Xueba’s medical black technology system

Chapter 211 Imitation, improvement of synthetic routes
The request for help quickly caused an uproar online.

More than 1000 families signed a request for help. Each bright red fingerprint represents a family's desperate plight. This scene undoubtedly touched the heartstrings of netizens.

Many people on the Internet have expressed support.

While there was a commotion on the Internet, Chen Shen was already very busy in the Drug Research Institute.

The calls came one after another, leaving Chen Shen a little overwhelmed.

"I know that our research institute has already established a project for clobazam generics, and we are currently seizing the time to develop it."

“As you know, clobazam is an orphan drug, and we didn’t pay much attention to this drug before.

But now that we know about these things and that there are such a number of patients, we will also find ways to solve the problem of drug shortage as soon as possible. "

"Don't worry, I will copy the drug as soon as possible."
After hanging up the phone, Chen Shen breathed a long sigh of relief as if relieved. He put down the phone and rubbed his swollen eyebrows.

This incident happened so suddenly that Chen Shen was caught off guard.

Almost as soon as he learned about this matter, Chen Shen had already arranged for people from the institute to start the research and development of clobazam generics.

However, just this still made Chen Shen feel uneasy. After hesitating for a moment, Chen Shen picked up his cell phone and dialed Lu Liang's number.

He decided to let Lu Liang also participate in this project. The purpose of doing so was to give the project an extra layer of insurance.

After all, the imitation of Clobazam is extremely important now, and there is no room for any mistakes.

With Lu Liang as insurance, if anything goes wrong on the institute's side, Lu Liang can ensure that there are no problems with the project.

Soon, the call was connected, and Lu Liang's voice came from the other end of the phone: "Suo Chen, what's going on?"

Chen Shen said in a solemn tone: "Xiao Lu, do you know about the Internet Clobazan thing?"

"I know, what's wrong?"

Chen Shen continued: "Currently, the institute has approved a clobazam generic project. Can you participate in this project?"

Chen Shen was not sure whether Lu Liang would agree to participate in the project. After all, Lu Liang had only made original drugs before and had never made generic drugs.

However, Lu Liang agreed very readily: "No problem."

This made Chen Shen relax a little. With Lu Liang's insurance, the entire project would become much safer.

Chen Shen continued to ask: "Xiao Lu, when can you start? This project is urgent now?"

Lu Liang on the other end of the phone was silent for a moment: "Chen Suo, actually, I have already started."

After hearing what Lu Liang said, Chen Shen was stunned for a moment, and then his expression became weird.

After hanging up the phone, Lu Liang looked at his computer screen.

Before copying clobazam, Lu Liang naturally read the research on epilepsy.

Epilepsy is when neurons in the brain discharge abnormally, causing the brain to become intensely excited.

In layman's terms, it's epilepsy.

Epilepsy is a common chronic neurological disease that can occur at any age, but is most common in children.

So far, the pathogenesis of epilepsy has not been clearly studied because there are too many factors that induce epilepsy.

Cerebral cortical dysplasia, temporal lobe sclerosis, central nervous system infection, traumatic brain injury and other factors can all induce epilepsy.

Refractory epilepsy is a type of epilepsy. It is not a specific disease, but a synonym for a certain type of disease.

Intractable epilepsy includes infantile spasms, Dravet syndrome, LGS syndrome, Ohtawara syndrome, tuberous sclerosis, sequelae of encephalitis, etc.

The number and types of these diseases made Lu Liang feel a little stunned.

Sick children will have repeated epileptic seizures, dozens or even hundreds of times a day. If some children are not rescued in time, this kind of epilepsy will be fatal.

This is why adults with refractory epilepsy are rarely seen.

Because most children with the disease do not live to adulthood.

Later, Lu Liang reviewed Clobazam's research.

It has to be said that the research on clobazam is simply pitiful.

If you switch to papers on other common anti-cancer drugs, you can search for 10,000+ research results online.

But when it comes to Clobazan, there are only a few hundred results.

Lu Liang glanced at Clobazan's research documents.

The reason why clobazam exerts its anti-epileptic effect is mainly through the gamma-aminobutyric acid receptor (GABAA).

这是一种氯离子通道型受体，这种受体由5个亚基组成，分别是α1、α2、β1、β2和γ。

α1 mediates sedative effects, α2 mediates anxiolytic effects, and both subtypes have antiepileptic effects.

Clobazam plays an anti-epileptic role by binding to γ-aminobutyric acid receptors, increasing the inhibition of γ-aminobutyric acid on neurons and weakening the abnormal excitability of neurons.Lu Liang briefly understood the principle of clobazam's efficacy. However, this was not what he cared about. What he really cared about was the imitation of clobazam.

How to synthesize clobazam, that is the key!

氯巴占属于1，5-苯二氮类药物，其化学式是C16H13ClN2O2，在第1和第5位上有氮原子。

At present, most people will choose to use 5-chloro-2-nitrobenzidine as the raw material.

5-Chloro-2-aminobenzidine is obtained through reduction reaction.

Then use 5-chloro-2-aminobenzidine to acylate malonate monoethyl chloride, or react with malonyl chloride in tetrahydrofuran to obtain the important intermediate C10H10ClNO.

At this point, it is already very close to Clobazan.

Next, only a small reaction of methyl iodide is required under alkaline conditions to obtain the crude product of clobazam.

However, this is not what Lu Liang wants!
The overall yield of clobazam produced by the acylation reaction of monoethyl malonate acyl chloride is extremely low, and the final yield is only 11%.
What is the concept? From 100g of raw materials, the final clobazam produced may be less than 10g.

10g is even a very ideal result.

Clobazam, which is prepared by reacting malonyl chloride in tetrahydrofuran, has a yield of 60%.

However, this step requires noble metal nanoparticles as a catalyst, and the cyclization step uses an equivalent amount of aluminum trichloride as the acylating reagent.

The costs are almost reaching the ceiling.

Lu Liang frowned and thought, what he needed was a cheaper method.

At this moment, the door of the study room was pushed open, and Wang Wentao walked in from the door with wet hands.

"How is it?" Lu Liang asked.

Wang Wentao shook his head: "The total yield is only 8%, which is even lower."

In the past few days, Lu Liang and Wang Wentao have been improving the synthesis method of monoethyl malonate acyl chloride reaction in an attempt to increase the yield. If the improvement is successful, this will be a good method.

But it didn't work out.

If nothing else, the problem lies in the acylation reaction of monoethyl malonate acyl chloride.

Lu Liang did not hesitate, he chose to exchange 0.2 Source Points for an overclocking capsule in the Source Point Mall.

The moment the capsule was taken down, Lu Liang suddenly felt that some kind of shackles had been broken, as if an invisible hood had been taken off his head, and his five senses instantly became extremely clear.

All kinds of ideas surged towards Lu Liang like a huge wave.

At that moment, all the chemical structural formulas were constantly dismantling and balancing in Lu Liang's mind like a storm.

To obtain the intermediate, you must first reduce 5-chloro-2-nitrobenzidine to 5-chloro-2-aminobenzidine. This step requires the addition of hydrogen atoms.

Then use reduced 5-chloro-2-aminobenzidine to carry out acylation reaction.
Wait, why does it have to be reduced first and then acylated?

At that moment, Lu Liang seemed to be thinking about something.

In fact, it is possible to acylate first and then reduce!
However, it is more difficult to carry out the acylation reaction without going through the reduction reaction, if the acylation reaction of malonate monoethyl chloride is carried out first.
No, why must we use monoethyl malonate chloride?
The yield of monoethyl malonate acyl chloride is low. Would it be better to use another reagent to complete the acylation reaction?
Various chemical molecular formulas flashed quickly in Lu Liang's mind. Lu Liang quickly sifted through these molecular formulas, and kept matching the reaction formulas one by one.

Suddenly, a possible structure appeared in Lu Liang's mind.

Malonate monomethyl ester chloride!

There was no problem with the trimming, it was theoretically feasible, and Lu Liang's eyes suddenly lit up.

Then the decision is yours, C4H5ClO3!

Malonate monomethyl chloride can also be used as an acylating agent, supplemented by triethylamine as an acid binding agent.
Lu Liang quickly opened Word on the computer and quickly typed a line of text on Word.

After completing the acylation reaction, a reduction reaction is also required. What should be used for reductive cyclization?
Substances in which volatile electrons are oxidized during chemical reactions are often used as reducing agents.

A second after this question appeared in Lu Liang's mind, various reducing agents flashed through Lu Liang's mind uncontrollably, as if he were watching a flower on a horse.

NaBH4、LiAlH4、O2、Cl2、Br2、MnO4、KClO3、H2SO4、HNO3、Zn
Wait a moment.

Zn?

Lu Liang suddenly stopped with his foot!

Yes, it’s zinc!
First, 5-chloro-2-nitrobenzidine is acylated with malonate monomethyl chloride, and then zinc is used for reduction and cyclization to generate the intermediate C10H10ClNO.

Finally, the crude product of clobazam can be obtained by methylation reaction of the intermediate with methyl iodide.

Lu Liang's fingers were tapping quickly on the keyboard. Lu Liang could only give a rough range for the conditions of temperature and reaction time.

As for more detailed reaction conditions, we need to continue to explore.

After typing the last word on the screen, Lu Liang let out a long sigh of relief.

After handing over the improved synthesis route of clobazan to Wang Wentao, Lu Liang hurriedly left the study room.

(End of this chapter)