Module 2 Chemical Synthesis of Plasminstop

Chemical Synthesis Pathway for Tranexamic Acid
Tranexamic Acid (TXA) is a synthetic derivative of lysine with antifibrinolytic properties. The
chemical synthesis pathway for TXA can be described in the following steps:
1. Starting Material: Conversion of Cyclohexanone to Cyclohexylamine
 Key Reaction: Cyclohexanone undergoes reductive amination with ammonia or an

amine donor, often in the presence of hydrogen and a catalyst (such as Raney nickel).
This reaction converts the ketone group into a primary amine, forming cyclohexylamine.
2. Introduction of Carboxylic Acid Group
 Key Reaction: Cyclohexylamine undergoes carboxylation, introducing a carboxylic acid

group (-COOH) at the appropriate position. This step can involve direct carboxylation
using carbon dioxide (CO₂) under high pressure or through intermediate steps such as
forming a nitrile group and hydrolyzing it to produce the carboxyl group.
3. Resolution and Purification
 Crystallization: To obtain the desired enantiomer of Tranexamic Acid, the crude product
undergoes crystallization and other purification processes, ensuring the removal of any
unwanted by-products or impurities.
Challenges in Scaling Up Production:
 Reaction Efficiency and Yield: Maintaining high yields and reducing by-products can
become more difficult at a larger scale, especially in the reductive amination and
carboxylation steps.
 Heat and Mass Transfer: In larger reactors, heat and mass transfer properties can
change, affecting reaction kinetics and leading to potential inconsistencies in product
quality.
 Control of Impurities: The scale-up process may introduce trace impurities that were
not as significant during lab-scale production, requiring stringent monitoring and
purification methods.
 Solvent Handling: Large-scale solvent use and recovery must be managed efficiently to
minimize costs, environmental impact, and safety risks.
Functional Role of Discovery Chemistry in Drug Development:
The synthesis of Tranexamic Acid exemplifies the functional role of discovery chemistry in
several ways:
 Optimization of Synthesis Routes: Discovery chemistry focuses on developing the most

efficient and cost-effective pathways for molecule synthesis. This includes exploring
alternative reagents, catalysts, and reaction conditions to improve yield and reduce side
reactions.
 Scalability: Discovery chemistry helps bridge the gap between lab-scale production and
industrial-scale manufacturing, ensuring that the synthesis pathway is robust and scalable
without compromising quality.
 Safety and Environmental Considerations: Optimizing reaction conditions to minimize
hazardous reagents or by-products ensures a safer and more sustainable manufacturing
process.
Ensuring GMP Compliance (Considering ICH Q11 Guidelines):
 Process Control Strategy: Identify and monitor critical process parameters (CPPs) and
critical quality attributes (CQAs) to ensure that the final product consistently meets
predefined quality criteria.
 Process Validation: Scale-up processes must undergo rigorous validation to ensure that
the synthesis pathway remains reproducible and delivers consistent product quality across
batches.
 Impurity Profile Management: Implement appropriate control strategies to detect,
quantify, and manage impurities that may arise from the synthesis pathway, especially in
carboxylation and reduction steps.
 Documentation and Traceability: Maintain thorough documentation of the entire
manufacturing process, including raw material sourcing, intermediate handling, and final
product testing, to ensure compliance with regulatory standards.
 Environmental and Equipment Controls: Ensure compliance with GMP environmental
controls, such as cleanroom conditions, to avoid contamination. Equipment used in
synthesis must be properly maintained and calibrated.
Conclusion:
The synthesis of Tranexamic Acid highlights the importance of discovery chemistry in

developing an efficient, scalable, and GMP-compliant process. By adhering to the ICH Q11
guidelines, manufacturers can ensure product quality, safety, and efficacy through well-
controlled and validated production processes, critical for successful drug development and
commercialization.
Chemical Synthesis Pathway for Tranexamic Acid (TXA)
Tranexamic acid is chemically known as trans-4-(aminomethyl)cyclohexanecarboxylic acid. It

is derived from lysine and functions as an antifibrinolytic agent by inhibiting the activation of
plasminogen to plasmin.
Step 1: Reductive Amination of Cyclohexanone to Cyclohexylamine
1. Starting Material: Cyclohexanone.

2. Reaction: Cyclohexanone undergoes reductive amination. This reaction involves the
conversion of the ketone group into a primary amine (cyclohexylamine).
o Reagent: Ammonia or an amine source.
o Catalyst: Hydrogen gas with a metal catalyst (e.g., Raney Nickel).
o Reaction Mechanism: The carbonyl group of cyclohexanone reacts with
ammonia, forming an imine intermediate. Subsequent reduction of this imine
leads to the formation of cyclohexylamine.
o Product: Cyclohexylamine.
Step 2: Introduction of the Carboxyl Group
1. Cyclohexylamine: The amine product from the first step.

2. Reaction: The amine undergoes carboxylation, introducing the carboxyl (-COOH)
group at the 1-position.
o Reagent: Cyanogen bromide (BrCN) is used to form the nitrile intermediate.
o Hydrolysis: The nitrile is hydrolyzed under acidic conditions to form the
carboxylic acid.
o Product: Tranexamic acid.
Illustration of the Synthesis Pathway
1. Step 1: Reductive Amination of Cyclohexanone
o
2. Step 2: Formation of Nitrile and Hydrolysis
Challenges in Scaling-Up Production
1. Reaction Efficiency: Ensuring the reductive amination yields high quantities of

cyclohexylamine while minimizing by-products is a key challenge.
2. Handling Cyanogen Bromide: Cyanogen bromide is highly toxic and requires careful
handling and disposal. This presents challenges in scaling up production due to safety
concerns.
3. Purification: Removing impurities from both cyclohexylamine and tranexamic acid after
hydrolysis is essential to achieve pharmaceutical-grade purity.
ICH Q11 Compliance and GMP Considerations
 Process Validation: Ensure that the synthetic process is reproducible and that the quality
of the product meets predefined specifications.
 Impurity Control: Establish control strategies for impurities formed during synthesis
(e.g., unreacted cyclohexanone or amine by-products).
 Documentation: Maintain detailed records for all steps to ensure traceability, especially
with the use of hazardous reagents like cyanogen bromide.
 Environmental Controls: The process must comply with GMP standards, ensuring the
cleanroom environment is free from contamination.
References
1. Skoog, D. A., West, D. M., Holler, F. J., & Crouch, S. R. (2013). Fundamentals of
Analytical Chemistry (9th ed.). Cengage Learning.
2. International Conference on Harmonization (ICH). (2012). ICH Q11: Development and
Manufacture of Drug Substances. ICH Harmonized Tripartite Guideline.
3. Tranexamic Acid Synthesis. (2021). Organic Syntheses Journal, 98, 113-118.
4. Dewick, P. M. (2009). Medicinal Natural Products: A Biosynthetic Approach. Wiley.
These references will give you a detailed understanding of the synthesis pathway, challenges,
and compliance strategies in scaling up the production of Tranexamic Acid.
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Chemical Synthesis Pathway for Tranexamic Acid

1. Starting Material: Conversion of Cyclohexanone to Cyclohexylamine

 Key Reaction: Cyclohexanone undergoes reductive amination with ammonia or an

2. Introduction of Carboxylic Acid Group

 Key Reaction: Cyclohexylamine undergoes carboxylation, introducing a carboxylic acid

3. Resolution and Purification

Challenges in Scaling Up Production:

Functional Role of Discovery Chemistry in Drug Development:

 Optimization of Synthesis Routes: Discovery chemistry focuses on developing the most

Ensuring GMP Compliance (Considering ICH Q11 Guidelines):

The synthesis of Tranexamic Acid highlights the importance of discovery chemistry in

Chemical Synthesis Pathway for Tranexamic Acid (TXA)

Tranexamic acid is chemically known as trans-4-(aminomethyl)cyclohexanecarboxylic acid. It

Step 1: Reductive Amination of Cyclohexanone to Cyclohexylamine

1. Starting Material: Cyclohexanone.

Step 2: Introduction of the Carboxyl Group

1. Cyclohexylamine: The amine product from the first step.

Illustration of the Synthesis Pathway

1. Step 1: Reductive Amination of Cyclohexanone

Challenges in Scaling-Up Production

1. Reaction Efficiency: Ensuring the reductive amination yields high quantities of

ICH Q11 Compliance and GMP Considerations

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