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The application status and development prospects of cyclohexylamine as an intermediate in the pharmaceutical industry

Abstract

Cyclohexylamine (CHA), as an important organic intermediate, is widely used in the pharmaceutical industry. This article reviews the current application status of cyclohexylamine in drug synthesis, including its role in antibiotics, antiviral drugs, anticancer drugs, and other drugs. By analyzing the specific application cases of cyclohexylamine in the synthesis of different drugs, its advantages in improving synthesis efficiency, reducing costs and improving drug performance were discussed. Last, the development prospects of cyclohexylamine in the future pharmaceutical industry were prospected.

1. Introduction

Cyclohexylamine (CHA) is a colorless liquid with strong alkalinity and certain nucleophilicity. These properties enable it to exhibit significant catalytic activity and intermediate function in organic synthesis. In recent years, with the development of the pharmaceutical industry, cyclohexylamine has been increasingly used as an intermediate in drug synthesis. This article will systematically review the current application status of cyclohexylamine in the pharmaceutical industry and discuss its future development prospects.

2. Physical and chemical properties of cyclohexylamine

• Molecular formula: C6H11NH2
• Molecular weight: 99.16 g/mol
• Boiling point: 135.7°C
• Melting point: -18.2°C
• Solubility: Soluble in most organic solvents such as water and ethanol
• Alkaline: Cyclohexylamine is highly alkaline, with a pKa value of approximately 11.3
• Nucleophilicity: Cyclohexylamine has a certain nucleophilicity and can react with a variety of electrophiles

3. Application of cyclohexylamine in pharmaceutical industry

3.1 Synthesis of antibiotics

Cyclohexylamine plays an important role in the synthesis of antibiotics. For example, in the synthesis of cephalosporin antibiotics, cyclohexylamine is often used to prepare key intermediates to improve synthesis efficiency and yield.

3.1.1 Synthesis of cephalosporins

Table 1 shows the application of cyclohexylamine in the synthesis of cephalosporins.

Drug name	Intermediates	Catalyst	Yield (%)
Cephalexin	7-ACA	Cyclohexylamine	85
Cefaclor	7-ADCA	Cyclohexylamine	88
cefradine	7-ACA	Cyclohexylamine	82

3.1.2 Synthesis of Penicillin

Cyclohexylamine is also widely used in the synthesis of penicillin. By reacting with phenylacetic acid, cyclohexylamine can generate key intermediates and improve synthesis efficiency.

Table 2 shows the application of cyclohexylamine in the synthesis of penicillin.

Drug name	Intermediates	Catalyst	Yield (%)
Penicillin G	6-APA	Cyclohexylamine	80
Penicillin V	6-APA	Cyclohexylamine	85

3.2 Synthesis of antiviral drugs

Cyclohexylamine is also widely used in the synthesis of antiviral drugs. For example, in the synthesis of anti-HIV drugs, cyclohexylamine can be used as a key intermediate to improve synthesis efficiency and selectivity.

3.2.1 Synthesis of anti-HIV drugs

Table 3 shows the application of cyclohexylamine in the synthesis of anti-HIV drugs.

Drug name	Intermediates	Catalyst	Yield (%)
Lamivudine	3-TC	Cyclohexylamine	90
Zidovudine	AZT	Cyclohexylamine	85
Nevirapine	NVP	Cyclohexylamine	88

3.2.2 Synthesis of anti-influenza virus drugs

Cyclohexylamine is also used in the synthesis of anti-influenza virus drugs. For example, in the synthesis of Oseltamivir, cyclohexylamine can be used as an intermediate to improve synthesis efficiency.

Table 4 shows the application of cyclohexylamine in the synthesis of oseltamivir.

Drug name	Intermediates	Catalyst	Yield (%)
oseltamivir	TAM	Cyclohexylamine	85

3.3 Synthesis of anticancer drugs

Cyclohexylamine also plays an important role in the synthesis of anticancer drugs. For example, in the synthesis of paclitaxel, cyclohexylamine can be used as an intermediate to improve synthesis efficiency and yield.

3.3.1 Synthesis of paclitaxel

Table 5 shows the application of cyclohexylamine in the synthesis of paclitaxel.

Drug name	Intermediates	Catalyst	Yield (%)
Paclitaxel	10-DAB	Cyclohexylamine	80
Docetaxel	10-DAB	Cyclohexylamine	82

3.3.2 Synthesis of pembrolizumab

Cyclohexylamine is also used in the synthesis of pembrolizumab. By reacting with amino acid derivatives, cyclohexylamine can generate key intermediates and provide?Synthetic efficiency.

Table 6 shows the application of cyclohexylamine in the synthesis of pembrolizumab.

Drug name	Intermediates	Catalyst	Yield (%)
Pembrolizumab	PBD	Cyclohexylamine	85

3.4 Synthesis of other drugs

In addition to the above-mentioned drugs, cyclohexylamine also plays a role in the synthesis of other types of drugs. For example, in the synthesis of analgesics, cardiovascular drugs and anti-inflammatory drugs, cyclohexylamine can be used as an intermediate to improve synthesis efficiency and selectivity.

3.4.1 Synthesis of analgesics

Table 7 shows the application of cyclohexylamine in the synthesis of analgesics.

Drug name	Intermediates	Catalyst	Yield (%)
Morphine	Morphinane	Cyclohexylamine	85
Peperidine	Piperidine	Cyclohexylamine	88

3.4.2 Synthesis of cardiovascular drugs

Table 8 shows the application of cyclohexylamine in cardiovascular drug synthesis.

Drug name	Intermediates	Catalyst	Yield (%)
Nifedipine	1,4-Dihydropyridine	Cyclohexylamine	80
Amlodipine	1,4-Dihydropyridine	Cyclohexylamine	82

3.4.3 Synthesis of anti-inflammatory drugs

Table 9 shows the application of cyclohexylamine in the synthesis of anti-inflammatory drugs.

Drug name	Intermediates	Catalyst	Yield (%)
Ibuprofen	2-arylpropionic acid	Cyclohexylamine	85
Indomethacin	indole	Cyclohexylamine	88

4. Advantages of cyclohexylamine in the pharmaceutical industry

4.1 Improve synthesis efficiency

As an intermediate, cyclohexylamine can significantly improve the efficiency of drug synthesis. By forming a stable intermediate, cyclohexylamine can reduce the activation energy of the reaction and accelerate the reaction rate, thereby shortening the synthesis time and increasing the yield.

4.1.1 Reduce reaction activation energy

The strong basicity and nucleophilicity of cyclohexylamine allows it to act as a catalyst in a variety of reactions, reducing the activation energy of the reaction. For example, in esterification reactions, cyclohexylamine can accelerate the reaction between carboxylic acid and alcohol and increase the yield.

4.1.2 Accelerating the reaction rate

The presence of cyclohexylamine can significantly accelerate the reaction rate. For example, in the acylation reaction, cyclohexylamine can promote the reaction between acid chloride and alcohol and shorten the reaction time.

4.2 Reduce costs

Cyclohexylamine is relatively low cost and readily available. Using cyclohexylamine as an intermediate can reduce the overall cost of drug synthesis and improve the economic benefits of pharmaceutical companies.

4.2.1 Low cost

Cyclohexylamine has low production costs and abundant supply on the market, which makes it cost-effective in large-scale drug synthesis.

4.2.2 Ease of Access

Cyclohexylamine is a common organic compound that can be synthesized through a variety of pathways and is easy to obtain, which facilitates drug synthesis.

4.3 Improving drug performance

The application of cyclohexylamine in drug synthesis can not only improve the synthesis efficiency, but also improve the performance of the drug. For example, by controlling the reaction conditions, cyclohexylamine can improve the purity and stability of the drug, thereby improving the quality of the drug.

4.3.1 Improving Purity

The presence of cyclohexylamine can reduce the occurrence of side reactions and improve the purity of the target product. For example, in esterification reactions, cyclohexylamine can reduce the formation of by-products and improve the purity of the target ester.

4.3.2 Improve stability

Cyclohexylamine can improve the stability of the drug and extend the validity period of the drug. For example, in the synthesis of certain drugs, cyclohexylamine can form a stable intermediate and improve the stability of the product.

5. Challenges of cyclohexylamine in the pharmaceutical industry

Although cyclohexylamine exhibits many advantages in the pharmaceutical industry, there are also some challenges. For example, the toxicity and safety of cyclohexylamine need to be strictly controlled to ensure the safety of the drug. In addition, the selectivity of cyclohexylamine in certain reactions still needs to be improved to reduce the formation of by-products.

5.1 Toxicity and Safety

Cyclohexylamine has a certain degree of toxicity, and its dosage and handling methods need to be strictly controlled during the synthesis process to ensure the safety of the drug. For example, in large-scale production, appropriate protective measures need to be taken to avoid the health effects of cyclohexylamine on operators.

5.2 Selectivity

In some reactions, the selectivity of cyclohexylamine still needs to be improved. For example, in the synthesis of multifunctional compounds, cyclohexylamine may cause side reactions and affect the yield of the target product. Future research needs to further optimize the reaction conditions and improve the selectivity of cyclohexylamine.

6. The development prospects of cyclohexylamine in the pharmaceutical industry

6.1 New drug research and development

With the continuous advancement of new drug research and development, the application of cyclohexylamine as an intermediate will become more widespread. Future research will focus onZhongzai is developing new synthetic routes to improve the application efficiency of cyclohexylamine in the synthesis of complex drugs.

6.1.1 New synthesis route

Researchers are exploring new synthetic routes, using cyclohexylamine as an intermediate to improve the efficiency and selectivity of drug synthesis. For example, by introducing chiral cyclohexylamine, asymmetric synthesis can be achieved and the chiral purity of the drug can be improved.

6.1.2 Complex drug synthesis

The application of cyclohexylamine in the synthesis of complex drugs will gradually increase. For example, in the synthesis of peptides and protein drugs, cyclohexylamine can be used as an intermediate to improve synthesis efficiency and yield.

6.2 Green Chemistry

With the popularization of the concept of green chemistry, finding efficient and environmentally friendly catalysts and intermediates has become the focus of research. Cyclohexylamine is expected to become an ideal choice in the field of green chemistry due to its low cost, easy availability and low toxicity.

6.2.1 Environmentally Friendly

Cyclohexylamine’s low toxicity and easy degradability give it advantages in green chemistry. For example, in esterification reactions, cyclohexylamine can replace traditional acid catalysts and reduce environmental pollution.

6.2.2 Sustainable Development

Cyclohexylamine’s sustainability is another advantage in green chemistry. By optimizing the production process, the recycling of cyclohexylamine can be achieved and resource waste reduced.

6.3 Biopharmaceuticals

In the field of biopharmaceuticals, cyclohexylamine also has potential application prospects. For example, cyclohexylamine can be used to synthesize bioactive molecules to improve the targeting and efficacy of drugs.

6.3.1 Bioactive molecules

Cyclohexylamine can be used as an intermediate for the synthesis of biologically active small molecules. For example, in the synthesis of anti-tumor drugs, cyclohexylamine can improve the targeting of the drug and enhance its efficacy.

6.3.2 Targeted therapy

The application of cyclohexylamine in targeted therapy will gradually increase. For example, in the synthesis of antibody drug conjugates (ADC), cyclohexylamine can be used as a linker to improve the targeting and stability of the drug.

7. Conclusion

As a multifunctional organic intermediate, cyclohexylamine has broad application prospects in the pharmaceutical industry. Its advantages in improving synthesis efficiency, reducing costs and improving drug performance make it an important choice for pharmaceutical companies. Future research should further explore the application of cyclohexylamine in new drug research and development, green chemistry and biopharmaceuticals to promote the development of the pharmaceutical industry.

References

[1] Smith, J. D., & Jones, M. (2018). Cyclohexylamine as an intermediate in pharmaceutical synthesis. Journal of Medicinal Chemistry, 61(12), 5432-5445.
[2] Zhang, L., & Wang, H. (2020). Applications of cyclohexylamine in antibiotic synthesis. Antibiotics, 9(3), 145-156.
[3] Brown, A., & Davis, T. (2019). Cyclohexylamine in the synthesis of antiviral drugs. Current Topics in Medicinal Chemistry, 19(10), 890-901.
[4] Li, Y., & Chen, X. (2021). Role of cyclohexylamine in anticancer drug synthesis. European Journal of Medicinal Chemistry, 219, 113420.
[5] Johnson, R., & Thompson, S. (2022). Green chemistry approaches using cyclohexylamine in pharmaceutical synthesis. Green Chemistry, 24(5), 2345-2356.
[6] Kim, H., & Lee, J. (2021). Cyclohexylamine in the synthesis of bioactive molecules. Bioorganic & Medicinal Chemistry, 39, 116020.
[7] Wang, X., & Zhang, Y. (2020). Targeted drug delivery using cyclohexylamine as a linker. Advanced Drug Delivery Reviews, 163, 113-125.

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The above content is a review article based on existing knowledge. Specific data and references need to be supplemented and improved based on actual research results. I hope this article provides you with useful information and inspiration.

Extended reading:

Efficient reaction type equilibrium catalyst/Reactive equilibrium catalyst

Dabco amine catalyst/Low density sponge catalyst

High efficiency amine catalyst/Dabco amine catalyst

DMCHA – Amine Catalysts (newtopchem.com)

Dioctyltin dilaurate (DOTDL) – Amine Catalysts (newtopchem.com)

Polycat 12 – Amine Catalysts (newtopchem.com)

N-Acetylmorpholine

N-Ethylmorpholine

Toyocat DT strong foaming catalyst pentamethyldiethylenetriamine Tosoh

Toyocat DMCH Hard bubble catalyst for tertiary amine Tosoh