Scalable synthesis of tranexamic acid under modest reaction conditions using early stage isomerization of dimethyl 1,4-cyclohexanedicarboxylate as a key step

• Published in: Synthetic communications Vol. 54; no. 19; pp. 1665 - 1678
• Main Authors: Patil, Pradip, Kulkarni, Kaivalya G., Jadhav, Sanket, More, Yogesh, Khaladkar, Tushar, Roychowdhury, Abhijit, Gurjar, Mukund K., Patil, S. R.
• Format: Journal Article
• Language: English
• Published: Philadelphia Taylor & Francis 01.10.2024; Taylor & Francis Ltd
• Subjects: antifabrinolytic; Chemical synthesis; Design for recycling; Isomerization; Isomers; Mixtures; Purity; Raw materials; Reagents; Stereochemistry; trans-4-aminomethyl cyclohexane-1-carboxylic acid
• ISSN: 0039-7911; 1532-2432
• DOI: 10.1080/00397911.2024.2399795

A commercially scalable five-step synthetic process starting from cis/trans (7:3) mixture of dimethyl 1,4-cyclohexanedicarboxylate is devised for preparation of tranexamic acid with more than 99.5% purity. All impurities are controlled as per monograph. 47% overall yield over five steps has been achieved based on recovery. Epimerization of a cis-predominant isomeric mixture to trans predominant isomeric mixture under mild conditions followed by exploiting the difference in solubility to obtain trans isomer in very high purity is the key feature of the synthesis. In addition to this, use of readily available and cost efficient raw materials/reagents, recycling of cis isomer, explicit design of downstream processing enabling the retention of the trans-stereochemistry until final API are some of the highlights of this synthesis. This process also circumvents the use of hazardous chemicals and harsh reaction conditions making it greener and safer compared to the previous reports."