How T3P is helping to advance API development

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Every day, researchers face a multitude of challenges in their efforts to identify, synthesize and develop promising drug-like molecules for the future.

From bench side to bedside is an arduous and expensive journey. But seasoned “Drug Hunters” like Dr. Gagan Kukreja, who was lead Medicinal Chemist in a discovery program aimed towards identifying first-in-class MALT1 inhibitors as a promising new class of drugs, understand only too well, how making the right choice of organic reagents early in the synthesis can go a long way to smoothing the path and expediating the journey of lead- to- candidate identification.

What is T3P?

T3P, or Propane Phosphonic Acid Anhydride, is a peptide coupling and water removal reagent with a remarkable set of USPs. Unlike many traditional agents, it is non-toxic, non-allergenic, and non-sensitizing. Its excellent safety profile means it has high thermal stability and is effective even at very mild reaction conditions of 0-25°C.

T3P is described to effectively supress racemization in organic reactions involving starting materials bearing sensitive chiral centres, thus affording products with higher chiral purity and eventually enhanced overall yields. What’s more, T3P’s safe handling, milder reaction conditions, simpler work involving water soluble ionic by-products avoids the need for sophisticated, time-consuming chromatographic column purifications, thus cutting the overall process costs.

Currently, the pharmaceutical industry is using this versatile product for amidations and esterification in small molecules, as well as linear and cyclic peptides. These transformations constitute the tip of the iceberg and the possible applications of T3P just do not stop there.
In fact, T3P can be used for various other functional group transformations, including nitrile formation, olefines formation, alcohol oxidations, reduction of carboxylic acids and various rearrangement reactions, such as Lossen and Beckman rearrangement.

Furthermore, just to name a few, T3P can be useful in synthesizing a broad range of heterocyclic compounds, including pyrazolone, indole, and quinoline.

MALT1 inhibitors: Innovation challenge

Dr. Kukreja lead the Medicinal Chemistry front in the MALT1 drug discovery program, from concept generation through the various stages of discovery.

While exploring MALT1 as a new and innovative approach in difficult to- treat cancers, the project team overcame many hurdles in the  hit-to-lead optimization phase while identifying the right chemical series which afforded the most promising compounds ready to be taken further for development.

However, the bigger challenge for Dr. Kukreja and his team, which needed a rapid response,  was to identify a stereoselective synthetic route towards constructing a thiazolo-pyridine class of MALT1 inhibitors bearing the functional group involving a chiral center.

The devised synthetic route involved a cyclo-condensation step towards building the key thiazolo-pyridine core bearing the racemization prone chemical functional group.

Dr. Kukreja explained: “Conventional reagents and thermal conditions known to bring about similar transformations proved too harsh to not disturb the vital stereocenter present in the starting material, and also resulted in lower reaction yields as well.

“I remember reading a review on T3P and recollecting a few reports which described T3P as an exceptional reagent for bringing about cyclo-condensations. I was already familiar with T3P application in amide bond formation with epimerization prone substrates, so we tried it,” he said, adding that what makes this reagent “versatile” is its availability in a broad range of organic solvents which gives lots of leverage for chemists to make the choice based on the solubility of starting material(s).

The chemistry team tested different reactions conditions using T3P in available solvents alone or in the presence of organic bases such as trimethylamine, diisopropylethylamine, pyridine, 4-dimethylamino pyridine. The use of T3P helped to increase the reaction rates and allowed the transformation to proceed at temperatures much lower than the boiling points of most of the tried solvents without T3P undergoing any observed thermal decomposition under the reaction conditions.

Scaling for success

“Once we hit upon T3P, we didn’t look back,” explained Dr. Kukreja. “We did parallel optimisations because we had all the variants of T3P, even though some of the samples were approaching the shelf life of 1-2 years.

organic reagent T3P“T3P not only brought about effective cyclization, but also proved quite effective in preserving the sensitive stereocenter, which eventually helped us scaleup this critical step. More importantly, no column separations were required.

“Cost wise, it was still within our reach and the workups were smooth.

“All this had a significant impact on the project’s timelines – and ultimately its success. We secured the material and advanced the molecule further for toxicity studies as part of preclinical development.

“Everything went well with the molecule and the rest is history1,” concluded Dr. Kukreja.

In December 2018, AbbVie announced it had gained exclusive global rights to develop a portfolio of small molecule inhibitors of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) to treat hematological cancers from another company at a cost of $30 million. The company is eligible to receive up to $947 million upon the successful completion of regulatory, development and commercial milestones and will receive royalties on any developed therapies, and will retain commercial rights to the MALT1 program in India2, 3.

Dr. Kukreja concluded: “All this was possible because we were able to secure a robust route to synthesize the lead molecules in the right quantity and desired purity. You can have the best molecule in the world, but if you do not have the right synthetic routes – routes that are scalable – you lose the charm, and no one is interested.”

Since this demonstration of the utility of T3P, it has become a clear favourite in his toolkit of synthetic reagents, said Dr. Kukreja, who is currently working for an agrochemical company, where he is leading the chemistry efforts in various research programs aimed towards discovering sustainable chemistries as new crop protection products for the future

Dr. Kukreja continues to have confidence in the T3P product, especially the superior quality of Curia’s T3P which is free of any halogens and sulfur. He values its versatility, adding it is ‘not limited to just one transformation’.

“What makes T3P unique is its ability to act as an oxidising agent whilst also participating in the reduction reactions– which not many reagents are known to achieve both at the same time.

“Whenever I see someone trying to crack a transformation, I suggest looking at T3P to make best use of its potential and, on the way, even hit upon unearthing some of its wider hidden applications,” said Dr. Kukreja

The future

T3P API development“T3P was developed about 40 years ago, but it is now coming into its own. As the literature grows, more chemists are becoming aware of its USPs and the role it can play in the future, knowing its synthetic applications is enormous,” said Dr. Kukreja.

“In the agrochemical industry, we are looking at new cost-effective solutions to bring about the next big innovations that will shape the future of agriculture, helping farmers to safely and sustainably feed the world.

“When we devise our synthetic routes and our synthesis, it’s imperative to look at cost, availability, safety and sustainability of reagents which would deliver affordable and robust chemistries, as production volumes in agriculture field are much higher than in pharma although structural complexity is similar.”

“It’s an ROI argument that could apply to all chemistry-driven sectors – extending beyond the pharmaceutical industry,” Dr. Kukreja concludes.

Curia is the owner of the original patented halogen and sulphur-free manufacturing process. This means Curia can produce T3P in a superior purity – and give researchers the flexibility, versatility, and confidence they need to go on discovering.


  2. India’s first-in-class MALT 1 blocker deal; Nature Biotechnology | VOL 37 | FEBRUARY 2019 | 109–117
  3. Lupin and AbbVie Announce Partnership to Develop and Commercialize Novel Oncology Drug to Treat Hematological Cancers, December 24, 2018;

About the author:

Dr. Gagan Kukreja is a Medicinal chemist who is passionate about Drug Discovery research with over 18 years of holistic experience in the business of hunting next generation of differentiated medicines.

Currently leading discovery research groups and project teams in collaborative integrated drug discovery programs in therapeutic areas such as oncology, diabetes & inflammation.

Besides, he has also been involved in the discovery of new crop protection products having a novel MOA to tackle the rise of resistance in the areas of fungicides, herbicides, and insecticides.

Disclaimer: Dr. Gagan Kukreja is not an employee of or affiliated with Curia Global, Inc. Any statements made by Dr. Kukreja herein express his views in his individual capacity, not those of his current or former employers.

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