Fully Continuous Flow Synthesis of a Key Intermediate of Vitamin B1

The Chen group at Fudan University, Shanghai have recently published work on the continuous flow synthesis of a key intermediate of Vitamin B1 in OPR&D (link).

Vitamin B1, also known as thiamine (Figure 1), is essential for glucose metabolism which enables the body to use carbohydrates as energy. Dietary sources of vitamin B1 include whole grains, meat, fish, and some vegetables such as cauliflower and kale.

The chemical structure of Vitamin B1
Figure 1: The chemical structure of Vitamin B1

In many parts of the world, breakfast cereals are enriched with Vitamin B1 (along with many other vitamins) to boost intake throughout the population, making synthetic Vitamin B1 a highly desirable compound commercially.

Work by the Chen group demonstrates an “expeditiously fully continuous flow synthesis of 5-(aminomethyl)-2-methylpyrimidin-4-amine, a key intermediate for vitamin B1” starting from commercially available 2-cyanoacetamide. The three-step process was performed across six sequential continuous flow devices, including the Coflore ACR for the second step (synthesis of 4-amino-2-methylpyrimidine-5-carbonitrile, 3, as outlined in Figure 2).

An overview of the step 2 reaction, republished from the paper.
Figure 2: An overview of the step 2 reaction, republished from the paper.

This second step afforded product as a slurry and the Chen group stated: “The precipitate formation presented huge challenges in a flow coil reactor, clogging was bound to be observed, which would definitely lead to pressure buildup and disruption of the flow process. In this reaction, we employed a Coflore Agitated Cell Reactor (ACR, 90 mL work

volume) to relieve any issues that would be caused by the formation of precipitation.”

 A comparison table of batch vs flow for step 2, republished from the paper.
Table 1: A comparison of batch vs flow for step 2, republished from the paper.

Optimum conditions for the conversion of starting material 4 to product 3 were found to be “55 °C, 6 Hz frequency, and 25−30 min residence time with 1.25 M compound 4 to afford 3 in nearly full conversion by GC/MS and 90% isolated yield”. A comparison of this flow synthesis to a literature reported batch method can be seen in Table 1, with the flow process achieving comparable yield and purity but at a vastly reduced reaction time (30 minutes compared to 12 hours).

If you would like to find out more about this work, you can access the paper here.

“One of today's most important tools for modernizing the pharmaceutical industry is a process known as continuous manufacturing”

Director of the FDA’s Center for Drug Evaluation and Research, Janet Woodcock M.D.