US 12,319,639 B2
Flow synthesis process for the production of oseltamivir
Cloudius Ray Sagandira, Port Elizabeth (ZA); and Paul Watts, Port Elizabeth (ZA)
Assigned to Nelson Mandela University, Port Elizabeth (ZA)
Appl. No. 17/438,518
Filed by Nelson Mandela University, Port Elizabeth (ZA)
PCT Filed Feb. 28, 2020, PCT No. PCT/IB2020/051707
§ 371(c)(1), (2) Date Sep. 13, 2021,
PCT Pub. No. WO2020/183281, PCT Pub. Date Sep. 17, 2020.
Claims priority of application No. 2022745 (NL), filed on Mar. 14, 2019.
Prior Publication US 2022/0144756 A1, May 12, 2022
Int. Cl. C07C 231/14 (2006.01)
CPC C07C 231/14 (2013.01) 20 Claims
 
1. A flow synthesis process for producing a compound of the Formula 33 and its pharmaceutically acceptable salts,

OG Complex Work Unit Chemistry
the process comprising the steps of:
a) preparing ethyl shikimate of Formula 39

OG Complex Work Unit Chemistry
by reacting shikimic acid with a reagent selected from the group consisting of (COCl)2, SOCl2, benzene sulphonic acid (BSA), p-toluene sulphonic acid (PTSA), and Amberlyst 15,
b) reacting the ethyl shikimate of Formula 39 with mesyl chloride in the presence of a base selected from the group consisting of trimethyl amine (TEA), 1,8-diazabicyclo(5.4.0) undec-7-ene (DBU), imidazole, and trihexyl amine (THA) to produce the O-trimesylate of Formula 40, wherein the base is present at a concentration of about 8 to about 20 molar equivalents relative to ethyl shikimate,

OG Complex Work Unit Chemistry
c) reacting the O-trimesylate of Formula 40 in an azidation reaction with an appropriate azidating agent to produce the azide of Formula 41

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d) reacting the azide of Formula 41 in an aziridation reaction with a trialkyl phosphite to produce the aziridine of Formula 42

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e) reacting the aziridine of Formula 42 with 3-pentanol in the presence of a Lewis acid catalyst to produce the 3-pentyl ether of Formula 43

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f) reacting the 3-pentyl ether of Formula 43 in an acetylation reaction with H2SO4, followed by Ac2O in the presence of a suitable base to produce the acetamide of Formula 44

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g) reacting the acetamide of Formula 44 in an azidation reaction with an appropriate azidating reagent produce the azide of Formula 32

OG Complex Work Unit Chemistry
and
h) reacting the azide of Formula 32 by mixing the azide with CoCl2, and reacting the mixture with NaBH4 to produce the compound of Formula 33.