CN101041619A - Preparation method of 1-chlorin -2-methyl -4-acetoxy-2- butylene - Google Patents

Abstract

The invention is a preparation method of 1-chloro-2-methyl-4-acetoxy-2-butene. In the existing method, isoprene and sodium hypochlorite aqueous solution are used for chloroalcoholization reaction, and the yield and content of the product are low; sodium hypochlorite aqueous solution reacts violently with isoprene, and it is difficult to adjust and control it with a pH regulator. In the present invention, isoprene is used as a raw material, and in the presence of a solvent, calcium hypochlorite solid and acetic acid, a pH regulator, are added to carry out chloroalcoholization reaction to obtain addition products at 1, 2 and 1, 4 respectively. The adducted product reacts with acetic anhydride under acid catalysis to give 1-chloro-2-methyl-4-acetoxy-2-butene. The present invention selects the calcium hypochlorite with high content of available chlorine, has mild reaction system, few miscellaneous ions, and high product content and yield.

Description

The preparation method of 1-chloro-2-methyl-4-acetoxy-2-butene

Technical field

The invention relates to the field of chemistry, in particular to a method for preparing an important intermediate 1-chloro-2-methyl-4-acetoxy-2-butene for the synthesis of _VA acetate.

Background technique

Vitamin A (V _A ) and its derivatives are a class of important drugs, and the products of major companies in the world are mainly based on _VA acetate ((Encyclopedia of Chemical Engineering) Editorial Board, Encyclopedia of Chemical Industry, Chemical Industry Press , 1996 first edition, Vol.16, P719-729). 4-Acetoxy-2-methyl-2-buten-1-al (MW142, referred to as five-carbon aldehyde) is a key intermediate for the synthesis of _VA acetate by the C ₁₅ +C ₅ route characterized by the Wittig reaction (Tanaka, USP 5,424,478, Process for producing Vitamin A Derivatives, [P] 1995; Tanaka, et al., JP 06,329,623, Preparation of Vitamin A Derivatives, [P] 1994; Zutter, Ulrich, Ep 648,735, Preparation of an intermediate for Vitamin Aacetate, [P] 1995; Wang Lanming, Beijing Medicine, New Synthetic Technology of Vitamin A, [J] 1992, 4, 10-12), so the study on the synthesis of five-carbon aldehyde has important theoretical significance and application value.

Reported its industrial synthesis method (H.Pommer, A.Nurrenbach, Pure.Appl.Chem., Industrial synthesis of Terpene compounds, [J] 1975, 43, 527 from the expert H.Pommer of BASF company etc. in the mid-seventies ) So far, its synthetic research has not been interrupted, and many of them are synthesized by 1-chloro-2-methyl-4-acetoxy-2-butene (MW162.5, hereinafter referred to as chloride) (Tanaka, et al., JP06,329,623, Preparation of Vitamin A Derivatives, [P] 1994; Ven Kataratnam, Revannuru V., et al., Indian IN 168,539, An improved process for the preparation of 4 -acetoxy-2-methyl-2-butenal, [P]1988; Kaneko, Tatsuhiko, et al., Jp.07, 61, 948, Preparation of 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 of 4-acetoxy-2-methyl-2-butenal, a Vitamin A precursor[J]1979, 44(10), 1716- 17), so it can be considered that chloride is an important intermediate for the synthesis of _VA .

The preparation of chloride mainly contains two kinds of methods: Babler, JamesH. take chloroacetone as raw material, first react with the Grignard reagent of allyl chloride to obtain tertiary alcohol, then esterify and rearrange to obtain chloride (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 of 4-acetoxy-2-methyl-2-butenal, a Vitamin A precursor[J]1979, 44(10), 1716-17);

Another method is to use isoprene and sodium hypochlorite aqueous solution to carry out chloroalcoholation reaction to obtain 1,2 and 1,4 addition products respectively, and the reaction mixture reacts with acetic anhydride under acid catalysis to obtain chloride (Tanaka, et al., JP 06, 329, 623, Preparation of Vitamin A Derivatives, [P] 1994; Kuroda, Noritaka, et al., Jp. 06, 345, 689, Preparation of butenal derivatives, [P] 1994).

In comparison, the latter method has cheap raw materials and is more industrially valuable; in the chlorohydrination reaction, the pH value can be maintained by passing CO ₂ or adding sulfuric acid, hydrochloric acid or acetic acid dropwise. Because in above-mentioned chloroalcoholization reaction, the available chlorine content of sodium hypochlorite is about 10%, and available chlorine content is low, and corresponding miscellaneous ion is many, relatively unfavorable to reaction, makes the yield and content of product lower; The pH value of sodium hypochlorite aqueous solution is greater than 10. Strong alkalinity, violent reaction with isoprene, difficult to adjust and control with pH regulator; sodium hypochlorite in reaction is an aqueous solution, which is bulky, has a lot of waste water, and is troublesome for storage and transportation.

Because the acidity of acetic acid is milder, the sodium acetate and acetic acid formed buffer system should be very beneficial to the reaction atmosphere of the stable system, and the milder reaction system should help the improvement of the yield. When adjusting the pH value, the yield is relatively high, and the impurities are relatively few (the content is 83%, and the yield is 52%), but it is not very ideal.

Usually the chloroalcoholation reaction of olefins can pass chlorine gas in the calcium hydroxide aqueous suspension, and utilize the active hypochlorous acid of generation to directly carry out chlorohydrinization (Encyclopedia of Chemical Industry) Editorial Committee, Encyclopedia of Chemical Industry, Chemical Industry Press, the first in 1996 Edition, Vol.16, P719-729); but we found that the content of the product was very poor after experimental verification, which may be due to the presence of free chlorine and other miscellaneous ions that caused the double bond of olefins to undergo side reactions such as dichloro addition , resulting in an increase in impurities.

Contents of Invention

The technical problem to be solved by the present invention is to overcome the defects of the above-mentioned prior art, and provide a kind of 1-chloro-2-methyl-4-acetoxy-2-butanol with high content of available chlorine in the reaction raw material and milder reaction system. The preparation method of alkenes can greatly improve the reaction system, reduce heteroions, and increase the content and yield of products.

For this reason, the present invention adopts following technical scheme: the preparation method of 1-chloro-2-methyl-4-acetoxy-2-butene comprises the following steps: taking isoprene as raw material, in the presence of solvent , add solid calcium hypochlorite and pH regulator acetic acid to carry out chloroalcoholization reaction, respectively get 1,2 and 1,4 addition products, the mixed addition products react with acetic anhydride under acid catalysis to get 1 -Chloro-2-methyl-4-acetoxy-2-butene. Calcium hypochlorite is solid, can play a slow-release effect, mild reaction, less waste water produced, convenient storage and transportation; calcium hypochlorite is weak in alkalinity, pH value is less than 9, and reacts mildly with isoprene. It is easy to adjust and control with pH regulator acetic acid. The chloroalcoholization reaction is carried out under the milder reaction system formed by calcium hypochlorite solid and acetic acid, and the product content and yield are high.

In the above preparation method, the calcium hypochlorite is selected from bleaching powder with 30% available chlorine content or bleaching essence with high available chlorine content. The higher the available chlorine content, the fewer heteroions, the more favorable the reaction is.

In the above-mentioned preparation method, the concentration of the aqueous solution of the pH regulator acetic acid is preferably 50-80%. If the concentration is too low, the volume of the reaction system will increase, and the effective contact of the reactants will become poor; In this way, the pH value can be better adjusted.

In the above preparation method, the reaction temperature is between -20°C and 40°C, preferably between -5°C and 10°C, high temperature will greatly increase the by-products, and too low temperature will meet the refrigeration requirements in industrial applications difficulty.

The above-mentioned preparation method, the described reaction can be carried out in the presence of organic or inorganic solvents, and the solvents that can be used are polar solvents such as lower alcohols; medium polar solvents such as ketones, esters or halogenated hydrocarbons, etc. Polar solvents.

The invention has the following beneficial effects: calcium hypochlorite with high available chlorine content is selected as the reaction raw material, the reaction system is mild, the miscellaneous ions are less, the content and yield of the product are high; the waste water produced by the reaction is less, and the storage and transportation are convenient.

The present invention will be further described below in conjunction with embodiment.

Detailed ways

Analytical instruments and equipment used in the examples: GC-MS, MS5973N-GC6890N (Agilent, USA); NMR, AVANCE DMX 500 (TMS internal standard); Infrared spectrometer, NICOLET 360FT-IR.

Example 1: Preparation of 1-chloro-2-hydroxyl-2-methyl-3-butene and 1-chloro-2-methyl-4-hydroxyl-2-butene mixture

Put the 1000ml four-neck bottle equipped with a thermometer, a solid feeding port and a dropping funnel into an alcohol cooling bath; add 68g (1mol) isoprene, 100ml water and 0.1g inhibitor hydroquinone; Put 150g of 50% acetic acid aqueous solution in the funnel, stir and add the acetic acid aqueous solution dropwise at 0-5°C, while adding slowly, add bleaching powder (30% available chlorine) in batches from another feeding port, totaling 150g, and continuously measure the pH value , keep the pH value between 7.5 and 8.5 (test paper or pH meter can be used), after about three hours, the dropwise addition is completed, then continue to insulate and stir for 1 hour, filter, wash the filter cake with dichloromethane, and leave the filtrates to separate after merging. After the organic layer was washed with water, 118 g of the crude product was recovered under reduced pressure at a temperature lower than 40°C. Gas phase analysis showed that the total content of the product was 90.5%, and the yield was 88.6%. It can be directly used in the next reaction. The mixture can be separated by rectification, and the structure of the pure product is verified separately; 1-chloro-2-hydroxy-2-methyl-3-butene: IR (ν/cm ^-1 ): 3430 (-CH ₂ OH, alcohol Class 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-hydroxy-2-butene: IR (ν/cm ^-1 ): 3430 (-CH ₂ OH, alcohol 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 )

Example 2: Preparation of 1-chloro-2-hydroxyl-2-methyl-3-butene and 1-chloro-2-methyl-4-hydroxyl-2-butene mixture

Ratio of materials, operating temperature and aftertreatment are the same as in Example 1, the difference is that 50% acetic acid aqueous solution is disposablely added in the reaction flask, bleaching powder (30% available chlorine) is added in batches, and the pH value of the system is constantly changing, from the beginning The 3 or so becomes between 7.5 and 8 at the end. 103 g of crude product was obtained, gas phase analysis showed that the total product content was 86.5%, and the yield was 74%.

Example 3: Preparation of 1-chloro-2-methyl-4-acetoxy-2-butene by esterification rearrangement reaction

In a 250ml three-necked flask, add 64g (content 90.5%, 0.48mol) of the crude product obtained in Example 1 and 80g (0.78mol) of acetic anhydride, stir and add 1g p-toluenesulfonic acid, heat up to 60°C and stir for 5 hours, then cool down. Add 100ml of water to separate the layers, discard the upper waste water, add 100ml of water to the lower organic layer and wash with water to obtain 63g of crude product chloride (content 90%), and obtain 55g of colorless transparent liquid (content 93.5%) after rectification, yield 66 %. GC-MS (m/e): 127, 102, 84, 67, 43 (100%), 29; IR (ν/cm ^-1 ): 1735 (-OCO-, carbonyl); 1230 (-CO-CO- , ν ^as ) 1035 (-CO-CO-, ν ^s ); ¹ HNMR (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 example 1: Chloroalcoholation reaction under sodium hypochlorite and acetic acid system

Put the 1000ml four-neck bottle equipped with a thermometer and two dropping funnels into an alcohol cooling bath; add 68g (1mol) isoprene, 100ml water and 0.1g inhibitor hydroquinone; Put 150g of 50% acetic acid aqueous solution and 500g of 10% sodium hypochlorite in the funnel respectively, stir at 0-5°C and add the feed liquid of two dropping funnels dropwise at the same time, measure the pH value while slowly adding it, and keep the pH value at 7.5 to Between 8.5 (test paper or pH meter can be used), the dropwise addition is completed after about three hours, and then continue to keep warm and stir for 1 hour, and let stand to separate layers. 88 g of the organic layer was obtained, and the gas phase analysis showed that the total product content was about 65%, while the unreacted raw material olefin was about 20%. The organic layer was lowered to 40°C under normal pressure to recover unreacted raw material olefins, and 76 g of residual liquid was obtained. Gas phase analysis showed that the total product content was 83%, and the yield was 52%.

Comparative Example 2: Chloroalcoholation reaction under sodium hypochlorite and sulfuric acid system

Material ratio, operating temperature and aftertreatment are the same as Comparative Example 1, the difference is that 50% acetic acid aqueous solution is replaced by 50% sulfuric acid aqueous solution 75g, the pH value of the system is constantly changing, it is difficult to keep stable at the beginning, try to control it at 6 to Between 8.5. Finally, 63 g of the crude product was obtained, and the gas phase analysis showed that the total product content was 76.1%, and the yield was 28.6%.

Comparative example 3: Chloroalcoholization reaction under sodium hypochlorite and hydrochloric acid system

Material ratio, operating temperature and aftertreatment are the same as Comparative Example 1, the difference is that 50% acetic acid aqueous solution is replaced by 20% hydrochloric acid aqueous solution 350g, the pH value of the system is constantly changing, it is difficult to keep stable at the beginning, try to control it at 6 to Between 8.5. Finally, 52 g of the crude product was obtained, and gas phase analysis showed that the total content of the product was 63.2%, and the yield was 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.