Synthesis method of 3-(3-bromopyridine-4-yl)-5-(chloromethyl)-1, 2, 4-oxadiazole

Abstract

The invention relates to the technical field of organic synthesis, in particular to a synthesis method of 3-(3-bromopyridine-4-yl)-5-(chloromethyl)-1, 2, 4-oxadiazole, which at least comprises the following steps: S1, stirring and dissolving 3-bromo-4-cyanopyridine in an organic solvent A, adding hydroxylamine hydrochloride and triethylamine, stirring for 10-20 minutes, heating to 70-90 DEG C, and carrying out reflux stirring reaction for 2-4 hours, so as to obtain 3-(3-bromopyridine-4-yl)-5-(chloromethyl)-1, 2, 4-oxadiazole; performing post-treatment to obtain a compound A; s2, uniformly stirring the compound A, potassium carbonate and an organic solvent B, dropwise adding chloroacetyl chloride at the temperature of 0 DEG C, stirring and reacting at normal temperature for 2-4 hours after dropwise adding, and performing post-treatment to obtain a compound B; s3, dissolving the compound B in an organic solvent C, heating to 110-130 DEG C, and carrying out reflux reaction for 10-14 hours; and performing post-treatment to obtain a target product. The target product is prepared through a three-step reaction path, the yield can reach 69% or above, and the product purity is larger than or equal to 98%.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a synthesis method of 3-(3-bromopyridine-4-yl)-5-(chloromethyl)-1,2,4-oxadiazole. BACKGROUND

[0002] 3-(3-bromopyridine-4-yl)-5-(chloromethyl)-1,2,4-oxadiazole is an important nitrogen-containing heterocyclic compound, and has potential application value in the field of pharmaceutical and pesticide intermediates. However, there is no effective synthesis process of the compound reported at present, and there is a lack of operable reaction path, which leads to the difficulty in preparation and limits the further research and application.

[0003] The synthesis of traditional oxadiazole compounds mostly depends on severe reaction conditions such as high temperature and strong corrosive reagents. For example, the Chinese patent application CN116396237A provides a green synthesis method of oxadiazole compounds, which uses inexpensive inorganic metal additives and green and environmentally friendly inorganic oxidizing agents, avoids the problems of material cost increase caused by the use of ligands and additives, and the problems of separation and purification caused by the use of organic oxidizing agents, but there are still problems such as low yield and poor purity.

[0004] Therefore, it is of great significance to develop a synthesis method of 3-(3-bromopyridine-4-yl)-5-(chloromethyl)-1,2,4-oxadiazole with high yield, high purity and environmental friendliness. SUMMARY

[0005] In order to solve the problems in the prior art, the present application provides a synthesis method of 3-(3-bromopyridine-4-yl)-5-(chloromethyl)-1,2,4-oxadiazole, which at least comprises the following steps:

[0006] S1, stirring and dissolving 3-bromo-4-cyanopyridine in an organic solvent A, adding hydroxylamine hydrochloride and triethylamine, stirring for 10-20 min, and then heating to 70-90 DEG C to reflux and stirring for 2-4 h, and then obtaining compound A through post-treatment;

[0007] S2, stirring the compound A, potassium carbonate and an organic solvent B uniformly, adding chloroacetyl chloride dropwise at 0 DEG C, and then stirring at room temperature for 2-4 h, and then obtaining compound B through post-treatment;

[0008] S3, dissolving the compound B in an organic solvent C, heating to 110-130 DEG C to reflux for 10-14 h, and then obtaining the target product through post-treatment.

[0009] In an embodiment, the organic solvent A is ethanol.

[0010] In an embodiment, the mass-volume ratio of the 3-bromo-4-cyanopyridine and the organic solvent A is 1 g: 8-12 mL. For example, 1 g: 8 mL, 1 g: 9 mL, 1 g: 10 mL, 1 g: 11 mL, 1 g: 12 mL.

[0011] In an embodiment, the molar ratio of the 3-bromo-4-cyanopyridine and hydroxylamine hydrochloride is 1:(3-4).

[0012] In the first step of the present application, the cyano group (-CN) of the 3-bromo-4-cyanopyridine needs to react with hydroxylamine hydrochloride to form an imide structure (compound A). This reaction belongs to nucleophilic addition reaction, and hydroxylamine hydrochloride acts as a nucleophile. In order to promote the complete conversion of the cyano group, hydroxylamine hydrochloride needs to be in excess. The present application limits the molar ratio of 3-bromo-4-cyanopyridine and hydroxylamine hydrochloride to 1:(3-4). By using excess hydroxylamine hydrochloride to fully attack the cyano group, the reaction is promoted to generate compound A, ensuring complete conversion of the raw material. If the amount of hydroxylamine hydrochloride is insufficient, the unreacted cyano group may undergo other side reactions, such as self-polymerization or reaction with other components in the system, generating impurities and reducing the purity of compound A.

[0013] In an embodiment, the molar ratio of the 3-bromo-4-cyanopyridine and triethylamine is 1:(3-4).

[0014] In the first step of the present application, the raw material hydroxylamine hydrochloride needs to be dissociated into free hydroxylamine to undergo nucleophilic addition reaction with the cyano group of 3-bromo-4-cyanopyridine. By limiting the molar ratio of 3-bromo-4-cyanopyridine and triethylamine to 1:(3-4), triethylamine can fully neutralize the hydrochloric acid in the system, ensuring that hydroxylamine hydrochloride is completely dissociated into free hydroxylamine, providing sufficient active reagent for the nucleophilic addition of the cyano group, and avoiding the slow reaction rate caused by insufficient free hydroxylamine, thereby providing high-purity compound A for subsequent reactions.

[0015] In an embodiment, the post-treatment in the S1 step includes: after the reaction is completed, the reaction solution is extracted with saturated brine and ethyl acrylate for 2-3 times, the organic phase is combined, dried, and concentrated to obtain compound A.

[0016] The molecular structure of the compound A is:

[0017]

[0018] In an embodiment, the organic solvent B is dichloromethane.

[0019] In an embodiment, the molar ratio of the compound A and chloroacetyl chloride is 1:(1.7-2). For example, 1:1.7, 1:1.8, 1:1.9, 1:2.

[0020] In the second step of the present application, compound A needs to react with chloroacetyl chloride to generate the ring-opening intermediate compound B. The molar ratio of compound A to chloroacetyl chloride is controlled in the range of 1:(1.7-2). The moderate excess of chloroacetyl chloride can fully react with compound A, promote the forward reaction, ensure the complete conversion of compound A, and reduce the residual raw materials. The moderate excess of chloroacetyl chloride can preferentially react with compound A, reduce the occurrence of side reactions, and thus improve the purity of the ring-opening intermediate and provide high-purity raw materials for the ring-closing reaction in the third step.

[0021] In an embodiment, the post-treatment in the S2 step includes: after the reaction is completed, LCMS and TLC are monitored, ice water and ethyl acrylate are added to the reaction system, white solids are precipitated, and compound B is obtained by filtration and drying.

[0022] The molecular structural formula of the compound B is:

[0023]

[0024] In an embodiment, the organic solvent C is toluene.

[0025] In an embodiment, the post-treatment in the S3 step includes: after the reaction is completed, LCMS and TLC are monitored, water and ethyl acrylate are extracted, and the organic phase is dried and concentrated to obtain the target product 3-(3-bromopyridine-4-yl)-5-(chloromethyl)-1,2,4-oxadiazole.

[0026] The molecular structural formula of the target product 3-(3-bromopyridine-4-yl)-5-(chloromethyl)-1,2,4-oxadiazole is:

[0027]

[0028] In the present application, LCMS and TLC are used to monitor the reaction progress. First, the plate is observed to determine whether there is raw material, and then LCMS detection is performed to ensure that there is no absorption peak of raw material. The LCMS detection is used as a reference to ensure that the reaction is complete.

[0029] Advantages

[0030] 1. By limiting the molar ratio of 3-bromo-4-cyanopyridine to hydroxylamine hydrochloride to 1:(3-4) and the molar ratio of 3-bromo-4-cyanopyridine to triethylamine to 1:(3-4), the present application can ensure complete conversion of raw materials, improve reaction rate, and improve purity of the target product.

[0031] 2. By controlling the molar ratio of compound A to chloroacetyl chloride in the range of 1:(1.7-2), the present application can reduce the occurrence of side reactions, ensure complete conversion of compound A, and provide high-purity raw materials for the ring-closing reaction in the third step.

[0032] 3、The three-step reaction path of the application is reasonable in design: first, hydroxylamine hydrochloride, triethylamine and 3-bromo-4-cyanopyridine are reacted to generate the corresponding imide, then the imide is reacted with chloroacetyl chloride under alkaline conditions to generate the ring-opened intermediate, and finally the ring is closed under the condition of refluxing toluene to obtain the target product 3-(3-bromopyridine-4-yl)-5-(chloromethyl)-1,2,4-oxadiazole; the yield can reach more than 69%, and the product purity is ≥98%.

[0033] 4、The reaction condition of the application is mild, the solvents used are low in toxicity and can be recycled, and meet the requirements of green chemical industry.

[0034] 5、The synthesis method provided by the application is easy to operate and suitable for large-scale production. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 It is the reaction equation diagram of Example 1 of the application.

[0036] Figure 2 It is the nuclear magnetic hydrogen spectrum diagram of the sample prepared in Example 1.

[0037] Figure 3 It is the GC-MS spectrum diagram of the sample prepared in Example 1. DETAILED DESCRIPTION

[0038] In order to make the purpose, technical scheme and advantages of the application clearer, the application is further described in detail below in combination with examples and drawings. It should be understood that the specific examples described herein are only used to explain the application and not to limit the application. The experimental methods not specified in the examples are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments not specified by the manufacturer are all conventional products that can be purchased on the market.

[0039] Example 1

[0040] The present embodiment provides a synthesis method of 3-(3-bromopyridine-4-yl)-5-(chloromethyl)-1,2,4-oxadiazole, comprising the following steps:

[0041] S1, 26g of 3-bromo-4-cyanopyridine (1eq) was dissolved by stirring in 250mL of ethanol, 29.62g of hydroxylamine hydrochloride (3eq) and 43.13g of triethylamine (3eq) were added, and after stirring for 10min, the temperature was raised to 80℃ and refluxed for 3h, LCMS and TLC were used to monitor the completion of the reaction, the reaction liquid was extracted with saturated brine and ethyl acrylate for 2-3 times, the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated to obtain compound A;

[0042] S2, 27 g of the compound A (1 eq), 23.58 g of potassium carbonate (1.5 eq) and 200 mL of dichloromethane were stirred uniformly, 16.282 mL of chloroacetyl chloride (1.8 eq) was added dropwise at 0°C, after the dropwise addition was completed, the reaction was stirred at room temperature for 3 h, after the reaction was completed, the reaction system was extracted with ice water and ethyl acrylate, white solid was precipitated, and the compound B was obtained by filtration and drying;

[0043] S3, 25 g of the compound B was dissolved in 200 mL of toluene, and the reaction was refluxed at 120°C for 12 h; after the reaction was completed, the reaction system was extracted with water and ethyl acrylate, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 3-(3-bromopyridin-4-yl)-5-(chloromethyl)-1,2,4-oxadiazole.

[0044] The yield of 3-(3-bromopyridin-4-yl)-5-(chloromethyl)-1,2,4-oxadiazole prepared in this example was 69.76%, and the purity was 99%.

[0045] Figure 1 The reaction equation of this example 1 is shown in the figure; the nuclear magnetic hydrogen spectrum of 3-(3-bromopyridin-4-yl)-5-(chloromethyl)-1,2,4-oxadiazole is shown in Figure 2 : 1 H NMR (400 MHz, DMSO) δ 8.87 (s, 1H), 8.66 (d, J = 4.8 Hz, 1H), 7.53 (d, J = 4.8 Hz, 1H), 7.28 (s, 2H), 4.52 (s, 2H);

[0046] The GC-MS spectrum is shown in Figure 3 .

[0047] Example 2

[0048] The specific implementation of this example is the same as that of example 1, except that the equivalent of chloroacetyl chloride in S2 is 2.0 eq.

[0049] The yield of 3-(3-bromopyridin-4-yl)-5-(chloromethyl)-1,2,4-oxadiazole prepared in this example was 69%, and the purity was 98%.

[0050] Comparative Example 1

[0051] The specific implementation of this example is the same as that of example 1, except that the equivalent of chloroacetyl chloride in S2 is 2.0 eq.

[0052] The yield of 3-(3-bromopyridin-4-yl)-5-(chloromethyl)-1,2,4-oxadiazole prepared in this example was 69%, and the purity was 98%.

[0053] Comparative Example 2

[0054] The specific implementation of the present comparative example is the same as that of Example 1, except that the S1 step is: 26 g of 3-bromo-4-cyanopyridine (1 eq) is stirred and dissolved in 250 mL of ethanol, 29.62 g of hydroxylamine hydrochloride (3 eq) and 43.13 g of triethylamine (3 eq) are added, and after stirring for 10 min, the reaction is stirred at 50°C under reflux for 3 h. The reaction is not complete, and the purification is not clean, so the subsequent step cannot be carried out.

[0055] Comparative Example 3

[0056] The specific implementation of the present comparative example is the same as that of Example 1, except that the equivalent of hydroxylamine hydrochloride in S1 is 2.5 eq.

[0057] The S1 step of the present example is not complete, the purification is not clean, and the subsequent step cannot be carried out.

[0058] Comparative Example 4

[0059] The specific implementation of the present comparative example is the same as that of Example 1, except that the equivalent of chloroacetyl chloride in S2 is 1.6 eq.

[0060] In the S2 step of the present example, the amount of chloroacetyl chloride is insufficient, and the reaction time needs to be extended to 12 h. The impurities increase, and after purification, there is a large loss, the yield is reduced, and the yield of 3-(3-bromopyridin-4-yl)-5-(chloromethyl)-1,2,4-oxadiazole prepared is 57.2%, with a purity of 98%.

[0061] Comparative Example 5

[0062] The specific implementation of the present comparative example is the same as that of Example 1, except that the S3 step is: 25 g of the compound B is dissolved in 200 mL of toluene, and the temperature is raised to 100°C under reflux for 24 h; after the reaction is completed, it is extracted with water and ethyl acrylate, and the organic phase is dried over anhydrous sodium sulfate and concentrated to obtain 3-(3-bromopyridin-4-yl)-5-(chloromethyl)-1,2,4-oxadiazole.

[0063] In the S3 step of the present example, the ring closure temperature is reduced to 100°C, and the reaction time needs to be extended to 24 h. The efficiency and yield are reduced, and the yield of 3-(3-bromopyridin-4-yl)-5-(chloromethyl)-1,2,4-oxadiazole prepared is 62.3%, with a purity of 98%.

Claims

1. A method for the synthesis of 3-(3-bromopyridin-4-yl)-5-(chloromethyl)-1,2,4- oxadiazole, characterized in that, At least comprising the following steps: S1, stirring and dissolving 3-bromo-4-cyanopyridine in organic solvent A, adding hydroxylamine hydrochloride and triethylamine, stirring for 10-20 min, then heating to 70-90℃ and refluxing for 2-4 h, and then treating to obtain compound A; S2, stirring the compound A, potassium carbonate and organic solvent B uniformly, adding chloroacetyl chloride dropwise at 0℃, stirring at room temperature for 2-4 h after dropping, and then treating to obtain compound B; S3, dissolving the compound B in organic solvent C, heating to 110-130℃ and refluxing for 10-14 h, and then treating to obtain the target product.

2. The method of synthesis of claim 1, wherein, The organic solvent A is ethanol.

3. The method of synthesis of claim 2, wherein, The mass-volume ratio of 3-bromo-4-cyanopyridine to organic solvent A is 1g:8-12mL.

4. The method of synthesis of claim 3, wherein, The molar ratio of 3-bromo-4-cyanopyridine to hydroxylamine hydrochloride is 1:(3-4).

5. The method of synthesis of claim 4, wherein, The molar ratio of 3-bromo-4-cyanopyridine to triethylamine is 1:(3-4).

6. The method of synthesis of claim 1, wherein, The post-treatment in the S1 step comprises: after monitoring the reaction completion by LCMS and TLC, extracting the reaction liquid with saturated brine and ethyl acrylate for 2-3 times, combining the organic phase, drying, and concentrating to obtain compound A.

7. The method of synthesis of claim 1, wherein, The organic solvent B is dichloromethane.

8. The method of synthesis of claim 1, wherein, The molar ratio of compound A to chloroacetyl chloride is 1:(1.7-2).

9. The method of synthesis of claim 1, wherein, The post-treatment in the S2 step comprises: after monitoring the reaction completion by LCMS and TLC, adding ice water and ethyl acrylate to the reaction system, precipitating white solid, and then filtering and drying to obtain compound B.

10. The method of synthesis of claim 1, wherein, The post-treatment in the S3 step comprises: after monitoring the reaction completion by LCMS and TLC, extracting with water and ethyl acrylate, and then drying and concentrating the organic phase to obtain the target product 3-(3-bromopyridin-4-yl)-5-(chloromethyl)-1,2,4-oxadiazole.

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