CN101041619A - Preparation method of 1-chlorin -2-methyl -4-acetoxy-2- butylene - Google Patents
Preparation method of 1-chlorin -2-methyl -4-acetoxy-2- butylene Download PDFInfo
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- CN101041619A CN101041619A CN 200610050012 CN200610050012A CN101041619A CN 101041619 A CN101041619 A CN 101041619A CN 200610050012 CN200610050012 CN 200610050012 CN 200610050012 A CN200610050012 A CN 200610050012A CN 101041619 A CN101041619 A CN 101041619A
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Abstract
The invention discloses a making method of 1-chlorine-2-methyl-4-acetoxy-2-butene, which comprises the following steps: adopting isoprene as raw material; adding calcium hypochlorite solid and acetic acid as pH value adjuster to do chlorohydrin reaction; obtaining the additional product of 1, 2 position and 1, 4 position; reacting the additional product and acetic anhydride catalyzed by acid to produce the product; making the reacting system mild with little heteroion; improving the content and receiving rate of product.
Description
Technical field
The present invention relates to chemical field, specifically synthetic V
AThe preparation method of the important intermediate 1-chloro-2 methyl-4-acetoxyl group-2-butylene of acetic ester.
Background technology
Vitamin A (V
A) and derivative be the important medicine of a class, the product of each major company is all with V in the world
AAcetic ester be main ((chemical encyclopedia) editorial board, chemical encyclopedia, Chemical Industry Press, first version in 1996, Vol.16, P719-729).4-acetoxyl group-2-methyl-2-butene-1-aldehyde (MW142 is called for short five-carbon ring aldehydo) is to be the C of feature with the Wittig reaction
15+ C
5Route synthesizes V
AThe key intermediate of acetic ester (Tanaka, USP 5,424,478, Process for producingVitamin A Derivatives, [P] 1995; Tanaka, et al., JP 06,329,623, Preparation of Vitamin ADerivatives, [P] 1994; Zutter, Ulrich, Ep 648,735, Preparation of an intermediate for VitaminAacetate, [P] 1995; Wang Lanming, Beijing medicine, the vitamin A new synthesis process, [J] 1992,4,10-12), therefore the study on the synthesis to five-carbon ring aldehydo has important significance for theories and using value.
Reported its industrial preparative method (H.Pommer from expert H.Pommer of middle nineteen seventies BASF AG etc., A.Nurrenbach, Pure.Appl.Chem., Industrial synthesis of Terpene compounds, [J] 1975,43,527) so far, the study on the synthesis for it does not all have to interrupt, it all is by 1-chloro-2-methyl-4-acetoxyl group-2-butylene (MW162.5 that a lot of synthetic methods are wherein arranged, hereinafter to be referred as muriate) prepare (Tanaka, et al., the JP06 of five-carbon ring aldehydo, 329,623, Preparation of Vitamin A Derivatives, [P] 1994; Ven Kataratnam, Revannuru V., etal., Indian IN 168,539, An improved process for the preparation of4-acetoxy-2-methyl-2-butenal, [P] 1988; Kaneko, Tatsuhiko, et al., Jp.07,61,948, Preparationof α, β-unsaturated aldehydes, [P] 1995; Babler, James.H., PCT.Int.Appl.7900,485, E-4-Acetoxy-2-methyl-2-butenal, [P] 1979; Babler, JamesH., USP 4,175,204, E-4-Acetoxy-2-methyl-2-butenal, [P] 1979; Babler, JamesH., J.org.chem., Facile synthesis of4-acetoxy-2-methyl-2-butenal, a Vitamin A precursor[J] 1979,44 (10), 1716-17), can think that therefore muriate is synthetic V
AImportant intermediate.
Muriatic preparation mainly contains two kinds of method: Babler, JamesH. with the monochloroacetone raw material, earlier with the Grignard reagent of propenyl chloride react the tertiary alcohol, resterification reset muriate (Babler, James.H., PCT.Int.Appl.7900,485, E-4-Acetoxy-2-methyl-2-butenal, [P] 1979; Babler, JamesH., USP 4,175,204, E-4-Acetoxy-2-methyl-2-butenal, [P] 1979; Babler, JamesH., J.org.chem., Facile synthesis of4-acetoxy-2-methyl-2-butenal, a Vitamin A precursor[J] 1979,44 (10), 1716-17);
Another kind method is to carry out chlorohydrin action with isoprene and aqueous sodium hypochlorite solution, obtain 1 respectively, 2 and 1,4 's adduct, reaction mixture gets muriate (Tanaka with acetic anhydride under acid catalysis, et al., JP 06,329, and 623, Preparation of Vitamin A Derivatives, [P] 1994; Kuroda, Noritaka, et al., Jp.06,345,689, Preparation of butenal derivatives, [P] 1994).
Comparatively speaking, a kind of method raw material in back is cheap and easy to get, and industrial value is more arranged; In chlorohydrin action, can lead to CO
2Or dropping sulfuric acid, hydrochloric acid or acetate are kept the pH value.Because in above-mentioned chlorohydrin action, the available chlorine content of clorox is about 10%, available chlorine content is low, and corresponding hetero-ion is many, and is comparatively unfavorable to reaction, makes the yield of product and content lower; The pH value of aqueous sodium hypochlorite solution is greater than 10, and alkalescence is strong, and is violent with the isoprene reaction, regulates difficulty of control with pH value conditioning agent; The clorox of reaction is the aqueous solution, and bulky, waste water is many, storage transportation trouble.
Because the acidity of acetate is gentle, sodium acetate that generates and acetate are formed buffer system, should be highly beneficial to the reaction atmosphere of stabilising system, the reaction system of milder should help the raising of productive rate, find that after experimental verification yield is higher relatively when regulating the pH value with acetate, impurity is few relatively, and (content is 83%, but neither be very desirable yield 52%).
Usually the chlorohydrin action of alkene can lead to chlorine in the calcium hydroxide aqeous suspension, utilizes the active hypochlorous acid that generates directly to carry out chlorohydrination (chemical encyclopedia) editorial board, chemical encyclopedia, Chemical Industry Press, first version in 1996, Vol.16, P719-729); But we find that after experimental verification the product content of doing like this is very poor, may be that the existence of free chlorine and other hetero-ion makes two keys of alkene that side reactions such as dichloro addition take place, and cause impurity to increase.
Summary of the invention
Technical problem to be solved by this invention is to overcome the defective that above-mentioned prior art exists, the preparation method of the 1-chloro-2-methyl-4-acetoxyl group-2-butylene of a kind of reaction raw materials available chlorine content height, reaction system milder is provided, to improve reaction system greatly, reduce hetero-ion, improve the content and the yield of product.
For this reason, the present invention adopts following technical scheme: the preparation method of 1-chloro-2-methyl-4-acetoxyl group-2-butylene, may further comprise the steps: be raw material with the isoprene, in the presence of solvent, add Losantin solid and pH value conditioning agent acetate and carry out chlorohydrin action, get 1,2 and 1 respectively, 4 adduct, this blended adduct get 1-chloro-2-methyl-4-acetoxyl group-2-butylene with acetic anhydride under acid catalysis.Losantin is a solid, can play slow releasing function, reaction temperature and, the waste water of generation is less, the storage convenient transportation; The alkalescence of Losantin a little less than, the pH value is less than 9, with the isoprene reaction temperature and, it is easy to regulate control with pH value conditioning agent acetate.Chlorohydrin action carries out under the reaction system of the milder that is formed by Losantin solid and acetate, the content of product and yield height.
Above-mentioned preparation method, described Losantin is selected the bleaching essence of the chlorinated lime or the high available chlorine content of 30% available chlorine content for use, and available chlorine content is high more, and hetero-ion is few more, and is favourable more to reaction.
Above-mentioned preparation method, described pH value conditioning agent acetic acid water solution concentration is that 50-80% is better, the too low meeting of concentration makes the volume gain of reaction system, effective contact variation of reactant; It selects the mode that adds gradually in the reaction system for use, can better regulate the pH value like this.
Above-mentioned preparation method, described temperature of reaction are between-20 ℃ to 40 ℃, and between preferred-5 ℃ to 10 ℃, the temperature height will make by product increase greatly, and temperature is too low to be reached refrigeration when making industrial utilization again and require difficult.
Above-mentioned preparation method, described reaction can be carried out in the presence of the organic or inorganic solvent, operable solvent such as lower alcohols isopolarity solvent; Low polar solvent such as medium polar solvent such as ketone, ester class or halohydrocarbon.
The present invention has following beneficial effect: reaction raw materials is selected the high Losantin of available chlorine content for use, the reaction system gentleness, and hetero-ion is few, the content of product and yield height; The waste water that reaction produces is less, the storage convenient transportation.
The invention will be further described below in conjunction with embodiment.
Embodiment
Analytical instrument of using among the embodiment and equipment: gas chromatography mass spectrometry, MS5973N-GC6890N (U.S. Agilent company); Nuclear magnetic resonance analyser, AVANCE DMX 500 (mark in the TMS); Infrared spectrometer, NICOLET 360FT-IR.
The preparation of embodiment 1:1-chloro-2-hydroxy-2-methyl-3-butylene and 1-chloro-2-methyl-4-hydroxyl-2-butylene mixture
To be furnished with the 1000ml four-hole bottle of thermometer and solid feed inlet, addition funnel and put into the alcohol cryostat; Add 68g (1mol) isoprene, 100ml water and 0.1g hydroquinone of polymerization retarder; In addition funnel, put 50% acetic acid aqueous solution 150g, stir in 0～5 ℃ of dropping acetic acid aqueous solution, when slowly dripping, add chlorinated lime (30% available chlorine) in batches from another charging opening, be total to 150g, constantly survey the pH value, keep pH value (available test paper or pH meter) between 7.5 to 8.5, dropwise after about three hours, continued insulated and stirred afterwards 1 hour, filter, the filter cake methylene dichloride is washed, and filtrate merges the back standing demix.Be lower than 40 ℃ of reclaim under reduced pressure after the organic layer washing and get crude product 118g, gas phase analysis shows that the product total content is 90.5%, yield 88.6%.Can be directly used in the next step.Can be by rectifying with mixture separation, pure product carry out structure verification respectively; 1-chloro-2-hydroxy-2-methyl-3-butylene: IR (ν/cm
-1): 3430 (CH
2OH, the alcohols characteristic peak), 1640 (CH=CH
2); δ (ppm): 1.38 (s, 3H, CH
3), 193 (1H ,-OH), 3.55 (2H, Cl-CH
2-), 5.29 (dd, 2H ,=CH
2), 5.91 (1H ,-CH=); DEPT: δ (ppm): 138.142 (2H ,=CH
2), 116.051 (1H ,-CH=), 49.887 (3H ,-CH
3), 21.611 (2H ,-CH
2-Cl); 1-chloro-2-methyl-4-hydroxyl-2-butylene: IR (ν/cm
-1): 3430 (CH
2OH, the alcohols characteristic peak), 1640 (C=CH-); δ (ppm); 1.38 (s, 3H, CH
3), 2.15 (1H ,-OH), 3.55 (2H, Cl-CH
2-), 5.29 (dd, 2H ,=CH
2), 5.91 (1H ,-CH=); DEPT: δ (ppm): 141.469 (1H ,=CH-), 114.051 (2H ,-CH
2-OH), 54.135 (2H ,-CH
2-Cl), 25.488 (3H ,-CH
3)
The preparation of embodiment 2:1-chloro-2-hydroxy-2-methyl-3-butylene and 1-chloro-2-methyl-4-hydroxyl-2-butylene mixture
Material proportion, service temperature and aftertreatment are with embodiment 1, and difference is that chlorinated lime (30% available chlorine) adds in batches with in the disposable adding reaction flask of 50% acetic acid aqueous solution, the pH value of system constantly changes, and about 3 during by beginning becomes 7.5 to 8 when the finishing.Get crude product 103g, gas phase analysis shows that the product total content is 86.5%, yield 74%.
Embodiment 3: the esterification rearrangement reaction prepares 1-chloro-2-methyl-4-acetoxyl group-2-butylene
In the 250ml three-necked bottle, add the crude product 64g (content 90.5% that embodiment 1 obtains, 0.48mol) and diacetyl oxide 80g (0.78mol), stir adding 1g tosic acid, be warmed up to 60 ℃ and stirred 5 hours, cooling, add the 100ml water stratification, discard upper strata waste water, lower floor's organic layer adds 100ml washing back layering again and gets crude chloride 63g (content 90%), get water white transparency liquid 55g (content 93.5%), yield 66% after the rectifying.GC-MS (m/e): 127,102,84,67,43 (100%), 29; IR (ν/cm
-1): 1735 (OCO-, carbonyls); 1230 (C-O-CO-, ν
As) 1035 (C-O-CO-, ν
s);
1HNMR (500MHz, CDCl
3) δ (ppm): 1.83 (s, 3H ,-CH
3); 2.06 (s, 3H ,-COCH
3); 4.01 (2H, Cl-CH
2-); 4.62 (2H ,=CH
2); 5.69 (1H ,-CH=); DEPT: δ (ppm): 124.019 (1H ,=CH-); 62.535 (2H ,-OCH
2-); 50.135 (2H ,-CH
2-Cl); 21.106 (3H ,-CH
3); 14.807 (3H ,-CH
3).
Comparative Examples 1: the chlorohydrin action under clorox and the acetate system
To be furnished with the 1000ml four-hole bottle of thermometer and two addition funnel and put into the alcohol cryostat; Add 68g (1mol) isoprene, 100ml water and 0.1g hydroquinone of polymerization retarder; In two addition funnel, put 50% acetic acid aqueous solution 150g and 10% clorox 500g respectively, stir the feed liquid that drips two addition funnel simultaneously in 0～5 ℃, survey the pH value when slowly dripping, keep pH value (available test paper or pH meter) between 7.5 to 8.5, dropwise after about three hours, continued insulated and stirred afterwards 1 hour, standing demix.Get organic layer 88g, gas phase analysis shows that the product total content is about 65%, and unreacted raw material olefin is about 20%.Organic layer is lower than 40 ℃ of normal pressures reclaims unreacted raw material olefin, get debris 76g, gas phase analysis shows that the product total content is 83%, yield 52%.
Comparative Examples 2: the chlorohydrin action under clorox and the sulfuric acid system
Material proportion, service temperature and aftertreatment be with Comparative Examples 1, and difference is 50% acetic acid aqueous solution is changed to 50% aqueous sulfuric acid 75g, and the pH value of system constantly changes, and is difficult to during beginning keep stablizing, and is controlled between 6 to 8.5 as far as possible.Get crude product 63g at last, gas phase analysis shows that the product total content is 76.1%, yield 28.6%.
Comparative Examples 3: the chlorohydrin action under clorox and the hydrochloric acid system
Material proportion, service temperature and aftertreatment be with Comparative Examples 1, and difference is 50% acetic acid aqueous solution is changed to 20% aqueous hydrochloric acid 350g, and the pH value of system constantly changes, and is difficult to during beginning keep stablizing, and is controlled between 6 to 8.5 as far as possible.Get crude product 52g at last, gas phase analysis shows that the product total content is 63.2%, yield 19.5%.
Claims (6)
1, the preparation method of 1-chloro-2-methyl-4-acetoxyl group-2-butylene, may further comprise the steps: be raw material with the isoprene, in the presence of solvent, add Losantin solid and pH value conditioning agent acetate and carry out chlorohydrin action, get 1 respectively, 2 and 1,4 's adduct, this blended adduct gets 1-chloro-2-methyl-4-acetoxyl group-2-butylene with acetic anhydride under acid catalysis.
2, the preparation method of 1-chloro-2-methyl according to claim 1-4-acetoxyl group-2-butylene is characterized in that described Losantin selects the bleaching essence of the chlorinated lime or the high available chlorine content of 30% available chlorine content for use.
3, the preparation method of 1-chloro-2-methyl according to claim 1 and 2-4-acetoxyl group-2-butylene is characterized in that described pH value conditioning agent acetic acid water solution concentration is 50-80%, and it selects the mode that adds gradually in the reaction system for use.
4, the preparation method of 1-chloro-2-methyl according to claim 3-4-acetoxyl group-2-butylene is characterized in that described temperature of reaction is-20 ℃ to 40 ℃.
5, the preparation method of 1-chloro-2-methyl according to claim 4-4-acetoxyl group-2-butylene is characterized in that described temperature of reaction is-5 ℃ to 10 ℃.
6, the preparation method of 1-chloro-2-methyl according to claim 4-4-acetoxyl group-2-butylene is characterized in that described solvent is organic solvent or inorganic solvent.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101475471B (en) * | 2008-09-04 | 2012-06-13 | 浙江医药股份有限公司新昌制药厂 | Improved synthesizing method of 1-chlorine-2-methyl-4-hydrocarbon acyloxy-2-butene |
| CN106349029A (en) * | 2016-08-29 | 2017-01-25 | 国药集团化学试剂有限公司 | Preparation method of chromatographic-grade methyl tert-butyl ether |
| CN107445801A (en) * | 2017-07-31 | 2017-12-08 | 广州巨元生化有限公司 | A kind of preparation method of vitamin A intermediate |
| CN112028740A (en) * | 2020-09-15 | 2020-12-04 | 江西天新药业股份有限公司 | Process for producing chlorohydrin |
| CN112321421A (en) * | 2020-09-29 | 2021-02-05 | 宿迁科思化学有限公司 | Preparation method of 1-acetoxyl-4-chloro-3-methyl-2-butene |
-
2006
- 2006-03-24 CN CN 200610050012 patent/CN101041619A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101475471B (en) * | 2008-09-04 | 2012-06-13 | 浙江医药股份有限公司新昌制药厂 | Improved synthesizing method of 1-chlorine-2-methyl-4-hydrocarbon acyloxy-2-butene |
| CN106349029A (en) * | 2016-08-29 | 2017-01-25 | 国药集团化学试剂有限公司 | Preparation method of chromatographic-grade methyl tert-butyl ether |
| CN106349029B (en) * | 2016-08-29 | 2021-08-03 | 国药集团化学试剂有限公司 | Preparation method of chromatographic grade methyl tert-butyl ether |
| CN107445801A (en) * | 2017-07-31 | 2017-12-08 | 广州巨元生化有限公司 | A kind of preparation method of vitamin A intermediate |
| CN112028740A (en) * | 2020-09-15 | 2020-12-04 | 江西天新药业股份有限公司 | Process for producing chlorohydrin |
| CN112321421A (en) * | 2020-09-29 | 2021-02-05 | 宿迁科思化学有限公司 | Preparation method of 1-acetoxyl-4-chloro-3-methyl-2-butene |
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