Remdesivir

What is the remdesivir?

Remdesivir is a retroviral that has been developed by Gilead Sciences as a treatment for the Ebola virus and the Marburg. Then this company has reported its antiviral activity next to corona-virus.

Remdesivir RWWYLEGWBNMMLJ-YSOARWBDSA-N
Remdesivir RWWYLEGWBNMMLJ-YSOARWBDSA-N
3D structure

The structure is a derivative cycling of the α-D-ribose-5-phosphate with two substituents: 4-amino-pirrolotriazina and ciano in the carbon-2, which was replaced in the phosphate with a group 2-etilbutil-2-aminopropanoato as shown in the figure.

Synthesis

Gilead Science has patented a synthesis method convergent for Remdesivir from derivatives of ribose.

We prepare three intermediates (I, II and III) that will be used in the final steps of the synthesis.

In a first step, the intermediate I it is prepared from L-alanine and fenildiclorofosfato in the presence of triethylamine (TEA), and dichloromethane (DCM).

Alternatively, oxidized ribose protected with three bencilos, in particular the group –OH until carbonyl >C=O. For this, they used acetic anhydride (Ac2Or) in dimethylsulfoxide (DMSO), to form the lactone II.

In addition, to prepare the intermediate IIIfirst joke of the 4-amino-pirrolotriazina. After that, it protects the amino group (-NH2) chloride, trimethylsilyl (TMSCl). Once protected the amino group replaces the Br by Li using n-butyl lithium to produce the intermediate III.

Once obtained the three intermediate, proceeds to assemble them. The intermediate II is added drop by drop to a solution that contains the intermediate III.

After inactivate the reaction in an aqueous solution is weakly acidic, you get a racemic mixture.

Then, reacted with an excess of cyanide, trimethylsilyl (TMSCN) in dichloromethane (DCM). Added triflate-trimethylsilyl (TMSOTf) and when treated with Na2SO3 in water, it obtains an intermediate with the group, nitrile (-C≡N).

The protective group, benzyl, it is removed with trichloride boron(BCl3) in dichloromethane (DCM).

The isomers were separated by reversed-phase HPLC. And the compound optically pure and the intermediate I they react with phosphate trimetilo and methylimidazole to obtain a mixture diastereomérica of Remdesivir. In the end, you can get Remdesivir optically pure through the methods of resolution chiral.