cyclophase synthesis

Solid-phase synthesis has been the major manufacturing process for synthesizing biomolecules such as oligonucleotides and peptides. In solid-phase synthesis the reaction proceeds in a column charged with a solid support through which the reagents and solvents are flowed. One elongation typically requires several reactions, with a solvent wash for each step, to remove the remaining reagents from the column. Although this process has been fully automated and is rapid, the consumption of reagents and solvents is generally higher than that of solution-phase synthesis. Due to the heterogeneous nature, solid-phase synthesis is known to have limited scalability, with only up to kilogram-scale synthesis having been achieved. On the other side, for a synthesis reaction in a traditional solution phase, isolation of a desired compound requires skill and experience in process development and can be laborious especially by using column chromatography wherein a large amount of silica gel and a large volume of solvent(s) have to be consumed.

Biotide Core has invented Cyclover which combines the merits of high reactivity from the traditional solution phase synthesis and efficient separation from the solid phase synthesis. Cyclover reagent or Cyclover derivative comprises a lipophilic anchor which is soluble in one set of organic solvent(s) in which the reactions take place. This provides a uniform distribution of reactants in the system, and results in a higher homogeneity and efficiency of the reactions compared to solid-phase synthesis. Therefore, unlike solid-phase synthesis, the consumption of excess reagents can be decreased significantly. After completion of the reaction, a desired compound or product can be isolated as a solid with changes in solution composition. This technology overcomes the disadvantages of the difficulty in isolating a desired compound in the traditional solution phase synthesis, the cost of using excess reagents and solvents in solid phase synthesis and the scalability for industrial production of active pharmaceutical ingredients.

Cyclophase synthesis using Cyclover for a multi-step process:

(1) Dissolve in solution (use solvent such as dichloromethane, or THF). (2) React to completion (check the reaction by a method such as TLC). (3) Precipitate for separation (add a solvent such as 5 fold volume of methanol).

(4) Filter for collection (make it dry before next step of reaction).