CN103073391A - Novel synthesis process for 4-phenyl-1-butanol - Google Patents
Novel synthesis process for 4-phenyl-1-butanol Download PDFInfo
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- CN103073391A CN103073391A CN 201110326554 CN201110326554A CN103073391A CN 103073391 A CN103073391 A CN 103073391A CN 201110326554 CN201110326554 CN 201110326554 CN 201110326554 A CN201110326554 A CN 201110326554A CN 103073391 A CN103073391 A CN 103073391A
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- CDIIZULDSLKBKV-UHFFFAOYSA-N O=C(CCCCl)Cl Chemical compound O=C(CCCCl)Cl CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 description 1
- GHEFQKHLHFXSBR-UHFFFAOYSA-N O=C(CCCCl)c1ccccc1 Chemical compound O=C(CCCCl)c1ccccc1 GHEFQKHLHFXSBR-UHFFFAOYSA-N 0.000 description 1
- YEJRWHAVMIAJKC-UHFFFAOYSA-N O=C1OCCC1 Chemical compound O=C1OCCC1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N c1ccccc1 Chemical compound c1ccccc1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a novel synthesis process for 4-phenyl-1-butanol. According to the process, tetrahydrofuran is used as a raw material and rapidly and moderately reacts with acyl chloride under catalysis of zinc chloride so as to obtain high-yield high-purity 4-chlrobutanol ester; without separation, 4-chlrobutanol ester and benzene undergo Friedel-Crafts alkylation under catalysis of aluminum trichloride to obtain 4-phenyl-butanol ester; and 4-phenyl-butanol ester undergoes hydrolysis under an alkaline condition so as to produce 4-phenyl-1-butanol. The process has the advantages of easiness, greenness, environment-friendliness, safety and low cost.
Description
One, technical field
The invention belongs to medical technical field, relate to the preparation method of 4-phenyl-n-butyl alcohol.
Two, technical background
4-phenyl-n-butyl alcohol is widely used in the industries such as medicine, agricultural chemicals, dyestuff, spices, is an important intermediate of synthetic a lot of compounds.This product is the key intermediate of the medicines such as treatment asthmatic medicament-Pu Leinster, long acting β_2 agonistics Salmeterol (salmeterol), also can be used for synthetic coffic acid benzene butyl alcohol ester with anti-tumor activity etc.In order to seek productive rate height, synthetic method that cost is low, people conduct extensive research, and have proposed a lot of synthetic methods, but there is no at present a more perfect synthetic route.Early fifties Searles has reported one take chloro benzyl, 1，3-epoxypropane as raw material, prepares the synthetic route of benzene propyl carbinol through grignard reaction.Thereafter Detar and Weis and Badger and Kimber have reported respectively synthetic route separately.In these methods, to use respectively inflammable and explosive Grignard reagent and tetrahydrochysene lithium aluminium, severe reaction conditions, productive rate is low, is unfavorable in batches scale production.Wherein the most common a kind of method is as starting raw material take benzene and Succinic anhydried; the gram acylations obtains 4-carbonyl benzenebutanoic acid through paying through an intermediary in a business deal; then with zinc-amalgam reduction method carbonyl reduction is become methylene radical, become hydroxyl to obtain target product carboxyl reduction with lithium aluminum hydride at last.But this technique is used mercury reagent and the dangerous and expensive lithium aluminum hydride of severe toxicity, is not suitable for suitability for industrialized production.
Niu Zhigang etc. (chemical reagent, 1995,17 (5), 317,288) propose take gamma-butyrolactone as starting raw material, through the synthetic 4-phenyl n-butyl alcohol of the steps such as open loop, friedel-crafts reaction, reduction and alkaline hydrolysis.Reaction process is as follows:
This technique is used the mercury reagent of severe toxicity, and is very large to environmental influence, and gamma-butyrolactone is more expensive, is difficult to realize industrialization.
Wang Xiaoqin (Guangzhou chemistry, 2005,30 (1), 31-34) above-mentioned experiment route is improved, replace the zinc amalgam reducing carbonyl to become methylene radical by the Wollf-Kishner reduction method, then synthesized 4-phenyl-n-butyl alcohol by reactions such as esterification and Ester Reduction with Sodium Borohydrides, made total recovery be not less than 35%.Concrete synthetic route is as follows:
Although this route has been avoided hypertoxic mercury reagent, the Wollf-Kishner reaction produces a large amount of waste lyes, and high temperature highly basic is serious to equipment corrosion, and the step overall yield is low simultaneously, and uses sodium borohydride that certain risk is also arranged.
Chen Hua waits very that (Chinese Journal of Pharmaceuticals 2007,38 (10) is raw material with benzene and gamma-butyrolactone 692-694), makes 4-phenylbutyrate through friedel-crafts reaction one step, then reduces to get 4-phenylbutyrate through sodium borohydride iodine.Technique total recovery after the improvement is 67%.But sodium borohydride and iodine are all comparatively expensive, and production cost is high.
(the meticulous and specialty chemicals such as Dong Danhong, 2007,15 (9) 15-16), (the meticulous and specialty chemicals such as Zhao Yougui, 2010,18 (3) 28-30), Chinese patent (CN101450943A) etc. has been reported with hydrogenchloride the tetrahydrofuran (THF) open loop has been prepared the 4-butylene-chlorohydrin, then produce the method for 4-phenyl butanols with benzene generation friedel-crafts reaction, synthetic route:
This operational path is short, and raw materials cost is low, but the reaction time consumption of tetrahydrofuran (THF) open loop 4-butylene-chlorohydrin processed under the HCl effect is long, productive rate is low, is looped back to tetrahydrofuran (THF) because the 4-butylene-chlorohydrin closes easily, and therefore simultaneously also easily polymerization is difficult to obtain highly purified 4-butylene-chlorohydrin.
Also have hydrogen chloride gas strong to equipment corrosion, have potential safety hazard.
Three, 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 of 4-phenyl n-butyl alcohol, compare with existing method, equipment requirements of the present invention is simple, easy to operate, the reaction process environmental protection, starting material are inexpensive, and easily control has good industrial prospect.
For achieving the above object, technical scheme of the present invention is:
A kind of preparation method of 4-phenyl n-butyl alcohol may further comprise the steps:
Take tetrahydrofuran (THF) as raw material, under zinc chloride catalysis with acyl chloride reaction fast gentle, obtain 4-neoprene alcohol ester to high yield.
1) acyl chlorides can be the acyl chlorides of aliphatic or aromatic acid here, such as Acetyl Chloride 98Min., Benzoyl chloride.
2) at 4-butylene-chlorohydrin acetic ester and benzene in the unseparated situation gram alkylated reaction occuring under Using Aluminium Trichloride as Catalyst to pay obtains 4-phenyl butyl alcohol ester.
3) hydrolysis generates 4-phenyl butanols in the methanol-hydrogen sodium hydroxide solution.
Preferably:
Described step 1) mol ratio of tetrahydrofuran (THF) and acyl chlorides is 1～1.5: 1 in, and more preferably 1.10: 1.0, temperature of reaction was-5 ℃～30 ℃, and more preferably 0 ℃～25 ℃, the consumption of zinc chloride and the mol ratio of tetrahydrofuran (THF) are 10%～0.1%.
Described step 2) catalyst system therefor is AlCl in
3, with the mol ratio of tetrahydrofuran (THF) be 1: 1.5～1.0, benzene is 2～8 equivalents of tetrahydrofuran (THF), preferably 2-5 equivalent.Temperature of reaction is 0 ℃～50 ℃, and preferably 0 ℃～20 ℃, the reaction times is 3～5 hours.
Described step 3) solvent for use is ethanol, methyl alcohol etc. in, and used alkali is NaOH, KOH, Na
2CO
3, K
2CO
3Deng, temperature of reaction is 0-60 ℃, preferably 20-60 ℃.
Route involved in the present invention is as follows:
Four, specific embodiments
Key point of the present invention is take tetrahydrofuran (THF) as raw material, under zinc chloride catalysis with acyl chloride reaction fast, gentleness, high yield, obtain 4-neoprene alcohol ester to high purity.At 4-neoprene alcohol ester and benzene in the unseparated situation gram alkylated reaction occuring under Using Aluminium Trichloride as Catalyst to pay obtains 4-phenyl butyl alcohol ester.Avoided tetrahydrofuran (THF) open loop under the hydrogen chloride gas effect to produce the potential safety hazard of the poor efficiency of 4-butylene-chlorohydrin, time-consuming, low-yield, hydrogen chloride gas, unstable and the low levels of 4-butylene-chlorohydrin have been avoided, the 4-butylene-chlorohydrin does not need separation and purification, is directly used in the next step.Simultaneously simple, the safety of whole process, low cost.The following examples can more specifically be understood the present invention, but in fact illustrate rather than limit the scope of the invention.
Embodiment 1
Add Zinc Chloride Anhydrous 1 gram in 250 milliliters of there-necked flasks, Acetyl Chloride 98Min. 78.5 grams stir lower tetrahydrofuran (THF) 72 grams that drip, the ice bath cooling is lower to drip off rear insulation 1 hour to maintain the temperature at below 30 degree, and the water pump underpressure distillation gets 4-butylene-chlorohydrin ethyl ester 145 grams, productive rate 96%, purity 99.5%.
30 gram 4-butylene-chlorohydrin ethyl esters, 78 gram benzene add respectively in 250 milliliters the there-necked flask, stir lower 0 degree that is cooled to, and add 30 gram aluminum trichloride (anhydrous)s in batches, the control temperature 10 spend below.Add rear insulation and spend 3 hours 10, the vapor detection raw material reaction is complete.Reaction solution slowly poured in the trash ice be hydrolyzed, stirred 30 minutes, separate organic phase.Organic phase is water, saturated common salt water washing respectively, anhydrous magnesium sulfate drying.After reclaiming benzene, underpressure distillation gets product 27 grams, productive rate: 70%.Above-mentioned product 27 grams are dissolved in 60 ml methanol, add the 10 ml water solution that fill 6 gram sodium hydroxide, heated and stirred 1 hour reacts completely.Behind the Distillation recovery methyl alcohol, wash neutrality with water, a minute oil-yielding stratum gets 20 gram benzene butanols, productive rate 95%.
Embodiment 2
Add Zinc Chloride Anhydrous 1 gram in 1000 milliliters of there-necked flasks, Acetyl Chloride 98Min. 78.5 grams stir lower tetrahydrofuran (THF) 72 grams that drip, and the ice bath cooling is lower to maintain the temperature at below 30 degree, drips off rear insulation reaction in 1 hour and finishes vapor detection 4-butylene-chlorohydrin acetate content 97%.In this reaction solution, add 390 gram benzene, cool to 0 degree.Add aluminum chloride 160 grams in batches, maintain the temperature at below 10 degree.Be incubated 3 hours, the gas chromatographic detection raw material disappears.Reaction solution slowly poured in the frozen water be hydrolyzed, stirred 30 minutes, tell organic phase, respectively water and saturated common salt water washing, anhydrous magnesium sulfate drying.After benzene was removed in distillation, the oil pump underpressure distillation got colourless liquid benzene butanols acetic ester 144 grams, productive rate 75%.Add 300 ml methanol in gained 144 gram benzene butanols acetic ester, contain 50 ml water solution of 31.5 gram sodium hydroxide, reflux stirred 2 hours, reacted completely.Behind the Distillation recovery methyl alcohol, add 100 ml waters, minute oil-yielding stratum is distinguished water again, the saturated common salt water washing, and anhydrous magnesium sulfate drying gets benzene butanols 109 grams, productive rate 97%.
Embodiment 3
Add Zinc Chloride Anhydrous 1 gram in 250 milliliters of there-necked flasks, Benzoyl chloride 141 grams stir lower room temperature and drip tetrahydrofuran (THF) 72 grams, drip in the process and to keep being stabilized in below 40 degree, drip off rear insulation 2 hours, underpressure distillation gets 4-butylene-chlorohydrin benzoic ether 200 grams, productive rate 94%, purity 99.35%.
42.5 gram 4-butylene-chlorohydrin benzoic ether, 78 gram benzene add respectively in 250 milliliters the there-necked flask, stir lower 0 degree that is cooled to, and add 30 gram aluminum trichloride (anhydrous)s in batches, the control temperature 10 spend below.The following insulation of 10 degree is 3 hours after adding, and the vapor detection raw material reaction is complete.Reaction solution slowly poured in the trash ice be hydrolyzed, stirred 30 minutes, separate organic phase.Organic phase is water, saturated common salt water washing respectively, anhydrous magnesium sulfate drying.After reclaiming benzene, underpressure distillation gets product 4-benzene butanols benzoic ether 38 grams, productive rate: 75%.
Above-mentioned product 38 grams are dissolved in 60 ml waters, add the 10 ml water solution that fill 6 gram sodium hydroxide, heated and stirred 1 hour reacts completely.Behind the Distillation recovery methyl alcohol, wash neutrality with water, a minute oil-yielding stratum gets 21.6 gram benzene butanols, productive rate 96%.
Claims (7)
1. the synthetic method of a 4-phenyl-n-butyl alcohol, may further comprise the steps: take tetrahydrofuran (THF) as raw material, under zinc chloride catalysis with acyl chloride reaction fast gentle, obtain 4-neoprene alcohol ester to high yield, under Using Aluminium Trichloride as Catalyst, occur to pay at 4-butylene-chlorohydrin acetic ester and benzene in the unseparated situation-the Ke alkylated reaction obtains 4-phenyl butyl alcohol ester, and subsequently hydrolysis generates 4-phenyl butanols.
2. synthetic side according to claim 1, it is characterized in that: tetrahydrofuran (THF) fast, leniently generates 4-neoprene acid esters with acyl chlorides under the zinc chloride effect of catalytic amount.
3. synthetic side according to claim 2, it is characterized in that: in the described step, the mol ratio of tetrahydrofuran (THF) and acyl chlorides is 1～1.5: 1, more preferably 1.10: 1.0.For fatty acid chloride, temperature of reaction is-5 ℃～30 ℃, more preferably 0 ℃～25 ℃.For the aromatic acid acyl chlorides, temperature of reaction is 0～50 degree, preferably 30-50 degree.The consumption of zinc chloride and the mol ratio of tetrahydrofuran (THF) are 10%～0.1%.
4. synthetic side according to claim 2, it is characterized in that: used acyl chlorides can be that fatty acid chloride also can be aromatic acid acyl chlorides such as Acetyl Chloride 98Min., Benzoyl chloride etc.
5. synthetic side according to claim 1, it is characterized in that: the 4-neoprene ester that generates can be directly used in next step friedel-crafts reaction without separation and purification.
6. synthetic side according to claim 1, it is characterized in that: catalyst system therefor is AlCl in the friedel-crafts reaction
3, with the mol ratio of tetrahydrofuran (THF) be 1: 1.5～1.0, benzene is 2～8 equivalents of tetrahydrofuran (THF), preferably 2-5 equivalent.Temperature of reaction is 0 ℃～50 ℃, and preferably 0 ℃～20 ℃, the reaction times is 3～5 hours.
7. synthetic side according to claim 1 is characterized in that: solvent for use is ethanol, methyl alcohol etc. in the hydrolysis of 4-phenyl butyl alcohol ester, and used alkali is NaOH, KOH, Na
2CO
3, K
2CO
3Deng, temperature of reaction is 0-60 ℃, preferably 20-60 ℃.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108484398A (en) * | 2018-03-30 | 2018-09-04 | 黑龙江大学 | A kind of preparation method of 4- halobutyls acetic acid esters |
| CN109776484A (en) * | 2017-11-14 | 2019-05-21 | 石家庄圣泰化工有限公司 | The synthetic method of 1,4- butane sultones |
| CN111410600A (en) * | 2020-01-21 | 2020-07-14 | 安徽省诚联医药科技有限公司 | Preparation method of p-phenylbutoxy benzoic acid |
| CN111499547A (en) * | 2020-03-03 | 2020-08-07 | 江汉大学 | Preparation method and application of alkyl ether sulfonyl fluoride compound |
-
2011
- 2011-10-25 CN CN 201110326554 patent/CN103073391A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109776484A (en) * | 2017-11-14 | 2019-05-21 | 石家庄圣泰化工有限公司 | The synthetic method of 1,4- butane sultones |
| CN109776484B (en) * | 2017-11-14 | 2023-05-09 | 河北圣泰材料股份有限公司 | Synthesis method of 1, 4-butane sultone |
| CN108484398A (en) * | 2018-03-30 | 2018-09-04 | 黑龙江大学 | A kind of preparation method of 4- halobutyls acetic acid esters |
| CN108484398B (en) * | 2018-03-30 | 2021-01-22 | 黑龙江大学 | Preparation method of 4-halobutyl acetate |
| CN111410600A (en) * | 2020-01-21 | 2020-07-14 | 安徽省诚联医药科技有限公司 | Preparation method of p-phenylbutoxy benzoic acid |
| CN111499547A (en) * | 2020-03-03 | 2020-08-07 | 江汉大学 | Preparation method and application of alkyl ether sulfonyl fluoride compound |
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Application publication date: 20130501 |