A preparation method of 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole

Abstract

The present invention belongs to the field of compound synthesis, and in particular to a preparation method of 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazoles. The preparation method comprises the following steps: first reacting trifluoroacetylhydrazine, chloroacetyl chloride, an acid binding agent and a first solvent, removing the solvent after the reaction is completed, and recrystallizing to obtain an intermediate compound; then the intermediate compound is mixed with a dehydrating agent and a photosensitizer, and a cyclization reaction is performed under the action of blue light to obtain the obtained product. The synthetic method of 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazoles provided by the present invention, by optimizing the reaction process, reaches a target product with relatively ideal yield and purity, and its reaction conditions are mild and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of compound synthesis, and particularly relates to a method for preparing 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole. Background Art

[0002] Heterocyclic compounds such as pyrimidine, pyrrole, thiazole, oxazole and imidazole and their derivatives have been widely used in medicine, agriculture and materials due to their high biological activity, and have gradually attracted the attention of chemists.

[0003] 1,3,4-oxadiazole compounds and their derivatives are an extremely important class of five-membered heterocyclic compounds. Many drugs contain 1,3,4-oxadiazole fragments in their structures. For example, the antibiotic furamizole, the antihypertensive drug tiodazosin, and the AIDS drug Raltegravir all contain 1,3,4-oxadiazole fragments.

[0004] In addition, 1,3,4-oxadiazole compounds and their derivatives have excellent luminescence and electron transport properties and have been successfully applied in scintillation counting materials and coatings industries. They also have good thermal and chemical stability and are widely studied and applied in electron transport materials.

[0005] Therefore, the synthesis of such compounds is of vital importance. Currently, there are three main routes for synthesizing such compounds:

[0006] First, the dihydrazide cyclization method is used, which requires a dehydrating agent and a relatively high temperature, such as phosphorus oxychloride, phosphorus pentoxide, thionyl chloride, polyphosphoric acid, etc., which is not environmentally friendly.

[0007] The second method is to oxidize N-acylaldehyde hydrazone, but this type of reaction requires aldehydes as raw materials, and most aldehyde compounds are highly toxic, which limits their application.

[0008] The third method is to synthesize aldazine with aromatic aldehyde and hydrazine hydrate as raw materials, and then oxidize and cyclize the aldazine to generate 2,5-disubstituted-1,3,4-oxadiazole compounds. The reaction is time-consuming and complicated.

[0009] The preparation methods disclosed in the prior art are relatively expensive, and the reaction time is generally long, and the yield needs to be further improved. Therefore, developing a preparation method with faster reaction, greenness, high yield and high purity is an urgent problem to be solved in this field. Summary of the Invention

[0010] The present invention addresses the problems existing in the prior art and provides a method for preparing 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole. The method has readily available raw materials, mild reaction, high yield, high purity, and is suitable for industrial production.

[0011] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0012] A method for preparing 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole comprises the following steps:

[0013] (1) Trifluoroacetylhydrazine, chloroacetyl chloride, and an acid-binding agent are mixed and reacted. After the reaction is completed, water is added, the layers are separated, and the organic phase is removed from the solvent and recrystallized to obtain an intermediate;

[0014] (2) The intermediate is mixed with aluminosilicate and a photosensitizer, and reacted under the action of blue light to obtain the product.

[0015] Preferably, the molar ratio of trifluoroacetylhydrazine, chloroacetyl chloride and acid binding agent in step (1) is 0.5-1.2:0.5-1.2:0.1-10; preferably 0.8-1.2:0.8-1.2:0.1-8; preferably 0.8-1.2:0.8-1.2:0.5-5; preferably 0.8-1.2:0.8-1.2:0.5-1.2.

[0016] Preferably, the solvent for the reaction in step (1) is selected from one or more of ethyl acetate, dichloromethane, and methyl isobutyl ketone;

[0017] Preferably, the acid binding agent is sodium bicarbonate or lithium carbonate.

[0018] Preferably, the solvent for the recrystallization in step (1) is a mixed solvent of n-heptane acetone and ethyl acetate in a volume ratio of 0.5-1.5:1:1.

[0019] Preferably, the recrystallization in step (1) is performed by adding a solvent dropwise, first heating the mixture to 30-35°C with stirring, then cooling the mixture to -5-0°C and keeping the temperature for 20-50 minutes, then cooling the mixture to -8-10°C and keeping the temperature for 1-2 hours, and filtering the mixture to obtain a solid.

[0020] Preferably, the solvent for the reaction in step (2) is dichloromethane, dichloroethane or 1,4-dioxane.

[0021] Preferably, the photosensitizer in step (2) is an acridinium salt.

[0022] Preferably, the mass ratio of the aluminosilicate to the intermediate in step (2) is 1:3-6.

[0023] Preferably, the blue light irradiation time is 1-3 hours.

[0024] Preferably, the molar ratio of the intermediate compound to the photosensitizer is 1:0.01-0.1.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] (1) The method for synthesizing 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole provided by the present invention achieves the target product with relatively ideal yield and purity by optimizing the reaction process. The reaction conditions are mild and suitable for industrial production.

[0027] (2) The present invention further improves the yield and purity of the product by selecting sodium bicarbonate and lithium carbonate as the acidifying agent, determining the recrystallization reagent, optimizing the recrystallization process, and controlling the reaction conditions.

[0028] (3) The cyclization reaction of the present invention does not require the addition of phosphorus oxychloride, which is highly polluting to the environment. Aluminosilicate is used as both an inorganic support and a catalyst. The reaction is rapidly and efficiently promoted by blue light irradiation. The post-processing of the reaction product is simple, and conventional filtration and distillation are directly performed. The operation is simple and has good application prospects. DETAILED DESCRIPTION

[0029] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work are within the scope of protection of the present invention. In addition, it is worth noting that the raw materials and processes involved in the present invention are all common commercially available products and processes unless otherwise specified.

[0030] Example 1

[0031] (1) To a 1000 mL three-necked flask, add 450 mL of dichloromethane, 113 g of chloroacetyl chloride, 128 g of trifluoroacetylhydrazine, and 86 g of sodium bicarbonate, respectively. Stir at room temperature and react for 1 h. Add 150 mL of water to separate the layers. Take the organic phase and distill under reduced pressure to remove the solvent to obtain a crude product. Add 1 amount of a mixed solvent of n-heptane, acetone, and ethyl acetate in a volume ratio of 0.5:1:1 to the crude product. First, heat to 35 ° C and stir to fully dissolve. Then cool to 0 ° C and keep warm for 30 min. Then cool to -8 ° C and keep warm for 1 h. Filter and dry at 55 ° C to obtain the intermediate. The yield is 99.2% and the purity is 99.8%.

[0032] (2) 180 g of the above intermediate and 450 ml of dichloromethane were added to a three-necked flask in sequence, and then 50 g of aluminosilicate (Guangzhou Changyu Chemical Co., Ltd., sodium aluminosilicate powder) was poured into the three-necked flask. 0.05 mol of photosensitizer acridinium salt (NSP-SA-NHS) was added and mixed. The mixture was irradiated under 12 W blue light at room temperature and stirred for 2 h. Dehydration and cyclization reaction occurred. After the reaction was completed, the mixture was filtered and vacuum distilled to obtain the product.

[0033] Example 2

[0034] (1) To a 1000 mL three-necked flask, add 400 mL of dichloromethane, 113 g of chloroacetyl chloride, 128 g of trifluoroacetylhydrazine, and 52 g of sodium bicarbonate, respectively. Stir at room temperature and react for 2 h. Add 100 mL of water to separate the layers. Take the organic phase and remove the solvent by vacuum distillation to obtain a crude product. Add 1 times the amount of a mixed solvent of n-heptane, acetone, and ethyl acetate in a volume ratio of 1:1:1 to the crude product. First, heat to 30 ° C and stir to fully dissolve. Then cool to -5 ° C and keep warm for 50 min. Then cool to -8 ° C and keep warm for 1 h. Filter and dry at 50 ° C to obtain the intermediate. The yield is 98.5% and the purity is 99.7%.

[0035] (2) 200 g of the above intermediate and 400 ml of dichloromethane were added to a three-necked flask in sequence, and then 45 g of aluminosilicate (Guangzhou Changyu Chemical Co., Ltd., sodium aluminosilicate powder) was poured into the three-necked flask. 0.06 mol of photosensitizer acridinium salt (NSP-SA-NHS) was added and mixed. The mixture was irradiated under 12 W blue light at room temperature and stirred for 2 h. Dehydration and cyclization reaction occurred. After the reaction was completed, the mixture was filtered and vacuum distilled to obtain the product.

[0036] Example 3

[0037] (1) To a 1000 mL three-necked flask, add 450 mL of dichloromethane, 113 g of chloroacetyl chloride, 128 g of trifluoroacetylhydrazine, and 50 g of lithium carbonate, respectively. Stir at room temperature and react for 1 h. Add 150 mL of water to separate the layers. Take the organic phase and distill under reduced pressure to remove the solvent to obtain a crude product. Add 1 times the amount of a mixed solvent of n-heptane, acetone, and ethyl acetate in a volume ratio of 1.5:1:1 to the crude product. First, heat to 35 ° C and stir to fully dissolve. Then cool to 0 ° C and keep warm for 20 min. Then cool to -10 ° C and keep warm for 1 h. Filter and dry at 40 ° C to obtain the intermediate. The yield is 98.9% and the purity is 99.6%.

[0038] (2) 200 g of the above intermediate and 450 ml of dichloromethane were added to a three-necked flask in sequence, and then 50 g of aluminosilicate (Guangzhou Changyu Chemical Co., Ltd., sodium aluminosilicate powder) was poured into the three-necked flask, and 0.05 mol of a photosensitizer acridinium salt (NSP-SA-NHS) was added and mixed. Under a blue light with a power of 12 W, the mixture was irradiated at room temperature and stirred for 1 h. Dehydration and cyclization reaction occurred. After the reaction was completed, the mixture was filtered and vacuum distilled to obtain the product. The yield was 92.1%, and the liquid phase purity was determined to be 98.5%.

[0039] Example 4

[0040] (1) To a 1000 mL three-necked flask, add 450 mL of dichloromethane, 113 g of chloroacetyl chloride, 128 g of trifluoroacetylhydrazine, and 50 g of lithium carbonate, respectively. Stir at room temperature and react for 1 h. Add 150 mL of water to separate the layers. Take the organic phase and remove the solvent by vacuum distillation to obtain a crude product. Add 1 amount of a mixed solvent of n-heptane, acetone, and ethyl acetate in a volume ratio of 0.5:1:1 to the crude product. First, heat to 30 ° C and stir to fully dissolve. Then cool to 0 ° C and keep warm for 50 min. Then cool to -8 ° C and keep warm for 2 h. Filter and dry at 55 ° C to obtain the intermediate. The yield is 98.3% and the purity is 99.5%.

[0041] (2) 200 g of the above intermediate and 450 ml of dichloromethane were added to a three-necked flask in sequence, and then 35 g of aluminosilicate (Guangzhou Changyu Chemical Co., Ltd., sodium aluminosilicate powder) was poured into the three-necked flask. 0.03 mol of photosensitizer acridinium salt (NSP-SA-NHS) was added and mixed. The mixture was irradiated under 12 W blue light at room temperature and stirred for 2 h. Dehydration and cyclization reaction occurred. After the reaction was completed, the mixture was filtered and vacuum distilled to obtain the product.

[0042] Comparative Example 1

[0043] The difference between this comparative example and Example 1 is that the acid binding agent is magnesium carbonate.

[0044] Comparative Example 2

[0045] The difference between this comparative example and Example 1 is that the recrystallization step is different. The temperature is first raised to 45 ° C and stirred to fully dissolve, then cooled to -10 ° C and kept warm for 2h, filtered, and dried at 55 ° C to obtain the intermediate.

[0046] Comparative Example 3

[0047] The difference between this comparative example and Example 1 is that the recrystallization step is different, and a 0.5:2 mixed solvent of n-heptane and acetone is used for recrystallization.

[0048] Comparative Example 4

[0049] The difference between this comparative example and Example 1 is that the recrystallization step is different, and a 0.5:2 mixed solvent of n-heptane and ethyl acetate is used for recrystallization.

[0050] Comparative Example 5

[0051] The difference between this comparative example and Example 1 is that the aluminosilicate is removed and an equal amount of acidic alumina is added.

[0052] Comparative Example 6

[0053] The difference between this comparative example and Example 1 is that the aluminosilicate is removed and an equal amount of silicate (sodium orthosilicate, Jinan Liangfeng Trading Co., Ltd.) is added.

[0054] The yield and purity of the product 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole finally prepared in the above examples and comparative examples are shown in Table 1.

[0055] Table 1

[0056] Group Yield % purity% Example 1 97.0 99.6 Example 2 95.6 99.1 Example 3 92.3 98.5 Example 4 94.7 98.2 Comparative Example 1 92.9 97.7 Comparative Example 2 85.7 94.0 Comparative Example 3 83.3 88.2 Comparative Example 4 91.0 94.4 Comparative Example 5 58.2 79.0 Comparative Example 6 84.6 98.9

[0057] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing 5-chloromethyl-2-trifluoromethyl-1,3,4-oxadiazole, comprising the following steps: (1) Trifluoroacetylhydrazine, chloroacetyl chloride, and an acid-binding agent are mixed and reacted. After the reaction is completed, water is added, the layers are separated, and the organic phase is removed from the solvent and recrystallized to obtain an intermediate; (2) The intermediate is mixed with aluminosilicate and a photosensitizer, and reacted under the action of blue light to obtain the product.

2. The preparation method according to claim 1, characterized in that The molar ratio of trifluoroacetylhydrazine, chloroacetyl chloride and acid binding agent in step (1) is 0.5-1.2:0.5-1.2:0.1-10.

3. The preparation method according to claim 1, characterized in that The solvent for the reaction in step (1) is selected from one or more of ethyl acetate, dichloromethane, and methyl isobutyl ketone; and the acid binding agent is sodium bicarbonate or lithium carbonate.

4. The preparation method according to claim 1, characterized in that The solvent for the recrystallization in step (1) is a mixed solvent of n-heptane acetone and ethyl acetate in a volume ratio of 0.5-1.5:1:

1.

5. The preparation method according to claim 1, characterized in that The recrystallization in step (1) is as follows: after adding the solvent dropwise, first heating to 30-35°C and stirring, then cooling to -5-0°C and keeping warm for 20-50 minutes, then cooling to -8--10°C and keeping warm for 1-2 hours, and filtering to obtain the solid.

6. The preparation method according to claim 1, characterized in that The solvent for the reaction in step (2) is dichloromethane, dichloroethane or 1,4-dioxane.

7. The preparation method according to claim 1, characterized in that The photosensitizer in step (2) is an acridinium salt.

8. The preparation method according to claim 1, characterized in that The mass ratio of the aluminosilicate to the intermediate in step (2) is 1:3-6.

9. The preparation method according to claim 1, characterized in that The blue light irradiation time is 1-3 hours.

10. The preparation method according to claim 1, characterized in that The molar ratio of the intermediate compound to the photosensitizer is 1:0.01-0.1.