CN101391941A - Method for preparing 3,5-dihydroxybenzylalcohol - Google Patents
Method for preparing 3,5-dihydroxybenzylalcohol Download PDFInfo
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- CN101391941A CN101391941A CN 200810172449 CN200810172449A CN101391941A CN 101391941 A CN101391941 A CN 101391941A CN 200810172449 CN200810172449 CN 200810172449 CN 200810172449 A CN200810172449 A CN 200810172449A CN 101391941 A CN101391941 A CN 101391941A
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- alcohol
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- resorcylic acid
- dihydroxybenzyl
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Abstract
The invention discloses a preparing method of 3, 5-dihydroxybenzyl methanol, which comprises the following steps: 1) 3, 5-Dihydroxy-benzoic acid and methanol are carried out with esterification reaction under the condition of taking sulphuric acid as a catalyst to obtain 3, 5-dihydroxy-benzoic acid ester; 2) the 3, 5-dihydroxy-benzoic acid ester is dissolved in an organic solvent to obtain the organic solution of 3, 5-dihydroxy-benzoic acid ester; and 3) Lewis acid and hydroboron are sequentially or simultaneously added in an organic solvent which is the same with that in the step 2) and dissolved, and reduction reaction is carried out by dripping the organic solution of 3, 5-dihydroxy-benzoic acid ester obtained in the step 2) to obtain the 3, 5-dihydroxybenzyl methanol. The method has the advantages of easy process, lower cost, no environmental pollution and being suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of medicine intermediate, be specifically related to a kind of 3, the preparation method of 5-dihydroxybenzyl alcohol.
Background technology
3, the 5-dihydroxybenzyl alcohol is in preparation armillarisin, the rich Nikon and the important intermediate of medicine such as bromine Moses woods, can also prepare 3 in addition, materials such as 5-Dihydroxy benzaldehyde, 3,5-resacetophenone.
Li Yuling etc. disclose 3 on the 26th the 1st phase of volume of " guizhou chemical industry " March calendar year 2001; 5-dihydroxybenzyl alcohol synthesising process research: this technology is with 3; the 5-resorcylic acid is a raw material; obtain 3 through over-churning; the 5-methyl dihydroxy benzoate obtains 3,5-diacetoxy methyl benzoate through acidylate then; reduction obtains 3, the 5-dihydroxybenzyl alcohol through Lithium Aluminium Hydride at last.
This method needs to use expensive protection reagent to carry out acidylate in building-up process to protect hydroxyl, so production cost is than higher.
Summary of the invention
The objective of the invention is to overcome the problems referred to above, provide a kind of production cost lower, be suitable for 3 of suitability for industrialized production, the preparation method of 5-dihydroxybenzyl alcohol.
The technical scheme that realizes the object of the invention is: a kind of 3, the preparation method of 5-dihydroxybenzyl alcohol has following steps: 1. with 3,5-resorcylic acid and alcohol carry out esterification at sulfuric acid under as the condition of catalyzer and obtain 3,5-resorcylic acid ester; 2. with 3,5-resorcylic acid ester is dissolved in the organic solvent, obtains 3, the organic solution of 5-resorcylic acid ester; 3. successively or join simultaneously and step in 2. in the identical organic solvent, and make it dissolving with Lewis acid and hydroborate, drip that 2. step obtain 3, the organic solution of 5-resorcylic acid ester is carried out reduction reaction and is obtained 3, the 5-dihydroxybenzyl alcohol.
The alcohol of above-mentioned steps described in 1. is methyl alcohol and/or ethanol, alcohol and 3 wherein, and the mol ratio of 5-resorcylic acid is 10:1～25:1.
The vitriolic weight of above-mentioned steps described in 1. is 3,0.1%～20% of 5-resorcylic acid weight.
Above-mentioned steps 2. and the organic solvent of step described in 3. be tetrahydrofuran (THF), diethylene glycol dimethyl ether, 1, a kind of in the 4-dioxane or two kinds.
The hydroborate of above-mentioned steps described in 3. is sodium borohydride, POTASSIUM BOROHYDRIDE or their mixture, hydroborate and 3 wherein, and the mol ratio of 5-resorcylic acid ester is 1.5:1～4:1.
The Lewis acid of above-mentioned steps described in 3. is a kind of in aluminum chloride, zinc chloride, the boron trifluoride or two kinds, and wherein the mol ratio of Lewis acid and hydroborate is 0.2:1～0.5:1.
The positively effect that the present invention has: the present invention adopts hydroborate+Lewis acid as the composite reduction system, and directly with 3,5-resorcylic acid ester is reduced into 3, the 5-dihydroxybenzyl alcohol in organic solvents such as tetrahydrofuran (THF).Make technology simpler, and cost is lower, the used reagent of reduction reaction is anhydrous reagent, also non-environmental-pollution.Therefore method of the present invention is suitable for suitability for industrialized production.
Embodiment
(embodiment 1)
3 of present embodiment, the preparation method of 5-dihydroxybenzyl alcohol has following steps:
1. in there-necked flask, add 3 of 25g, the methyl alcohol (3.7mol) of 5-resorcylic acid (0.16mol) and 118g, stirring and dissolving drips the vitriol oil of 0.3g then.Drip off restir, and be warming up to reflux temperature, back flow reaction 8 hours removes methyl alcohol then under reduced pressure, obtains 3,5-methyl dihydroxy benzoate crude product.Then use rare NaHCO
3Aqueous solution recrystallization filters, and drying obtains 26g white 3, the 5-methyl dihydroxy benzoate.
2. add tetrahydrofuran (THF) in there-necked flask, vigorous stirring adds the aluminum chloride (0.05mol) of 7g then, and solid is dissolved fully.The POTASSIUM BOROHYDRIDE (0.14mol) that adds 7.5g then continues to stir.Then drip contain that 1. the 6.7g step obtain 3, the tetrahydrofuran solution of 5-methyl dihydroxy benzoate (0.04mol), thus take place to generate 3, the reaction of 5-dihydroxybenzyl alcohol, drip off the reflux temperature that slowly is warmed up to tetrahydrofuran (THF), insulation reaction 6 hours cools to 20 ℃ again.The concentration that then reaction system is joined 100ml is termination reaction in the aqueous hydrochloric acid of 10wt%.Through extracting as extraction agent with tetracol phenixin, steam again and remove the tetrahydrofuran (THF) organic solvent, obtain the white solid crude product.Then crude product is joined recrystallization in the hot water, obtain 3 of 4.8g, 5-dihydroxybenzyl alcohol white crystal.Yield is 77%, and purity is 98.5%.
(embodiment 2～embodiment 6)
The preparation method of each embodiment is substantially the same manner as Example 1, and difference sees Table 1.
Table 1
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | |
| 3, the 5-resorcylic acid | 25g、? 0.16mol | 31g、 0.2mol | 46g、 0.3mol | 46g、 0.3mol | 31g、 0.2mol | 31g、 0.2mol |
| Alcohol | 118g methyl alcohol, 3.7mol | 128g methyl alcohol, 4mol | 184g ethanol, 4mol | 96g methyl alcohol, 3mol | 64g methyl alcohol, 2mol and 92g ethanol, 2mol | 160g methyl alcohol, 5mol |
| Sulfuric acid | 0.3g | 0.3g | 2g | 4.6g | 6g | 1g |
| Obtain 3,5-resorcylic acid ester | The methyl esters of 26g | The methyl esters of 32g | The ethyl ester of 50g | The methyl esters of 48g | The ethyl ester of the methyl esters 17g of 16g | The methyl esters of 33g |
| Organic solvent | Tetrahydrofuran (THF) | Tetrahydrofuran (THF) | Diethylene glycol dimethyl ether | Tetrahydrofuran (THF) and 1, the 4-dioxane | Tetrahydrofuran (THF) | 1, the 4-dioxane |
| Lewis acid | The aluminum chloride of 7g, 0.05mol | 5.44g zinc chloride, 0.04mol | 3.4g boron trifluoride, 0.05mol | 8.16g zinc chloride, 0.06mol | 2.7g aluminum chloride, the boron trifluoride of 0.02mol 2g, 0.03mol | The aluminum chloride of 4g, 0.03mol |
| Hydroborate | 7.5g POTASSIUM BOROHYDRIDE, 0.14mol | 7.6g sodium borohydride, 0.2mol | 3.8g sodium borohydride, 0.1mol and 5.4 POTASSIUM BOROHYDRIDE, 0.1mol | 16.2g POTASSIUM BOROHYDRIDE, 0.3mol | 3.8g sodium borohydride, 0.1mol | 4.9g POTASSIUM BOROHYDRIDE, 0.09mol |
| 3 of dropping, 5-resorcylic acid ester | 6.7g methyl esters, 0.04mol | The methyl esters of 10g, 0.06mol | 14.6g ethyl ester, 0.08mol | 13.4g methyl esters, 0.08mol | 3.4g methyl esters, the ethyl ester of 0.02mol 3.6g, 0.02mol | The methyl esters of 10g, 0.06mol |
| Obtain 3, the 5-dihydroxybenzyl alcohol | 4.8g | 7.3g | 9.2g | 9.6g | 4.7g | 7g |
| Yield | 77％ | 78％ | 75％ | 77％ | 76％ | 75％ |
| Purity | 98.5％ | 98.8％ | 98.3％ | 98.1％ | 98.6％ | 98.5％ |
Annotate: methyl esters represents 3 in the table 1, the 5-methyl dihydroxy benzoate, and ethyl ester represents 3, the 5-dihydric ethyl benzoate.
Claims (6)
1, a kind of 3, the preparation method of 5-dihydroxybenzyl alcohol is characterized in that having following steps:
1. with 3,5-resorcylic acid and alcohol carry out esterification at sulfuric acid under as the condition of catalyzer and obtain 3,5-resorcylic acid ester;
2. with 3,5-resorcylic acid ester is dissolved in the organic solvent, obtains 3, the organic solution of 5-resorcylic acid ester;
3. successively or join simultaneously and step in 2. in the identical organic solvent, and make it dissolving with Lewis acid and hydroborate, drip that 2. step obtain 3, the organic solution of 5-resorcylic acid ester is carried out reduction reaction and is obtained 3, the 5-dihydroxybenzyl alcohol.
2, according to claim 13, the preparation method of 5-dihydroxybenzyl alcohol is characterized in that: the alcohol of step described in 1. is methyl alcohol and/or ethanol, alcohol and 3 wherein, and the mol ratio of 5-resorcylic acid is 10:1～25:1.
3, according to claim 13, the preparation method of 5-dihydroxybenzyl alcohol is characterized in that: the vitriolic weight of step described in 1. is 3,0.1%～20% of 5-resorcylic acid weight.
4, according to claim 13, the preparation method of 5-dihydroxybenzyl alcohol is characterized in that: step 2. and the organic solvent of step described in 3. be tetrahydrofuran (THF), diethylene glycol dimethyl ether, 1, a kind of in the 4-dioxane or two kinds.
5, according to claim 13, the preparation method of 5-dihydroxybenzyl alcohol, it is characterized in that: the hydroborate of step described in 3. is sodium borohydride, POTASSIUM BOROHYDRIDE or their mixture, hydroborate and 3 wherein, and the mol ratio of 5-resorcylic acid ester is 1.5:1～4:1.
6, according to claim 13, the preparation method of 5-dihydroxybenzyl alcohol, it is characterized in that: the Lewis acid of step described in 3. is a kind of in aluminum chloride, zinc chloride, the boron trifluoride or two kinds, and wherein the mol ratio of Lewis acid and hydroborate is 0.2:1～0.5:1.
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| CN2008101724490A CN101391941B (en) | 2008-11-11 | 2008-11-11 | Method for preparing 3,5-dihydroxybenzylalcohol |
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| CN2008101724490A CN101391941B (en) | 2008-11-11 | 2008-11-11 | Method for preparing 3,5-dihydroxybenzylalcohol |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102134182A (en) * | 2010-12-17 | 2011-07-27 | 胶州市精细化工有限公司 | Method for preparing saligenol |
| CN108341768A (en) * | 2018-03-12 | 2018-07-31 | 成都平和安康医药科技有限公司 | A kind of method that reduction method prepares vitamin B6 |
| CN108358836A (en) * | 2018-03-01 | 2018-08-03 | 成都平和安康医药科技有限公司 | The method that 2- methyl -3- pyridone -4,5- dicarboxylic acid esters reduction prepares vitamin B6 |
| CN111943806A (en) * | 2020-09-03 | 2020-11-17 | 中国林业科学研究院资源昆虫研究所 | Method for preparing higher alkanol by reducing white wax through sodium borohydride system under normal pressure |
| CN113121578A (en) * | 2019-12-31 | 2021-07-16 | 中国科学院福建物质结构研究所 | Preparation method of benzoborazole compound |
| CN113620777A (en) * | 2021-07-02 | 2021-11-09 | 江西犇牛医药化工有限公司 | Preparation method of 2, 6-difluorobenzyl alcohol |
| CN114773165A (en) * | 2019-05-13 | 2022-07-22 | 南京制药厂有限公司 | Refining method of drug intermediate 3, 5-dihydroxy benzyl alcohol |
| CN115925590A (en) * | 2022-12-30 | 2023-04-07 | 湖北龙翔药业科技股份有限公司 | Preparation method of florfenicol intermediate |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000191570A (en) * | 1998-12-24 | 2000-07-11 | Sumitomo Chem Co Ltd | Production of hydroxyphenylpropanol |
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2008
- 2008-11-11 CN CN2008101724490A patent/CN101391941B/en not_active Expired - Fee Related
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| CN102134182A (en) * | 2010-12-17 | 2011-07-27 | 胶州市精细化工有限公司 | Method for preparing saligenol |
| CN102134182B (en) * | 2010-12-17 | 2013-03-06 | 胶州市精细化工有限公司 | Method for preparing saligenol |
| CN108358836A (en) * | 2018-03-01 | 2018-08-03 | 成都平和安康医药科技有限公司 | The method that 2- methyl -3- pyridone -4,5- dicarboxylic acid esters reduction prepares vitamin B6 |
| CN108358836B (en) * | 2018-03-01 | 2021-04-27 | 成都平和安康医药科技有限公司 | Method for preparing vitamin B6 by reducing 2-methyl-3-hydroxypyridine-4, 5-diformate |
| CN108341768A (en) * | 2018-03-12 | 2018-07-31 | 成都平和安康医药科技有限公司 | A kind of method that reduction method prepares vitamin B6 |
| CN114773165A (en) * | 2019-05-13 | 2022-07-22 | 南京制药厂有限公司 | Refining method of drug intermediate 3, 5-dihydroxy benzyl alcohol |
| CN113121578A (en) * | 2019-12-31 | 2021-07-16 | 中国科学院福建物质结构研究所 | Preparation method of benzoborazole compound |
| CN113121578B (en) * | 2019-12-31 | 2022-12-06 | 中国科学院福建物质结构研究所 | Preparation method of benzoborazole compound |
| CN111943806A (en) * | 2020-09-03 | 2020-11-17 | 中国林业科学研究院资源昆虫研究所 | Method for preparing higher alkanol by reducing white wax through sodium borohydride system under normal pressure |
| CN113620777A (en) * | 2021-07-02 | 2021-11-09 | 江西犇牛医药化工有限公司 | Preparation method of 2, 6-difluorobenzyl alcohol |
| CN113620777B (en) * | 2021-07-02 | 2024-02-23 | 江西犇牛医药化工有限公司 | Preparation method of 2, 6-difluorobenzyl alcohol |
| CN115925590A (en) * | 2022-12-30 | 2023-04-07 | 湖北龙翔药业科技股份有限公司 | Preparation method of florfenicol intermediate |
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