WO2013026392A1 - 3-(α-甲氧基)甲烯基苯并呋喃-2(3H)-酮的合成方法 - Google Patents

3-(α-甲氧基)甲烯基苯并呋喃-2(3H)-酮的合成方法 Download PDF

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WO2013026392A1
WO2013026392A1 PCT/CN2012/080436 CN2012080436W WO2013026392A1 WO 2013026392 A1 WO2013026392 A1 WO 2013026392A1 CN 2012080436 W CN2012080436 W CN 2012080436W WO 2013026392 A1 WO2013026392 A1 WO 2013026392A1
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acid
synthesis
water
reduced pressure
under reduced
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French (fr)
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丁永良
邹志刚
韩丹
邓术清
杨莹
曹超
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重庆紫光化工股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/83—Oxygen atoms

Definitions

  • the present invention relates to a process for the synthesis of a chemical substance, and in particular to a process for the synthesis of 3-( ⁇ -methoxy)nonenylbenzofuran-2 (33 ⁇ 4-one).
  • O-chlorophenylacetic acid, 3% sodium hydroxide solution and catalyst 8-hydroxyquinone copper were placed in a high pressure reactor, reacted at 165 ⁇ 170 °C for 2 hours, cooled, and the reaction solution was neutralized with hydrochloric acid to neutral.
  • the mother liquor is a dilute acid solution containing a large amount of sodium chloride.
  • the o-hydroxyphenylacetic acid and the toluene solution are mixed, and a catalyst (sulfuric acid, p-toluenesulfonic acid, etc.) is added thereto, and the reaction is refluxed, and the water formed by the reaction is separated until no water is formed, and the organic phase is washed with sodium hydrogencarbonate solution and water, respectively. Drying, distillation to recover benzene, the residue is distilled under reduced pressure to obtain a lactone product, and it is also possible to directly proceed to the next reaction without separation.
  • a catalyst sulfuric acid, p-toluenesulfonic acid, etc.
  • the lactone is mixed with tridecyl phthalate and acetic anhydride in a certain ratio at 100 ° C to collect the by-product acetate. After the reaction, the acetic acid and excess acetic anhydride are distilled under reduced pressure, and the residue is distilled. The product was recrystallized from decyl alcohol to give the product.
  • o-hydroxyphenylacetic acid has a high solubility in an acidic aqueous solution, more o-hydroxyphenylacetic acid remains in the aqueous phase, and salting out or extraction cannot increase the yield, resulting in lower atomic economy.
  • the autoclave was reacted at 170 ° C for 2 h.
  • the synthesis of o-hydroxyphenylacetic acid is basically consistent with the improvement.
  • the reaction solution was taken out and neutralized to pH 7 with concentrated hydrochloric acid.
  • the above liquid product was heated in a certain ratio with tridecyl phthalate and acetic anhydride for a certain period of time, and then the reaction mixture was concentrated under reduced pressure in an oil bath at 85 ° C to give a black oil.
  • This oil was mixed with hot solvent sterol/ethanol, cooled, filtered, and crystallized to obtain a solid target product.
  • the total yield of the three-step reaction was about 78%.
  • the core of the process is to change the process of lactone synthesis, so that the yield is improved by an earlier technical solution; but the amount of benzene is increased, it needs to be washed with aqueous sodium hydrogencarbonate, washed with water, dried with anhydrous magnesium sulfate. , increased waste emissions.
  • the disadvantages of this process are:
  • sulfuric acid is a strong acid, it can react with by-product sodium chloride to form hydrogen chloride and sodium sulfate, which produces a large amount of acid gas.
  • a primary object of the present invention is to provide a process for the synthesis of 3-( ⁇ -decyloxy)nonenylbenzofuran-2 (3-ketone) which significantly increases product yield and reduces waste emissions.
  • the technical scheme adopted by the present invention is: a method for synthesizing 3-(o-decyloxy)nonenylbenzofuran-2 (3-ketone), the steps include: synthesis of o-hydroxyphenylacetic acid, synthesis of lactone Synthesis of 3-( ⁇ -decyloxy)nonenylbenzofuran-2 (3-ketone), characterized in that: the synthesis step of the lactone comprises:
  • a removing the acid water from the filtrate obtained in the synthesis step of o-hydroxyphenylacetic acid; b, adding the catalyst acetic acid, azeotropic distillation to remove the water formed by the reaction, until there is no more water in the system and/or o-hydroxybenzene in the reaction mixture
  • the content of acetic acid is less than 1%;
  • the reaction mixture is cooled to precipitate sodium chloride, filtered, and the solid is washed with toluene; the filtrate and the washing liquid are combined, and concentrated under reduced pressure to recover toluene and the catalyst acetic acid to obtain the target product.
  • the target product is also the residual red liquid.
  • the improvement of the present invention is to improve the process of lactone synthesis, and the raw material ratio, the amount of catalyst charged, the process temperature control index, etc. are determined according to theoretical calculations, etc., and those skilled in the art can determine without creative labor;
  • the synthesis of o-hydroxyphenylacetic acid and the synthesis of 3-( ⁇ -mercaptooxy)nonenylbenzofuran-2 ⁇ )-one can be referred to the prior art, and will not be described in detail for the sake of space saving.
  • the vacuum distillation is usually carried out under heating in an oil bath, the heating temperature is uniform, and the distillation efficiency is increased; the pressure under reduced pressure is -0.01 to -0.095 MPa, that is, the degree of vacuum is 0.01 to 0.095 MPa, which is convenient for energy saving;
  • the oil bath is heated at a temperature of 80 to 100 ° C; that is, the vacuum distillation in the step a is usually carried out in an oil bath heated and decompressed, and the pressure under reduced pressure is -0.01 to -0.095 MPa, and the oil bath is heated. 80 ⁇ 100 °C.
  • the purpose of vacuum distillation is to remove a large amount of acid water.
  • the vacuum pump is turned off, a certain amount of toluene is added to the system, heated to above 110 ° C, and azeotropically distilled until no more water is distilled out of the system, so that the moisture in the system is removed as completely as possible.
  • the catalyst acetic acid is further added, and the water formed by the reaction is removed by azeotropic distillation.
  • the heating temperature of the distillation is 110 to 130 ° C until no water is formed in the system, and preferably the content of o-hydroxyphenylacetic acid in the reaction mixture is less than 1% (HPLC detection). That is, the heating temperature of the distillation in the step b is 110 to 130 ° C until no water is formed in the system and the content of o-hydroxyphenylacetic acid in the reaction mixture is less than 1% (HPLC detection). It was confirmed that the lactone synthesis reaction has been carried out completely. In other words, the reaction of the synthetic lactone is carried out as much as possible under anhydrous conditions to increase the catalytic efficiency.
  • reaction mixture is then cooled to room temperature, i.e., a large amount of solid sodium chloride is precipitated, filtered, and the solid is washed with benzene, usually twice.
  • the filtrate and the washing liquid are combined, and the toluene and the catalyst acetic acid are recovered by distillation under reduced pressure, and the pressure under reduced pressure is -0.01 to -0.095 MPa, and the oil bath temperature is 70 to 100 °C.
  • step c washing twice with terpene, then combining the filtrate and the washing liquid, and distilling and distilling under reduced pressure to recover the benzene and the catalyst acetic acid, and the pressure under reduced pressure is -0.01 ⁇ -0.095 MPa, and the oil bath temperature is 70 ⁇ 100 ° C.
  • the residue obtained in the step c treatment is added to tridecyl orthophthalate and acetic anhydride, and the reaction is carried out at 100 ° C to control the temperature of the fraction not exceeding 7 (TC, collected by-products Ethyl acetate, until no more distillate is distilled off and the content of lactone is less than 1%, at -0. 01 ⁇ -0. 095MPa, the oil bath temperature is 80 ⁇ 100 °C, and the by-product acetic acid is distilled under reduced pressure. Excess acetic anhydride until no more distillate is distilled off, adding sterol/ethanol while hot, cooling and crystallization, filtering the solid with decyl alcohol and drying to obtain a finished product.
  • TC collected by-products Ethyl acetate
  • the crude product obtained by vacuum distillation by-product acetic acid and excess acetic anhydride until the distillate is no longer distilled is a brown oil.
  • sterol/ethanol is added and cooled to obtain a large amount of pale yellow solid. Filtration, the solid is washed with decyl alcohol, usually twice, and then dried to give the finished product.
  • the purity of the final product was greater than 95% by HPLC, and the total yield of the three-step reaction was greater than 80%.
  • the process was stable and reliable.
  • the yield of the prior art product is significantly improved.
  • the main chemical reaction formula for production is:
  • acetic acid acetic acid
  • sodium chloride is removed by filtration, and then the distillation is carried out under reduced pressure to distill off the benzene and acetic acid under reduced pressure.
  • the distilled terpene and acetic acid can be separated and applied, no neutralization or washing process is required, no waste water is produced, and no drying process is required. Therefore, the technical features and effects of the present invention can be summarized as follows:
  • the catalyst is removed by distillation under reduced pressure without washing and drying; No salty wastewater is produced;
  • the lactone is reacted with acetic anhydride and tridecyl ortho-decanoate to form, in addition to the desired product, decyl acetate and acetic acid, which can be used as a by-product to be used as a lactone synthesis catalyst. Therefore, the atomic economy of the reaction is strong.
  • the concentration of dilute hydrochloric acid recovered by distillation treatment for synthesizing lactone is 8-12%, which can be distilled under normal pressure, and the fractions are separately collected, and the concentration of hydrochloric acid in each fraction is determined by titration, and the fraction having a concentration of less than 2% is determined.
  • For wastewater treatment 5-15% of the fraction is distilled again to finally obtain hydrochloric acid having a concentration of 20 to 25%.
  • This hydrochloric acid can be used for the neutralization of the o-hydroxyphenylacetic acid synthesis reaction solution.
  • the recovered acetic acid and acetic anhydride rectification are respectively obtained as pure products, and the acetic acid portion is used as a lactone synthesis catalyst, and the others can be sold as a by-product, and acetic anhydride is reused.
  • By-product ethyl acetate is treated according to prior art treatment schemes or sold as a by-product.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • the o-chlorophenylacetic acid 34. lg (0.2 mol), the catalyst 8-hydroxyquinoline copper 7.04 g (0.02 mol) and 253.6 g of an aqueous sodium hydroxide solution were weighed into the autoclave, and reacted at 170 ° C for 2 h. After cooling to room temperature, the reaction solution was taken out and neutralized with concentrated hydrochloric acid to pH 7. After filtration, the filter cake is dried and recovered. The filtrate is further acidified to pH 1 with concentrated hydrochloric acid, and then transferred to a three-neck round bottom flask with stirring, thermometer and condenser.
  • the oil bath temperature is 95 ° C, -0.08 Mpa, and distilled under reduced pressure until The acid water is evaporated to dryness.
  • To the residue is added 250 mL of toluene.
  • the temperature of the oil bath is adjusted to 120 ° C.
  • the azeotropic distillation is carried out until no more water is distilled out.
  • the addition of 20 mL of acetic acid is continued until no more water is formed.
  • HPLC The o-hydroxyphenylacetic acid content was determined to be 0.3%, cooled, filtered, and the solid was washed twice with 50 mL of hydrazine.
  • the filtrate and the washing liquid were combined, and distilled under reduced pressure (_0.08 MPa, oil bath temperature: 80 ° C) to recover toluene and the catalyst acetic acid.
  • After cooling add a thorn-type rectification column to the flask, add 40 g of tridecyl ortho-decanoate and 89.5 g of acetic anhydride, heat to 100 ° C, collect the fraction at a temperature not higher than 70 ° C, and no longer after 10.5 hours.
  • the fraction was distilled off, and the rectification unit was changed into a distillation apparatus.
  • the reaction liquid was concentrated under reduced pressure in a 90 ° C oil bath at -0.08 MPa, and 68.5 g of the fraction was collected.
  • the content of acetic acid and acetic anhydride was determined by GC. 33.5°/. And 63.7°/. The residue was a black oil, which was then weighed, and then weighed, and then weighed, and then weighed, and then weighed, and then weighed, and then weighed, lyophilized, lyophilized, filtered, and dried to give a pale yellow solid (28.7 g, HPLC, 99.1%, yield: 80.8%).
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • the acid water is evaporated to dryness. 500 mL of toluene is added to the residue. The temperature of the oil bath is adjusted to 125 ° C. Azeotropic distillation is carried out until no more water is distilled out. 30 mL of acetic acid is added to continue heating until no more water is formed. HPLC The content of o-hydroxyphenylacetic acid was detected to be 0.45%, cooled, filtered, and the solid was washed twice with 100 mL of hydrazine. The filtrate and the washing liquid were combined, and distilled under reduced pressure (-0.02 MPa, oil bath temperature: 90 ° C) to recover toluene and the catalyst acetic acid.
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • the o-chlorophenylacetic acid 34. lg (0.2 mol), the catalyst 8-hydroxyquinoline copper 7.04 g (0.02 mol) and the sodium hydroxide aqueous solution 253.6 g were weighed and placed in an autoclave, and reacted at 170 ° C for 2 h. After completion of the reaction, the reaction solution was taken out and neutralized with concentrated hydrochloric acid to pH 7. After filtration, the filter cake is dried and recovered. The filtrate is further acidified to pH 1 with concentrated hydrochloric acid, and then transferred to a three-neck round bottom flask with stirring, thermometer and condenser.
  • the oil bath temperature is 80 ° C, -0.075 Mpa, and distilled under reduced pressure until The acid water was evaporated to dryness. To the residue was added 200 mL of benzene. The temperature of the oil bath was adjusted to 115 ° C. Azeotropic distillation was carried out until no more water was distilled out. 15 mL of acetic acid was added to continue heating until no more water was formed. HPLC The content of o-hydroxyphenylacetic acid was detected to be 0.5 ° /. Cool, filter, and wash the solid twice with 50 mL of hydrazine.
  • the filtrate and the washing liquid were combined, and distilled under reduced pressure (-0.075 MPa, oil bath temperature: 80 ° C) to concentrate to recover toluene and the catalyst acetic acid. Cooling, add a thorn-type rectification column to the flask, and add 40 g of tridecanoate And 89.5g acetic anhydride, heated to 100 ° C, collecting fractions not higher than 70 ° C, no more distillate after 10 hours, the distillation unit was changed to a distillation unit, the reaction liquid at 85 ° C The mixture was concentrated under reduced pressure in a bath at -0.075 MPa, and a total of 70.5 g of a fraction was collected.
  • the content of acetic acid and acetic anhydride was determined to be 33.5 °/ by GC, respectively. And 63.4%, the residue as a dark oil to give a dark oil, was added 80mL Yue hot alcohol, mixed, cooled, crystallized, filtered and dried to give a light yellow solid was 29.3g, HPLC detected content 97.6%, yield 81.3% 0
  • the o-chlorophenylacetic acid 34. lg (0.2 mol), the catalyst 8-hydroxyquinoline copper 7.04 g (0.02 mol) and the sodium hydroxide aqueous solution 253.6 g were weighed and placed in an autoclave, and reacted at 170 ° C for 2 h. After cooling to room temperature, the reaction solution was taken out and neutralized with concentrated hydrochloric acid to pH 7. After filtration, the filter cake is dried and recovered. The filtrate is further acidified to pH 1 with concentrated hydrochloric acid, and then transferred to a three-neck round bottom flask with stirring, thermometer and condenser.
  • the oil bath temperature is 80 ° C, -0.05 Mpa, and distilled under reduced pressure until The acid water was evaporated to dryness.
  • To the residue was added 200 mL of toluene.
  • the temperature of the oil bath was adjusted to 115 ° C.
  • the azeotropic distillation was carried out until no more water was distilled out.
  • the addition of 15 mL of acetic acid was added to Example 5 to continue heating. Water formation, HPLC detection of o-hydroxyphenylacetic acid content of 0.8 ° /. Cool, filter, and wash the solid twice with 50 mL of hydrazine.

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Abstract

一种合成3-(α-甲氧基)甲烯基苯并呋喃-2-(3Η)-酮的方法，包括邻羟基苯乙酸的合成，内酯的合成以及终产物的合成，重点改进在于内酯合成，从而使三步反应为串联进行，而不对中间体邻羟基苯乙酸和内酯进行分离纯化。

Description

3-(α -甲氧基）甲烯基苯并呋喃 -2 (3¾)-酮的合成方法 技术领域
本发明涉及一种化学物质的合成工艺， 具体涉及合成 3-(α-曱 氧基）曱烯基苯并呋喃 -2 (3¾-酮的方法。
背景技术
(E) -2- [2- (6-氯嘧啶 -4-基氧基）苯基] -3-曱氧基丙烯酸曱酯是 合成嘧菌酯的一个重要的中间体。 3-(α -曱氧基）曱烯基苯并呋喃 -2 H) -酮是合成（Ε) -2- [2- (6-氯嘧啶 _4 -基氧基）苯基] _3 -曱氧基丙 烯酸曱酯的重要中间体。 （Ε) -2- [2- (6-氯嘧啶 -4-基氧基）苯基] -3- 曱氧基丙烯酸曱酯的合成工艺例如一锅法：
以 3_ ( α -曱氧基）亚曱基苯并呋喃 -2_ (3Η) -酮为起始原料，与曱 醇钠和 4， 6-2 二氯嘧啶（DCP)采用一锅法合成，该法耗时比较长（约 50h)。 化学反应式为：
Figure imgf000002_0001
而 3_(α -曱氧基）曱婦基苯并呋喃 -2 (3 _酮的合成主要是以邻 氯苯乙酸为起始原料， 经过三步反应合成而得， 化学反应方程式如 下：
、COOH NaOH
catalyst
Figure imgf000002_0002
+ CH3COOH
Figure imgf000003_0001
三步反应也就是：
1、 邻羟基苯乙酸的合成
将邻氯苯乙酸、 1 3%氢氧化钠溶液以及催化剂 8-羟基喹淋铜放于 高压反应釜内， 在 165 ~ 170 °C下反应 2小时， 冷却， 反应液用盐酸 中和至中性， 过滤， 回收催化剂， 滤液用盐酸酸化至 pH=2 , 析出大 量固体， 过滤得产品。 母液为含有大量氯化钠的稀酸溶液。
2、 内酯的合成
将邻羟基苯乙酸和曱苯溶液混合， 同时加入催化剂（硫酸、 对曱 苯磺酸等）， 回流反应， 分离反应生成的水直到无水生成， 有机相分 别用碳酸氢钠溶液和水洗涤， 干燥， 蒸馏回收曱苯， 残余物减压蒸 馏得内酯产品， 也可不经分离直接进入下一步反应。
3、 3_ ( α -曱氧基）曱婦基苯并呋喃- 2 (3 -酮的合成
内酯与原曱酸三曱酯和醋酸酐混合按一定比例， 100 °C下反应， 收集产生的副产物乙酸曱酯， 反应结束后， 减压蒸馏副产乙酸和过 量的醋酸酐， 蒸馏残余物用曱醇重结晶得产品。
该工艺的缺点是：
1、 因为邻羟基苯乙酸在酸性水溶液中溶解度较大， 导致较多的 邻羟基苯乙酸残留在水相中， 用盐析或萃取均无法提高收率， 导致 原子经济性较低。
2、 产生大量的含盐废酸， 处理难度较大。
3、 使用硫酸或对曱苯磺酸作为内酯合成的催化剂， 在反应结束 后必须除去， 否则会影响下步反应， 而采用碱洗、 水洗的方法又会 产生大量的废水。
4、 水洗后的有机相需要干燥， 损失产品， 废干燥剂需要另行处 理。
改进的合成方法也就是与本发明最接近的技术方案 （ " 3_ ( α - 曱氧基）曱婦基苯并呋喃 -2 (3 _酮的合成与优化"，周林芳等，农药， 第 414-416页， 2004年 9月第 43卷第 9期） ：
Figure imgf000004_0001
主要合成步骤是： 称取一定量的邻氯苯乙酸、催化剂和氢氧化钠 水溶液（邻氯苯乙酸： 氢氧化钠： 催化剂 A = l : 4： 0. 1 (摩尔比） ）， 一次性投入高压釜， 在 170°C反应 2h。 邻羟基苯乙酸的合成与改进前 基本一致。 反应结束后， 将反应液取出， 用浓盐酸中和至 pH值为 7。
过滤， 滤饼进行干燥回收， 滤液浓缩。 加入上述浓缩液和 5倍体 积的曱苯， 一边搅拌， 一边滴加过量的浓 酸。 加热升温， 共沸带水 至反应完全。 过滤， 滤液用饱和碳酸氢钠水溶液洗涤， 再用水洗涤、 无水硫酸镁干燥、 过滤、 蒸干得红色液体目标产物。
将上述液体产物与原曱酸三曱酯和乙酸酐按一定比例，加热反应 一定时间后， 将反应液在 85 °C油浴中减压浓缩得到黑色油状物。 将此 油状物与热的溶剂曱醇 /乙醇混合， 冷却、 过滤、 结晶得到固体目标 产物， 三步反应总收率 78%左右。
可见， 该工艺的核心在于改变了内酯合成的工艺， 从而较早期 的技术方案提高了收率； 但曱苯使用量加大、 需要碳酸氢钠水溶液洗 涤， 再用水洗涤、 无水硫酸镁干燥， 增加了废物的排放。 此工艺的缺点是：
1、因为硫酸是强酸，能与副产氯化钠反应生成氯化氢和硫酸钠， 产生大量的酸性气体。
2、反应结束后， 过量的硫酸以及副产的硫酸钠需要依次用碱水 和水洗涤， 产生大量的含盐废水。
3、 水洗后的有机相需要干燥， 损失产品， 废干燥剂需要另行 处理。
发明内容
本发明的主要目的是提供一种合成 3- ( α -曱氧基）曱烯基苯并呋 喃 -2 (3 -酮的方法， 该方法可明显提高产品收率和减少废物排放。
本发明所采取的技术方案是： 一种合成 3- ( o -曱氧基）曱烯基苯 并呋喃 -2 (3 -酮的方法， 步骤包括： 邻羟基苯乙酸的合成、 内酯的 合成、 3- ( α -曱氧基）曱烯基苯并呋喃 -2 (3 -酮的合成，其特征在于： 所述的内酯的合成步骤包括：
a、 将邻羟基苯乙酸的合成步骤中得到的滤液除去酸水； b、 加入催化剂醋酸， 共沸蒸馏除去反应生成的水， 直到体系内 不再有水生成和 /或反应混合物中邻羟基苯乙酸的含量小于 1%;
c、 将反应混合物冷却析出氯化钠， 过滤， 固体用曱苯洗涤； 合 并滤液和洗涤液， 减压蒸馏浓缩回收曱苯和催化剂醋酸得目标产物。 目标产物也就是残留的红色液体。
本发明的改进在于重点改进了内酯合成的工艺过程，至于原料配 比、催化剂的投料量，工艺温度控制指标等则是根据理论计算等方式， 本领域技术人员无需创造性劳动即可确定的；邻羟基苯乙酸的合成和 3- ( α -曱氧基）曱烯基苯并呋喃 -2 Η) -酮的合成可以参考利用现有 技术， 为节约篇幅不再详细描述。
更进一步来说：所述的除去酸水的步骤最好是先向滤液中继续加 浓盐酸至 ρΗ=1 , 减压蒸馏除去大量的酸水， 再加一定量的曱苯， 共 沸蒸馏除去剩余的酸水。 这样可以大大节省曱苯用量， 减少原料消耗 和废物排放。
具体来说： 其中减压蒸馏通常在油浴加热条件下进行，加热温度 均匀， 蒸馏效率提高； 减压的压力在 -0.01 ~ -0.095MPa，也就是真空 度在 0.01 ~ 0.095MPa, 便于节能； 油浴加热温度 80 ~ 100°C； 也就是 所述的步骤 a中减压蒸馏通常在油浴加热并减压的环境下进行，减压 的压力在 -0.01 ~ - 0.095MPa，油浴加热温度 80~ 100°C。 减压蒸馏目 的是除去大量的酸水。
然后关闭真空泵，往体系中加一定量的曱苯，加热至 110°C以上， 共沸蒸馏， 直到体系中不再有水蒸出， 这样就尽可能彻底地除去了体 系中的水分。
再加入催化剂醋酸，共沸蒸馏除去反应生成的水， 蒸馏的加热温 度在 110~ 130°C, 直到体系内不再有水生成且最好是反应混合物中 邻羟基苯乙酸的含量小于 1%(HPLC检测）。 也就是所述的步骤 b中蒸 馏的加热温度在 110~ 130°C, 直到体系内不再有水生成并且反应混 合物中邻羟基苯乙酸的含量小于 1% (HPLC检测）。 证明内酯合成反应 已经进行完全。换句话说就是合成内酯的反应尽可能在无水条件下进 行， 以提高催化效率。 当然， 由上述分析可见， 预先不进行除水的操 作也是可以的， 只是后续醋酸催化进行内酯化反应的效率会降低。
再将反应混合物冷却至室温， 即有大量固体氯化钠析出， 过滤， 固体用曱苯洗涤干净， 通常洗涤两次即可。 合并滤液和洗涤液， 减压 蒸馏浓缩回收曱苯和催化剂醋酸， 减压压力在 -0.01 ~ -0.095MPa, 油浴温度 70~ 100°C。 即： 所述的步骤 c中， 用曱苯洗涤两次， 然后 合并滤液和洗涤液， 减压蒸馏浓缩回收曱苯和催化剂醋酸， 减压压力 在- 0.01 ~-0.095MPa,油浴温度 70~ 100°C。
进一步的，所述的步骤 c处理得到的残留物加入原曱酸三曱酯和 醋酸酐， 100°C下反应， 控制馏分温度不超过 7 (TC, 收集产生的副产 物乙酸曱酯，直到不再有馏分蒸出且内酯的含量小于 1 %后，在- 0. 01 ~ -0. 095MPa 下，油浴温度 80 ~ 1 00 °C减压蒸馏副产乙酸和过量的醋酸 酐直到不再有馏分蒸出， 趁热加入曱醇 /乙醇， 冷却析晶， 过滤后固 体用曱醇洗涤， 干燥得到成品。 其中减压蒸馏副产乙酸和过量的醋酸 酐直到不再有馏分蒸出后得到的粗产品是褐色油状物，趁热向此油状 物中加入曱醇 /乙醇， 冷却， 得大量淡黄色固体， 过滤， 固体用曱醇 洗涤， 通常洗涤两次， 然后干燥得到成品。
最终产品经 HPLC检测纯度大于 95% , 三步反应总收率大于 80% 并且工艺稳定可靠。 较现有技术产品收率显著提高。
生产的主要化学反应式为：
Figure imgf000007_0001
最接近的现有技术中， 因为使用的催化剂是强酸硫酸，硫酸与体 系中大量的氯化钠反应生成硫酸钠和氯化氢；过量的硫酸还需用碳酸 氢钠中和， 水洗、 干燥剂干燥， 产生大量的固体废物硫酸钠、 无水硫 酸镁以及废水。
而本发明使用乙酸（醋酸）为催化剂， 不与氯化钠反应， 反应完 毕过滤除去氯化钠后减压蒸馏将曱苯和醋酸一起减压蒸出即可。且蒸 出的曱苯和醋酸可以分离然后套用， 不需要中和、 洗涤过程， 不会产 生废水， 也不需要干燥过程。 因此本发明的技术特点和效果可以概括 为：
弱酸催化内酯合成；
催化剂通过减压蒸馏除去， 不需洗涤干燥过程； 无含盐废水产生；
内酯与醋酸酐和原曱酸三曱酯反应， 除生成目标产物外，还生成 了乙酸曱酯和乙酸， 乙酸可以作为副产物可以再用作内酯合成催化 剂。 因此反应的原子经济性强。
上述反应中为了合成内酯而蒸馏处理回收的稀盐酸浓度在 8 ~ 12%, 可将其在常压下蒸馏， 分别收集馏分， 滴定法测定各馏分中盐 酸的浓度， 浓度小于 2%的馏分作废水处理， 5 ~ 15%的馏分再次蒸馏， 最终得到浓度为 20 ~ 25%的盐酸， 此部分盐酸可用于将邻羟基苯乙酸 合成反应液的中和。
回收的乙酸和乙酸酐精馏分别得到纯品， 乙酸部分作为内酯合成 催化剂， 其余可作为副产出售， 乙酸酐回用。 副产的乙酸乙酯按现有 技术的处理方案处理或者是作为副产品出售。
具体实施方式
为使本领域技术人员详细了解本发明的生产工艺和技术效果， 下面以具体的生产实例来进一步介绍本发明的应用和技术效果。
实施例一：
称取邻氯苯乙酸 34. l g (0. 2mo l) 、 催化剂 8-羟基喹啉铜 7. 04g (0. 02mo l)和氢氧化钠水溶液 253. 6g , —次性投入高压釜， 在 170 °C反应 2h。 冷却至室温， 将反应液取出， 用浓盐酸中和至 pH值 为 7。 过滤， 滤饼进行干燥回收， 滤液继续用浓盐酸酸化至 pH值为 1 后转入带搅拌、 温度计、 冷凝管三口圆底烧瓶， 油浴温度为 80 °C、 -0. 095Mpa下减压蒸馏直到酸水基本蒸干， 向残留物中加入 200mL曱 苯， 调节油浴温度至 115 °C , 共沸蒸馏至体系中不再有水蒸出， 加入 15mL醋酸继续加热至不再有水生成， HPLC检测邻羟基苯乙酸的含量 为 0. 5°/。， 冷却， 过滤， 固体用 50mL曱苯洗涤两次。 合并滤液和洗涤 液， 减压蒸馏（-0. 095MPa , 油浴温度 75 °C )浓缩回收曱苯和催化剂 醋酸。 冷却， 在烧瓶上加一刺型精馏柱， 分别加入 40g原曱酸三曱酯 和 89.5g乙酸酐，加热至 100°C, 收集温度不高于 70°C的馏分， 10小 时后不再有馏分蒸出， 将精馏装置改成蒸馏装置， 将反应液在 85°C 油浴中、 -0.095MPa下减压浓缩， 共收集收集馏分 70.6g, GC测得乙 酸和乙酸酐的含量分别为 34.1%和 62.5°/。， 残余物为黑色油状物， 趁 热加入 80mL曱醇， 混合、 冷却、 结晶、 过滤、 干燥得到淡黄色固体 29.5g, HPLC检测含量为 98.4%, 收率 82.5%。
实施例二：
称取邻氯苯乙酸 34. lg(0.2mol) 、 催化剂 8-羟基喹啉铜 7.04g(0.02mol)和氢氧化钠水溶液 253.6g, —次性投入高压釜， 在 170°C反应 2h。 冷却至室温， 将反应液取出， 用浓盐酸中和至 pH值 为 7。 过滤， 滤饼进行干燥回收， 滤液继续用浓盐酸酸化至 pH值为 1 后转入带搅拌、 温度计、 冷凝管三口圆底烧瓶， 油浴温度为 95°C、 -0.08Mpa下减压蒸馏直到酸水基本蒸干， 向残留物中加入 250mL 曱 苯， 调节油浴温度至 120°C, 共沸蒸馏至体系中不再有水蒸出， 加入 20mL醋酸继续加热至不再有水生成， HPLC检测邻羟基苯乙酸的含量 为 0.3%, 冷却， 过滤， 固体用 50mL曱苯洗涤两次。 合并滤液和洗涤 液， 减压蒸馏（_0.08MPa, 油浴温度 80°C ) 浓缩回收曱苯和催化剂 醋酸。 冷却， 在烧瓶上加一刺型精馏柱， 分别加入 40g原曱酸三曱酯 和 89.5g乙酸酐，加热至 100°C, 收集温度不高于 70°C的馏分， 10.5 小时后不再有馏分蒸出， 将精馏装置改成蒸馏装置， 将反应液在 90 °C油浴中、 -0.08MPa下减压浓缩， 共收集馏分 68.5g，GC测得乙酸和 乙酸酐的含量分别为 33.5°/。和 63.7°/。， 残余物为黑色油状物， 称热加 入 85mL 曱醇， 混合， 冷却、 结晶、 过滤、 干燥得到淡黄色固体 28.7g， HPLC检测含量为 99.1%, 收率 80.8%。
实施例三：
称取邻氯苯乙酸 68.2g(0.4mol) 、 催化剂 8-羟基喹啉铜 14.08g(0.04mol)和氢氧化钠水溶液 507.3g, —次性投入高压釜， 在 170°C反应 2h。 冷却至室温， 将反应液取出， 用浓盐酸中和至 pH值 为 7。 过滤， 滤饼进行干燥回收， 滤液继续用浓盐酸酸化至 pH值为 1 后转入带搅拌、 温度计、 冷凝管三口圆底烧瓶， 油浴温度为 100°C、 -0.02Mpa下减压蒸馏直到酸水基本蒸干， 向残留物中加入 500mL 曱 苯， 调节油浴温度至 125°C, 共沸蒸馏至体系中不再有水蒸出， 加入 30mL醋酸继续加热至不再有水生成， HPLC检测邻羟基苯乙酸的含量 为 0.45%, 冷却， 过滤， 固体用 lOOmL曱苯洗涤两次。 合并滤液和洗 涤液， 减压蒸馏 ( -0.02MPa,油浴温度 90°C )浓缩回收曱苯和催化剂 醋酸。 冷却， 在烧瓶上加一刺型精馏柱， 分别加入 80g原曱酸三曱酯 和 169g 乙酸酐，加热至 100°C, 收集温度不高于 70°C的馏分， 10小 时后不再有馏分蒸出， 将精馏装置改成蒸馏装置， 将反应液在 95°C 油浴中， -0.02MPa下减压浓缩， 共收集馏分 135g，GC测得乙酸和乙 酸酐的含量分别为 34.7°/。和 61.2%,残余物为黑色油状物，加入 170mL 曱醇， 混合， 冷却、 结晶、 过滤、 干燥得到淡黄色固体 59.9g，HPLC 检测含量为 97.9%, 收率 83.3%。
实施例四：
称取邻氯苯乙酸 34. lg(0.2mol) 、 催化剂 8-羟基喹啉铜 7.04g(0.02mol)和氢氧化钠水溶液 253.6g, —次性投入高压釜， 在 170°C反应 2h。 反应结束后， 将反应液取出， 用浓盐酸中和至 pH值 为 7。 过滤， 滤饼进行干燥回收， 滤液继续用浓盐酸酸化至 pH值为 1 后转入带搅拌、 温度计、 冷凝管三口圆底烧瓶， 油浴温度为 80°C、 -0.075Mpa下减压蒸馏直到酸水基本蒸干， 向残留物中加入 200mL曱 苯， 调节油浴温度至 115°C, 共沸蒸馏至体系中不再有水蒸出， 加入 15mL醋酸继续加热至不再有水生成， HPLC检测邻羟基苯乙酸的含量 为 0.5°/。， 冷却， 过滤， 固体用 50mL曱苯洗涤两次。 合并滤液和洗涤 液， 减压蒸馏（-0.075MPa，油浴温度 80°C ) 浓缩回收曱苯和催化剂 醋酸。 冷却， 在烧瓶上加一刺型精馏柱， 分别加入 40g原曱酸三曱酯 和 89.5g乙酸酐，加热至 100°C, 收集温度不高于 70°C的馏分， 10小 时后不再有馏分蒸出， 将精馏装置改成蒸馏装置， 将反应液在 85°C 油浴中、 -0.075MPa下减压浓缩， 共收集馏分 70.5g， GC测得乙酸和 乙酸酐的含量分别为 33.5°/。和 63.4%, 残余物为黑色油状物得到黑色 油状物， 趁热加入 80mL曱醇， 混合， 冷却、 结晶、 过滤、 干燥得到 淡黄色固体 29.3g， HPLC检测含量为 97.6%, 收率 81.3%0
实施例五（回收醋酸醋酐精馏 ):
称取实施例一、 二、 三中得到的回收乙酸、 乙酸酐混合物 25 Og, 放入 500毫升带机械搅拌和温度计的四口烧瓶中，烧瓶上加 1.5米长 内装玻璃弹簧填料的精馏柱以及活芯式精馏头， 调节油浴温度 85 ~ 90°C, 真空度 100匪 Hg，减压蒸馏， 分别收集乙酸和乙酸酐馏分， 得 乙酸 62g, GC测得含量 98.6%,得乙酸酐 145克， GC测得含量 98.9%0 实施例六（回收醋酸套用 ):
称取邻氯苯乙酸 34. lg(0.2mol) 、 催化剂 8-羟基喹啉铜 7.04g(0.02mol)和氢氧化钠水溶液 253.6g, —次性投入高压釜， 在 170°C反应 2h。 冷却到室温， 将反应液取出， 用浓盐酸中和至 pH值 为 7。 过滤， 滤饼进行干燥回收， 滤液继续用浓盐酸酸化至 pH值为 1 后转入带搅拌、 温度计、 冷凝管三口圆底烧瓶， 油浴温度为 80°C、 -0.05Mpa下减压蒸馏直到酸水基本蒸干， 向残留物中加入 200mL 曱 苯， 调节油浴温度至 115°C, 共沸蒸馏至体系中不再有水蒸出， 加入 实施例 5回收醋酸 15mL继续加热至不再有水生成， HPLC检测邻羟基 苯乙酸的含量为 0.8°/。， 冷却， 过滤， 固体用 50mL曱苯洗涤两次。 合 并滤液和洗涤液， 减压蒸馏 (-0.05MPa,油浴温度 75°C )浓缩回收曱 苯和催化剂醋酸。 冷却， 在烧瓶上加一刺型精馏柱， 分别加入 40g原 曱酸三曱酯和和实施例 5回收的乙酸酐 89.5g，加热至 100°C,收集温 度不高于 70°C的馏分， 10小时后不再有馏分蒸出， 将精馏装置改成 蒸馏装置， 将反应液在 85°C油浴中、 -0.05MPa下减压浓缩得到黑色 油状物， 趁热加入 80mL曱醇， 混合， 冷却、 结晶、 过滤、 干燥得到 淡黄色固体 29.7g， HPLC检测含量为 98.1%, 收率 82.8%0

Claims

权 利 要 求
1、 一种合成 3_(α-曱氧基）曱婦基苯并呋喃 _2(3 -酮的方法， 步骤包括： 邻羟基苯乙酸的合成、 内酯的合成、 3-(α-曱氧基）曱烯 基苯并呋喃 -2(3 -酮的合成， 其特征在于： 所述的内酯的合成步骤 包括：
a、 将邻羟基苯乙酸的合成步骤中得到的滤液除去酸水； b、 加入催化剂醋酸， 共沸蒸馏除去反应生成的水， 直到体系内 不再有水生成和 /或反应混合物中邻羟基苯乙酸的含量小于 1%;
c、 将反应混合物冷却析出氯化钠， 过滤， 固体用曱苯洗涤； 合 并滤液和洗涤液， 减压蒸馏浓缩回收曱苯和催化剂醋酸得目标产物。
2、 根据权利要求 1所述的方法， 其特征在于： 所述的步骤 a中， 先向滤液中继续加浓盐酸至 pH=l, 减压蒸馏除去大量的酸水， 再加 一定量的曱苯， 共沸蒸馏除去剩余的酸水。
3、 根据权利要求 1所述的方法， 其特征在于： 所述的步骤 a中 减压蒸馏通常在油浴加热条件下进行， 减压压力在 -0.01 ~ -0.095MPa,油浴加热温度 80 ~ 100°C。
4、 根据权利要求 1所述的方法， 其特征在于： 所述的步骤 b中 蒸馏的加热温度在 110~ 130°C, 直到体系内不再有水生成并且反应 混合物中邻羟基苯乙酸的含量小于 1%。
5、 根据权利要求 1所述的方法， 其特征在于： 所述的步骤 c中， 用曱苯洗涤两次；所述的减压的压力在 -0.01 ~ -0.095MPa,油浴温度 70~ 100°C。
6、 根据权利要求 1到 5中任意一项所述的方法， 其特征在于： 所述的步骤 c处理得到的残留物加入原曱酸三曱酯和醋酸酐， 100°C 下反应， 控制馏分温度不超过 70°C, 收集产生的副产物乙酸曱酯， 直到不再有馏分蒸出且内酯的含量小于 1%后， 在- 0.01 ~ -0.095MPa 下，油浴温度 80 ~ 100 °C减压蒸馏副产乙酸和过量的醋酸酐直到不再 有馏分蒸出， 趁热加入曱醇 /乙醇， 冷却析晶， 过滤后固体用曱醇洗 涤、 干燥得到成品。
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