University of Alicante

The most relevant features of this complex A are: 1) is the first described and published complex formed by a phosphoramidite unit (a) and a silver(I) salt (b); 2) R6 can be an hydrogen atom, alkyl radical (C1-C6), aryl group (C5-C14) or an alkylaryl substituent; 3) R8 can be an alkyl group (C1-C6), alkoxyalkyl, (dialkylamino)alkyl (C1-C6) or aryl; 4) R7 can be hydrogen or an alkyl (C1-C6), aryl (C5-C14) or arylalkyl groups; 5) X is selected from fluoride, acetate, perchlorate, trifluoromethanesulfonate, tetrafluoroborate, nitrate, hexafluorophosphate o hexafluoroantimoniate; and 6) (---) represents an optional chemical bond, which can be present or not.

It was also developed an optimised procedure where the new complex B could be obtained using a similar method but varying the stoichiometry of the reagents. It is composed by two equivalents of a chiral phosphoramidite (a) and an equivalent of silver(I) salt (b). The nature of R6-R8 and X groups has been described previously.


Both chiral complexes (A y B) are prepared by mixing one or two equivalents of chiral phosphoramidite (a), respectively, together with one equivalent of silver(I) salt (b) in the presence of an organic solvent, at room temperature and avoiding the light exposure.

The catalysed 1,3-dipolar cycloaddition between azomethine ylides, generated from iminoesters (III), and acrylates (IV) has been also optimised using substoichiometric amounts of the mentioned chiral silver complexes A and B.



In the case of compounds (III) and (IV) R2 is and alkyl group (C1-C6), R3 is an alkyl (C1-C6) or arylalkyl group, R4 is a selected radical from alkoxy, alkylamino, arylamino, or dialkylamino, whilst R5 is a heteroaryl substituent. In this way, a series of intermediates and final products possessing similar structures (I) or (II) are obtained.


R1 and R5 are: R1 hydrogen, aroyl, R2 hydrogen or alkyl group (C1-C6), R3 alkyl (C1-C6) or arylalkyl, R4 can be hydroxy, alkoxy, alkylamino, arylamino or dialkylamino, y R5 heteroaryl group.

The enantiomerically enriched antiviral compounds derived from proline posses a general structure (I) or (II), where R1 is aroyl, R2 is hydrogen, R3 is an alkyl (C1-C6) or arylalkyl group, R4 is hydroxy, alkylamino, arylamino or dialkylamino, and R5 is a heteroaryl group.

The presence of the aroyl group in the final antiviral molecule is crucial for ensuring the inhibitory activity against the mentioned virus of the hepatitis C. The atom array of this substituent will allow the increment of the permeability of these drugs through cellular membranes.

Compound C has been also prepared.




Here, R2 is an alkyl group (C1-C6), R3 is an alkyl (C1-C6) or arylalkyl group, R4 is an alkoxy, alkylamino, arylamino or dialkylamino, and R5 is a heteroaryl group.

The final absolute configurations of the C structures are: C(I)=(2S,4S,5R) and C(II)=(2R,4R,5S):




General structures D can be easily obtained from compound C. In this case R1 is aroyl and R2-R5 such as it was described previously.



The absolute configurations of each stereogenic centre are the following: D(I)=(2S,4S,5R) and D(II)=(2R,4R,5S):


Finally, it has been elaborated a compound whose general structure obeys to E. The analogous compounds D are their precursors, where R1 is aroyl, whilst R3 and R5 have been detailed before.




The absolute configuration of each stereocentre of products E are: E(I)=(2S,4S,5R) and E(II)=(2R,4R,5S):

MAIN ADVANTAGES:

• The processes are highly enantioselectives. The final antiviral agents are obtained with very good ee’s.

• The chemical yields are very good, and the purity of the compounds is very high.

• The procedure is efficient and reproducible.

INNOVATION FEATURES

At this moment, this methodology is the unique dealing with the production of these antiviral agents in an highly enantioselective manner. This enantioselective synthesis is very reliable, reproducible and allows to react very bulky starting materials giving high chemical yields. This method is a clear example of the atom economy.

The general process has been optimised in a laboratory scale after multiple tests and structural modifications. The results are:

¿ High purities (more than 97%).

¿ High chemical yields (more than 70%).

¿ High enantiomeric ratios (at least 94:6 re).

The Pilot Plant of the Department of Organic Chemistry of the University of Alicante offers many possibilities to implement and perform this synthesis in an industrial scale. It is fully equipped an ready to develop the production in a range between milligrams and multi-kilo batches.

The facilities of this pilot plant are numerous, for example, the coverage of the production scale allows reactions up to 300 L, multiple chemical and physical treatments, storage, analysis, and the full control of the process. The pilot plant operates under certified Norma ISO 9001, maintaining the cGMPs (current Good Manufacturing Procedures).

PHARMACEUTICAL COMPANIES: they represent a very promising therapy against the proliferation and development of the virus responsible of the hepatitis C. Their efficiency and biological potential has been demonstrated in infected mice IC50= 0.3-0.5 ¿M, (even lower according to the new structures published in the literature).

The research group is looking for companies in acquiring the above described technology for a future exploitation. For that reason the group is ready to deal whatever kind of technological transfer under the supervision of the University of Alicante.

The technology is protected according to a patent application:

• International Publication Number: WO2009/121989 A1.

• International Publication Date: 08.10.2009.