WO2022134297A1 - Preparation method for carboxylate ester compound - Google Patents

Preparation method for carboxylate ester compound Download PDF

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WO2022134297A1
WO2022134297A1 PCT/CN2021/077321 CN2021077321W WO2022134297A1 WO 2022134297 A1 WO2022134297 A1 WO 2022134297A1 CN 2021077321 W CN2021077321 W CN 2021077321W WO 2022134297 A1 WO2022134297 A1 WO 2022134297A1
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reaction
nitrite
product
carboxylate compound
compound
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Chinese (zh)
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万小兵
郑永高
陶苏艳
李星星
成雄略
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苏州大学
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    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • C07D209/28—1-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof
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    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D313/12—[b,e]-condensed
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/49—Esterification or transesterification
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
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    • C07C2601/00—Systems containing only non-condensed rings
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    • C07C2601/14—The ring being saturated
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    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • the invention relates to the technical field of carboxylate synthesis, in particular to a preparation method for synthesizing a carboxylate compound.
  • the methods for synthesizing esters reported at present mostly have the following shortcomings: the raw materials need preactivation, the reaction conditions are harsh, the substrates used are harmful to the environment, the catalysts used are noble metals or heavy metals, the price is relatively expensive, the substrate scope is narrow, and the atom economy is relatively low. What's more, because general drug molecules have multiple functional groups, including sensitive functional groups, and traditional esterification methods have poor functional group tolerance, traditional esterification methods are generally not suitable for the esterification of drug molecules. Based on this, it is particularly important to develop an esterification method including but not limited to drug molecule carboxylic acid.
  • the purpose of the present invention is to provide a preparation method of a carboxylate compound.
  • the present invention has the advantages of mild reaction conditions; Fatty carboxylic acids such as carboxylic acids with pharmaceutical properties and biologically active amino acids are modified.
  • the invention discloses a method for preparing a carboxylate compound. In the presence of nitrite, a carboxylate compound and methanol are used as raw materials to react to prepare the carboxylate compound.
  • the invention discloses the application of nitrite in catalyzing the reaction of carboxylic acid compound and methanol to prepare carboxylic acid ester compound.
  • the preparation method of the carboxylate compound of the present invention is as follows: in the air, sequentially adding nitrite, carboxylic acid compound and methanol into a reaction test tube; then reacting at 25-49° C. for 20-50 hours to obtain the carboxylic acid ester compound.
  • the general formula of the carboxylic acid compound is: .
  • the general formula of the carboxylate compound is: .
  • R 1 is selected from hydrogen, C1-C12 alkyl, alkoxy, phenyl, benzyl, substituted phenyl, thienyl, indolyl, phenol, naphthyl, biphenyl, and amide A kind of;
  • R 2 is selected from a kind of in hydrogen, methyl, methylene, ethyl, isopropyl, hydroxyl, hydroxymethyl, phenyl;
  • R 3 is selected from hydrogen, methyl, methylene, One of ethyl, isopropyl, propyl, butyl and phenyl; the substituent on the substituted phenyl is selected from hydrogen, methyl, methoxy, hydroxyl, nitro, phenyl, acetamido , one or more of fluorine, chlorine, bromine, iodine, etc.
  • the nitrite is one or more of isopropyl nitrite, butyl nitrite, isobutyl nitrite and tert-butyl nitrite, preferably, the nitrite is tert-butyl nitrite ( t -butyl nitrite). BuONO).
  • the molar ratio of the carboxylic acid compound and the nitrite is 10:1-10; preferably, the molar ratio of the carboxylic acid compound and the nitrite is 5:2.
  • the dosage ratio of the carboxylic acid compound and the alcohol is 0.5 mmol:2 mL.
  • reaction time is 20-50 hours, preferably, the reaction time is 48 hours; the reaction temperature is 25-50°C, preferably, the reaction temperature is 40°C.
  • reaction is carried out in air.
  • the reaction is quenched with sodium thiosulfate, and the carboxylate compound is conventionally separated.
  • the product is extracted with ethyl acetate, and the solvent is removed, and the silica gel adsorption can be obtained by column chromatography.
  • the product carboxylate compound is obtained by column chromatography.
  • the present invention has at least the following advantages: the reaction substrate used in the present invention is readily available commercially, and has good medical and industrial application prospects; the present invention can react without the presence of additives such as metals, strong bases, strong acids, etc. It is carried out under the air condition of room temperature, which meets the requirements of green safety; the atom economy of the invention is high, and the by-product is water; the reaction system is simple, the substrate range is wide, the functional group compatibility is good, the reaction conditions are mild, the post-operation treatment is convenient, and the compensation The defects of the existing synthesis methods are eliminated; a series of esterified compounds of aliphatic carboxylic acids such as carboxylic acids with pharmaceutical properties and biologically active amino acids can be easily synthesized.
  • the raw materials of the present invention are all existing commercial products, and the specific preparation operations and testing methods are conventional methods.
  • the invention only uses nitrite, carboxylic acid compound and methanol as raw materials for the reaction without the addition of other substances, can prepare carboxylic acid ester in the air under mild conditions, and solves the problem that the prior art requires metal or metal compound catalytic reaction , which overcomes the problem that the traditional esterification method is not suitable for the esterification of drug molecules.
  • the drug molecule 1a ( Naproxen ) (0.5 mmol, 115.2 mg), methanol containing 40 mol% tert-butyl nitrite (2 mL of methanol, 0.2 mmol of tert-butyl nitrite, the same as the following examples) were added to the reaction test tube in turn; Then react in the air at 40°C for 48 hours; after the reaction, add sodium thiosulfate to stir and quench, then use a rotary evaporator to remove the solvent, adsorb on silica gel, and finally use a mixed solvent of ethyl acetate and petroleum ether (1 : 1)
  • the product 3a can be obtained by column chromatography with a yield of 95% (isolation yield).
  • the main test data of the obtained product are as follows. It can be seen from the analysis that the actual synthetic product is consistent with the theoretical analysis.
  • tert-butyl nitrite with isopropyl nitrite, butyl nitrite or isobutyl nitrite, and the rest remain unchanged, and the product yields are 13%, 42%, and 35%, respectively; replace tert-butyl nitrite with It is an oxidizing agent, such as tert-butyl hydroperoxide, hydrogen peroxide, tert-butyl hypochlorite, and the rest remain unchanged, and the product yields are ⁇ 5%, ⁇ 5%, and 60%, respectively.
  • oxidizing agent such as tert-butyl hydroperoxide, hydrogen peroxide, tert-butyl hypochlorite, and the rest remain unchanged, and the product yields are ⁇ 5%, ⁇ 5%, and 60%, respectively.
  • the drug molecule 1a Naproxen
  • methanol containing 40 mol% tert-butyl nitrite were added to the reaction test tube in turn; then the reaction was carried out under the condition of 25 °C in air for 48 hours; after the reaction was completed, sulfur Sodium sulfate was stirred and quenched, then the solvent was removed by rotary evaporator, adsorbed on silica gel, and finally the product 3a was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether (1:1) with a yield of 63%.
  • the drug molecule 1b ( Carprofen ) (0.5 mmol, 136.9 mg) and methanol containing 40 mol% tert-butyl nitrite were added to the reaction test tube in turn; then the reaction was carried out under the condition of 40 °C in air for 48 hours; after the reaction was completed, sulfur Sodium sulfate was stirred and quenched, and then the solvent was removed with a rotary evaporator, adsorbed on silica gel, and finally the product 3b was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 90%.
  • the main test data of the obtained product are as follows. It can be seen from the analysis that the actual synthetic product is consistent with the theoretical analysis.
  • Example 3 On the basis of Example 3, the drug molecule 1b was replaced with the drug molecule 1e ( Indomthacin ) (0.5 mmol, 178.9 mg) to obtain the product 3e with a yield of 86%.
  • Example 3 On the basis of Example 3, the drug molecule 1b was replaced with the drug molecule 1f ( Flurbiprofen ) (0.5 mmol, 122.2 mg) to obtain the product 3f with a yield of 87%.
  • Example 3 On the basis of Example 3, the drug molecule 1b was replaced with a drug molecule 1g ( Ciprofibrate ) (0.5 mmol, 144.6 mg) to obtain 3g of the product with a yield of 79%.
  • Example 3 On the basis of Example 3, the drug molecule 1b was replaced with the drug molecule 1h ( Bendazac ) (0.5 mmol, 141.2 mg) to obtain the product 3h with a yield of 96%.
  • the drug molecule 1 k ( Myristic acid ) (0.5 mmol, 114.2 mg) and methanol containing 40 mol% tert-butyl nitrite were sequentially added to the reaction test tube; then the reaction was carried out under the condition of 40 °C in air for 48 hours; after the reaction, the Add sodium thiosulfate to stir and quench, then use a rotary evaporator to remove the solvent, adsorb on silica gel, and finally perform column chromatography with a mixed solvent of ethyl acetate and petroleum ether to obtain the product 3k with a yield of 99%.
  • the main test data of the obtained product are as follows. It can be seen from the analysis that the actual synthetic product is consistent with the theoretical analysis.
  • the drug molecule 1 n ( Isoxepac ) (0.5 mmol, 134.2 mg) and methanol containing 40 mol% tert-butyl nitrite were added to the reaction test tube in turn; then the reaction was carried out under the condition of 40 °C in the air for 48 hours; Sodium thiosulfate was stirred and quenched, then the solvent was removed with a rotary evaporator, adsorbed on silica gel, and finally the product 3n was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether with a yield of 96%.

Abstract

The present invention relates to a preparation method for a carboxylate ester compound, comprising: under the catalysis of a nitrite ester, reacting carboxylic acid and methanol in air, so as to obtain an ester compound. The preparation method of the present invention has the advantages of abundant raw material sources, cheap and easily available catalysts, mild reaction conditions, simple operations, and the like, and high-yield modification of a series of fatty carboxylic acids can be achieved. In particular, it should be noted that conventional esterification methods are generally not suitable for the esterification of drug molecules. Using the present method, a series of known drug molecules can be modified, thereby providing a shortcut for the discovery of new drug molecules.

Description

一种羧酸酯化合物的制备方法A kind of preparation method of carboxylate compound 技术领域technical field
本发明涉及羧酸酯合成技术领域，尤其涉及一种合成羧酸甲酯化合物的制备方法。The invention relates to the technical field of carboxylate synthesis, in particular to a preparation method for synthesizing a carboxylate compound.
背景技术Background technique
目前报道的合成酯的方法，大都具备以下缺点：原料需要预活化、反应条件苛刻、所用底物对环境有害、所用催化剂为贵金属或重金属，价格较昂贵、底物范围较窄、原子经济性较差；更为重要的是，由于一般的药物分子具有多个官能团，包括敏感官能团，而传统的酯化方法官能团耐受性差，因此传统的酯化方法一般不适合药物分子的酯化。基于此，发展一种包括但不限于药物分子羧酸的酯化方法显得尤为重要。The methods for synthesizing esters reported at present mostly have the following shortcomings: the raw materials need preactivation, the reaction conditions are harsh, the substrates used are harmful to the environment, the catalysts used are noble metals or heavy metals, the price is relatively expensive, the substrate scope is narrow, and the atom economy is relatively low. What's more, because general drug molecules have multiple functional groups, including sensitive functional groups, and traditional esterification methods have poor functional group tolerance, traditional esterification methods are generally not suitable for the esterification of drug molecules. Based on this, it is particularly important to develop an esterification method including but not limited to drug molecule carboxylic acid.
技术问题technical problem
为解决上述技术问题，本发明的目的是提供一种羧酸酯化合物的制备方法，本发明具有反应条件温和；原料来源丰富；反应底物普适性广；操作简便等优点，可对一系列具有药物属性的羧酸以及生物活性的氨基酸等脂肪羧酸进行修饰。In order to solve the above technical problems, the purpose of the present invention is to provide a preparation method of a carboxylate compound. The present invention has the advantages of mild reaction conditions; Fatty carboxylic acids such as carboxylic acids with pharmaceutical properties and biologically active amino acids are modified.
技术解决方案technical solutions
本发明公开了一种羧酸酯化合物的制备方法，在亚硝酸酯存在下，以羧酸化合物、甲醇为原料，反应制备羧酸酯化合物。The invention discloses a method for preparing a carboxylate compound. In the presence of nitrite, a carboxylate compound and methanol are used as raw materials to react to prepare the carboxylate compound.
本发明公开了亚硝酸酯在催化羧酸化合物、甲醇反应制备羧酸酯化合物中的应用。The invention discloses the application of nitrite in catalyzing the reaction of carboxylic acid compound and methanol to prepare carboxylic acid ester compound.
本发明羧酸酯化合物的制备方法为：空气中，依次加入亚硝酸酯、羧酸化合物、甲醇于反应试管中；然后在25～49℃的条件下反应20～50小时，得到所述羧酸酯化合物。The preparation method of the carboxylate compound of the present invention is as follows: in the air, sequentially adding nitrite, carboxylic acid compound and methanol into a reaction test tube; then reacting at 25-49° C. for 20-50 hours to obtain the carboxylic acid ester compound.
本发明中，所述羧酸化合物的通式为：
Figure 261305dest_path_image001
。 In the present invention, the general formula of the carboxylic acid compound is:
Figure 261305dest_path_image001
.
所述羧酸酯化合物的通式为：
Figure 766236dest_path_image002
。 The general formula of the carboxylate compound is:
Figure 766236dest_path_image002
.
以上式中，R 1选自氢、C1-C12烷基、烷氧基、苯基、苄基、取代苯基、噻吩基、吲哚基、苯酚基、萘基、联苯基、酰胺基中的一种；R 2选自氢、甲基、亚甲基、乙基、异丙基、羟基、羟甲基、苯基中的一种；R 3选自氢、甲基、亚甲基、乙基、异丙基、丙基、丁基、苯基中的一种；所述取代苯基上的取代基选自氢、甲基、甲氧基、羟基、硝基、苯基、乙酰氨基、氟、氯、溴、碘等中的一种或几种。 In the above formula, R 1 is selected from hydrogen, C1-C12 alkyl, alkoxy, phenyl, benzyl, substituted phenyl, thienyl, indolyl, phenol, naphthyl, biphenyl, and amide A kind of; R 2 is selected from a kind of in hydrogen, methyl, methylene, ethyl, isopropyl, hydroxyl, hydroxymethyl, phenyl; R 3 is selected from hydrogen, methyl, methylene, One of ethyl, isopropyl, propyl, butyl and phenyl; the substituent on the substituted phenyl is selected from hydrogen, methyl, methoxy, hydroxyl, nitro, phenyl, acetamido , one or more of fluorine, chlorine, bromine, iodine, etc.
所述亚硝酸脂为亚硝酸异丙酯、亚硝酸丁酯、亚硝酸异丁酯和亚硝酸叔丁酯中的一种或几种，优选地，亚硝酸脂为亚硝酸叔丁酯（ tBuONO）。 The nitrite is one or more of isopropyl nitrite, butyl nitrite, isobutyl nitrite and tert-butyl nitrite, preferably, the nitrite is tert-butyl nitrite ( t -butyl nitrite). BuONO).
进一步地，所述羧酸化合物、亚硝酸酯的摩尔比为10∶1～10；优选地，羧酸化合物、亚硝酸酯的摩尔比为5:2。羧酸化合物、醇的用量比例为0.5mmol∶2mL。Further, the molar ratio of the carboxylic acid compound and the nitrite is 10:1-10; preferably, the molar ratio of the carboxylic acid compound and the nitrite is 5:2. The dosage ratio of the carboxylic acid compound and the alcohol is 0.5 mmol:2 mL.
进一步地，反应时间为20～50小时，优选地，反应时间为48小时；反应温度为25～50℃，优选的，反应温度为40℃。Further, the reaction time is 20-50 hours, preferably, the reaction time is 48 hours; the reaction temperature is 25-50°C, preferably, the reaction temperature is 40°C.
进一步地，反应在空气中进行。Further, the reaction is carried out in air.
进一步地，反应结束后，用硫代硫酸钠淬灭反应，常规分离出羧酸酯化合物，比如，淬灭反应后用乙酸乙酯萃取产物，除去溶剂、硅胶吸附后通过柱层析即可得产物羧酸酯化合物。Further, after the reaction is completed, the reaction is quenched with sodium thiosulfate, and the carboxylate compound is conventionally separated. For example, after quenching the reaction, the product is extracted with ethyl acetate, and the solvent is removed, and the silica gel adsorption can be obtained by column chromatography. The product carboxylate compound.
有益效果beneficial effect
本发明至少具有以下优点：本发明使用的反应底物商业易获得，有很好的医药及工业应用前景；本发明无需金属、强碱、强酸等添加剂的存在即可发生反应，可在低至室温的空气条件下进行，符合绿色安全的要求；本发明原子经济性高，副产物为水；反应体系简单且底物范围广，官能团兼容性好，反应条件温和，操后处理操作方便，弥补了现有合成方法的缺陷；可操作简单的合成一系列具有药物属性的羧酸以及生物活性的氨基酸等脂肪羧酸的酯化化合物。The present invention has at least the following advantages: the reaction substrate used in the present invention is readily available commercially, and has good medical and industrial application prospects; the present invention can react without the presence of additives such as metals, strong bases, strong acids, etc. It is carried out under the air condition of room temperature, which meets the requirements of green safety; the atom economy of the invention is high, and the by-product is water; the reaction system is simple, the substrate range is wide, the functional group compatibility is good, the reaction conditions are mild, the post-operation treatment is convenient, and the compensation The defects of the existing synthesis methods are eliminated; a series of esterified compounds of aliphatic carboxylic acids such as carboxylic acids with pharmaceutical properties and biologically active amino acids can be easily synthesized.
本发明的实施方式Embodiments of the present invention
本发明的原料都是现有市售产品，具体制备操作以及测试方法都为常规方法。本发明仅仅以亚硝酸酯、羧酸化合物、甲醇为原料进行反应无需其他物质的加入，可以在空气中，温和条件下制备羧酸酯，解决了现有技术需要金属或者金属化合物催化反应的问题，更克服了传统的酯化方法不适合药物分子的酯化的问题。The raw materials of the present invention are all existing commercial products, and the specific preparation operations and testing methods are conventional methods. The invention only uses nitrite, carboxylic acid compound and methanol as raw materials for the reaction without the addition of other substances, can prepare carboxylic acid ester in the air under mild conditions, and solves the problem that the prior art requires metal or metal compound catalytic reaction , which overcomes the problem that the traditional esterification method is not suitable for the esterification of drug molecules.
实施例一。Example 1.
Figure 392389dest_path_image003
。
Figure 392389dest_path_image003
.
往反应试管中依次加入药物分子 1a （Naproxen ）（0.5 mmol, 115.2mg）、含有40mol%亚硝酸叔丁酯的甲醇（甲醇为2mL，亚硝酸叔丁酯为0.2mmol，以下实施例一样）；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂，硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂（1∶1）进行柱层析即可得产物 3a，收率为95%（分离收率）。所制得产物的主要测试数据如下，通过分析可知，实际合成产物与理论分析一致。 The drug molecule 1a ( Naproxen ) (0.5 mmol, 115.2 mg), methanol containing 40 mol% tert-butyl nitrite (2 mL of methanol, 0.2 mmol of tert-butyl nitrite, the same as the following examples) were added to the reaction test tube in turn; Then react in the air at 40°C for 48 hours; after the reaction, add sodium thiosulfate to stir and quench, then use a rotary evaporator to remove the solvent, adsorb on silica gel, and finally use a mixed solvent of ethyl acetate and petroleum ether (1 : 1) The product 3a can be obtained by column chromatography with a yield of 95% (isolation yield). The main test data of the obtained product are as follows. It can be seen from the analysis that the actual synthetic product is consistent with the theoretical analysis.
1H NMR (400 MHz, CDCl 3) δ 7.76 – 7.68 (m, 3H), 7.45 – 7.43 (m, 1H), 7.20 – 7.11 (m, 2H), 3.93 – 3.86 (m, 4H), 3.69 (s, 3H), 1.62 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 175.0, 157.5, 135.6, 133.6, 129.2, 128.8, 127.1, 126.1, 125.8, 118.9, 105.4, 55.1, 51.9, 45.2, 18.5; HRMS (ESI-TOF): Anal. Calcd. For C 14H 20O 2+Na +: 267.0992, Found: 267.1007; IR (neat, cm -1): υ 3005, 2975, 2932, 1733, 1603, 1504, 1448, 1173, 1027, 855, 823。 1 H NMR (400 MHz, CDCl 3 ) δ 7.76 – 7.68 (m, 3H), 7.45 – 7.43 (m, 1H), 7.20 – 7.11 (m, 2H), 3.93 – 3.86 (m, 4H), 3.69 (s , 3H), 1.62 (d, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 175.0, 157.5, 135.6, 133.6, 129.2, 128.8, 127.1, 126.1, 125.8, 118.9, 105.4, 55.1 , 51.9, 45.2, 18.5; HRMS (ESI-TOF): Anal. Calcd. For C 14 H 20 O 2 +Na + : 267.0992, Found: 267.1007; IR (neat, cm -1 ): υ 3005, 2975, 2932 , 1733, 1603, 1504, 1448, 1173, 1027, 855, 823.
将亚硝酸叔丁酯更换为亚硝酸异丙酯、亚硝酸丁酯或者亚硝酸异丁酯，其余不变，产物收率分别为13%、42%、35%；将亚硝酸叔丁酯更换为氧化剂，比如叔丁基过氧化氢、过氧化氢、次氯酸叔丁酯，其余不变，产物收率分别为<5%、<5%、60%。Replace tert-butyl nitrite with isopropyl nitrite, butyl nitrite or isobutyl nitrite, and the rest remain unchanged, and the product yields are 13%, 42%, and 35%, respectively; replace tert-butyl nitrite with It is an oxidizing agent, such as tert-butyl hydroperoxide, hydrogen peroxide, tert-butyl hypochlorite, and the rest remain unchanged, and the product yields are <5%, <5%, and 60%, respectively.
实施例二。Example two.
Figure 858137dest_path_image004
。
Figure 858137dest_path_image004
.
往反应试管中依次加入药物分子 1a （Naproxen ）（0.5 mmol, 115.2mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中25℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂，硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂（1∶1）进行柱层析即可得产物 3a，收率为63%。通过分析所制得产物的主要测试数据可知，实际合成产物与理论分析一致。 The drug molecule 1a ( Naproxen ) (0.5 mmol, 115.2 mg) and methanol containing 40 mol% tert-butyl nitrite were added to the reaction test tube in turn; then the reaction was carried out under the condition of 25 ℃ in air for 48 hours; after the reaction was completed, sulfur Sodium sulfate was stirred and quenched, then the solvent was removed by rotary evaporator, adsorbed on silica gel, and finally the product 3a was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether (1:1) with a yield of 63%. By analyzing the main test data of the prepared product, it can be known that the actual synthetic product is consistent with the theoretical analysis.
实施例三。Example three.
Figure 493518dest_path_image005
。
Figure 493518dest_path_image005
.
往反应试管中依次加入药物分子1b （Carprofen ）（0.5 mmol, 136.9mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3b，收率为90%。所制得产物的主要测试数据如下，通过分析可知，实际合成产物与理论分析一致。 The drug molecule 1b ( Carprofen ) (0.5 mmol, 136.9 mg) and methanol containing 40 mol% tert-butyl nitrite were added to the reaction test tube in turn; then the reaction was carried out under the condition of 40 ℃ in air for 48 hours; after the reaction was completed, sulfur Sodium sulfate was stirred and quenched, and then the solvent was removed with a rotary evaporator, adsorbed on silica gel, and finally the product 3b was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 90%. The main test data of the obtained product are as follows. It can be seen from the analysis that the actual synthetic product is consistent with the theoretical analysis.
1H NMR (400 MHz, CDCl 3) δ 8.28 (s, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.34 – 7.29 (m, 2H), 7.25 – 7.21 (m, 1H), 7.18 (dd, J = 8.1, 1.4 Hz, 1H), 3.90 (q, J = 7.2 Hz, 1H), 3.72 (s, 3H), 1.61 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 175.5, 140.3, 139.0, 138.0, 125.7, 124.7, 124.1, 121.5, 120.5, 119.8, 119.4, 111.5, 109.5, 52.2, 45.7, 18.8; HRMS (ESI-TOF): Anal. Calcd. For C 16H 14 35ClNO 2+Na +: 310.0605, Found: 310.0600. Anal. Calcd. For C 16H 14 37ClNO 2+Na +: 312.0576, Found: 312.0570; IR (neat, cm -1): υ 3407, 2985, 1731,1605, 1449, 1376, 1174, 1153, 810。 1 H NMR (400 MHz, CDCl 3 ) δ 8.28 (s, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.34 – 7.29 (m, 2H) , 7.25 – 7.21 (m, 1H), 7.18 (dd, J = 8.1, 1.4 Hz, 1H), 3.90 (q, J = 7.2 Hz, 1H), 3.72 (s, 3H), 1.61 (d, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 175.5, 140.3, 139.0, 138.0, 125.7, 124.7, 124.1, 121.5, 120.5, 119.8, 119.4, 111.5, 109.5, 52.2, 45.8 H (RMS) ESI-TOF): Anal. Calcd. For C 16 H 14 35 ClNO 2 +Na + : 310.0605, Found: 310.0600. Anal. Calcd. For C 16 H 14 37 ClNO 2 +Na + : 312.0576, Found: 312.0570; IR (neat, cm -1 ): υ 3407, 2985, 1731, 1605, 1449, 1376, 1174, 1153, 810.
实施例四。Example four.
Figure 384113dest_path_image006
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Figure 384113dest_path_image006
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在实施例三的基础上将药物分子1b更换为药物分子1c （Ibuprofen ）（0.5 mmol, 103.2mg），得到产物 3c，收率为85%。 On the basis of Example 3, drug molecule 1b was replaced with drug molecule 1c ( Ibuprofen ) (0.5 mmol, 103.2 mg) to obtain product 3c with a yield of 85%.
实施例五。Example five.
Figure 384430dest_path_image007
。
Figure 384430dest_path_image007
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在实施例三的基础上将药物分子1b更换为药物分子 1d （Ketoprofen ）（0.5 mmol, 127.2mg），得到产物 3d，收率为86%。 On the basis of Example 3, drug molecule 1b was replaced with drug molecule 1d ( Ketoprofen ) (0.5 mmol, 127.2 mg) to obtain product 3d with a yield of 86%.
实施例六。Example six.
Figure 258845dest_path_image008
。
Figure 258845dest_path_image008
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在实施例三的基础上将药物分子1b更换为药物分子 1e （Indomethacin ）（0.5 mmol, 178.9mg），得到产物 3e，收率为86%。 On the basis of Example 3, the drug molecule 1b was replaced with the drug molecule 1e ( Indomthacin ) (0.5 mmol, 178.9 mg) to obtain the product 3e with a yield of 86%.
实施例七。Embodiment 7.
Figure 760234dest_path_image009
。
Figure 760234dest_path_image009
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在实施例三的基础上将药物分子1b更换为药物分子 1f （Flurbiprofen ）（0.5 mmol, 122.2mg），得到产物 3f，收率为87%。 On the basis of Example 3, the drug molecule 1b was replaced with the drug molecule 1f ( Flurbiprofen ) (0.5 mmol, 122.2 mg) to obtain the product 3f with a yield of 87%.
实施例八。Embodiment eight.
Figure 36494dest_path_image010
。
Figure 36494dest_path_image010
.
在实施例三的基础上将药物分子1b更换为药物分子 1g （Ciprofibrate ）（0.5 mmol, 144.6mg），得到产物 3g，收率为79%。 On the basis of Example 3, the drug molecule 1b was replaced with a drug molecule 1g ( Ciprofibrate ) (0.5 mmol, 144.6 mg) to obtain 3g of the product with a yield of 79%.
实施例九。Example nine.
Figure 207713dest_path_image011
。
Figure 207713dest_path_image011
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在实施例三的基础上将药物分子1b更换为药物分子 1h （Bendazac ）（0.5 mmol, 141.2mg），得到产物 3h，收率为96%。 On the basis of Example 3, the drug molecule 1b was replaced with the drug molecule 1h ( Bendazac ) (0.5 mmol, 141.2 mg) to obtain the product 3h with a yield of 96%.
实施例十。Example ten.
Figure 569424dest_path_image012
。
Figure 569424dest_path_image012
.
在实施例三的基础上将药物分子1b更换为药物分子 1i （Nateglinide ）（0.5 mmol, 158.8mg），得到产物 3i，收率为87%。 On the basis of Example 3, drug molecule 1b was replaced with drug molecule 1i ( Nateglinide ) (0.5 mmol, 158.8 mg) to obtain product 3i with a yield of 87%.
实施例十一。Embodiment eleven.
Figure 359657dest_path_image013
。
Figure 359657dest_path_image013
.
往反应试管中依次加入药物分子1 j （MCPA ）（0.5 mmol, 100.4mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3j，收率为99%。通过分析所制得产物的主要测试数据可知，实际合成产物与理论分析一致。 Add drug molecule 1 j ( MCPA ) (0.5 mmol, 100.4 mg) and methanol containing 40 mol% tert-butyl nitrite into the reaction test tube in turn; then react under the condition of 40 ℃ in air for 48 hours; after the reaction, add Sodium thiosulfate was stirred and quenched, then the solvent was removed with a rotary evaporator, adsorbed on silica gel, and finally the product 3j was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether with a yield of 99%. By analyzing the main test data of the prepared product, it can be known that the actual synthetic product is consistent with the theoretical analysis.
实施例十二。Example twelve.
Figure 224844dest_path_image014
。
Figure 224844dest_path_image014
.
往反应试管中依次加入药物分子1 k （Myristic acid ）（0.5 mmol, 114.2mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3k，收率为99%。所制得产物的主要测试数据如下，通过分析可知，实际合成产物与理论分析一致。 The drug molecule 1 k ( Myristic acid ) (0.5 mmol, 114.2 mg) and methanol containing 40 mol% tert-butyl nitrite were sequentially added to the reaction test tube; then the reaction was carried out under the condition of 40 ℃ in air for 48 hours; after the reaction, the Add sodium thiosulfate to stir and quench, then use a rotary evaporator to remove the solvent, adsorb on silica gel, and finally perform column chromatography with a mixed solvent of ethyl acetate and petroleum ether to obtain the product 3k with a yield of 99%. The main test data of the obtained product are as follows. It can be seen from the analysis that the actual synthetic product is consistent with the theoretical analysis.
1H NMR (400 MHz, CDCl 3) δ 3.63 (s, 3H), 2.27 (t, J = 7.6 Hz, 2H), 1.63 – 1.55 (m, 2H), 1.26 – 1.23 (m, 20H), 0.85 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 174.2, 51.3, 34.0,31.9, 29.63, 29.60, 29.55, 29.4, 29.3, 29.2, 29.1, 24.9, 22.6, 14.0; MS (EI) calculated for [C 15H 30O 2]: 242.2, Found: 242.3; IR (neat, cm -1): υ 2923, 2853, 1742, 1465, 1436, 1362, 1169, 1016, 722。 1 H NMR (400 MHz, CDCl 3 ) δ 3.63 (s, 3H), 2.27 (t, J = 7.6 Hz, 2H), 1.63 – 1.55 (m, 2H), 1.26 – 1.23 (m, 20H), 0.85 ( t, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 174.2, 51.3, 34.0, 31.9, 29.63, 29.60, 29.55, 29.4, 29.3, 29.2, 29.1, 24.9, 22.6, 14.0; MS (EI) calculated for [C 15 H 30 O 2 ]: 242.2, Found: 242.3; IR (neat, cm -1 ): υ 2923, 2853, 1742, 1465, 1436, 1362, 1169, 1016, 722.
实施例十三。Example thirteen.
Figure 629281dest_path_image015
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Figure 629281dest_path_image015
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往反应试管中依次加入药物分子1 m （Aceclofenac ）（0.5 mmol, 117.1mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3m，收率为63%。通过分析所制得产物的主要测试数据可知，实际合成产物与理论分析一致。 Add 1 m of drug molecule ( Aceclofenac ) (0.5 mmol, 117.1 mg) and methanol containing 40 mol% tert-butyl nitrite into the reaction test tube in turn; then react under the condition of 40 ℃ in air for 48 hours; after the reaction, add Sodium thiosulfate was stirred and quenched, then the solvent was removed with a rotary evaporator, adsorbed on silica gel, and finally the product 3m was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 63%. By analyzing the main test data of the prepared product, it can be known that the actual synthetic product is consistent with the theoretical analysis.
实施例十四。Example fourteen.
Figure 415971dest_path_image016
。
Figure 415971dest_path_image016
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往反应试管中依次加入药物分子1 n （Isoxepac ）（0.5 mmol, 134.2mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3n，收率为96%。通过分析所制得产物的主要测试数据可知，实际合成产物与理论分析一致。 The drug molecule 1 n ( Isoxepac ) (0.5 mmol, 134.2 mg) and methanol containing 40 mol% tert-butyl nitrite were added to the reaction test tube in turn; then the reaction was carried out under the condition of 40 ℃ in the air for 48 hours; Sodium thiosulfate was stirred and quenched, then the solvent was removed with a rotary evaporator, adsorbed on silica gel, and finally the product 3n was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether with a yield of 96%. By analyzing the main test data of the prepared product, it can be known that the actual synthetic product is consistent with the theoretical analysis.
实施例十五。Example fifteen.
Figure 931266dest_path_image017
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Figure 931266dest_path_image017
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往反应试管中依次加入化合物1 o（0.5 mmol, 109.6mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3o，收率为86%。通过分析所制得产物的主要测试数据可知，实际合成产物与理论分析一致。 Add compound 1 o (0.5 mmol, 109.6 mg) and methanol containing 40 mol% tert-butyl nitrite into the reaction test tube in turn; then react in the air at 40 ° C for 48 hours; after the reaction, add sodium thiosulfate After stirring and quenching, the solvent was removed by a rotary evaporator, adsorbed on silica gel, and finally the product 3o was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 86%. By analyzing the main test data of the prepared product, it can be known that the actual synthetic product is consistent with the theoretical analysis.
实施例十六。Example sixteen.
Figure 244436dest_path_image018
。
Figure 244436dest_path_image018
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往反应试管中依次加入化合物1 p（0.5 mmol, 155.7mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3p，收率为95%。通过分析所制得产物的主要测试数据可知，实际合成产物与理论分析一致。 Compound 1p (0.5 mmol, 155.7 mg) and methanol containing 40 mol% tert-butyl nitrite were added to the reaction test tube in turn; then the reaction was carried out at 40°C in air for 48 hours; after the reaction, sodium thiosulfate was added. After stirring and quenching, the solvent was removed by a rotary evaporator, adsorbed on silica gel, and finally the product 3p was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 95%. By analyzing the main test data of the prepared product, it can be known that the actual synthetic product is consistent with the theoretical analysis.
实施例十七。Example seventeen.
Figure 819774dest_path_image019
。
Figure 819774dest_path_image019
.
往反应试管中依次加入化合物1 q（0.5 mmol, 148.7mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3q，收率为95%。通过分析所制得产物的主要测试数据可知，实际合成产物与理论分析一致。 Compound 1q (0.5 mmol, 148.7 mg) and methanol containing 40 mol% tert-butyl nitrite were sequentially added to the reaction test tube; then the reaction was carried out under the condition of 40 ℃ in air for 48 hours; after the reaction, sodium thiosulfate was added. After stirring and quenching, the solvent was removed by a rotary evaporator, adsorbed on silica gel, and finally the product 3q was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 95%. By analyzing the main test data of the prepared product, it can be known that the actual synthetic product is consistent with the theoretical analysis.
实施例十八。Example eighteen.
Figure 93760dest_path_image020
。
Figure 93760dest_path_image020
.
往反应试管中依次加入化合物1 r（0.5 mmol, 205.8mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3r，收率为71%。通过分析所制得产物的主要测试数据可知，实际合成产物与理论分析一致。 Compound 1 r (0.5 mmol, 205.8 mg) and methanol containing 40 mol% tert-butyl nitrite were added to the reaction test tube in turn; then the reaction was carried out at 40°C in air for 48 hours; after the reaction, sodium thiosulfate was added. After stirring and quenching, the solvent was removed with a rotary evaporator, adsorbed on silica gel, and finally the product 3r was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 71%. By analyzing the main test data of the prepared product, it can be known that the actual synthetic product is consistent with the theoretical analysis.
实施例十九。Example nineteen.
Figure 412746dest_path_image021
。
Figure 412746dest_path_image021
.
往反应试管中依次加入化合物1 s（0.5 mmol, 205.3mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3s，收率为66%。通过分析所制得产物的主要测试数据可知，实际合成产物与理论分析一致。 Add compound 1 s (0.5 mmol, 205.3 mg) and methanol containing 40 mol% tert-butyl nitrite to the reaction test tube in turn; then react in air at 40°C for 48 hours; after the reaction, add sodium thiosulfate After stirring and quenching, the solvent was removed with a rotary evaporator, adsorbed on silica gel, and finally the product 3s was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 66%. By analyzing the main test data of the prepared product, it can be known that the actual synthetic product is consistent with the theoretical analysis.
实施例二十。Example 20.
Figure 252526dest_path_image022
。
Figure 252526dest_path_image022
.
往反应试管中依次加入化合物1 t（0.5 mmol, 104.6mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3t，收率为92%。所制得产物的主要测试数据如下，通过分析可知，实际合成产物与理论分析一致。 Compound 1 t (0.5 mmol, 104.6 mg) and methanol containing 40 mol% tert-butyl nitrite were sequentially added to the reaction test tube; then the reaction was carried out at 40°C in air for 48 hours; after the reaction, sodium thiosulfate was added. After stirring and quenching, the solvent was removed by a rotary evaporator, adsorbed on silica gel, and finally the product 3t was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 92%. The main test data of the obtained product are as follows. It can be seen from the analysis that the actual synthetic product is consistent with the theoretical analysis.
1H NMR (400 MHz, CDCl 3) δ 7.39 – 7.27 (m, 5H), 5.50 (s, 1H), 5.11 (s, 2H), 3.94 (d, J = 5.7 Hz, 2H), 3.72 (s, 3H); 13C NMR (100 MHz, CDCl 3) δ 170.4, 156.2, 136.1, 128.6, 128.0, 127.9, 66.9, 52.1, 42.5; HRMS (ESI-TOF): Anal. Calcd. For C 11H 13NO 4 +Na +: 246.0737, Found: 246.0755; IR (neat, cm -1): υ 3347, 2954, 2923, 2851, 1703, 1522, 1438, 1367, 1205, 1053, 1003, 697。 1 H NMR (400 MHz, CDCl 3 ) δ 7.39 – 7.27 (m, 5H), 5.50 (s, 1H), 5.11 (s, 2H), 3.94 (d, J = 5.7 Hz, 2H), 3.72 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.4, 156.2, 136.1, 128.6, 128.0, 127.9, 66.9, 52.1, 42.5; HRMS (ESI-TOF): Anal. Calcd. For C 11 H 13 NO 4 +Na + : 246.0737, Found: 246.0755; IR (neat, cm -1 ): υ 3347, 2954, 2923, 2851, 1703, 1522, 1438, 1367, 1205, 1053, 1003, 697.
实施例二十一。Example 21.
Figure 811815dest_path_image023
。
Figure 811815dest_path_image023
.
往反应试管中依次加入化合物1 u（0.5 mmol, 89.6mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3u，收率为95%。通过分析所制得产物的主要测试数据可知，实际合成产物与理论分析一致。 Compound 1 u (0.5 mmol, 89.6 mg) and methanol containing 40 mol% tert-butyl nitrite were added to the reaction test tube in turn; then the reaction was carried out at 40°C in air for 48 hours; after the reaction, sodium thiosulfate was added. After stirring and quenching, the solvent was removed with a rotary evaporator, adsorbed on silica gel, and finally the product 3u was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 95%. By analyzing the main test data of the prepared product, it can be known that the actual synthetic product is consistent with the theoretical analysis.
实施例二十二。Example twenty-two.
Figure 369835dest_path_image024
。
Figure 369835dest_path_image024
.
往反应试管中依次加入化合物1 v（0.5 mmol, 111.7mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3v，收率为93%。通过分析所制得产物的主要测试数据可知，实际合成产物与理论分析一致。 Compound 1 v (0.5 mmol, 111.7 mg) and methanol containing 40 mol% tert-butyl nitrite were sequentially added to the reaction test tube; then the reaction was carried out under the condition of 40 °C in air for 48 hours; after the reaction, sodium thiosulfate was added. After stirring and quenching, the solvent was removed by a rotary evaporator, adsorbed on silica gel, and finally the product 3v was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 93%. By analyzing the main test data of the prepared product, it can be known that the actual synthetic product is consistent with the theoretical analysis.
实施例二十三。Example 23.
Figure 430195dest_path_image025
。
Figure 430195dest_path_image025
.
往反应试管中依次加入化合物 1w（0.5 mmol, 155.7mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3w，收率为80%。通过分析所制得产物的主要测试数据可知，实际合成产物与理论分析一致。 Add compound 1w (0.5 mmol, 155.7 mg) and methanol containing 40 mol% tert-butyl nitrite to the reaction test tube in turn; then react in the air at 40°C for 48 hours; after the reaction, add sodium thiosulfate and stir After quenching, the solvent was removed by a rotary evaporator, adsorbed on silica gel, and finally the product 3w was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 80%. By analyzing the main test data of the prepared product, it can be known that the actual synthetic product is consistent with the theoretical analysis.
实施例二十四。Example twenty-four.
Figure 390061dest_path_image026
。
Figure 390061dest_path_image026
.
往反应试管中依次加入化合物 1x（0.5 mmol, 77.1mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3x，收率为65%。通过分析所制得产物的主要测试数据可知，实际合成产物与理论分析一致。 Compound 1x (0.5 mmol, 77.1 mg) and methanol containing 40 mol% t-butyl nitrite were added to the reaction test tube in turn; then the reaction was carried out under the condition of 40 °C in air for 48 hours; after the reaction, sodium thiosulfate was added and stirred After quenching, the solvent was removed by a rotary evaporator, adsorbed on silica gel, and finally the product 3× was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 65%. By analyzing the main test data of the prepared product, it can be known that the actual synthetic product is consistent with the theoretical analysis.
1H NMR (400 MHz, CDCl 3) δ 7.27 – 7.21 (m, 2H), 7.04 – 6.97 (m, 2H), 3.69 (s, 3H), 3.60 (s, 2H); 13C NMR (100 MHz, CDCl 3) δ 171.8, 162.0 (d, J = 245.4 Hz), 130.8 (d, J = 8.1 Hz), 129.6 (d, J = 3.3 Hz), 115.4 (d, J = 21.5 Hz), 52.1, 40.2; 19F NMR (376 MHz, CDCl 3) δ -115.73; MS (EI) calculated for [C 9H 9FO 2]: 168.1, Found: 168.1; IR (neat, cm -1): υ 3044, 2976, 2955, 1736, 1604, 1509, 1436, 1259, 1221, 1154, 1014, 823。 1 H NMR (400 MHz, CDCl 3 ) δ 7.27 – 7.21 (m, 2H), 7.04 – 6.97 (m, 2H), 3.69 (s, 3H), 3.60 (s, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 171.8, 162.0 (d, J = 245.4 Hz), 130.8 (d, J = 8.1 Hz), 129.6 (d, J = 3.3 Hz), 115.4 (d, J = 21.5 Hz), 52.1, 40.2; 19 F NMR (376 MHz, CDCl 3 ) δ -115.73; MS (EI) calculated for [C 9 H 9 FO 2 ]: 168.1, Found: 168.1; IR (neat, cm -1 ): υ 3044, 2976, 2955 , 1736, 1604, 1509, 1436, 1259, 1221, 1154, 1014, 823.
实施例二十五。Example twenty-five.
Figure 369518dest_path_image027
。
Figure 369518dest_path_image027
.
往反应试管中依次加入化合物 1ah（0.5 mmol, 116.6mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3ah，收率为85%。通过分析产物的主要测试数据可知实际合成产物与理论一致。 Compound 1ah (0.5 mmol, 116.6 mg) and methanol containing 40 mol% tert-butyl nitrite were added to the reaction test tube in turn; then the reaction was carried out under the condition of 40 ° C in air for 48 hours; after the reaction was completed, sodium thiosulfate was added and stirred After quenching, the solvent was removed by a rotary evaporator, adsorbed on silica gel, and finally the product 3ah was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 85%. By analyzing the main test data of the product, it can be known that the actual synthetic product is consistent with the theory.
实施例二十六。Example twenty-six.
Figure 680414dest_path_image028
。
Figure 680414dest_path_image028
.
往反应试管中依次加入化合物 1ai（0.5 mmol, 96.2mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3ai，收率为95%。所制得产物的主要测试数据如下，通过分析可知，实际合成产物与理论分析一致。 Compound 1ai (0.5 mmol, 96.2 mg) and methanol containing 40 mol% tert-butyl nitrite were sequentially added to the reaction test tube; then the reaction was carried out at 40°C in air for 48 hours; after the reaction, sodium thiosulfate was added and stirred After quenching, the solvent was removed by a rotary evaporator, adsorbed on silica gel, and finally the product 3ai was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 95%. The main test data of the obtained product are as follows. It can be seen from the analysis that the actual synthetic product is consistent with the theoretical analysis.
1H NMR (400 MHz, CDCl 3) δ 7.95 – 7.89 (m, 2H), 7.55 – 7.49 (m, 1H), 7.43 – 7.40 (m, 2H), 3.64 (s, 3H), 3.01 (t, J = 7.2 Hz, 2H), 2.41 (t, J = 7.2 Hz, 2H), 2.07 – 2.00 (m, 2H); 13C NMR (100 MHz, CDCl 3) δ 199.2, 173.5, 136.6, 132.9, 128.4, 127.9, 51.4, 37.3, 32.9, 19.2; HRMS (ESI-TOF): Anal. Calcd. For C 12H 14O 3+Na +: 229.0835, Found: 229.0836; IR (neat, cm -1): υ 2952, 1732, 1683, 1598, 1448, 1210, 1001, 741, 690。 1 H NMR (400 MHz, CDCl 3 ) δ 7.95 – 7.89 (m, 2H), 7.55 – 7.49 (m, 1H), 7.43 – 7.40 (m, 2H), 3.64 (s, 3H), 3.01 (t, J = 7.2 Hz, 2H), 2.41 (t, J = 7.2 Hz, 2H), 2.07 – 2.00 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 199.2, 173.5, 136.6, 132.9, 128.4, 127.9 , 51.4, 37.3, 32.9, 19.2; HRMS (ESI-TOF): Anal. Calcd. For C 12 H 14 O 3 +Na + : 229.0835, Found: 229.0836; IR (neat, cm -1 ): υ 2952, 1732 , 1683, 1598, 1448, 1210, 1001, 741, 690.
实施例二十七。Example twenty-seven.
Figure 278885dest_path_image029
。
Figure 278885dest_path_image029
.
往反应试管中依次加入化合物 1aj（0.5 mmol, 88.6mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3aj，收率为88%。所制得产物的主要测试数据如下，通过分析可知，实际合成产物与理论分析一致。 Compound 1aj (0.5 mmol, 88.6 mg) and methanol containing 40 mol% tert-butyl nitrite were sequentially added to the reaction test tube; then the reaction was carried out under the condition of 40 °C in the air for 48 hours; after the reaction, sodium thiosulfate was added and stirred After quenching, the solvent was removed with a rotary evaporator, adsorbed on silica gel, and finally the product 3aj was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 88%. The main test data of the obtained product are as follows. It can be seen from the analysis that the actual synthetic product is consistent with the theoretical analysis.
实施例二十八。Example twenty-eight.
Figure 827678dest_path_image030
。
Figure 827678dest_path_image030
.
往反应试管中依次加入化合物 1ak（0.5 mmol, 97.6mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3ak，收率为89%。所制得产物的主要测试数据如下，通过分析可知，实际合成产物与理论分析一致。 Compound 1ak (0.5 mmol, 97.6 mg) and methanol containing 40 mol% tert-butyl nitrite were sequentially added to the reaction test tube; then the reaction was carried out under the condition of 40 ℃ in the air for 48 hours; after the reaction, sodium thiosulfate was added and stirred After quenching, the solvent was removed by a rotary evaporator, adsorbed on silica gel, and finally the product 3ak was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 89%. The main test data of the obtained product are as follows. It can be seen from the analysis that the actual synthetic product is consistent with the theoretical analysis.
1H NMR (400 MHz, CDCl 3) δ 8.09 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 3.63 (s, 3H), 3.02 (t, J = 7.5 Hz, 2H), 2.65 (t, J = 7.5 Hz, 2H); 13C NMR (100 MHz, CDCl 3) δ 172.4, 148.2, 146.5, 129.1, 123.6, 51.6, 34.6, 30.5; HRMS (ESI-TOF): Anal. Calcd. For C 10H 11NO 4+Na +: 232.0580, Found: 232.0580; IR (neat, cm -1): υ 3083, 2958, 1728, 1514, 1345, 1296, 1191, 1170, 854, 750。 1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 3.63 (s, 3H), 3.02 (t, J = 7.5 Hz , 2H), 2.65 (t, J = 7.5 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 172.4, 148.2, 146.5, 129.1, 123.6, 51.6, 34.6, 30.5; HRMS (ESI-TOF): Anal. Calcd. For C 10 H 11 NO 4 +Na + : 232.0580, Found: 232.0580; IR (neat, cm -1 ): υ 3083, 2958, 1728, 1514, 1345, 1296, 1191, 1170, 854, 750 .
实施例二十九。Example 29.
Figure 181299dest_path_image031
。
Figure 181299dest_path_image031
.
往反应试管中依次加入化合物 1al（0.5 mmol, 114.6mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3al，收率为93%。所制得产物的主要测试数据如下，通过分析可知，实际合成产物与理论分析一致。 Compound 1al (0.5 mmol, 114.6 mg) and methanol containing 40 mol% tert-butyl nitrite were sequentially added to the reaction test tube; then the reaction was carried out at 40°C in air for 48 hours; after the reaction, sodium thiosulfate was added and stirred After quenching, the solvent was removed by a rotary evaporator, adsorbed on silica gel, and finally the product 3al was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 93%. The main test data of the obtained product are as follows. It can be seen from the analysis that the actual synthetic product is consistent with the theoretical analysis.
实施例三十。Example Thirty.
Figure 524031dest_path_image032
。
Figure 524031dest_path_image032
.
往反应试管中依次加入化合物 1am（0.5 mmol, 105.2mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即得产物 3am，收率为95%。分析产物的主要测试数据可知，实际合成产物与理论一致。 Compound 1am (0.5 mmol, 105.2 mg) and methanol containing 40 mol% tert-butyl nitrite were added to the reaction test tube in turn; then the reaction was carried out under the condition of 40 °C in air for 48 hours; after the reaction, sodium thiosulfate was added and stirred After quenching, the solvent was removed by a rotary evaporator, adsorbed on silica gel, and finally the product 3am was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 95%. Analysis of the main test data of the product shows that the actual synthetic product is consistent with the theory.
实施例三十一。Embodiment 31.
Figure 988511dest_path_image033
。
Figure 988511dest_path_image033
.
往反应试管中依次加入化合物 1an0.5 mmol, 175.7mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3an，收率为78%。分析产物的主要测试数据可知，实际合成产物与理论分析一致。 Add compound 1an 0.5 mmol, 175.7 mg) and methanol containing 40 mol% tert-butyl nitrite into the reaction test tube in turn; then react under the condition of 40 ℃ in air for 48 hours; after the reaction, add sodium thiosulfate and stir to quench Then, the solvent was removed by a rotary evaporator, adsorbed on silica gel, and finally the product 3an was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 78%. The main test data of the analyzed product showed that the actual synthetic product was consistent with the theoretical analysis.
实施例三十二。Example thirty-two.
Figure 595072dest_path_image034
。
Figure 595072dest_path_image034
.
往反应试管中依次加入化合物 1ao（0.5 mmol, 84.6mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，用饱和氯化钠溶液淬灭，再用乙酸乙酯萃取后，利用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3ao，收率为96%。分析产物的主要测试数据可知，实际合成产物与理论分析一致。 Compound 1ao (0.5 mmol, 84.6 mg) and methanol containing 40 mol% tert-butyl nitrite were sequentially added to the reaction test tube; then the reaction was carried out at 40 °C in air for 48 hours; after the reaction, saturated sodium chloride solution was used. After quenching and extraction with ethyl acetate, the solvent was removed with a rotary evaporator, adsorbed on silica gel, and finally the product 3ao was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether with a yield of 96%. The main test data of the analyzed product showed that the actual synthetic product was consistent with the theoretical analysis.
实施例三十三。Example 33.
Figure 119595dest_path_image035
。
Figure 119595dest_path_image035
.
往反应试管中依次加入化合物 1ap（0.5 mmol, 82.1mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3ap，收率为86%。分析产物的主要测试数据可知，实际合成产物与理论分析一致。 Compound 1ap (0.5 mmol, 82.1 mg) and methanol containing 40 mol% tert-butyl nitrite were sequentially added to the reaction test tube; then the reaction was carried out under the condition of 40 ℃ in air for 48 hours; after the reaction, sodium thiosulfate was added and stirred After quenching, the solvent was removed with a rotary evaporator, adsorbed on silica gel, and finally the product 3ap was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 86%. The main test data of the analyzed product showed that the actual synthetic product was consistent with the theoretical analysis.
实施例三十四。Example thirty-four.
Figure 201820dest_path_image036
。
Figure 201820dest_path_image036
.
往反应试管中依次加入化合物 1aq（0.5 mmol, 83.1mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3aq，收率为90%。通过分析产物的主要测试数据可知，实际合成产物与理论一致。 Compound 1aq (0.5 mmol, 83.1 mg) and methanol containing 40 mol% tert-butyl nitrite were added to the reaction test tube in turn; then the reaction was carried out under the condition of 40 °C in air for 48 hours; after the reaction was completed, sodium thiosulfate was added and stirred After quenching, the solvent was removed by a rotary evaporator, adsorbed on silica gel, and finally the product 3aq was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 90%. By analyzing the main test data of the product, it can be known that the actual synthetic product is consistent with the theory.
实施例三十五。Example thirty-five.
Figure 938832dest_path_image037
。
Figure 938832dest_path_image037
.
往反应试管中依次加入化合物 1ar（0.5 mmol, 106.2mg）、含有40mol%亚硝酸叔丁酯的甲醇；然后在空气中40℃的条件下反应48小时；反应结束后，加硫代硫酸钠搅拌淬灭，再用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物 3ar，收率为98%。所制得产物的主要测试数据如下，通过分析可知，实际合成产物与理论分析一致。 Compound 1ar (0.5 mmol, 106.2 mg) and methanol containing 40 mol% tert-butyl nitrite were sequentially added to the reaction test tube; then the reaction was carried out under the condition of 40 °C in air for 48 hours; after the reaction, sodium thiosulfate was added and stirred After quenching, the solvent was removed by a rotary evaporator, adsorbed on silica gel, and finally the product 3ar was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, and the yield was 98%. The main test data of the obtained product are as follows. It can be seen from the analysis that the actual synthetic product is consistent with the theoretical analysis.
1H NMR (400 MHz, CDCl 3) δ 7.66 – 7.59 (m, 4H), 7.50 – 7.46 (m, 2H), 7.44 – 7.36 (m, 3H), 3.76 (s, 3H), 3.72 (s, 2H); 13C NMR (100 MHz, CDCl 3) δ 171.9, 140.6, 140.0, 132.9, 129.6, 128.7, 127.21, 127.17, 126.9, 52.0, 40.7; HRMS (ESI-TOF): Anal. Calcd. For C 15H 14O 2 +Na +: 249.0886, Found: 249.0890; IR (neat, cm -1): υ 3029, 2951, 1733, 1488, 1435, 1250, 1154, 1009, 754, 697。以上所述仅是本发明的优选实施方式，并不用于限制本发明，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变型，这些改进和变型也应视为本发明的保护范围。 1 H NMR (400 MHz, CDCl 3 ) δ 7.66 – 7.59 (m, 4H), 7.50 – 7.46 (m, 2H), 7.44 – 7.36 (m, 3H), 3.76 (s, 3H), 3.72 (s, 2H) ); 13 C NMR (100 MHz, CDCl 3 ) δ 171.9, 140.6, 140.0, 132.9, 129.6, 128.7, 127.21, 127.17, 126.9, 52.0, 40.7; HRMS (ESI-TOF): Anal. Calcd. For C 15 H 14 O 2 +Na + : 249.0886, Found: 249.0890; IR (neat, cm -1 ): υ 3029, 2951, 1733, 1488, 1435, 1250, 1154, 1009, 754, 697. The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. It should be pointed out that for those skilled in the art, some improvements can be made without departing from the technical principles of the present invention. These improvements and modifications should also be regarded as the protection scope of the present invention.

Claims (10)

  1. 一种羧酸酯化合物的制备方法，其特征在于，在亚硝酸酯存在下，以羧酸化合物、甲醇为原料，反应制备羧酸酯化合物。A method for preparing a carboxylate compound is characterized in that, in the presence of a nitrite, a carboxylate compound is prepared by reaction with a carboxylate compound and methanol as raw materials.
  2. 根据权利要求1所述羧酸酯化合物的制备方法，其特征在于，所述羧酸化合物的通式为
    Figure 987935dest_path_image001
    ；式中R 1选自氢、C1～C12烷基、烷氧基、苯基、苄基、取代苯基、噻吩基、吲哚基、苯酚基、萘基、联苯基、酰胺基中的一种；R 2选自氢、甲基、亚甲基、乙基、异丙基、羟基、羟甲基、苯基中的一种；R 3选自氢、甲基、亚甲基、乙基、异丙基、丙基、丁基、苯基中的一种；所述取代苯基上的取代基选自氢、甲基、甲氧基、羟基、硝基、苯基、乙酰氨基、氟、氯、溴、碘等中的一种或几种。     The method for preparing a carboxylate compound according to claim 1, wherein the general formula of the carboxylate compound is:
    Figure 987935dest_path_image001
    In the formula, R 1 is selected from hydrogen, C1～C12 alkyl, alkoxy, phenyl, benzyl, substituted phenyl, thienyl, indolyl, phenol, naphthyl, biphenyl, and amide One; R 2 is selected from one of hydrogen, methyl, methylene, ethyl, isopropyl, hydroxyl, hydroxymethyl, and phenyl; R 3 is selected from hydrogen, methyl, methylene, ethyl One of the group, isopropyl group, propyl group, butyl group and phenyl group; the substituent on the substituted phenyl group is selected from hydrogen, methyl, methoxy, hydroxyl, nitro, phenyl, acetamido, One or more of fluorine, chlorine, bromine, iodine, etc.
  3. 根据权利要求1所述羧酸酯化合物的制备方法，其特征在于，所述亚硝酸脂为亚硝酸异丙酯、亚硝酸丁酯、亚硝酸异丁酯和亚硝酸叔丁酯中的一种或几种。The preparation method of carboxylate compound according to claim 1, is characterized in that, described nitrite is a kind of in isopropyl nitrite, butyl nitrite, isobutyl nitrite and tert-butyl nitrite or several.
  4. 根据权利要求1所述羧酸酯化合物的制备方法，其特征在于，所述羧酸化合物、亚硝酸酯的摩尔比为10∶1～10。The method for preparing a carboxylate compound according to claim 1, wherein the molar ratio of the carboxylate compound and the nitrite is 10:1-10.
  5. 根据权利要求1所述羧酸酯化合物的制备方法，其特征在于，所述羧酸化合物、亚硝酸酯的摩尔比为5:2。The preparation method of the carboxylate compound according to claim 1, wherein the molar ratio of the carboxylate compound and the nitrite is 5:2.
  6. 根据权利要求1所述羧酸酯化合物的制备方法，其特征在于，反应的时间为20～50小时；反应的温度为25～50℃。The method for preparing a carboxylate compound according to claim 1, wherein the reaction time is 20-50 hours; and the reaction temperature is 25-50°C.
  7. 根据权利要求1所述羧酸酯化合物的制备方法，其特征在于，反应在空气中进行。The method for preparing a carboxylate compound according to claim 1, wherein the reaction is carried out in air.
  8. 根据权利要求1所述羧酸酯化合物的制备方法制备的羧酸酯化合物。The carboxylate compound prepared according to the preparation method of the carboxylate compound of claim 1.
  9. 亚硝酸酯在催化羧酸化合物、甲醇反应制备羧酸酯化合物中的应用。The application of nitrite in catalyzing the reaction of carboxylic acid compound and methanol to prepare carboxylic acid ester compound.
  10. 根据权利要求9所述的应用，其特征在于，所述反应不含金属或者金属化合物。The use according to claim 9, wherein the reaction is free of metals or metal compounds.
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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101602736A (en) * 2009-07-22 2009-12-16 山东京博控股发展有限公司 A kind of synthetic method of quizalofopPethyl
WO2010037807A1 (en) * 2008-10-01 2010-04-08 Basf Se Method for producing polycarboxylic acid alkyl esters
CN101914014A (en) * 2010-09-03 2010-12-15 北京博瑞创奇科技有限公司 Method for synthesizing and purifying synthetic ester oil for cosmetics and synthetic ester oil for cosmetics obtained by same
CN107033002A (en) * 2016-02-04 2017-08-11 中国科学院大连化学物理研究所 A kind of method for synthesizing aromatic esters
WO2017222692A1 (en) * 2016-06-22 2017-12-28 Exxonmobil Chemical Patents Inc. Aromatic esters and polyesters, production without esterification catalyst, and use
CN108503549A (en) * 2018-03-26 2018-09-07 江西师范大学 Aromatic carboxylic acid trifluoroethyl ester type compound and preparation method thereof
CN108707057A (en) * 2018-03-26 2018-10-26 江西师范大学 Fatty trifluoro ethyl ester class compound and preparation method thereof
CN109369394A (en) * 2018-11-28 2019-02-22 浙江工业大学 A kind of photochemical catalytic oxidation synthetic method of benzhydrol ester

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010037807A1 (en) * 2008-10-01 2010-04-08 Basf Se Method for producing polycarboxylic acid alkyl esters
CN101602736A (en) * 2009-07-22 2009-12-16 山东京博控股发展有限公司 A kind of synthetic method of quizalofopPethyl
CN101914014A (en) * 2010-09-03 2010-12-15 北京博瑞创奇科技有限公司 Method for synthesizing and purifying synthetic ester oil for cosmetics and synthetic ester oil for cosmetics obtained by same
CN107033002A (en) * 2016-02-04 2017-08-11 中国科学院大连化学物理研究所 A kind of method for synthesizing aromatic esters
WO2017222692A1 (en) * 2016-06-22 2017-12-28 Exxonmobil Chemical Patents Inc. Aromatic esters and polyesters, production without esterification catalyst, and use
CN108503549A (en) * 2018-03-26 2018-09-07 江西师范大学 Aromatic carboxylic acid trifluoroethyl ester type compound and preparation method thereof
CN108707057A (en) * 2018-03-26 2018-10-26 江西师范大学 Fatty trifluoro ethyl ester class compound and preparation method thereof
CN109369394A (en) * 2018-11-28 2019-02-22 浙江工业大学 A kind of photochemical catalytic oxidation synthetic method of benzhydrol ester

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YANG XU-HENG, SONG REN-JIE, LI JIN-HENG: "Metal-Free [4+2] Annulation of Arylalkynes with tert- Butyl Nitrite through C( sp 2 )H Oxidation to Assemble Benzo[ e ][1,2]oxazin-4-ones", ADVANCED SYNTHESIS AND CATALYSIS, vol. 357, no. 18, 14 December 2015 (2015-12-14), pages 3849 - 3856, XP055946649, ISSN: 1615-4150, DOI: 10.1002/adsc.201500656 *

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