Preparation method of 2-oxazoline compound

Abstract

The invention discloses a preparation method of a 2-oxazoline compound. Specifically, the invention discloses a preparation method of a compound as shown in a formula IV, which comprises the following steps: in a solvent, in the presence of alkali and a catalyst, carrying out ring closing reaction on a compound as shown in a formula III to prepare the compound as shown in the formula IV, wherein R1 is an alkyl group of C1 to C6 or an alkenyl group of C2 to C6; r < 2 > and R < 3 > are respectively and independently hydrogen or alkyl with 1 to 6 carbon atoms; the catalyst is sulfonyl chloride and sulfonic anhydride. The method disclosed by the invention is cheap and stable in raw materials, low in preparation cost and environment-friendly; the method provided by the invention also has the advantages of better yield and purity, and is suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a method for preparing 2-oxazoline compounds. Background Art

[0002] The uses of 2-substituted oxazolines (PIPOx) are mainly concentrated in the biomedical field. The following are some specific applications:

[0003] Thermoresponsive pseudopeptides: Poly(2-oxazoline) is known as a thermoresponsive pseudopeptide, which exhibits a phase change in aqueous solution at temperatures close to body temperature and is non-toxic to many cell lines, making it potentially attractive for many biological applications.

[0004] Biomedical multifunctional polymers: PIPOx has reactive 2-oxazoline side groups and can be easily prepared in a controllable manner by several controlled / living polymerization methods. The reactivity of the side-chain 2-substituted oxazolines allows for selective reactions with thiols and carboxyl-containing compounds in the absence of any catalyst. In addition, PIPOx has been proven to be a non-cytotoxic polymer with immunomodulatory properties. The post-polymerization functionalization of PIPOx has been used to prepare thermosensitive or cationic polymers, drug conjugates, hydrogels, brush materials, and polymer coatings, which can be used in drug and gene delivery, tissue engineering, blood-like materials, antibacterial materials, etc.

[0005] Synthetic hydrogel materials: Using PIPOx as a biocompatible functional polymer, a library of hydrogels was obtained by chemical crosslinking. These hydrogels can regulate the equilibrium swelling degree of the final material by changing the composition of the reaction mixture, including changing the polymer concentration in the feed ratio between the 2-oxazoline side groups and the carboxylic acid groups, as well as the length of the crosslinker. These hydrogels exhibit thermoresponsiveness and pH degradability under physiological conditions, and a proof-of-concept drug delivery experiment was demonstrated, showing potential as ophthalmic materials or in drug delivery applications.

[0006] Self-healing and moldable supramolecular hydrogels: The use of PIPOx modified by TPy in self-healing and moldable synthesis, triggering hydrogelation by adding divalent transition metal ions. The resulting hydrogels show rapid self-healing properties at room temperature and can be molded into various complex geometries, potentially applicable in various fields from soft robotics to dynamic self-repair coatings.

[0007] In summary, due to their unique chemical and physical properties, 2-substituted oxazolines have broad application prospects in the biomedical field, especially in the synthesis of hydrogel materials, drug delivery systems, tissue engineering, and the development of self-healing materials.

[0008] Currently, there are few synthesis methods for 2-substituted oxazoline compounds. The main synthesis methods are as follows:

[0009] (1) Wuhan Luohua Patent (CN 113773271 A) synthesizes an intermediate by using acryloyl chloride and chloroethylamine hydrochloride with water as a solvent under the catalysis of potassium carbonate, and then synthesizes 2-substituted oxazoline under alkaline conditions. This invention uses acryloyl chloride as a raw material, which is volatile, has a strong odor, and is unstable and prone to hydrolysis, so it is not suitable for industrial production.

[0010] (2) The reaction processes of the oxazoline compounds reported in the literature (Organic Letters, 18(23), 6116 - 6119, 2016; Mediterranean Journal of Chemistry, 2(5), 648 - 657, 2014; Journal of Organic Chemistry, 58(22), 5976 - 80, 1993) are as follows:

[0011]

[0012] However, the methods reported in the literature have defects such as high cost, strong corrosiveness and toxicity of thionyl chloride, which make the reaction process difficult to operate, and incomplete industrial reactions. SUMMARY OF THE INVENTION

[0013] The technical problem to be solved by the present invention is to provide a new preparation method of 2-oxazoline compounds in view of the defects existing in the prior art. The preparation method of the present invention uses cheap and stable raw materials, has low preparation cost, is environmentally friendly, and has better yield (89% - 95%) and purity (99% - 99.7%). Therefore, it is suitable for industrial production.

[0014] The present invention solves the above technical problems through the following technical solutions:

[0015] The present invention provides a preparation method of a compound of formula IV, which comprises the following steps: in a solvent, in the presence of a base and a catalyst, the compound of formula III undergoes a ring closure reaction to obtain the compound of formula IV;

[0016] ;

[0017] wherein, R1 is an alkyl group with 1 - 6 carbon atoms or an alkenyl group with 2 - 6 carbon atoms; R2 and R3 are each independently hydrogen or an alkyl group with 1 - 6 carbon atoms; the catalyst is sulfonyl chloride and sulfonic anhydride.

[0018] In some embodiments of the present invention, R1 is an alkyl group with 1 - 4 carbon atoms or an alkenyl group with 2 - 4 carbon atoms, such as methyl, ethyl, propyl, butyl, isopropyl, vinyl, allyl or propenyl, and for another example, vinyl or methyl.

[0019] In some embodiments of the present invention, R2 and R3 are each independently hydrogen or a C1-C3 alkyl group. For example, R2 and R3 are each independently hydrogen or methyl.

[0020] In some embodiments of the present invention, the sulfonyl chloride is methylsulfonyl chloride and / or p-toluenesulfonyl chloride. For example, it is methylsulfonyl chloride.

[0021] In some embodiments of the present invention, the sulfonic anhydride is methylsulfonic anhydride and / or p-toluenesulfonic anhydride. For example, it is methylsulfonic anhydride.

[0022] In some embodiments of the present invention, the compound of formula III is N-(2-hydroxyethyl)acetamide, N-(2-hydroxyethyl)acrylamide or N-(1-hydroxypropan-2-yl)acrylamide.

[0023] In the present invention, the solvent is a conventional solvent for this type of ring-closing reaction in the art.

[0024] In some embodiments of the present invention, the solvent is an aprotic solvent; preferably, the aprotic solvent is one or more of halogenated hydrocarbon solvents, amide solvents and sulfoxide solvents.

[0025] In some embodiments of the present invention, the halogenated hydrocarbon solvent is dichloromethane and / or chloroform. For example, it is dichloromethane.

[0026] In some embodiments of the present invention, the amide solvent is N,N-dimethylacetamide.

[0027] In some embodiments of the present invention, the sulfoxide solvent is dimethyl sulfoxide.

[0028] In the present invention, the amount of the solvent used is the conventional amount for ring-closing reactions in the art.

[0029] In some embodiments of the present invention, the volume-mass ratio of the solvent to the compound of formula III is 5-10 mL / g. For example, it is 7-9 mL / g, or 7.8 mL / g or 8.7 mL / g.

[0030] In the present invention, the base is a conventional base for this type of ring-closing reaction in the art.

[0031] In some embodiments of the present invention, the base is an inorganic base and / or an organic base.

[0032] In some embodiments of the present invention, the inorganic base is one or more of alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, alkali metal hydrogen phosphates and alkali metal hydroxides. For example, it is one or more of alkali metal carbonates, alkali metal hydrogen phosphates and alkali metal hydroxides.

[0033] In some embodiments of the present invention, the alkali metal carbonate is sodium carbonate and / or potassium carbonate.

[0034] In some embodiments of the present invention, the alkali metal bicarbonate is sodium bicarbonate.

[0035] In some embodiments of the present invention, the alkali metal phosphate is potassium phosphate and / or sodium phosphate.

[0036] In some embodiments of the present invention, the alkali metal hydrogen phosphate is disodium hydrogen phosphate and / or dipotassium hydrogen phosphate.

[0037] In some embodiments of the present invention, the alkali metal hydroxide is sodium hydroxide and / or potassium hydroxide.

[0038] In some embodiments of the present invention, the organic base is an amine compound.

[0039] In some embodiments of the present invention, the amine compound is triethylamine and / or diisopropylethylamine.

[0040] In some embodiments of the present invention, the molar ratio of the base to the compound of formula III is (0.5 - 3):1, such as (0.5 - 1.1):1, and further such as 0.5:1, 1:1 or 1.1:1.

[0041] In some embodiments of the present invention, the molar ratio of the sulfonyl chloride to the compound of formula III is (1.0 - 2.0):1, such as 1.3:1 or 1.4:1, and further such as (1.05 - 1.07):1.

[0042] In some embodiments of the present invention, the molar ratio of the sulfonic anhydride to the compound of formula III is (1.0 - 1.2):1, such as 1:1 or 1.1:1, and further such as (1.1 - 1.15):1.

[0043] In the present invention, the reaction temperature of the ring - closing reaction is the conventional reaction temperature for this type of ring - closing reaction in the art.

[0044] In some embodiments of the present invention, the reaction temperature of the ring - closing reaction is 20 - 100 °C, such as 20 - 30 °C, and further such as 50 °C or 80 °C.

[0045] In some embodiments of the present invention, the feeding method of the ring - closing reaction is as follows: first, the compound of formula III, the sulfonyl chloride and the sulfonic anhydride are mixed to obtain a mixed solution, and then at 0 - 20 °C, the base and the solvent are added to the mixed solution.

[0046] In the present invention, the progress of the ring-closing reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and generally, the disappearance of the compound of formula III is taken as the reaction end point; the time of the ring-closing reaction is 5 - 12 h, such as 5 - 6 h, or 12 h.

[0047] In the present invention, the post-treatment of the ring-closing reaction is the conventional post-treatment of this type of ring-closing reaction in the art.

[0048] In some embodiments of the present invention, the post-treatment of the ring-closing reaction further includes the following steps: adjusting the pH of the reaction solution to 1 - 2, liquid separation, concentration, rectification, and that's it.

[0049] In some embodiments of the present invention, in the post-treatment step of the ring-closing reaction, the adjustment is carried out with an acid, such as hydrochloric acid, or 10% hydrochloric acid.

[0050] In some embodiments of the present invention, in the post-treatment step of the ring-closing reaction, the adjustment is to adjust the pH of the reaction solution to 1.

[0051] In some embodiments of the present invention, the preparation method of the compound of formula IV further includes the following steps: in the presence of an organic base, the compound of formula I and the compound of formula II undergo an amine-ester exchange reaction to obtain the compound of formula III;

[0052] ;

[0053] Wherein, R1, R2 and R3 are as described above; R4 is an alkyl group with 1 - 6 carbon atoms.

[0054] In some embodiments of the present invention, the R4 is methyl, ethyl, propyl, butyl or isopropyl, such as methyl.

[0055] In some embodiments of the present invention, the compound of formula I is methyl acrylate or methyl acetate.

[0056] In some embodiments of the present invention, the compound of formula II is ethanolamine, aminopropanol or 2,2-dimethyl ethanolamine, such as ethanolamine or aminopropanol.

[0057] In the present invention, the organic base is a conventional organic base for this type of amine-ester exchange reaction in the art.

[0058] In some embodiments of the present invention, the organic base is sodium methoxide and / or sodium ethoxide.

[0059] In the present invention, the dosage of the organic base is the conventional dosage for this type of amine-ester exchange reaction in the art.

[0060] In some embodiments of the present invention, the molar ratio of the organic base to the compound of formula I is (0.02 - 0.1):1, for example (0.04 - 0.1):1, and for example 0.04:1, 0.05:1 or 0.06:1.

[0061] In some embodiments of the present invention, the molar ratio of the compound of formula I to the compound of formula II is (0.95 - 1.1):1, for example 1:1.

[0062] In some embodiments of the present invention, the amine transesterification reaction is carried out under a protective gas; the protective gas can be nitrogen, argon or helium, for example nitrogen.

[0063] In the present invention, the reaction temperature of the amine transesterification reaction is the conventional reaction temperature for this type of amine transesterification reaction in the art.

[0064] In some embodiments of the present invention, the reaction temperature of the amine transesterification reaction can be 0 - 30 °C, for example 15 °C.

[0065] In the present invention, the reaction time of the amine transesterification reaction is the conventional time for this type of amine transesterification reaction in the art.

[0066] In some embodiments of the present invention, the progress of the amine transesterification reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and generally the reaction end point is when the compound of formula III is no longer formed; preferably, the reaction time of the amine transesterification reaction can be 12 - 48 h, for example 24 h.

[0067] In the present invention, the feeding mode of the amine transesterification reaction is the conventional feeding mode for this type of amine transesterification reaction in the art.

[0068] In some embodiments of the present invention, the feeding mode of the amine transesterification reaction is: mixing the compound of formula II with the organic base to obtain a mixture, and then adding the compound of formula I to the mixture at -5 °C to 0 °C; the addition can be dropwise addition.

[0069] In the present invention, the post-treatment of the amine transesterification reaction is the conventional post-treatment for this type of amine transesterification reaction in the art.

[0070] In some embodiments of the present invention, the post-treatment of the amine transesterification reaction further includes the following steps: concentrating the reaction solution after the reaction, washing, separating the liquid, and drying, that's all.

[0071] On the basis of not violating the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0072] The reagents and raw materials used in the present invention are all commercially available.

[0073] The positive and progressive effects of the present invention are as follows:

[0074] (1) The present invention provides a preparation method of a new 2-substituted oxazoline compound. The raw materials of this method are cheap and stable, the preparation cost is low, and it is environmentally friendly;

[0075] (2) The preparation method of the present invention also has the advantages of relatively good yield (89%-95%) and purity (99.5%-99.9%), and is suitable for industrial production. Detailed implementation manners

[0076] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0077] Example 1

[0078] I. Synthesis of N-(2-hydroxyethyl)acrylamide

[0079]

[0080] 61 g of ethanolamine was added, and 2.7 g of sodium methoxide as an alkali catalyst was added. After stirring well under nitrogen protection, the temperature was controlled below 0 °C, and 86.0 g of methyl acrylate was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 12 hours, and nitrogen was passed throughout the process. After the reaction was completed, methanol was concentrated off, then water was added to wash the catalyst, and after liquid separation, it was dried to obtain 111.5 g of the product, with an HPLC purity of 95% and a yield of 97%.

[0081] 1 HNMR (400 MHz, CDCl3): δ7.6 (s, 1H), 5.79 (d, 2H), 5.31 (s, 1H) 4.86 (s, 1H), 3.59 (t, 2H), 3.47 (t, 2H).

[0082] II. Synthesis of 2-vinyl-2-oxazoline

[0083]

[0084] Add 11.5 g of N-(2-hydroxyethyl)acrylamide to a four-necked flask, then add 14.4 g of methanesulfonyl chloride and 17.4 g of methanesulfonic anhydride. After stirring and dissolving thoroughly, control the temperature below 20 °C, add 11 g of triethylamine and 100 ml of dichloromethane, and continue stirring at room temperature for 5 - 6 hours. After the reaction is completed, wash with dilute hydrochloric acid solution, then separate the layers, concentrate, and rectify to obtain 8.92 g of 2-vinyl oxazoline with a purity of 99.9% and a yield of 92%.

[0085] 1 H NMR (400 MHz, CDCl3): 5.8 (s, 1H), 5.42 (s, 1H), 5.31 (s, 1H), 4.29 (t, 2H), 3.95 (t, 2H).

[0086] Example 2

[0087] I. Synthesis of N-(2-hydroxyethyl)acrylamide

[0088]

[0089] Add 61 g of ethanolamine and 3.0 g of sodium ethoxide as an alkali catalyst. Under nitrogen protection, stir thoroughly, control the temperature below 0 °C, and dropwise add 86.0 g of methyl acrylate. After addition, stir at room temperature for 14 hours while passing nitrogen throughout the process. After the reaction is completed, concentrate to remove methanol, then wash the catalyst with water, separate the layers, and dry to obtain 108 g of the product N-(2-hydroxyethyl)acrylamide with an HPLC purity of 93.8% and a yield of 95.3%.

[0090] II. Synthesis of 2-vinyl-2-oxazoline

[0091]

[0092] Add 11.5 g of N-(2-hydroxyethyl)acrylamide to a four-necked flask, then add 15.8 g of methanesulfonyl chloride and 19.1 g of methanesulfonic anhydride. After stirring and dissolving thoroughly, control the temperature below 20 °C, add 11 g of triethylamine and 100 ml of dichloromethane, and continue stirring at room temperature for 5 - 6 hours. After the reaction is completed, wash with dilute hydrochloric acid solution, then separate the layers, concentrate, and rectify to obtain 9.21 g of 2-vinyl-2-oxazoline with a purity of 99.9% and a yield of 95%.

[0093] Example 3

[0094] I. Synthesis of N-(2-hydroxyethyl)acrylamide

[0095]

[0096] 61 g of ethanolamine was added with 3.0 g of sodium methoxide as an alkali catalyst. Under nitrogen protection, after sufficient stirring, the temperature was controlled below 0 °C, and 86.0 g of methyl acrylate was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 12 hours while nitrogen was passed throughout the process. After the reaction was completed, methanol was concentrated off, and then water was added to wash the catalyst. After liquid separation, it was dried to obtain 111.5 g of the product with an HPLC purity of 96% and a yield of 97%.

[0097] II. Synthesis of 2-vinyl-2-oxazoline

[0098]

[0099] 11.5 g of N-(2-hydroxyethyl)acrylamide was added to a four-necked flask, and then 15.12 g of methanesulfonyl chloride and 18.27 g of methanesulfonic anhydride were added. After sufficient stirring and dissolution, the temperature was controlled below 20 °C, 12.9 g of diisopropylethylamine and 100 ml of dichloromethane were added, and the mixture was continuously stirred at room temperature for 5 - 6 hours. After the reaction was completed, it was washed with dilute hydrochloric acid solution, then liquid-separated, concentrated, and rectified to obtain 9.03 g of 2-vinyl-2-oxazoline with a purity of 99.9% and a yield of 93%.

[0100] Example 4

[0101] I. Synthesis of N-(2-hydroxyethyl)acetamide

[0102]

[0103] 61 g of ethanolamine was added with 3.0 g of sodium methoxide as an alkali catalyst. Under nitrogen protection, after sufficient stirring, the temperature was controlled below 0 °C, and 74.0 g of methyl acetate was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 12 hours while nitrogen was passed throughout the process. After the reaction was completed, methanol was concentrated off, and then water was added to wash the catalyst. After liquid separation, it was dried to obtain 99.15 g of the product with an HPLC purity of 97% and a yield of 98%.

[0104] II. Synthesis of 2-methyl-2-oxazoline

[0105]

[0106] 10.3 g of N-(2-hydroxyethyl)acetamide was added to a four-necked flask, and then 15.12 g of methanesulfonyl chloride and 18.27 g of methanesulfonic anhydride were added. After sufficient stirring and dissolution, the temperature was controlled below 20 °C, 12.9 g of diisopropylethylamine and 100 ml of dichloromethane were added, and the mixture was continuously stirred at room temperature for 5 - 6 hours. After the reaction was completed, it was washed with dilute hydrochloric acid solution, then liquid-separated, concentrated, and rectified to obtain 7.99 g of 2-methyl-2-oxazoline with a purity of 99.9% and a yield of 94%.

[0107] Example 5

[0108] I. Synthesis of N-(2-hydroxyethyl)acrylamide

[0109]

[0110] Add 61 g of ethanolamine and 2.7 g of sodium methoxide as the base catalyst. Under nitrogen protection, stir well, then control the temperature below 0 °C and add 86.0 g of methyl acrylate dropwise. After the addition is complete, stir at room temperature for 8 hours while passing nitrogen throughout the process. After the reaction is completed, concentrate to remove methanol, then wash the catalyst with water, separate the layers, and dry to obtain 108.6 g of the product with an HPLC purity of 93% and a yield of 94.5%.

[0111] II. Synthesis of 2-vinyl-2-oxazoline

[0112]

[0113] Add 11.5 g of N-(2-hydroxyethyl)acrylamide to a four-necked flask, then add 14.4 g of methanesulfonyl chloride and 17.4 g of methanesulfonic anhydride. After stirring and dissolving well, control the temperature below 20 °C, add 14.2 g of diisopropylethylamine and 100 ml of dichloromethane, and continue to stir and react at room temperature for 5 - 6 hours. After the reaction is completed, wash with dilute hydrochloric acid solution, then separate the layers, concentrate, and distill to obtain 9.02 g of 2-vinyl-2-oxazoline with a purity of 99.9% and a yield of 93%.

[0114] Example 6

[0115] I. Synthesis of N-(2-hydroxyethyl)acrylamide

[0116]

[0117] Add 61 g of ethanolamine and 2.7 g of sodium methoxide as the base catalyst. Under nitrogen protection, stir well, then control the temperature below 0 °C and add 86.0 g of methyl acrylate dropwise. After the addition is complete, stir at room temperature for 12 hours while passing nitrogen throughout the process. After the reaction is completed, concentrate to remove methanol, then wash the catalyst with water, separate the layers, and dry to obtain 111.5 g of the product with an HPLC purity of 95% and a yield of 97%.

[0118] II. Synthesis of 2-vinyl-2-oxazoline

[0119]

[0120] Add 11.5 g of N-(2-hydroxyethyl)acrylamide into a four-necked flask, then add 14.4 g of methylsulfonyl chloride and 17.4 g of methanesulfonic anhydride. After stirring and dissolving thoroughly, control the temperature below 20 °C, add 11 g of triethylamine and 100 ml of dichloromethane, and continue stirring at room temperature for 5 - 6 hours. After the reaction is completed, wash with dilute hydrochloric acid solution, then separate the liquid, concentrate, and rectify to obtain 8.92 g of 2-vinyl-2-oxazoline with a purity of 99.9% and a yield of 92%.

[0121] Example 7

[0122] I. Synthesis of N-(2-hydroxyethyl)acrylamide

[0123]

[0124] Add 61 g of ethanolamine and 2.7 g of sodium methoxide as an alkali catalyst. Under nitrogen protection, stir thoroughly, control the temperature below 0 °C, and dropwise add 86.0 g of methyl acrylate. After the addition is completed, stir at room temperature for 8 hours, and pass nitrogen throughout the process. After the reaction is completed, concentrate methanol, then wash the catalyst with water, separate the liquid, and dry to obtain 108.6 g of the product with an HPLC purity of 93% and a yield of 94.5%.

[0125] II. Synthesis of 2-vinyl-2-oxazoline

[0126]

[0127] Add 11.5 g of N-(2-hydroxyethyl)acrylamide into a four-necked flask, then add 14.4 g of methylsulfonyl chloride and 17.4 g of methanesulfonic anhydride. After stirring and dissolving thoroughly, control the temperature below 20 °C, add 2.0 g of sodium hydroxide and 100 ml of dichloromethane, and continue stirring at room temperature for 5 - 6 hours. After the reaction is completed, wash with dilute hydrochloric acid solution, then separate the liquid, concentrate, and rectify to obtain 9.8 g of 2-vinyl-2-oxazoline with a purity of 99.9% and a yield of 90.1%.

[0128] Example 8

[0129] I. Synthesis of N-(1-hydroxypropan-2-yl)acrylamide

[0130]

[0131] Add 75 g of aminopropanol and 2.7 g of sodium methoxide as an alkali catalyst. Under nitrogen protection, stir thoroughly, control the temperature below 0 °C, and dropwise add 86.0 g of methyl acrylate. After the addition is completed, stir at room temperature for 8 hours, and pass nitrogen throughout the process. After the reaction is completed, concentrate methanol, then wash the catalyst with water, separate the liquid, and dry to obtain 124.5 g of the product with an HPLC purity of 95% and a yield of 96.5%.

[0132] II. Synthesis of 4-methyl-2-vinyl-4,5-dihydrooxazole

[0133]

[0134] Add 12.9 g of N-(1-hydroxypropan-2-yl)acrylamide into a four-necked flask, then add 14.4 g of methanesulfonyl chloride and 17.4 g of methanesulfonic anhydride. After stirring and dissolving thoroughly, while controlling the temperature below 20 °C, add 2.0 g of sodium hydroxide and 100 ml of dichloromethane. Continue stirring the reaction at room temperature for 5 - 6 hours. After the reaction is completed, wash with dilute hydrochloric acid solution, then separate the layers, concentrate, and rectify to obtain 10.2 g of 4-methyl-2-vinyl-4,5-dihydrooxazole with a purity of 99%, and the yield is 92%.

[0135] Example 9

[0136] I. Synthesis of N-(2-hydroxyethyl)acrylamide

[0137]

[0138] Add 61 g of ethanolamine and 2.7 g of the base catalyst sodium methoxide. Under nitrogen protection, after stirring thoroughly, control the temperature below 0 °C and dropwise add 86.0 g of methyl acrylate. After the addition is completed, stir at room temperature for 8 hours, and pass nitrogen throughout the process. After the reaction is completed, concentrate to remove methanol, then wash the catalyst with water, separate the layers, and dry to obtain 108.6 g of the product with an HPLC purity of 93% and a yield of 94.5%.

[0139] II. Synthesis of 2-vinyl-2-oxazoline

[0140]

[0141] Add 11.5 g of N-(2-hydroxyethyl)acrylamide into a four-necked flask, then add 14.4 g of methanesulfonyl chloride and 17.4 g of methanesulfonic anhydride. After stirring and dissolving thoroughly, while controlling the temperature below 20 °C, add 11 g of triethylamine and 100 ml of N,N-dimethylformamide. Continue stirring the reaction at room temperature for 5 - 6 hours. After the reaction is completed, add 100 ml of dilute hydrochloric acid solution, then extract and separate with ethyl acetate, concentrate, and rectify to obtain 9.02 g of 2-vinyl-2-oxazoline with a purity of 99.7%, and the yield is 93%.

[0142] Example 10

[0143] I. Synthesis of N-(2-hydroxyethyl)acrylamide

[0144]

[0145] 61 g of ethanolamine was added with 2.7 g of sodium methoxide as a base catalyst. Under nitrogen protection, after sufficient stirring, the temperature was controlled below 0 °C, and 86.0 g of methyl acrylate was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 8 hours with nitrogen passing through the whole process. After the reaction was completed, methanol was concentrated off, then water was added to wash the catalyst. After liquid separation, it was dried to obtain 108.6 g of the product, with an HPLC purity of 93% and a yield of 94.5%.

[0146] II. Synthesis of 2-vinyl-2-oxazoline

[0147]

[0148] 11.5 g of N-(2-hydroxyethyl)acrylamide was added to a four-necked flask, then 14.4 g of methanesulfonyl chloride and 17.4 g of methanesulfonic anhydride were added. After sufficient stirring and dissolution, the temperature was controlled below 20 °C, 11 g of triethylamine and 100 ml of dimethyl sulfoxide were added, and the reaction was continued to stir at room temperature for 5 - 6 hours. After the reaction was completed, 100 ml of dilute hydrochloric acid solution was added, then extracted and separated with ethyl acetate, concentrated, and rectified to obtain 8.63 g of 2-vinyl-2-oxazoline with a purity of 99.7% and a yield of 89%.

[0149] Comparative Example 1 Yields of the ring-closing reaction of formula III catalyzed by thionyl chloride in different solvents

[0150]

[0151] Comparative Example 2 Yields of the ring-closing reaction of formula III catalyzed by other catalysts at different temperatures

[0152] .

Claims

1. A method for preparing a compound of formula IV, characterized in that, It includes the following steps: In a solvent, in the presence of a base and a catalyst, the compound of formula III undergoes a ring-closing reaction to obtain the compound of formula IV; ； Wherein, R1 is an alkyl group with 1-6 carbon atoms or an alkenyl group with 2-6 carbon atoms; R2 and R3 are each independently hydrogen or an alkyl group with 1-6 carbon atoms; the catalyst is sulfonyl chloride and sulfonic anhydride.

2. The method for preparing the compound of formula IV according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) R1 is an alkyl group with 1-4 carbon atoms or an alkenyl group with 2-4 carbon atoms; (2) R2 and R3 are each independently hydrogen or an alkyl group with 1-3 carbon atoms; (3) The sulfonyl chloride is methylsulfonyl chloride and / or p-toluenesulfonyl chloride; (4) The sulfonic anhydride is methylsulfonic anhydride and / or p-toluenesulfonic anhydride; (5) The solvent is an aprotic solvent; (6) The volume-mass ratio of the solvent to the compound of formula III is 5-10 mL / g; (7) The base is an inorganic base and / or an organic base; (8) The molar ratio of the base to the compound of formula III is (0.5-3):1; (9) The molar ratio of the sulfonyl chloride to the compound of formula III is (1.0-2.0):1; (10) The molar ratio of the sulfonic anhydride to the compound of formula III is (1.0-1.2):1; (11) The reaction temperature of the ring-closing reaction is 20-100 °C; (12) The feeding method of the ring-closing reaction is: first mix the compound of formula III, the sulfonyl chloride and the sulfonic anhydride to obtain a mixed solution, and then add the base and the solvent to the mixed solution at 0-20 °C; and (13) The ring-closing reaction includes the following post-treatment steps: adjusting the pH of the reaction solution to 1-2, liquid separation, concentration, rectification, and that's it.

3. The preparation method of the compound of formula IV according to claim 2, characterized in that, It satisfies one or more of the following conditions: (1) R1 is methyl, ethyl, propyl, butyl, isopropyl, vinyl, allyl or propenyl; (2) R2 and R3 are independently hydrogen or methyl; (3) The sulfonyl chloride is methylsulfonyl chloride; (4) The sulfonic anhydride is methylsulfonic anhydride; (5) The aprotic solvent is one or more of halogenated hydrocarbon solvents, amide solvents and sulfoxide solvents; (6) The volume-mass ratio of the solvent to the compound of formula III is 7-9 mL / g; (7) The inorganic base is one or more of alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, alkali metal hydrogen phosphates and alkali metal hydroxides; (8) The organic base is an amine compound; (9) The molar ratio of the base to the compound of formula III is (0.5-1.1):1; (10) The molar ratio of the sulfonyl chloride to the compound of formula III is (1.05-1.07):1; (11) The molar ratio of the sulfonic anhydride to the compound of formula III is (1.1-1.15):1; (12) The reaction temperature of the ring-closing reaction is 20-30 °C; (13) In the post-treatment step of the ring-closing reaction, the adjustment is carried out with an acid; and In the post-treatment step of the ring-closing reaction described, the adjustment is to adjust the pH of the reaction solution to 1.

4. The method for preparing the compound of formula IV according to claim 3, characterized in that, It satisfies one or more of the following conditions: (1) The halogenated hydrocarbon solvent is dichloromethane and / or chloroform; (2) The amide solvent is N,N-dimethylacetamide; (3) The sulfoxide solvent is dimethyl sulfoxide; (4) The inorganic base is one or more of alkali metal carbonates, alkali metal hydrogen phosphates, and alkali metal hydroxides; (5) The amine compound is triethylamine and / or diisopropylethylamine; (6) In the post-treatment step of the ring-closing reaction, the adjustment is carried out using hydrochloric acid; and (7) The compound of formula III is N-(2-hydroxyethyl)acetamide, N-(2-hydroxyethyl)acrylamide, or N-(1-hydroxypropan-2-yl)acrylamide.

5. The method for preparing the compound of formula IV according to claim 2, characterized in that, It satisfies one or more of the following conditions: (1) The volume-mass ratio of the solvent to the compound of formula III is 7.8 mL / g or 8.7 mL / g; (2) The molar ratio of the sulfonyl chloride to the compound of formula III is 1.3:1 or 1.4:1; (3) The molar ratio of the sulfonic anhydride to the compound of formula III is 1:1 or 1.1:1; (4) The molar ratio of the base to the compound of formula III is 0.5:1, 1:1, or 1.1:1; and (5) The reaction temperature of the ring-closing reaction is 50°C or 80°C.

6. The method for preparing the compound of formula IV according to claim 3, characterized in that, It satisfies one or more of the following conditions: (1) The halogenated hydrocarbon solvent is dichloromethane; (2) The alkali metal carbonate is sodium carbonate and / or potassium carbonate; (3) The alkali metal bicarbonate is sodium bicarbonate; (4) The alkali metal phosphate is potassium phosphate and / or sodium phosphate; (5) The alkali metal hydrogen phosphate is disodium hydrogen phosphate and / or dipotassium hydrogen phosphate; (6) The alkali metal hydroxide is sodium hydroxide and / or potassium hydroxide; and (7) In the post-treatment step of the ring-closing reaction, the adjustment is carried out using 10% hydrochloric acid.

7. The preparation method of the compound of formula IV according to any one of claims 1-6, characterized in that, It further includes the following step: in the presence of an organic base, the compound of formula I and the compound of formula II undergo an amine-ester exchange reaction to obtain the compound of formula III; ； wherein, R4 is an alkyl group with 1-6 carbon atoms; R1, R2, and R3 are as described in any one of claims 1-6.

8. The method for preparing the compound of formula IV as claimed in claim 7, wherein, It satisfies one or more of the following conditions: (1) In the amine-ester exchange reaction, R4 is methyl, ethyl, propyl, butyl, or isopropyl; (2) In the amine-ester exchange reaction, the organic base is sodium methoxide and / or sodium ethoxide; (3) In the amine-ester exchange reaction, the molar ratio of the organic base to the compound of formula I is (0.02-0.1):1; (4) In the amine-ester exchange reaction, the molar ratio of the compound of formula I to the compound of formula II is (0.95-1.1):1; (5) The amine-ester exchange reaction is carried out under a protective gas; (6) The reaction temperature of the amine-ester exchange reaction is 0-30°C; The feeding method of the amine transesterification reaction is as follows: Mix the compound of Formula II with the organic base to obtain a mixture, and then add the compound of Formula I to the mixture at -5 °C to 0 °C; and (8) The amine transesterification reaction includes the following post-treatment steps: Concentrate, wash, separate the liquid, and dry the reaction solution after the reaction is completed.

9. The method for preparing the compound of formula IV as claimed in claim 8, characterized in that, It satisfies one or more of the following conditions: (1) In the amine transesterification reaction, R4 is methyl; (2) The compound of Formula I is methyl acrylate or methyl acetate; (3) In the amine transesterification reaction, the compound of Formula II is ethanolamine, aminopropanol, or 2,2-dimethyl ethanolamine; (4) In the amine transesterification reaction, the molar ratio of the organic base to the compound of Formula I is (0.04 - 0.1):1; (5) In the amine transesterification reaction, the molar ratio of the compound of Formula I to the compound of Formula II is 1:1; (6) In the amine transesterification reaction, the protective gas is nitrogen, argon, or helium; (7) The reaction temperature of the amine transesterification reaction is 15 °C; and (8) In the feeding method of the amine transesterification reaction, the addition is dropwise addition.

10. The preparation method of the compound of formula IV as described in claim 9, characterized in that, It satisfies one or more of the following conditions: (1) In the amine transesterification reaction, the compound of Formula II is ethanolamine or aminopropanol; (2) In the amine transesterification reaction, the molar ratio of the organic base to the compound of Formula I is 0.04:1, 0.05:1, or 0.06:1; and (3) In the amine transesterification reaction, the protective gas is nitrogen.

Images