WO2021037022A1 - 4-甲基-5-烷氧基噁唑的制备方法 - Google Patents

4-甲基-5-烷氧基噁唑的制备方法 Download PDF

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WO2021037022A1
WO2021037022A1 PCT/CN2020/111066 CN2020111066W WO2021037022A1 WO 2021037022 A1 WO2021037022 A1 WO 2021037022A1 CN 2020111066 W CN2020111066 W CN 2020111066W WO 2021037022 A1 WO2021037022 A1 WO 2021037022A1
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methyl
solid acid
reaction
acid catalyst
formylalanine
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PCT/CN2020/111066
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French (fr)
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林波
王玉岗
陈卫勇
邵闪
梁昊
赵雷
王海涛
盛美兰
吴元元
杨小春
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山东新和成精化科技有限公司
浙江新和成股份有限公司
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Publication of WO2021037022A1 publication Critical patent/WO2021037022A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D263/36—One oxygen atom
    • C07D263/42—One oxygen atom attached in position 5

Definitions

  • the invention belongs to the field of chemical synthesis, and specifically relates to a preparation method of 4-methyl-5-alkoxyoxazole.
  • R is a C1-C4 saturated alkyl group.
  • Reference 1 discloses an industrial preparation method of 4-methyl-5-ethoxyoxazole, and specifically discloses the following steps: Put N-ethoxyoxalanine into the cyclization reactor in a certain proportion Ethyl acid, solid phosgene, chloroform, triethylamine, catalyst; wherein the catalyst is pyridine or acid chloride for cyclization. After the cyclization reaction is completed, after washing with water and saponification, the chloroform is recovered, and alkali is added to remove the produced ethanol. After decarboxylation, neutralization, distillation and rectification, 4-methyl-5-ethoxy oxazole is obtained. The reaction time is long, much more than 10 hours, and the highest yield is only 80%.
  • Reference 2 discloses a synthesis process of vitamin B 6 intermediate 4-methyl-5-alkoxy oxazole, and specifically discloses the use of N-alkoxy oxalyl- ⁇ -aminopropionate in trichlorooxy Phosphorus, aliphatic tertiary amine, and aromatic hydrocarbon cyclization agent system cyclize to produce 4-methyl-5-alkoxy-2-oxazole ester, which is hydrolyzed, acidified and decarboxylated to synthesize 4-methyl-5-alkoxyoxazole .
  • the reaction time is more than 10 hours, and the total yield is 81.3% (the yields of the two steps are 90.4% and 89.9%, respectively).
  • Reference 3 discloses a preparation method of 4-methyl-5-ethoxyoxazole, and specifically discloses the use of phosphorus oxychloride, triethylamine, and dimethylformamide as cyclization dehydrating agent, N- The ethyl oxyoxalanine ethyl ester is dehydrated under the action of a cyclization dehydrating agent. Then ethanol is distilled out, decarboxylated with sulfuric acid, extracted with chloroform, dried with anhydrous sodium sulfate, and chloroform is distilled off under normal pressure to obtain 4-methyl-5-ethoxyoxazole. The maximum yield of this reaction is 82.0%.
  • the main problems in the prior art are the use of phosphorus pentoxide, or the use of phosphorus oxychloride will produce a large amount of phosphorus-containing wastewater, a large amount of waste salt, and a series of safe production that needs to be solved in terms of transportation and process operations. , Safe operation, difficulty in handling environmental pollution, and other issues, ultimately resulting in an increase in production costs.
  • the cyclization agent is highly toxic and requires high equipment. There are many side reactions, many impurities, low yield, low selectivity, stoichiometric catalysts are required, and long reaction steps are not conducive to industrial production.
  • the purpose of the present invention is to provide a 4-methyl-5-alkoxy with few reaction steps, high yield, low waste liquid discharge, easy pollution control, and low production cost.
  • the present invention provides a preparation method of 4-methyl-5-alkoxyoxazole, said method comprising: subjecting a compound represented by the following formula (I) to a cyclization reaction to obtain said 4 -Methyl-5-alkoxyoxazole,
  • R represents a C1-C6 alkyl group
  • the cyclization reaction is carried out in the presence of a solid acid catalyst.
  • the compound of the formula (I) structure is selected from N-formylalanine methyl ester, N-formylalanine ethyl ester, N-formylalanine propyl ester, N-formylalanine n-butyl One or a combination of two or more of esters and N-formylalanine isopropyl ester.
  • the solid acid catalyst is selected from solid acids containing -OSO 3 H.
  • the solid acid catalyst is selected from at least one compound having the following structural formula (II):
  • R 1 are the same or different, and independently represent hydrogen, halogen, cyano, or -OSO 3 H, provided that at least one R 1 is -OSO 3 H.
  • the solid acid catalyst is selected from:
  • the solid acid catalyst is supported on the carrier.
  • the molar ratio of the compound represented by the formula (I) to the solid acid catalyst is 1:(0.01-0.1).
  • the cyclization reaction is carried out in the presence of a solvent, and the molar ratio of the compound represented by the formula (I) to the solvent is 1:(0.5-5).
  • the temperature of the cyclization reaction is 60-110°C, and the reaction time is 2-10h.
  • a post-treatment step is further included, and the post-treatment step includes: filtration and/or rectification steps.
  • the present invention also provides a preparation method of vitamin B 6 or its derivatives, including the aforementioned preparation method of 4-methyl-5-alkoxyoxazole.
  • the catalyst has no corrosive effect on the reactor and has low requirements on equipment.
  • cyclization reaction and “cyclization reaction” have the same meaning. That is, a linear or branched compound undergoes a condensation reaction to close to form a ring reaction.
  • references to “some specific/preferred embodiments”, “other specific/preferred embodiments”, “embodiments”, etc. refer to the specific elements described in relation to the embodiment (for example, Features, structures, properties, and/or characteristics) are included in at least one of the embodiments described herein, and may or may not be present in other embodiments.
  • the described elements may be combined in various embodiments in any suitable manner.
  • the present invention provides a method for preparing 4-methyl-5-alkoxyoxazole, which is characterized in that the method comprises: subjecting a compound represented by the following formula (I) to a cyclization reaction to To obtain the 4-methyl-5-alkoxy oxazole,
  • R represents a C1-C6 alkyl group
  • the cyclization reaction is carried out in the presence of a solid acid catalyst.
  • the starting reactant used is the compound of formula (I), that is, N-formylalanine ester.
  • the starting reactant may be a single type of N-formylalanine ester or a mixture of multiple types of N-formylalanine esters.
  • the compound of formula (I) is cyclized by dehydration. 4-methyl-5-alkoxyoxazole is formed.
  • R in formula (I) represents an alkyl group including but not limited to C1 to C6, which can be a straight chain alkyl group, or a branched chain alkyl group, or an alkyl group substituted with heteroatoms; preferably, R Represents a C1-C4 saturated alkyl group.
  • R represents a C1-C4 saturated alkyl group, which can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tertiary Butyl.
  • the compound of the structure of formula (I) is selected from the group consisting of N-formylalanine methyl ester, N-formylalanine ethyl ester, N-formylalanine alanine One or a combination of two or more of esters, n-butyl N-formylalanine and isopropyl N-formylalanine.
  • a solid acid is a solid that can give protons and accept electron pairs, it can chemically adsorb alkali, and can change the color of the alkali indicator.
  • Solid acid catalysts are an important class of catalysts whose catalytic function comes from the acidic sites with catalytic activity on the solid surface, called acid centers. Most of them are oxides or mixed oxides of non-transition elements, and their catalytic performance is different from oxide catalysts containing transition elements. Such catalysts are widely used in catalyzed reactions of ionic mechanism, and there are many types.
  • Solid acid catalysts usually have the characteristics of being hard to volatilize, low toxicity, odorless, less corrosive to equipment and environmental pollution, easy to recycle, and reusable. Generally, the catalyzed reaction conditions are mild, the yield and selectivity are high, and the post-treatment is simple. It is widely used in organic synthesis and cannot be replaced by liquid catalysts. The inventors of the present invention unexpectedly discovered that the solid acid catalyst has a high-efficiency catalytic effect on the cyclization reaction involved in the present invention, and the solid acid catalyst has a high recovery rate and is applicable in production.
  • the solid acid catalyst is selected from solid acids containing -OSO 3 H.
  • the solid acid catalyst is selected from at least one compound having the following structural formula (II):
  • R 1 are the same or different, and independently represent hydrogen, halogen, cyano, or -OSO 3 H, provided that at least one R 1 is -OSO 3 H.
  • the halogen when R 1 is halogen, the halogen may be fluorine, chlorine, or bromine; preferably fluorine and chlorine; more preferably fluorine.
  • the solid acid catalyst is selected from:
  • the solid acid catalyst is applicable in a series of traditional homogeneous and heterogeneous catalytic reactions.
  • the solid acid catalyst is supported on a carrier. Since part of the acid catalyst containing -OSO 3 H can be dissolved or partly dissolved in the reaction system, the catalyst cannot be recovered after the reaction is completed, resulting in products undergoing processes such as neutralization, water washing, and drying, and subsequent treatment processes are complicated. Therefore, the catalyst can be loaded on another carrier to make a supported catalyst, which has the advantages of good stability, reusability, simple operation, etc., and meets the needs of green chemistry development.
  • the carrier includes, but is not limited to, silica gel (SiO 2 ), activated carbon, TiO 2 , activated alumina, MCM-41 molecular sieve, SBA-15 molecular sieve, diatomaceous earth, mesoporous materials, ion exchange resins, etc. .
  • the common features of these carriers are high specific surface area, active functional groups and regular pores.
  • the method for supporting the solid acid catalyst on the carrier includes, but is not limited to, an adsorption method, an impregnation method, a hydrothermal dispersion method, a sol-gel method, a grafting method, and the like.
  • the solid acid catalyst is supported on silica gel.
  • the hydroxyl groups on the surface of the silica react with the compound X-OSO 3 H containing -OSO 3 H to generate a SiO 2 -X-OSO 3 H solid acid catalyst.
  • the compound of formula (I) (i.e., N-formylalanine ester) undergoes a dehydration ring to synthesize 4-methyl-5-alkoxyoxazole in the presence of a solid acid catalyst.
  • the molar ratio of the compound represented by the formula (I) to the solid acid catalyst is 1:(0.01-0.1).
  • the molar ratio of the compound represented by formula (I) to the solid acid catalyst is 1: (0.01-0.05).
  • the cyclization reaction is carried out in the presence of a solvent.
  • a solvent Preferably, the molar ratio of the compound represented by the formula (I) to the solvent is 1:(0.5-5).
  • the molar ratio of the compound represented by formula (I) to the solvent includes but is not limited to 1:1, 1:2, 1:3, 1:4, and 1:4.5.
  • reaction time of the cyclization reaction is 2-10h.
  • the reaction time of the cyclization reaction is preferably 7-10h.
  • the reaction temperature of the cyclization reaction is 60-110°C.
  • the reaction temperature of the cyclization reaction is preferably 80-100°C.
  • the solvent used in the reaction system is a type of solvent with a relatively low dielectric constant.
  • Such solvents hardly carry out proton autotransmission reactions, do not weaken the attraction of electrolyte ions, and do not solvate with solutes.
  • the reaction solvent may be:
  • Alkane solvents such as pentane, cyclopentane, methylcyclopentane, hexane, cyclohexane, heptane, octane, etc.;
  • Aromatic solvents such as toluene, xylene, benzene, etc.;
  • Halogenated hydrocarbon solvents such as carbon tetrachloride, dichloroethane, etc.
  • Ester solvents such as ethyl acetate, propyl acetate, etc.
  • reaction solvents one of them or a mixed solvent of two or more can be used.
  • the solvent for the cyclization reaction is toluene.
  • a post-treatment step is further included, and the post-treatment step includes, but is not limited to, filtration and/or rectification steps.
  • the specific method of the filtration step is not particularly limited, that is, the liquid in the suspension can be passed through the pores of the porous medium (ie, the filter medium), so that the solid particles in the suspension can be trapped in the medium. On the top, a filter cake is formed to realize solid and liquid separation.
  • gravity, pressure (or pressure difference), and/or centrifugal force can be used to drive the liquid through the filter medium.
  • pressure is preferably used.
  • the step of filtering may further include washing the filter cake, recovering the filtrate, and performing subsequent processing.
  • the specific method of the rectification step is not particularly limited, that is, the mixed liquid can be almost completely separated through multiple partial vaporization and condensation processes.
  • continuous, two-component distillation can be carried out under normal pressure.
  • the solid acid catalyst in the preparation method of 4-methyl-5-alkoxyoxazole, after one preparation is completed, the solid acid catalyst can be put into the next batch of reaction system directly or after solvent washing. Use after the catalyst is regenerated.
  • the solid acid catalyst can be directly put into the next batch of reaction system for production.
  • the solid acid catalyst can be put into the next batch of reaction system for production after being washed with a solvent.
  • the obtained solid acid catalyst is added to toluene of the same quality, heated to reflux, fully stirred for 2 hours, allowed to stand, cooled, filtered, and washed with a small amount of ethanol
  • the vacuum drying oven is activated to obtain a solid acid catalyst. It is directly used in the cyclization reaction without further treatment.
  • Heating device Gongyi Yuhua Instrument Co., Ltd.
  • Insulation device Gongyi Yuhua Instrument Co., Ltd.
  • the preparation method of 4-methyl-5-alkoxyoxazole of the present invention can be implemented industrially.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Catalysts (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

本发明公开了一种4-甲基-5-烷氧基噁唑的制备方法，属于化学合成领域。所述方法包括将N-甲酰丙氨酸酯类进行成环化反应，以得到所述4-甲基-5-烷氧基噁唑，所述成环化反应是在固体酸催化剂的存在下进行的。本发明的目的是提供一种具有反应步骤少、收率高、废液排放量少，污染容易治理，生产成本低的4-甲基-5-烷氧基噁唑的制备方法。本发明所述方法可以应用到实验室制备或者工业生产中，用于维生素B6合成中间体的制备中。

Description

4-甲基-5-烷氧基噁唑的制备方法 技术领域
本发明属于化学合成领域，具体涉及一种4-甲基-5-烷氧基噁唑的制备方法。
背景技术
4-甲基-5-烷氧基噁唑，具体结构如下所示，其是合成维生素B 6的重要中间体
Figure PCTCN2020111066-appb-000001
式中，R为C1～C4的饱和烷基。
目前4-甲基-5-烷氧基噁唑的合成方法大多以N-烷氧草酰丙氨酸酯为原料经脱水剂脱水环合，再对得到的环合液进行皂化、脱羧、精馏得到目标产物。
引用文献1公开了一种4-甲基-5-乙氧基噁唑的工业制备方法，并具体公开了包括如下步骤：向环合反应釜中按一定比例投入N-乙氧草酰丙氨酸乙酯、固体光气、氯仿、三乙胺、催化剂；其中催化剂为吡啶或酰氯，进行环合。环合反应完毕后，经水洗、皂化后，回收氯仿，加碱，脱去所产生的乙醇。再经过脱羧、中和、蒸馏、精馏得到4-甲基-5-乙氧基噁唑。反应时间长，远多于10小时，收率最高仅为80％。
引用文献2公开了一种维生素B 6中间体4-甲基-5-烷氧基噁唑的合成工艺，并具体公开了用N-烷氧草酰-α-氨基丙酸酯在三氯氧磷、脂肪叔胺、芳烃环合剂体系中环合生成4-甲基-5-烷氧基-2-噁唑酸酯，经水解、酸化、脱羧合成4-甲基-5-烷氧基噁唑。反应时长，多于10h，总收率为81.3％(两步收率分别为90.4％和89.9％)。
引用文献3公开了一种4-甲基-5-乙氧基噁唑的制备方法，并具体公开了用三氯氧磷、三乙胺、二甲基甲酰胺做环合脱水剂，N-乙氧草酰丙氨酸乙酯在环合脱水剂作用下脱水。后蒸馏出乙醇，加硫酸脱羧、氯仿萃取、无水硫酸钠干燥后，常压蒸馏出氯仿，得到4-甲基-5-乙氧基噁唑。该反应收率最高为82.0％。
此外也有一些以N-甲酰丙氨酸乙酯为原料直接合成噁唑的报道。
Shasad Sharif等人(J.AM.CHEM.SOC.2007，129，4440-4455)则报道了以N-甲酰丙氨酸乙酯为原料，在二氯甲烷/P 2O 5的环合体系中，加热至回流进行环合反应，反应时间24h，加碱液终止反应，再经过后处理得到4-甲基-5-乙氧基噁唑，收率78％。
现有技术中存在的问题主要有使用五氧化二磷，或使用三氯氧磷会产生大量含磷废水、废盐量大，以及运输和工艺操作方面给厂家带来一系列需要解决的安全生产，安全操作，环境污染处理困难等问题，最终造成生产成本的上升。环合剂毒性较强，对设备要求高。副反应多，杂质多，收率低，选择性低，需要化学计量的催化剂，反应步骤较长等不利于工业化生产。
引用文献：
引用文献1：CN104447605A；
引用文献2：CN86101512A；
引用文献3：CN102321043A；
引用文献4：J.AM.CHEM.SOC.2007，129，4440-4455。
发明内容
发明要解决的问题
针对现有技术中存在的上述问题，本发明的目的是提供一种具有反应步骤少、收率高、废液排放量少，污染容易治理，生产成本低的4-甲基-5-烷氧基噁唑的制备方法。
用于解决问题的方案
本发明提供了一种4-甲基-5-烷氧基噁唑的制备方法，所述的方法包括：将如下式(I)结构所示的化合物进行成环化反应，以得到所述4-甲基-5-烷氧基噁唑，
Figure PCTCN2020111066-appb-000002
其中，R表示C1～C6的烷基；
所述成环化反应是在固体酸催化剂的存在下进行的。
所述式(I)结构的化合物选自N-甲酰丙氨酸甲酯、N-甲酰丙氨酸乙酯、N-甲酰丙氨酸丙酯、N-甲酰丙氨酸正丁酯、N-甲酰丙氨酸异丙酯中的一种或两种以上的组合。
所述固体酸催化剂选自含有-OSO 3H的固体酸。
所述固体酸催化剂选自具有以下结构式(II)的化合物的至少一种：
其中，
C-(R 1) 4   .......式(II)
R 1之间相同或不同，并且相互独立的表示氢、卤素、氰基、或-OSO 3H，条件是，至少一个R 1为-OSO 3H。
所述固体酸催化剂选自：
Figure PCTCN2020111066-appb-000003
中的一种或多种。
所述固体酸催化剂负载于载体之上。
所述式(I)表示的化合物与所述固体酸催化剂的摩尔比为1:(0.01～0.1)。
所述成环化反应在溶剂的存在下进行，所述式(I)表示的化合物与溶 剂摩尔比为1:(0.5～5)。
所述成环化反应的温度为60～110℃，反应时间为2～10h。
在所述成环化反应后，还包括后处理步骤，所述后处理步骤包括：过滤和/或精馏的步骤。
本发明还提供了一种维生素B 6或其衍生物的制备方法，包括上述的4-甲基-5-烷氧基噁唑的制备方法。
发明的效果
(1)反应的选择性和转化率较高，最高分别能达到97.8％和93％以上；且反应条件温和、反应过程易控、总成本低，副产物少，脚料率低；
(2)用固体酸作为催化剂，反应生成物与催化剂容易分离，而且催化剂可以反复套用；
(3)避免使用了三乙胺作为反应溶剂，避免了有机废盐的产生，引起的“三废”问题较少；
(4)催化剂对反应器无腐蚀作用，对设备要求低。
具体实施方式
以下，针对本发明的内容进行详细说明。以下所记载的技术特征的说明基于本发明的代表性的实施方案、具体例子而进行，但本发明不限定于这些实施方案、具体例子。
需要说明的是：
本说明书中，使用“数值A～数值B”表示的数值范围是指包含端点数值A、B的范围。
本说明书中，使用“可以”或“可”表示的含义包括了进行某种处理以及不进行某种处理两方面的含义。
本说明书中，“任选的”或“任选地”是指接下来描述的事件或情况可发生或可不发生，并且该描述包括该事件发生的情况和该事件不发生的情况。
本说明书中，术语“成环化反应”和“环合反应”具有相同的含义。也即直链或支链的化合物经过缩合反应闭合形成环的反应。
本说明书中，所提及的“一些具体/优选的实施方案”、“另一些具体/优选的实施方案”、“实施方案”等是指所描述的与该实施方案有关的特定要素(例如，特征、结构、性质和/或特性)包括在此处所述的至少一种实施方案中，并且可存在于其它实施方案中或者可不存在于其它实施方案中。另外，应理解，所述要素可以任何合适的方式组合在各种实施方案中。
本发明提供了一种4-甲基-5-烷氧基噁唑的制备方法，其特征在于，所述的方法包括：将如下式(I)结构所示的化合物进行成环化反应，以得到所述4-甲基-5-烷氧基噁唑，
Figure PCTCN2020111066-appb-000004
其中，R表示C1～C6的烷基；
所述成环化反应是在固体酸催化剂的存在下进行的。
<N-甲酰丙氨酸酯>
在本发明中4-甲基-5-烷氧基噁唑的制备方法中，所使用的起始反应物为所述式(I)化合物，也即N-甲酰丙氨酸酯。所述起始反应物可以为单一种类的N-甲酰丙氨酸酯也可以为多种类N-甲酰丙氨酸酯混合的起始反应物，所述式(I)化合物通过脱水环合形成4-甲基-5-烷氧基噁唑。
其中，式(I)中的R表示为包括但不限于C1～C6的烷基，可以为直链烷基，或支链烷基，也可以是含有杂原子取代的烷基；优选的，R表示C1～C4的饱和的烷基。在本发明的一些具体的实施方案中，R表示C1～C4的饱和的烷基，可以为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基。
在本发明的一些具体的实施方案中，所述式(I)结构的化合物选自N-甲酰丙氨酸甲酯、N-甲酰丙氨酸乙酯、N-甲酰丙氨酸丙酯、N-甲酰丙氨酸正丁酯、N-甲酰丙氨酸异丙酯中的一种或两种以上的组合。
<固体酸催化剂>
固体酸是一种能够给出质子和接受电子对的固体，其能够化学吸附碱，并且能够使碱指示剂改变颜色。固体酸催化剂是一类重要催化剂，催化功能来源于固体表面上存在的具有催化活性的酸性部位，称为酸中心。它们多数为非过渡元素的氧化物或混合氧化物，其催化性能不同于含过渡元素的氧化物催化剂。这类催化剂广泛应用于离子型机理的催化反应，种类很多。此外，还有润载型固体酸催化剂，是将液体酸附载于固体载体上而形成的，如固体磷酸催化剂。
固体酸催化剂通常具有难挥发、低毒、无味、对设备腐蚀及环境污染小、易回收、可重复使用等特点，通常所催化的反应条件温和、产率和选择性高、后处理简便，在有机合成中应用广泛，是液体催化剂所不能替代的。本发明人意外地发现，所述固体酸催化剂对本发明涉及的环化反应具有高效率的催化作用，且固体酸催化剂具有高回收率，在生产中具有套用性。
在本发明中，所述固体酸催化剂选自含有-OSO 3H的固体酸。
在本发明的一些具体的实施方案中，所述固体酸催化剂选自具有以下结构式(II)的化合物的至少一种：
C-(R 1) 4   .......式(II)
其中，
R 1之间相同或不同，并且相互独立的表示氢、卤素、氰基、或-OSO 3H，条件是，至少一个R 1为-OSO 3H。
在本发明中，当R 1为卤素时，所述卤素可为氟、氯、溴；优选为氟、氯；更进一步优选为氟。
在本发明的一些具体的实施方案中，所述固体酸催化剂选自：
Figure PCTCN2020111066-appb-000005
中的一种或多种。
在本发明中，所述固体酸催化剂在一系列传统的均相、异相催化反应中均能适用。
在本发明的一些具体的实施方案中，所述固体酸催化剂负载于载体之上。由于部分含有-OSO 3H的酸催化剂能够溶解或者部分溶解到反应体系中，导致反应结束后催化剂无法回收，导致产物要经过中和、水洗、干燥等工艺，后续处理工艺复杂。因此，可将催化剂负载到另一种载体上，制成负载型催化剂，具有稳定性好，能够重复利用，操作简便等优点，符合绿色化学发展的需要。
在本发明中，所述的载体包括但不限于硅胶(SiO 2)、活性炭、TiO 2、活性氧化铝、MCM-41分子筛、SBA-15分子筛、硅藻土、介孔材料、离子交换树脂等。这些载体共同的特点是有较高的比表面积、有活性官能团及规则的孔道。
在本发明中，使所述固体酸催化剂负载于载体之上的方法包括但不限于吸附法、浸渍法、水热分散法、溶胶-凝胶法、接枝法等。
在本发明的一些具体的实施方案中，所述固体酸催化剂负载于硅胶之上。二氧化硅表面的羟基与含有-OSO 3H的化合物X-OSO 3H反应，生成SiO 2-X-OSO 3H固体酸催化剂。
<成环化反应>
反应机理
在本发明中，所述式(I)化合物(即N-甲酰丙氨酸酯)在固体酸催化剂存在的条件下，经过脱水环合成4-甲基-5-烷氧基噁唑。
反应条件
在本发明中，所述式(I)表示的化合物与所述固体酸催化剂的摩尔比 为1:(0.01～0.1)。
在本发明的一些具体的实施方案中，优选的，所述式(I)表示的化合物与所述固体酸催化剂的摩尔比为1:(0.01～0.05)。
在本发明中，所述成环化反应在溶剂的存在下进行，优选的，所述式(I)表示的化合物与溶剂摩尔比为1：(0.5～5)。
在本发明的一些具体的实施方案中，所述式(I)表示的化合物与溶剂摩尔比包括但不限于1：1、1：2、1：3、1：4、1：4.5。
在本发明中，所述成环化反应的反应时间为2～10h。
在本发明的一些具体的实施方案中，所述成环化反应的反应时间优选为7～10h。
在本发明中，所述成环化反应的反应温度为60～110℃。
在本发明的一些具体的实施方案中，所述成环化反应的反应温度优选为80～100℃。
溶剂
在本发明中，反应体系所使用的溶剂为介电常数较低的一类溶剂。这类溶剂几乎不进行质子自递反应，不减弱电解质离子的引力，也不与溶质发生溶剂化作用。
所述反应溶剂可以为：
烷烃类溶剂，如戊烷、环戊烷、甲基环戊烷、己烷、环己烷、庚烷、辛烷等；
芳香类溶剂，如甲苯、二甲苯、苯等；
卤代烃类溶剂，如四氯化碳、二氯乙烷等；
酯类溶剂，如乙酸乙酯、乙酸丙酯等。
对于上述反应溶剂，可以使用其中的一种，或两种以上的混合溶剂。
在本发明的一些具体的实施方案中，所述成环化反应的溶剂为甲苯。
<后处理>
在本发明的一些具体的实施方案中，在所述成环化反应后，还包括后 处理步骤，所述后处理步骤包括但不限于过滤和/或精馏的步骤。
过滤
在本发明中，对所述过滤的步骤的具体方式没有特别的限定，也即能够使悬浮液中的液体通过多孔介质(即过滤介质)的孔道，使悬浮液中的固体颗粒被截留在介质上，形成滤饼，从而实现固、液分离。
在本发明的一些具体的实施方案中，可以利用重力、压力(或压差)和/或离心力，驱使液体通过过滤介质。在工业生产中，优选采用加压的方式。
在本发明的一些具体的实施方案中，所述过滤的步骤，可进一步包括对所述滤饼进行洗涤，回收滤液，在进行后续处理。
精馏
在本发明中，对所述精馏的步骤的具体方式没有特别的限定，也即能够通过多次部分气化与冷凝的过程，使混合液得到几乎完全分离方可。
在本发明的一些具体的实施方案中，可以在常压下、连续、双组分蒸馏。
<连续反应>
在本发明中，所述4-甲基-5-烷氧基噁唑的制备方法，在一次制备完成后，所述固体酸催化剂可直接或经过溶剂洗涤后投入下一批反应体系中或进行催化剂再生后使用。
在本发明的一些具体的实施方案中，所述固体酸催化剂可直接投入下一批反应体系中，进行生产。
在本发明的一些具体的实施方案中，所述固体酸催化剂可经过溶剂洗涤后，投入下一批反应体系中，进行生产。
催化剂再生
在催化剂连续催化使用一段时间发生催化活性降低的情况后，将获得的固体酸催化剂加入相同质量的甲苯，加热至回流，充分搅拌2小时，静置，冷却，过滤，再用少量乙醇洗涤催化剂，真空干燥箱活化得到固体酸催化 剂。无需进一步处理直接用于环合反应。
实施例
以下说明本发明的实施例，但本发明不限定于下述的实施例。
以下列举了本发明在进行实施例的实验时所使用的仪器和试剂：
N-甲酰丙氨酸乙酯：自制
N-甲酰丙氨酸甲酯：自制
甲苯：分析纯、国药集团
CH(OSO 3H) 3固体酸：阿拉丁
CF 3OSO 3H固体酸：阿拉丁
三口烧瓶：蜀牛玻璃仪器有限公司
搅拌装置：巩义予华仪器有限责任公司
加热装置：巩义予华仪器有限责任公司
保温装置：巩义予华仪器有限责任公司
转化率计算方法：转化率＝(转化的N-甲酰丙氨酸酯)/(初始N-甲酰丙氨酸酯)*100％
选择性计算方法：
选择性＝(生成4-甲基-5-烷氧基噁唑消耗的N-甲酰丙氨酸酯)/(转化的N-甲酰丙氨酸酯)*100％
实施例1：
在1L三口烧瓶中依次投入N-甲酰丙氨酸乙酯145g(1mol)、甲苯276g(3mol)以及20％CH(OSO 3H) 3/SiO 2固体酸(3.4g，0.2mol％，有效成分计)，开启搅拌装置进行搅拌，并升温至90℃，保温反应10h后，降至室温，过滤，分别得到固体酸和反应液，将得到的固体酸直接投入下一批反应而没有明显的催化失活现象，其中反应的转化率为93％，选择性为97.8％。
实施例2：
在1L三口烧瓶中依次投入N-甲酰丙氨酸甲酯131g(1mol)、甲苯276g (3mol)以及20％CH(OSO 3H) 3固体酸(3.4g，0.2mol％)，开启搅拌装置进行搅拌，并升温至80℃，保温反应10h后，降至室温，过滤，分别得到固体酸和反应液，将得到的固体酸直接投入下一批反应而没有明显的催化失活现象，其中反应的转化率为80.3％，选择性为90.4％。
实施例3：
在1L三口烧瓶中依次投入N-甲酰丙氨酸乙酯145g(1mol)、甲苯460g(5mol)以及20％CF 3OSO 3H/SiO 2固体酸(1.66g，0.2mol％)，开启搅拌装置进行搅拌，并升温至90℃，保温反应7h后，降至室温，过滤，分别得到固体酸和反应液，将得到的固体酸直接投入下一批反应而没有明显的催化失活现象，其中反应的转化率为85.1％，选择性为99.1％。
实施例4：
在1L三口烧瓶中依次投入N-甲酰丙氨酸乙酯145g(1mol)、甲苯276g(3mol)以及20％CH(OSO 3H) 3/SiO 2固体酸(3.4g，0.2mol％)，开启搅拌装置进行搅拌，并升温至100℃，保温反应8h后，降至室温，过滤，分别得到固体酸和反应液，将得到的固体酸直接投入下一批反应而没有明显的催化失活现象，其中反应的转化率为93.0％，选择性为95％。
需要说明的是，尽管以具体实例介绍了本发明的技术方案，但本领域技术人员能够理解，本公开应不限于此。
以上已经描述了本公开的各实施例，上述说明是示例性的，并非穷尽性的，并且也不限于所披露的各实施例。在不偏离所说明的各实施例的范围和精神的情况下，对于本技术领域的普通技术人员来说许多修改和变更都是显而易见的。本文中所用术语的选择，旨在最好地解释各实施例的原理、实际应用或对市场中的技术的改进，或者使本技术领域的其它普通技术人员能理解本文披露的各实施例。
产业上的可利用性
本发明所述4-甲基-5-烷氧基噁唑的制备方法，可以在工业上实施。

Claims (11)

  1. 一种4-甲基-5-烷氧基噁唑的制备方法，其特征在于，所述的方法包括：将如下式(I)结构所示的化合物进行成环化反应，以得到所述4-甲基-5-烷氧基噁唑，
    Figure PCTCN2020111066-appb-100001
    其中，R表示C1～C6的烷基；
    所述成环化反应是在固体酸催化剂的存在下进行的。
  2. 根据权利要求1所述的方法，其特征在于，所述式(I)结构的化合物选自N-甲酰丙氨酸甲酯、N-甲酰丙氨酸乙酯、N-甲酰丙氨酸丙酯、N-甲酰丙氨酸正丁酯、N-甲酰丙氨酸异丙酯中的一种或两种以上的组合。
  3. 根据权利要求1或2所述的方法，其特征在于，所述固体酸催化剂选自含有-OSO 3H的固体酸。
  4. 根据权利要求1～3任一项所述的方法，其特征在于，所述固体酸催化剂选自具有以下结构式(II)的化合物的至少一种：
    C-(R 1) 4.......式(II)
    其中，
    R 1之间相同或不同，并且相互独立的表示氢、卤素、氰基、或-OSO 3H，条件是，至少一个R 1为-OSO 3H。
  5. 根据权利要求1～4任一项所述的方法，其特征在于，所述固体酸催化剂选自：
    Figure PCTCN2020111066-appb-100002
    中的一种或多种。
  6. 根据权利要求1～5任一项所述的方法，其特征在于，所述固体酸催化 剂负载于载体之上。
  7. 根据权利要求1～6任一项所述的方法，其特征在于，所述式(I)表示的化合物与所述固体酸催化剂的摩尔比为1:(0.01～0.1)。
  8. 根据权利要求1～7任一项所述的方法，其特征在于，所述成环化反应在溶剂的存在下进行，所述式(I)表示的化合物与溶剂摩尔比为1：(0.5～5)。
  9. 根据权利要求1～8任一项所述的方法，其特征在于，所述成环化反应的温度为60～110℃，反应时间为2～10h。
  10. 根据权利要求1～9任一项所述的方法，其特征在于，在所述成环化反应后，还包括后处理步骤，所述后处理步骤包括：过滤和/或精馏的步骤。
  11. 一种维生素B 6或其衍生物的制备方法，其特征在于，包括根据权利要求1～10任一项所述的4-甲基-5-烷氧基噁唑的制备方法。
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