The active ingredient in the preparation, API, is intended to be used in any substance or mixture of substances in the manufacture of pharmaceuticals. Pharmaceutical intermediates are important raw materials for the production of APIs. The production of drugs can rely on the custom synthesis of intermediates. After the synthesis of APIs, mid-scale and industrialized mass production should also be considered. Often a drug can find multiple process routes. When preparing kilogram-level drug candidates and active ingredients, it is necessary to screen efficient API and intermediate process R&D routes to ensure the speed of drug R&D and save R&D costs.
Generally speaking, according to the development stage of drug development, the process route is generally divided into the emergency route at the initial stage of drug screening and the cost-effective route for formal drug development. The emergency route refers to the period during which the drug efficacy evaluation and the feasibility experiment of the compound are carried out. Due to the tight time, the small demand for API and intermediates, and the unclear development prospects, it only needs to get the target in the shortest time and in the shortest steps. Product, the route at this time often does not need to consider yield and cost. In the period of formal drug development and project approval, a large number of products need to be provided, and an optimal route that is low-cost and easy to scale-up is developed, which is an economic and effective route.
The following points should be paid attention to in the selection of economic and effective routes of API and intermediates:
(1) The route chosen must be technically feasible
After the API is produced through customized synthesis of intermediates, the subsequent scale-up production of the API may be required. The route of scale-up production is a reliable process. A reliable process requires certain key parameters, including feeding amount, feeding time, reaction time, temperature, insufficient and excessive materials, reaction and post-treatment pH, etc., so the most It is better to choose the condition of flat-top type, that is, to provide products of expected quality and yield within a relatively wide operating range. Sometimes the selected parameters are point conditions, so the production process in the workshop must be strictly monitored.
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(2) The selected route should have suitable and available equipment
The route selection should give priority to existing equipment, but some special reactions may involve proprietary equipment.
(3) Pay attention to the patent protection of production routes
Anyone who uses the materials and processes described in the patents of others must be authorized according to law, otherwise they will be prosecuted for infringement. In order to avoid helping competitors, some companies will not disclose the optimal process, but some details provided by the patent may be helpful for the development of similar compound processes. If the route of active pharmaceutical ingredients and key intermediates are protected by patents, we must develop new routes to circumvent patent protection.
(4) Long-term availability of cheap raw materials and reagents
Avoid a single supplier and ensure that there are multiple sources and suppliers of key raw materials, reagents and intermediates. In addition, the quality and price of the materials are equally important. Prices depend on market demand, and suppliers of outsourced products must also be reliable.
(5) Choice of convergence route
Convergent reaction means that an intermediate is split into two or one sub-parts and synthesized separately, and finally the intermediate is obtained from the sub-parts. Compared with the linear reaction, the convergent reaction will greatly increase the yield of the entire route, reduce the amount of intermediates used, and reduce the cost. At the same time, the intermediate cost in the middle and late stages of the linear reaction is high, and the operation risk is high, and the convergent reaction effectively reduces this shortcoming. The disadvantage of the convergent reaction is the addition of one or more intermediates.
(6) Use compressed post-processing
Separation of intermediates will cause material loss and increase costs. Therefore, in addition to the purification of key intermediates, we can appropriately compress to avoid separation. The product is directly put into the next reaction without separation, and proper compression can greatly increase the total yield.
(7) Minimize the impact of protecting groups
According to the consideration of atom economy, the introduction and removal of protecting groups increase the cost, so we should try to reduce the number of protecting groups. When a protecting group must be used, we should choose a protecting group with a lower unit molar cost and the least possible introduction and removal cost, and the steric influence of the protecting group should also be considered. Compared with traditional chemistry, enzyme-catalyzed reactions can effectively avoid protecting groups.
(8) Minimization of steps
Design the shortest step reaction route or optimize the reaction process, and multiple reaction steps are carried out by one-pot method.
(9) Avoid adjustment of oxidation state
Adjusting the oxidation state of the compound will greatly increase the cost and labor, so the compound in the proper oxidation state is beneficial to the establishment of the synthetic route. But sometimes in order to achieve the best yield, we still have to adjust the oxidation state appropriately.
(10) Corresponding to specific and three-dimensional specific responses
Resolution of corresponding isomers will greatly reduce the yield, so the corresponding specific and stereospecific reactions should be arranged in the early stage of the reaction route as much as possible.
(11) Use accidental discovery
Pay attention to details and develop reasonable and effective processes through unexpected discoveries. For example, reactions that occur at large steric hindrance sites can eliminate the use of protective groups.
(12) Use rearrangement reaction
Rearrangement is a key chemical method that highly controls the stereochemistry and regioselectivity of small molecules.
(13) Common terminal intermediates and key intermediates
The characterization of the terminal intermediates and key intermediates of drugs is very important. The different routes formed by process research often gather at the terminal and key intermediates.
(14) Simple rework of final products and intermediates
The economical and effective route should include rework procedures for unqualified products, generally after recrystallization, beating, and re-separation, and column chromatography should be avoided as much as possible.
(15) Minimize environmental impact
Reducing environmental impact is becoming more and more important. We can measure its “greenness” through the atomic economy of the process route, the ecological efficiency, and the quantity of the three wastes. The traditional method of reducing the three wastes is less solvent usage, volatilization and better recovery and recycling of solvents. A greener approach is to minimize the use of three wastes at the source.
In the end, cost accounting can be used to evaluate the final API and intermediate process R&D and production routes. The cost estimate can show which types of costs contribute to the product, and where optimization needs to be made, including the cost of raw materials and the quality of products of qualified quality. The yield and the total amount of intermediates required per kilogram of product also include production capacity, processing costs, the amount of raw and auxiliary materials recovered and recycled, and sometimes fixed expenses and labor costs need to be calculated. On this basis, consider the characteristics of each route and select a reliable process.