Tyclopyrazoflor is a pesticide developed for sap-sucking pests reported by the American company Corteva in 2013. This article mainly conducts a detailed study on the synthesis of the mother core structure (compound 4 ). The construction of the mother core is mainly constructed through the Ullmann reaction , but performing the Ullmann reaction at different stages has an impact on the overall yield and the stability of the process. It has a huge impact. This article discovered an optimal route through the study of Ullmann reaction at different stages and completed the scale-up production of 50kg .
As shown in Scheme 2 , the original process is to obtain the final product through 7-step reactions, in which the construction of the mother core is through a 3+2 cycloaddition reaction . The overall yield is okay, but with further route development, some of them The problem was also exposed:
- The main raw material 2 is 3-aminopyridine, which is obtained by diazotization and then reduction. The diazotization reaction is risky during the amplification process . Since compound 2 has good solubility in water, there are also difficulties in the separation and purification of compound 2 . Small problem .
- The fourth step reaction is nitrification reaction, which is also not an ideal reaction in industry and requires high equipment .
- The last step uses ethyl iodide and cesium carbonate, which are relatively expensive and pose a greater challenge to reducing subsequent larger-scale production costs. At the same time, because the last step reacts under strong alkaline conditions, both raw materials and products will Two impurities, 12 and 13 , are obtained through elimination . The removal of these two impurities in the final product is also quite challenging .
Based on the above problems, the customer developed three new routes, all of which are based on the Ullmann reaction to build the mother core ( Scheme 3 ).
Early Ullmann reaction builds the mother core
As shown in Scheme 4 , placing the Ulm ann reaction as the first step in the route has the advantage that the raw materials are cheap and available in large quantities. The first step of the Ullmann reaction does not require the addition of external ligands. The raw material 3-aminopyrazole itself can also be used as a ligand. In this step, 85% of the product is controlled, but the final yield is low because ~ will be produced during the reaction. 10% isomer impurities lead to low overall yield in the subsequent purification process. In the second step, the Sandmeyer reaction uses sodium nitrite to first convert the amino group into a diazonium salt, and then adds copper chloride to obtain the chlorinated product. The three or four steps of nitrification and reduction also gave good results, and the subsequent steps were the same as the original route. Therefore, this route only solves the problem of the price and availability of the initial raw materials. The subsequent reactions also involve diazonium salts and nitration reactions , and there are still safety risks.
The mid-stage Ullmann reaction builds the mother core
As shown in Scheme 5 , the raw material 4-nitropyrazole was subjected to Pd-catalyzed reductive chlorination in one step to obtain compound 22 , with a yield greater than 80% and a product purity greater than 99%. The second step is a simple acetylation reaction, but during the research process, it was found that this step can easily produce impurities in the acetylation of imidazole N. By adding inorganic base and water, side reactions can be effectively suppressed, with higher yield and purity. Compound 18 was obtained . For compound 18 , the author also hoped to try the method of acetylation using 4-aminoimidazole as the raw material, and then chlorination on NCS. However, during the first step of acetylation, it was found that the main product was a diacetylated product. By adjusting the equivalent , solvents and bases all achieved good results and were therefore abandoned.
For the third step of the Ullmann reaction, a good yield was obtained through simple condition screening, and the product purity was greater than 97%, and multiple batches were scaled up to 50kg. Then the fourth step is a critical step. Here, the acetyl group is directly reduced to build the ethyl group, which avoids various problems of the previous alkylation step . The last step of amide condensation using an inorganic base and a methylene chloride/water system can achieve a good conversion and good yield.
The late stage Ullmann reaction builds the mother core
The author tried two routes to construct the mother core through Ullmann reaction in the later stage. The starting materials of route a and route b are the same. The only difference is whether to alkylate N first or to build amide bond first. For route a, the biggest problem lies in the step of amide construction. The yield of this step is less than 50%, so this route was abandoned. For route b, the inherent alkylation problem in the last step is not solved, and the yield of the Ullmann reaction after the amide condensation is significantly reduced, only 53%, so it is not suitable for later amplification.
When designing a route, the same strategy may have a great impact on the difficulty and efficiency of synthesis due to the sequence of reactions. The author conducts a comprehensive evaluation of routes using Ullmann reaction at different stages from the perspectives of cost control , process stability , and safety. An optimal route was selected and multiple batches of 50kg were scaled up.
Xiaoyong Li et al. Org. Process Res. Dev. 2022 , 26 , 3290−3302.