methoxy-acetophenone as raw material, completes through multisteps such as chlorination, alkaline hydrolysis, acidifying, extractions, and yield is higher, is current main industrial process.But chlorine toxicity is large, α, that α-dichloroacetophenone derivative has is many compared with strong lacrimation and pungency, reactions steps, produce a large amount of sour waste water, seriously polluted.
4), so that the acid of hydroxyl tonsilla is made to (Hallas, G.and Yoon, Chun, Dyes and Pigments, 48 (2), 107-119 as raw material and methyl-sulfate, methyl iodide, methyl chloride or monobromethane generation etherificate; 2001).
Though the method route is short, methyl-sulfate toxicity is large, and methyl halide expensive (as methyl iodide, monobromethane) or boiling point are low not easy to operate.Also higher to hydroxyl tonsilla acid value lattice itself, this route is difficult to mass-producing.
5), in addition French Patent 2830861 is prepared the tonsilla acid of alkoxyl group replacement and the method for derivative thereof having reported oxoethanoic acid and alkoxyl group aromatic hydrocarbons under sulphuric acid catalysis.When although the method is used in the tonsilla acid of preparing multiple alkoxyl groups replacements, yield is higher, and in the production of success for the preparation of piperonylaldehyde and vanillin food grade,1000.000000ine mesh.But poor selectivity, yield low (45%) when the method for this patent report generates the acid of methoxyl group tonsilla for methyl-phenoxide.Also do not have so far other document to mention that the method is for the preparation of the example to the acid of methoxyl group tonsilla.
Due to method 5) have simple and clearly, starting material are cheap and easy to get, and the feature of environmental protection has the value of further research and development.Therefore the inventor has carried out careful research to this reaction, found that by adding certain auxiliary agent and can greatly improve the selectivity of reaction, kind and how many relations of selectivity, the speed of response etc. of simultaneously also finding this reaction to added auxiliary agent are very large, exist suitable kind and sufficient quantity.
Summary of the invention:
In order to overcome the deficiency of above-mentioned technique, the object of the present invention is to provide a kind of preparation method to the acid of methoxyl group tonsilla, compared with the existing methods, require the method for inventing to have that equipment requirements is simple, easy to operate, reaction process environmental protection, starting material are inexpensive, easily control, has good industrial prospect.
For achieving the above object, technical scheme of the present invention is:
To a preparation method for methoxyl group tonsilla acid, it is characterized in that:
1) take oxoethanoic acid, methyl-phenoxide as raw material, add appropriate water, under strong protonic acid catalysis, add a certain amount of auxiliary agent to generate the acid of methoxyl group tonsilla.
2) in described step 1, oxoethanoic acid is that concentration is more than 40% aqueous glyoxylic acid, and strong protonic acid is the vitriol oil, strong phosphoric acid, perchloric acid etc.
3), in described step 1, adjuvant used can be stable organic solvent under the condition of reaction, as acids, ethers, ketone, ester class or amides etc.
Preferably:
Described step 1) in the mol ratio of methyl-phenoxide and oxoethanoic acid be 1: 1～1.5, preferably 1: 1.1, temperature of reaction was-5 ℃～+ 5 ℃, preferably 0 ℃～5 ℃, for 50% oxoethanoic acid, the mole dosage of water is methyl-phenoxide 1～2 times, be preferably 1.5 times.
Described step 2) the preferred vitriol oil of strong acid that uses, preferred mole dosage is methyl-phenoxide 2 times, the reaction times is 7～15 hours.
Described step 3) in adjuvant used be acetic acid, ethyl acetate, 4-methylpenta-2-one, DMF, acetonitrile, pyridine, di-alcohol dme, tetraethyleneglycol dimethyl ether etc., preferred auxiliary agent is the gylcol ether that can dissolve each other with water, as diethylene glycol dimethyl ether, tetraethyleneglycol dimethyl ether etc., be more preferably diethylene glycol dimethyl ether.
Route involved in the present invention is as follows:
Embodiment
Key point of the present invention is take methyl-phenoxide and aqueous glyoxylic acid as raw material, reaction by adding a certain amount of secondary solvent to reach the object that improves selectivity and productive rate under protonic acid catalysis.Avoided using in existing method poisonous, environmental hazard large or the use of valuable raw material.Simultaneously simple, the safety of whole process, low cost.The following examples can more specifically be understood the present invention, but routine embodiment is further illustrating rather than limiting the scope of the invention patent.
Embodiment 1: do not add secondary solvent
In 250 milliliters of there-necked flasks, add 16.3 grams of 50% oxoethanoic acids (0.11mole), be cooled to 0 ℃ of mixing solutions that slowly splashes into below the vitriol oil 20 grams (0.2mole) and water 2.7 grams (0.15mole).Control temperature in a ℃ left and right, slowly drip 10.8 grams of (0.1mole) methyl-phenoxides.Methyl-phenoxide adds rear continuation temperature control at 0 degree left and right stirring reaction, and HPLC follows the tracks of reaction process.After 7 hours, methyl-phenoxide transformation efficiency is 97.7%, to methoxyl group tonsilla acid 33.7%, two (p-methoxyphenyl)-acetic acid 45.3%, methyl-phenoxide 2.3%.
Embodiment 2: add acetic acid
In 250 milliliters of there-necked flasks, add 50% oxoethanoic acid 16.3 grams of (0.11mol), 5 milliliters of acetic acid, be cooled to 0 ℃ of mixing solutions that slowly splashes into below the vitriol oil 20 grams (0.2mol) and water 2.7 grams (0.15mol).Control temperature 0 ℃ of left and right, slowly drip 10.8 grams of (0.1mol) methyl-phenoxides.Methyl-phenoxide adds rear continuation temperature control at 0 ℃ of left and right stirring reaction, and HPLC follows the tracks of reaction process.After 7 hours, methyl-phenoxide transformation efficiency is 95.2%, to methoxyl group tonsilla acid 47.2%, two-(p-methoxyphenyl)-acetic acid 44.1%, methyl-phenoxide 4.8%.
Embodiment 3: add 4-methyl-2 pentanone
In 250 milliliters of there-necked flasks, add 50% oxoethanoic acid 16.3 grams of (0.11mol), 5 milliliters of 4-methyl-2 pentanones, be cooled to 0 ℃ of mixing solutions that slowly splashes into below the vitriol oil 20 grams (0.2mol) and water 2.7 grams (0.15mol).Control temperature 0 ℃ of left and right, slowly drip 10.8 grams of (0.1mol) methyl-phenoxides.Methyl-phenoxide adds rear continuation temperature control at 0 ℃ of left and right stirring reaction, and HPLC follows the tracks of reaction process.After 7 hours, methyl-phenoxide transformation efficiency is 93.7%, to methoxyl group tonsilla acid 54.8%, two-(p-methoxyphenyl)-acetic acid 31.8%, methyl-phenoxide 6.3%.
Embodiment 4: add di-alcohol dme
In 250 milliliters of there-necked flasks, add 50% oxoethanoic acid 16.3 grams of (0.11mole), 5 milliliters of diethylene glycol dimethyl ethers, be cooled to 0 ℃ of mixing solutions that slowly splashes into below the vitriol oil 20 grams (0.2mol) and water 2.7 grams (0.15mol).Control temperature in a ℃ left and right, slowly drip 10.8 grams of (0.1mol) methyl-phenoxides.Methyl-phenoxide adds rear continuation temperature control at 0 degree left and right stirring reaction, and HPLC follows the tracks of reaction process.After 9.5 hours, methyl-phenoxide transformation efficiency is 92.2%, to methoxyl group tonsilla acid 66.0%, two-(p-methoxyphenyl)-acetic acid 17.6%, methyl-phenoxide 7.8%.
Embodiment 5: phosphoric acid replaces sulfuric acid not add secondary solvent
In 250 milliliters of there-necked flasks, add 16.3 grams of 50% oxoethanoic acids (0.11mole), be cooled to 0 ℃ slowly to splash into below 23 grams of 85% phosphoric acid (0.2mol).Control temperature in a ℃ left and right, slowly drip 10.8 grams of (0.1mol) methyl-phenoxides.Methyl-phenoxide adds rear continuation temperature control at 0 degree left and right stirring reaction, and HPLC follows the tracks of reaction process.Experiment finds that this reaction reacts hardly 0 ℃ and room temperature, after rise to 50 ℃ of reactions after 30 hours, methyl-phenoxide transformation efficiency is 67.5%, to methoxyl group tonsilla acid 13.8%, two-(p-methoxyphenyl)-acetic acid 41.2%, methyl-phenoxide 32.5%.
Embodiment 5: tetra-sodium replaces sulfuric acid not add secondary solvent
In 250 milliliters of there-necked flasks, add 16.3 grams of 50% oxoethanoic acids (0.11mol), be cooled to 0 ℃ slowly to splash into below 21 grams of tetra-sodiums.Control temperature 0 ℃ of left and right, slowly drip 10.8 grams of (0.1mol) methyl-phenoxides.Methyl-phenoxide adds rear continuation temperature control at 0 ℃ of left and right stirring reaction, HPLC follows the tracks of reaction process, after 30 hours, methyl-phenoxide transformation efficiency 82.6%, to methoxyl group tonsilla acid 58.1%, two-(p-methoxyphenyl)-acetic acid 15.5%, methyl-phenoxide 17.4%.
Embodiment 6: tetra-sodium replaces sulfuric acid to add 5ml diethylene glycol dimethyl ether secondary solvent
In 250 milliliters of there-necked flasks, add 50% oxoethanoic acid 16.3 grams of (0.11mol), 5 milliliters of di-alcohol dme, be cooled to 0 ℃ slowly to splash into below 21 grams of tetra-sodiums.Control temperature in a ℃ left and right, slowly drip 10.8 grams of (0.1mol) methyl-phenoxides.After methyl-phenoxide adds, room temperature continues stirring reaction, and HPLC follows the tracks of reaction process, and after 7 hours, methyl-phenoxide transformation efficiency is 85.2%, to methoxyl group tonsilla acid 48.1%, two-(p-methoxyphenyl)-acetic acid 27.8%, methyl-phenoxide 14.8%.
Claims (6)
1. the preparation method to the acid of methoxyl group tonsilla, is characterized in that: take oxoethanoic acid, methyl-phenoxide as raw material, add appropriate water, under strong protonic acid catalysis, add a certain amount of auxiliary agent to generate the acid of methoxyl group tonsilla.
2. according to claim 1 in step, oxoethanoic acid is that concentration is more than 40% aqueous glyoxylic acid, and strong protonic acid is the vitriol oil, strong phosphoric acid, perchloric acid etc.
3. according to claim 1 in step, adjuvant used can be stable organic solvent under the condition of reaction, as acids.Ethers, ketone, ester class or amides etc.
4. described in wanting 1 according to right in step, methyl-phenoxide and oxoethanoic acid mol ratio be 1: 1～1.5, more preferably 1: 1.1, temperature of reaction is-5 ℃～+ 5 ℃, more preferably 0 ℃～5 ℃, for 50% oxoethanoic acid, the mole dosage of water is 1～2 times of methyl-phenoxide, is more preferably 1.5 times.
5. according to claim 2, the preferred vitriol oil of strong acid using, preferred mole dosage is methyl-phenoxide 2 times, the reaction times is 7～15 hours.
6. according to claim 3 in step, adjuvant used is acetic acid, ethyl acetate, 4-methylpenta-2-one, DMF, acetonitrile, pyridine, diethylene glycol dimethyl ether, tetraethyleneglycol dimethyl ether etc., the gylcol ether that preferably can dissolve each other with water, as diethylene glycol dimethyl ether, tetraethyleneglycol dimethyl ether etc., be more preferably glycol dimethyl ether.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112076180A (en) * | 2019-06-12 | 2020-12-15 | 华东理工大学 | Antihypertensive polyol compounds and derivatives thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112076180A (en) * | 2019-06-12 | 2020-12-15 | 华东理工大学 | Antihypertensive polyol compounds and derivatives thereof |
| CN112076180B (en) * | 2019-06-12 | 2024-04-30 | 源道医药(苏州)有限公司 | Antihypertensive polyol compounds and derivatives thereof |
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Application publication date: 20140514 |