WO2022088244A1 - 一种醇羟基供体与活性氢供体进行光延反应的方法 - Google Patents

一种醇羟基供体与活性氢供体进行光延反应的方法 Download PDF

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WO2022088244A1
WO2022088244A1 PCT/CN2020/127698 CN2020127698W WO2022088244A1 WO 2022088244 A1 WO2022088244 A1 WO 2022088244A1 CN 2020127698 W CN2020127698 W CN 2020127698W WO 2022088244 A1 WO2022088244 A1 WO 2022088244A1
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donor
active hydrogen
reaction
reagent
azodicarboxylate
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PCT/CN2020/127698
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English (en)
French (fr)
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叶守陈
宋晓龙
徐爽
赵李亮
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江苏和成新材料有限公司
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Priority to JP2023548982A priority Critical patent/JP2023547270A/ja
Priority to US18/033,595 priority patent/US20230399281A1/en
Publication of WO2022088244A1 publication Critical patent/WO2022088244A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/09—Preparation of ethers by dehydration of compounds containing hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
    • C07C209/14—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of hydroxy groups or of etherified or esterified hydroxy groups
    • C07C209/16—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of hydroxy groups or of etherified or esterified hydroxy groups with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
    • C07C209/14—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of hydroxy groups or of etherified or esterified hydroxy groups
    • C07C209/18—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of hydroxy groups or of etherified or esterified hydroxy groups with formation of amino groups bound to carbon atoms of six-membered aromatic rings or from amines having nitrogen atoms bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/18—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by addition of thiols to unsaturated compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/34—Separation; Purification; Stabilisation; Use of additives
    • C07C41/46—Use of additives, e.g. for stabilisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the application belongs to the field of organic synthesis, and relates to a method for carrying out Mitsunobu reaction between an alcohol hydroxyl donor and an active hydrogen donor.
  • Mitsunobu reaction is a kind of organic reaction with great application value invented by Japanese organic chemist Mitsunobu Wangyang in 1967.
  • the intramolecular or intermolecular dehydration reaction that occurs in the presence of esters, the reaction mechanism is generally (take triphenylphosphine and diethyl azodicarboxylate as reagents and alcohol as an example of the reaction of chiral alcohol): triphenylphosphine
  • the phosphine and diethyl azodicarboxylate form an adduct, the proton of the nucleophile is removed, the alcohol and triphenylphosphine are combined and activated, and the nucleophile undergoes S N 2 reaction to obtain the product.
  • the reaction formula is as follows:
  • the Mitsunobu reaction is generally carried out under mild neutral conditions. If a chiral alcohol participates in the reaction, the configuration of the carbon atom attached to the hydroxyl group of the alcohol will generally be reversed, which can be used to form various chemical bonds, such as: C-O, C-N, Chemical bonds such as C-S and C-C, therefore, Mitsunobu reaction is widely used in the total synthesis of various natural products or the conversion of functional groups of compounds.
  • the Mitsunobu reaction is a dehydration condensation process, so the moisture in the reaction system must be controlled to avoid the loss of trihydrocarbyl phosphine and azodicarboxylate.
  • Such reaction medium usually adopts anhydrous aprotic solvent, such as toluene, tetrahydrofuran, ethyl tert-butyl ether, ethyl acetate, acetonitrile, dimethylformamide, dimethylacetamide, dichloromethane and the like.
  • This kind of aprotic solvent has low flash point, high odor and difficult recovery, which is not in line with the current trend of green chemistry.
  • the optimization and selection of reaction conditions is a research hotspot in the field of green chemistry today.
  • R represents the group from which the alcoholic hydroxyl donor leaves the hydroxyl group.
  • the above-mentioned by-products have high polarity and are difficult to be removed by conventional post-treatment methods.
  • the purification cost of the final product is relatively high, which greatly increases the "three wastes" emissions and preparation costs, and affects the purity and subsequent application of the final product.
  • the purpose of the present application is to provide a method for carrying out Mitsunobu reaction between an alcoholic hydroxyl group donor and an active hydrogen donor.
  • the method described in the present application can solve the problems in the prior art, such as difficulty in removing by-products in the Mitsunobu reaction, high post-treatment three wastes, low product purity, etc., can effectively reduce the generation of dicarboxylic hydrazine by-products, and the target product can be more easily removed from the reaction It is separated from the system, the reaction yield is high, the post-processing is convenient, the product purity is high, the subsequent application is not affected, and the method is environmentally friendly.
  • the present application provides a method for carrying out Mitsunobu reaction between an alcohol hydroxyl donor and an active hydrogen donor, the method specifically comprises the following steps:
  • the alcoholic hydroxyl donor, the active hydrogen donor, the trihydrocarbyl phosphine reagent and the azodicarboxylate reagent are reacted in the presence of an organic solvent to obtain the dehydration condensation product of the alcoholic hydroxyl donor and the active hydrogen donor;
  • the organic solvent is a straight-chain or branched alkane containing 8-16 carbon atoms (for example, normal or iso-alkane of C8, C10, C12, C14, and C16).
  • the dehydration condensation product of the above-mentioned alcohol hydroxyl donor and active hydrogen donor may be any compound among ethers, thioethers, esters, thioesters, amines, and amides.
  • the generation of dicarboxylic acid hydrazine by-products can be effectively reduced, and the target product is easier to separate from the reaction system, the reaction yield is high, the post-processing is convenient, and the product purity is high.
  • the organic solvent is any one or a combination of at least two of iso-decane, iso-dodecane, n-dodecane, or iso-pentadecane.
  • the organic solvent is isododecane.
  • the alcoholic hydroxyl group donor is an organic substance containing an alcoholic hydroxyl group; the alcoholic hydroxyl group may be combined with a substituted or unsubstituted linear alkyl group, a substituted or unsubstituted branched At least one of unsubstituted cyclic alkyl groups, substituted or unsubstituted aryl groups, etc., or a combination of groups is connected.
  • the active hydrogen donor is an organic compound containing an active hydrogen group, wherein the active hydrogen group is selected from -OH, -SH, -COOH, -COSH, -NH2 or -CONH2 Any one or a combination of at least two; the active hydrogen group can be combined with substituted or unsubstituted C1-C12 straight-chain alkyl, substituted or unsubstituted C1-C12 branched alkyl, substituted or unsubstituted C1-C12 At least one of the unsubstituted C3-C12 cyclic alkyl groups, the substituted or unsubstituted C6-C12 aryl groups, or the combined structure of the groups is connected.
  • the above-mentioned C1-C12 alkyl group can be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl
  • C3-C12 cyclic alkyl group can be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
  • An alternative, such as one or at least two -CH 2 - can be independently replaced by any one of -O-, -S-,
  • the trihydrocarbylphosphine reagent is selected from any one or a combination of at least two of triphenylphosphine, tributylphosphine, or trimethylphosphine.
  • the azodicarboxylate reagent is selected from the group consisting of diethyl azodicarboxylate, diisopropyl azodicarboxylate, bis-2-methoxyethylazodicarboxylate Any one or a combination of at least two of bis(4-chlorobenzyl)azodicarboxylate.
  • the molar ratio of the alcohol hydroxyl donor and the active hydrogen donor is 1:1 to 1.2, such as 1:1, 1:1.05, 1:1.1, 1:1.15 or 1:1.2 .
  • the molar ratio of the alcoholic hydroxyl donor and the trihydrocarbyl phosphine reagent is 1:1.05 ⁇ 1.3, for example, 1:1.05, 1:1.08, 1:1.1, 1:1.15, 1:1.2 , 1:1.25 or 1:1.3.
  • the molar ratio of the alcoholic hydroxyl donor and the azodicarboxylate reagent is 1:1.05 ⁇ 1.3, such as 1:1.05, 1:1.08, 1:1.1, 1:1.15, 1:1.2, 1:1.25 or 1:1.3.
  • the reaction temperature is 30-120°C (eg 30°C, 50°C, 80°C, 100°C, 110°C or 120°C), and the reaction time is 1-12h (eg 1h, 3h) , 5h, 7h, 9h, 10h, 11h or 12h).
  • the feeding sequence of the reaction described in the present application is: slowly drop the azodicarboxylate into the organic solvent containing the alcoholic hydroxyl donor, the active hydrogen donor, and the trihydrocarbyl phosphine reagent, Alternatively, the azodicarboxylate and the trihydrocarbyl phosphine reagent are mixed first, and then the alcoholic hydroxyl donor and the active hydrogen donor are added to the mixture.
  • the temperature of the dropwise addition process is controlled at 30-120°C, such as 30°C, 50°C, 80°C, 100°C, 110°C or 120°C.
  • the reaction is carried out under the protection of inert gas, including the raw material mixing process and the reaction process.
  • the reaction can be accelerated by sonication, microwaves, or the addition of organic bases (eg, triethylamine, etc.).
  • organic bases eg, triethylamine, etc.
  • the method specifically includes the following steps:
  • the alcohol hydroxyl donor, active hydrogen donor, trihydrocarbyl phosphine reagent and azodicarboxylate reagent are reacted at 30-120°C for 1-12h in the presence of an organic solvent;
  • the organic solvent is a straight-chain or branched-chain alkane containing 8-16 carbon atoms
  • the molar ratio of the alcoholic hydroxyl donor and the active hydrogen donor is 1:1-1.2, the molar ratio of the alcoholic hydroxyl donor and the trihydrocarbyl phosphine reagent is 1:1.05-1.3; the alcoholic hydroxyl donor and the coupler
  • the molar ratio of nitrogen dicarboxylate reagent is 1:1.05 ⁇ 1.3.
  • the product of the present application is easier to separate from the reaction system, which reduces the economic cost and time cost of post-processing;
  • the solvent used in this application has the characteristics of high flash point, no odor, low risk, and is more in line with the requirements of green environmental protection;
  • relevant reagents can be purchased from the market, wherein the GC testing instrument is Agilent 7820A gas chromatograph, the MS testing instrument is Agilent 7890B-5977A mass spectrometer, and the HPLC testing instrument is Shimadzu LC-20AB high-efficiency liquid phase chromatograph.
  • reaction solution was added with 200 mL of water and 200 mL of dichloromethane, stirred for 10 min, extracted and separated, the aqueous phase was extracted twice with 200 mL of dichloromethane, the organic phases were combined, the organic phase was washed twice with 200 mL of water, and the organic phase was evaporated under reduced pressure to obtain light A yellow solid, the solid was recrystallized with 150 mL of ethanol, filtered under reduced pressure, and the filter cake was dried to obtain 39.1 g of a white solid, GC: 80.2%, yield 78.7%.
  • the application selects C8-C16 straight-chain or branched-chain alkanes as the organic solvent of the Mitsunobu reaction, which can significantly reduce the generation of impurities, which is conducive to promoting product purity.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

一种醇羟基供体与活性氢供体进行光延反应的方法，具体包括如下步骤：将醇羟基供体、活性氢供体、三烃基膦试剂及偶氮二羧酸酯试剂在有机溶剂的存在下进行反应；其中，有机溶剂为含有8-16个碳原子的直链或支链烷烃。

Description

一种醇羟基供体与活性氢供体进行光延反应的方法 技术领域
本申请属于有机合成领域，涉及一种醇羟基供体与活性氢供体进行光延反应的方法。
背景技术
光延反应(Mitsunobu反应)是日本有机化学家光延旺洋在1967年发明的具有重大应用价值的一类有机反应，是指醇和具有酸性的亲核试剂前体在三烃基膦和偶氮二羧酸酯存在下发生的分子内或分子间的脱水反应，反应机理一般(以三苯基膦及偶氮二羧酸二乙酯作为反应试剂、醇为手性醇的反应为例)为：三苯基膦和偶氮二羧酸二乙酯形成加合物，脱掉亲核试剂的质子，醇和三苯基膦结合活化，亲核试剂进行S N2反应得到产物，反应式如下：
Figure PCTCN2020127698-appb-000001
Mitsunobu反应一般是在温和的中性条件下进行的，如果是手性醇参加反应，醇羟基所连碳原子的构型一般会发生翻转，可以用来形成多种化学键，例如：C-O、C-N、C-S及C-C等化学键，因此，Mitsunobu反应广泛应用于各类天然产物的全合成或化合物的官能团转化。
Mitsunobu反应是一个脱水缩合的过程，因此必须控制反应体系中的水分，避免三烃基膦和偶氮二羧酸酯的损耗。该类反应介质通常采用无水非质子溶剂，如甲苯、四氢呋喃、乙基叔丁基醚、乙酸乙酯、乙腈、二甲基甲酰胺、二甲基乙酰胺、二氯甲烷等。此类非质子溶剂存在闪点低、气味大，回收难，不符合现今绿色化学的趋势，与此同时，此类溶剂通常对产物的分布、收率及后处理的影响较大，因此对Mitsunobu反应条件的优化和选择是如今绿色化学领域的研究热点。
由上述反应机理可知，光延反应在反应过程中，偶氮二羧酸酯最终会转化成二羧酸肼(如
Figure PCTCN2020127698-appb-000002
)，二羧酸肼会进一步与醇羟基供体离去羟基后的基团继续反应，得到如下副产物：
Figure PCTCN2020127698-appb-000003
R表示醇羟基供体离去羟基后的基团。
上述副产物极性较高，很难通过常规后处理方法出去，终产物纯化成本较高，大幅增加了“三废”排放量与制备成本，且影响了终产物的纯度及后续应用。
因此，在本领域中，期望开发一种能够降低二羧酸肼类副产物的生成的高收率光延反应的绿色方法。
发明内容
本申请的目的在于提供一种醇羟基供体与活性氢供体进行光延反应的方法。本申请所述方法能够解决现有技术中光延反应存在的副产物难除、后处理三废高、产物纯度低等问题，可有效降低二羧酸肼类副产物的生成，并且目标产物更易从反应体系中分离出来，反应收率高，后处理方便，产物纯度高，对 后续应用无影响，并且绿色环保。
为达此目的，本申请采用以下技术方案：
一方面，本申请提供一种醇羟基供体与活性氢供体进行光延反应的方法，所述方法具体包括如下步骤：
将醇羟基供体、活性氢供体、三烃基膦试剂及偶氮二羧酸酯试剂在有机溶剂的存在下进行反应，得到醇羟基供体与活性氢供体脱水缩合的产物；
其中，所述有机溶剂为含有8-16个碳原子的直链或支链烷烃(例如C8、C10、C12、C14、C16的正构或异构烷烃)。
在本申请中，上述醇羟基供体与活性氢供体脱水缩合的产物可以为醚类、硫醚类、酯类、硫酯类、胺类、酰胺类中的任一种化合物。
在本申请中，通过反应溶剂体系的优化，可有效降低二羧酸肼类副产物的生成，并且目标产物更易从反应体系中分离出来，反应收率高，后处理方便，产物纯度高。
在本申请的一些实施方案中，所述有机溶剂为异构十烷、异构十二烷、正构十二烷或异构十五烷中的任意一种或至少两种的组合。可选地，所述有机溶剂为异构十二烷。
在本申请的一些实施方案中，所述醇羟基供体为含有醇羟基的有机物；所述醇羟基可与取代或未取代的直链烷基、取代或未取代的支链烷基、取代或未取代的环状烷基、取代或未取代的芳香基等中的至少一种基团或基团的组合结构相连。
在本申请的一些实施方案中，所述活性氢供体为含有活性氢基团的有机物，其中活性氢基团选自-OH、-SH、-COOH、-COSH、-NH 2或-CONH 2中的任意一 种或至少两种的组合；所述活性氢基团可与取代或未取代的C1-C12的直链烷基、取代或未取代的C1-C12的支链烷基、取代或未取代的C3-C12的环状烷基、取代或未取代的C6-C12的芳香基中的至少一种基团或基团的组合结构相连。
在本申请的一些实施方案中，上述C1-C12的烷基例如可以为甲基、乙基、正丙基、异丙基、正丁基、异丁基、正戊基、异戊基、正己基、异己基等，上述C3-C12的环状烷基例如可以为环丙基、环丁基、环戊基、环己基、环庚基等，所述C1-C12的烷基及C3-C12的环状烷基中可选地一个或至少两个-CH 2-独立地被-O-、-S-、-CO-、-CS-、-CH＝CH-或-C≡C-中任意一种替代，例如可以是一个或至少两个-CH 2-独立地被-O-、-S-、-CO-、-CS-、-CH＝CH-或-C≡C-中任意一种替代，或者没有-CH 2-被替代，例如乙基中的一个-CH 2-被-O-替代后的基团为甲氧基，以此逻辑类推，不再赘述；所述C6-C12的芳香族环烃基例如可以为苯基、取代或萘基，所述C6-C12的芳香族环烃基中可选地一个或至少两个-CH＝独立地被-N＝替代，例如可以是一个或至少两个-CH＝独立地被-N＝替代(吡啶基、嘧啶基等)，或者没有-CH＝被替代；所述芳香族环烃基中可选地一个或至少两个-H独立地被卤素、-CN、C1-C5的烷基或C1-C5的烷氧基替代，例如可以是一个或至少两个-H独立地被卤素、-CN、C1-C5的烷基或C1-C5的烷氧基替代，或者没有-H被替代。
在本申请的一些实施方案中，所述三烃基膦试剂选自三苯基膦、三丁基膦或三甲基膦中的任意一种或至少两种的组合。
在本申请的一些实施方案中，所述偶氮二羧酸酯试剂选自偶氮二甲酸二乙酯、偶氮二甲酸二异丙酯、双-2-甲氧基乙基偶氮二羧酸酯、双(4-氯苄基)偶氮二甲酸酯中的任意一种或至少两种的组合。
在本申请的一些实施方案中，所述醇羟基供体和活性氢供体的摩尔比为1:1～1.2，例如1:1、1:1.05、1:1.1、1:1.15或1:1.2。
在本申请的一些实施方案中，所述醇羟基供体和三烃基膦试剂的摩尔比为1:1.05～1.3，例如1:1.05、1:1.08、1:1.1、1:1.15、1:1.2、1:1.25或1:1.3。
在本申请的一些实施方案中，所述醇羟基供体和偶氮二羧酸酯试剂的摩尔比为1:1.05～1.3，例如1:1.05、1:1.08、1:1.1、1:1.15、1:1.2、1:1.25或1:1.3。
在本申请的一些实施方案中，所述反应温度为30-120℃(例如30℃、50℃、80℃、100℃、110℃或120℃)，反应时长为1-12h(例如1h、3h、5h、7h、9h、10h、11h或12h)。
在本申请的一些实施方案中，本申请所述反应的加料顺序为：将偶氮二羧酸酯缓慢滴加至含有醇羟基供体、活性氢供体、三烃基膦试剂的有机溶剂中，或者，将偶氮二羧酸酯与三烃基膦试剂先混合，然后向混合液中加入醇羟基供体和活性氢供体。
在本申请的一些实施方案中，所述滴加过程控温在30-120℃，例如30℃、50℃、80℃、100℃、110℃或120℃。
在本申请的一些实施方案中，所述反应在惰性气体保护下进行，包括原料混合过程及反应过程。
在本申请的一些实施方案中，可通过超声、微波或加入有机碱(如三乙胺等)加速反应。
作为本申请的可选技术方案，所述方法具体包括以下步骤：
将醇羟基供体、活性氢供体、三烃基膦试剂及偶氮二羧酸酯试剂在有机溶剂的存在下于30-120℃反应1-12h；
其中，所述有机溶剂为含有8-16个碳原子的直链或支链烷烃；
所述醇羟基供体和活性氢供体的摩尔比为1:1～1.2，所述醇羟基供体和三烃基膦试剂的摩尔比为1:1.05～1.3；所述醇羟基供体和偶氮二羧酸酯试剂的摩尔比为1:1.05～1.3。
相对于现有技术，本申请具有以下有益效果：
1.相对于常规的无水非质子溶剂，本申请选用高级饱和烷烃能够有效减少反应副产物的产生，产物纯度更高，对产物的后续应用无影响；
2.本申请的产物更易从反应体系中分离出来，减少了后处理的经济成本及时间成本；
3.本申请使用的溶剂具有闪点高、无气味的特点，危险性低，更加符合绿色环保的要求；
因此，采用本申请的醇羟基供体与活性氢供体进行光延反应的绿色方法，有利于实现工业化生产，具有极高的工业应用价值。
具体实施方式
下面通过具体实施方式来进一步说明本申请的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本申请，不应视为对本申请的具体限制。
以下实施例及对比例中，相关试剂均可从市场购得，其中GC测试仪器为安捷伦7820A气相色谱仪，MS测试仪器为安捷伦7890B-5977A质谱仪，HPLC测试仪器为岛津LC-20AB高效液相色谱仪。
实施例1
Figure PCTCN2020127698-appb-000004
在500mL的三口烧瓶中加入30g(4'-丙基-[1,1'-双(环己烷)]-4-基)甲醇、23g 4-乙氧基-2，3-二氟苯酚、35.31g三苯基膦及180mL异构十烷，氮气排空3次，搅拌升温至50℃，将28g偶氮二甲酸二异丙酯(DIAD)缓慢滴加至前述溶液中，滴加完后，升温至80℃，反应5h。将反应液趁热过滤，滤液于-10℃下冷冻4h，减压抽滤，滤饼干燥，得38.4g白色固体，GC：85.4％，收率为：77％。
化合物A的MS数据：55(5％)、69(5％)、95(5％)、146(25％)、174(50％)、220(5％)、394(5％)。
如下实施例2-4及对比例1-2的反应式与实施例1相同，仅改变具体反应条件。
实施例2
在500mL的三口烧瓶中加入30g(4'-丙基-[1,1'-双(环己烷)]-4-基)甲醇、23g 4-乙氧基-2，3-二氟苯酚、35.31g三苯基膦及180mL异构十二烷，氮气排空3次，搅拌升温至50℃，将28g偶氮二甲酸二异丙酯(DIAD)缓慢滴加至前述溶液中，滴加完后，升温至80℃，反应5h。将反应液趁热过滤，滤液于-10℃下冷冻4h，减压抽滤，滤饼干燥，得43.1g白色固体，GC：97.3％，收率为：86.8％。
实施例3
在500mL的三口烧瓶中加入30g(4'-丙基-[1,1'-双(环己烷)]-4-基)甲醇、23g 4-乙氧基-2，3-二氟苯酚、35.31g三苯基膦及180mL正构十二烷，氮 气排空3次，搅拌升温至50℃，将28g偶氮二甲酸二异丙酯(DIAD)缓慢滴加至前述溶液中，滴加完后，升温至80℃，反应5h。将反应液趁热过滤，滤液于-10℃下冷冻4h，减压抽滤，滤饼干燥，得42.3g白色固体，GC：93.7％，收率为：85.2％。
实施例4
在500mL的三口烧瓶中加入30g(4'-丙基-[1,1'-双(环己烷)]-4-基)甲醇、23g 4-乙氧基-2，3-二氟苯酚、35.31g三苯基膦及180mL异构十五烷，氮气排空3次，搅拌升温至50℃，将28g偶氮二甲酸二异丙酯(DIAD)缓慢滴加至前述溶液中，滴加完后，升温至80℃，反应5h。将反应液趁热过滤，滤液于-10℃下冷冻4h，减压抽滤，滤饼干燥，得41.7g白色固体，GC：89.7％，收率为：84％。
对比例1
在500mL的三口烧瓶中加入30g(4'-丙基-[1,1'-双(环己烷)]-4-基)甲醇、23g 4-乙氧基-2，3-二氟苯酚、35.31g三苯基膦及180mL甲苯，氮气排空3次，搅拌升温至50℃，将28g偶氮二甲酸二异丙酯(DIAD)缓慢滴加至前述溶液中，滴加完后，升温至80℃，反应5h，减压旋蒸，得淡黄色固体，固体用150mL乙醇重结晶，减压抽滤，滤饼干燥，得36.5g白色固体，GC：77.4％，收率为73.5％。
对比例2
在500mL的三口烧瓶中加入30g(4'-丙基-[1,1'-双(环己烷)]-4-基)甲醇、23g 4-乙氧基-2，3-二氟苯酚、35.31g三苯基膦及180mL DMF，氮气排空3次，搅拌升温至50℃，将28g偶氮二甲酸二异丙酯(DIAD)缓慢滴加至 前述溶液中，滴加完后，升温至80℃，反应5h。反应液加入200mL水及200mL二氯甲烷，搅拌10min，萃取分液，水相用200mL二氯甲烷提取2次，合并有机相，有机相用200mL水洗2次，有机相减压旋蒸，得淡黄色固体，固体用150mL乙醇重结晶，减压抽滤，滤饼干燥，得39.1g白色固体，GC：80.2％，收率为78.7％。
对比例3
在500mL的三口烧瓶中加入30g(4'-丙基-[1,1'-双(环己烷)]-4-基)甲醇、23g 4-乙氧基-2，3-二氟苯酚、35.31g三苯基膦及180mL正己烷，氮气排空3次，搅拌升温至50℃，将28g偶氮二甲酸二异丙酯(DIAD)缓慢滴加至前述溶液中，滴加完后，升温至80℃，反应5h。将反应液趁热过滤，滤液于-10℃下冷冻4h，减压抽滤，滤饼干燥，得38.7g白色固体，GC：81.2％，收率为：78％。
对比例4
在500mL的三口烧瓶中加入30g(4'-丙基-[1,1'-双(环己烷)]-4-基)甲醇、23g 4-乙氧基-2，3-二氟苯酚、35.31g三苯基膦及180mL环己烷，氮气排空3次，搅拌升温至50℃，将28g偶氮二甲酸二异丙酯(DIAD)缓慢滴加至前述溶液中，滴加完后，升温至80℃，反应5h。将反应液趁热过滤，滤液于-10℃下冷冻4h，减压抽滤，滤饼干燥，得35.2g白色固体，GC：80.8％，收率为：71％。
副产物含量测试：
通过HPLC法测试如上实施例1-4及对比例1-2中化合物4-((4-乙氧基-2,3-二氟苯氧基)甲基)-4'-丙基-1,1'-双(环己烷)的含量，结果如下表1：
表1
  杂质含量(％)
实施例1 3.18
实施例2 0.52
实施例3 1.21
实施例4 2.16
对比例1 4.65
对比例2 2.859
对比例3 4.57
对比例4 5.12
由表1可以看出，与现有技术中常用的非质子溶剂相比，本申请选用C8-C16的直链或支链烷烃作为光延反应的有机溶剂，可显著降低杂质的产生，有利于提升产物的纯度。
实施例5
Figure PCTCN2020127698-appb-000005
在500mL的三口烧瓶中加入30g 4-(4-乙基-2-氟苯基)环己醇、30.8g 4-(4-丙基环己基)苯胺、37.17g三苯基膦及180mL异构十二烷，氮气排空3次，搅拌升温至50℃，将29.2g偶氮二甲酸二异丙酯(DIAD)缓慢滴加至前述溶液中，滴加完后，升温至100℃，反应5h。将反应液趁热过滤，滤液于-10℃下冷冻4h，减压抽滤，滤饼干燥，得48.6g白色固体，GC：91.4％，收率为：85.4％。
化合物B的MS数据：123(15％)、216(55％)、392(10％)、421(20％)。
实施例6
Figure PCTCN2020127698-appb-000006
在500mL的三口烧瓶中加入30g 4-(2'，3'-二氟-4'-甲基-[1,1'-联苯]-4-基)环己醇、17.11g 4-丙基苯甲酸、27.33g三苯基膦及180mL异构十二烷，氮气排空3次，搅拌升温至50℃，将21.47g偶氮二甲酸二异丙酯(DIAD)缓慢滴加至前述溶液中，滴加完后，升温至100℃，反应5h。将反应液趁热过滤，滤液于-10℃下冷冻4h，减压抽滤，滤饼干燥，得40.6g白色固体，GC：98.1％，收率为：91.2％。
化合物C的MS数据：163(35％)、244(15％)、285(25％)、419(10％)、448(15％)。
实施例7
Figure PCTCN2020127698-appb-000007
在500mL的三口烧瓶中加入30g 4-(3-氟-4-异丙基苯基)环己醇、20.29g4-丙基苯硫醇、34.96g三苯基膦及180mL异构十二烷，氮气排空3次，搅拌升温至50℃，将23.66g偶氮二甲酸二异丙酯(DEAD)缓慢滴加至前述溶液中，滴加完后，升温至80℃，反应5h。将反应液趁热过滤，滤液于-10℃下冷冻4h，减压抽滤，滤饼干燥，得42.8g白色固体，GC：97.6％，收率为：91％。
化合物D的MS数据：137(10％)、151(45％)、327(25％)、341(10％)、370(10％)。
申请人声明，本申请通过上述实施例来说明本申请的工艺方法，但本申请并不局限于上述实施例，即不意味着本申请必须依赖上述实施例才能实施。

Claims (11)

  1. 一种醇羟基供体与活性氢供体进行光延反应的方法，其具体包括如下步骤：
    将醇羟基供体、活性氢供体、三烃基膦试剂及偶氮二羧酸酯试剂在有机溶剂的存在下进行反应，得到醇羟基供体与活性氢供体脱水缩合的产物；
    其中，所述有机溶剂为含有8-16个碳原子的直链或支链烷烃。
  2. 根据权利要求1所述的方法，其中，所述有机溶剂为异构十烷、异构十二烷、正构十二烷或异构十五烷中的任意一种或至少两种的组合。
  3. 根据权利要求2所述的方法，其中，所述有机溶剂为异构十二烷。
  4. 根据权利要求1-3中任一项所述的方法，其中，所述醇羟基供体为含有醇羟基的有机物；
    可选地，所述活性氢供体为含有活性氢基团的有机物，其中活性氢基团选自-OH、-SH、-COOH、-COSH、-NH 2或-CONH 2中的任意一种或至少两种的组合。
  5. 根据权利要求1-4中任一项所述的方法，其中，所述三烃基膦试剂选自三苯基膦、三丁基膦或三甲基膦中的任意一种或至少两种的组合。
  6. 根据权利要求1-5中任一项所述的方法，其中，所述偶氮二羧酸酯试剂选自偶氮二甲酸二乙酯、偶氮二甲酸二异丙酯、双-2-甲氧基乙基偶氮二羧酸酯、双(4-氯苄基)偶氮二甲酸酯中的任意一种或至少两种的组合。
  7. 根据权利要求1-6中任一项所述的方法，其中，所述醇羟基供体和活性氢供体的摩尔比为1:1～1.2；
    可选地，所述醇羟基供体和三烃基膦试剂的摩尔比为1:1.05～1.3；
    可选地，所述醇羟基供体和偶氮二羧酸酯试剂的摩尔比为1:1.05～1.3。
  8. 根据权利要求1-7中任一项所述的方法，其中，所述反应温度为30-120℃，反应时长为1-12h。
  9. 根据权利要求1-8中任一项所述的方法，其中，所述反应的加料顺序为：将偶氮二羧酸酯缓慢滴加至含有醇羟基供体、活性氢供体、三烃基膦试剂的有机溶剂中，或者，将偶氮二羧酸酯与三烃基膦试剂先混合，然后向混合液中加入醇羟基供体和活性氢供体；
    可选地，所述滴加过程控温在30-120℃。
  10. 根据权利要求1-9中任一项所述的方法，其中，所述反应在惰性气体保护下进行；
    可选地，所述反应中加入有机碱；
    可选地，所述有机碱为三乙胺；
    可选地，所述反应过程中利用超声或微波。
  11. 根据权利要求1-10中任一项所述的方法，其具体包括以下步骤：
    将醇羟基供体、活性氢供体、三烃基膦试剂及偶氮二羧酸酯试剂在有机溶剂的存在下于30-120℃反应1-12h，得到醇羟基供体与活性氢供体脱水缩合的产物；
    其中，所述有机溶剂为含有8-16个碳原子的直链或支链烷烃；
    所述醇羟基供体和活性氢供体的摩尔比为1:1～1.2，所述醇羟基供体和三烃基膦试剂的摩尔比为1:1.05～1.3；所述醇羟基供体和偶氮二羧酸酯试剂的摩尔比为1:1.05～1.3。
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