Three Mountains of Synthetic R&D

Synthetic research and development is a systematic and logical work, and it is a work with strong practicality. The author believes that synthetic research and development can be divided into three stages, and you can take your seats.

The scope of this discussion is only for the chemical synthesis of small molecule APIs and their intermediates.

The first stage: Design the synthesis route, open up the route, fish out the qualified products, the cost meets the market requirements, and the customer's acceptance is passed.

The second stage: successful scale-up, stable commercial production.

The third stage: After in-depth research, the craftsmanship will be the first in the world.

Every stage has its best people.

For example, the first stage:

There are many excellent synthesis masters in China, who check data, screen synthesis routes, or create a completely new synthesis route. They were able to develop the target product in the shortest time, including the structural identification of each impurity, the confirmation of the analytical method, and the relatively reasonable work-up plan. To be the best in the first stage, you need a solid basic experimental skills, a solid theoretical foundation in chemistry, and a solid ability to consult literature. According to the law of 28, through continuous efforts, the author estimates that 20% of scientific researchers can reach this stage. The author has seen that there are many excellent experimental workers who stay complacent in the first stage and stagnate. Including many excellent scientists who founded their own businesses.

For example, the second stage:

After doing tens of thousands of experiments on the production line, the author put forward an advanced theory at the end of 2017: in the factory, the only criterion for measuring the level of experimenters is to scale up production. And get complacent about it!

In order to reach the second stage, the requirements for scientific researchers have been greatly increased. There are very few outstanding people who have reached this level. The author often meets a variety of training experts, and also understands their experiences. This type of person is generally in the elite class of the country and plays a pivotal role in their gestures. When they see a molecular structure, they basically know how to synthesize it, how much the raw materials cost, what problems will occur in the production process, and how to solve them. They have many obvious common characteristics, that is, they have done a lot of projects, usually more than 50. The types of responses they do are also very varied. Generally, they are in high positions, or they are their own bosses, or they are the technical leaders of the enterprise. The author believes that there are actually relatively few types of chemical reactions, that is, several common functional groups change.

The second stage involves more and more intensive knowledge in terms of safety management, environmental protection of three wastes, and engineering equipment. Especially in terms of equipment, we want to ensure 100% success in scale-up. It requires scientists to be proficient in all the performance of various types of equipment and all the differences from the small test.

Here are three common examples of scale-up production:

1. For example, let’s talk about heat release, which is a common problem and accidents often occur. When a small test of 500ml was used, it was observed with the naked eye that the reaction kettle had a temperature rise of 1-2 °C. When you enlarge it to 5000L, the Reactor may fly to the sky! Because under normal circumstances, the unit heating area of the large production kettle is only between 1/15 and 1/50 of the small test. Certain products, of course, now have better microchannel reactions with little to no exothermic issues.

2. Another example is when you test 500ml in a water bath at 50°C, and the oil pump 3mmHg vacuum distillation to dryness. There are many problems here. When it is enlarged to 5000L, it is evaporated to dryness under reduced pressure. Because the exhaust volume of the vacuum pump and the evaporation of liquid per unit space are not enough, it may take more than 12 hours for the enlarged production to evaporate to dryness. A small test of 500ml may be distilled to dryness in less than 1 hour. In addition, after the reaction kettle is enlarged, the amount of solvent in the residual kettle may also be more.

The following problems are most likely:

1. Residual solvent affects the next reaction, resulting in incomplete reaction of the raw materials, or the generation of impurities, or a series of problems such as affecting the yield.

2. The distillation time is prolonged indefinitely, resulting in the decomposition of the product or the generation of impurities.

3. If the product is solid, it often happens that the motor is burned out after being distilled to dryness without stirring.

4. In the later stage of distillation, the thermometer of the reactor cannot reach below the liquid level, and the temperature is a false temperature, which leads to the deterioration of the product and even dangerous accidents such as explosion.

5. In the factory, the general heat exchange medium is generally saturated steam, and the temperature of the saturated steam is as high as 170 °C. When the distillation pot is distilled to solid precipitation, the uneven heating will cause the product to deteriorate or even cause an accident. happens sometimes.

6. After the distillation is over, you may add a second solvent. When venting, if the high-speed flowing air enters the high-temperature reactor, severe friction will be generated, and a lot of static electricity will be released continuously. From the perspective of safety management, this is the unsafe state of materials, the unsafe operation of people, and management defects, all three of which exist at the same time. There is a high probability that it will lead to safety production accidents.

According to the law of twenty-eight, scientists who reach the second stage are far less than 4%, but through decades of hard work, the immersion of dozens of products, and the continuous efforts of scientists themselves, it is possible for him to achieve of.

Three, such as centrifugal rejection. In the small test, it is generally filtered directly with a Buchner funnel, and the solvent is stirred with a spoon, and then you can get a product that meets the market demand. A stainless steel centrifuge is generally used for scale-up production. When rinsing, it cannot be rinsed evenly like a small test, and the residue of the mother liquor often leads to uneven product quality. The quality will be qualified for a while, unqualified for a while and so on. According to the requirements of GMP, this phenomenon is not allowed.

Note:

According to GMP requirements: According to the specified process conditions and supporting production equipment, it can consistently produce products that meet market demand.

Let's talk about the third stage. To be honest, it is not easy, too difficult, to be the first in the world. It is also a direction of the author's current efforts. Material balance, three wastes, operation, synthesis route, all materials, all conditions, all problems that other competitors may think of, have you checked them all, have you done everything to the extreme?

Whether a product needs to be No. 1 in the world, and whether it is worth it, needs the support of in-depth market research.

The author's level is limited, please let me know! As far as the author knows, there are many excellent companies in China. They can be invincible in the market with only one excellent product, and they are getting better and better through the rolling accumulation effect of capital.

According to the twenty-eight rule, scientists who reach the third stage are far less than 0.8%

In short, the three stages of synthetic research and development are the three mountains of synthetic research and development. They are not fixed. Each stage has the characteristics of each stage, each stage has tasks of each stage, and each stage has each stage. Excellent at this stage. Excellent people at each stage have their own characteristics.