	US 12,071,410 B2
	High-yielding continuous flow synthesis of antimalarial drug hydroxychloroquine
Frank B. Gupton, Richmond, VA (US); Saeed Ahmad, Chesterfield, VA (US); Hari P. R. Gunuru, Henrico, VA (US); and Nakul S. Telang, Richmond, VA (US)
Assigned to Virginia Commonwealth University, Richmond, VA (US)
Appl. No. 16/975,434
Filed by VIRGINIA COMMONWEALTH UNIVERSITY, Richmond, VA (US)
PCT Filed Feb. 25, 2019, PCT No. PCT/US2019/019336 § 371(c)(1), (2) Date Aug. 25, 2020, PCT Pub. No. WO2019/165337, PCT Pub. Date Aug. 29, 2019.
Claims priority of provisional application 62/635,036, filed on Feb. 26, 2018.
Prior Publication US 2020/0407321 A1, Dec. 31, 2020
Int. Cl. C07D 215/46 (2006.01); B01J 8/04 (2006.01); B01J 19/00 (2006.01); B01J 19/18 (2006.01); B01J 19/24 (2006.01)

CPC C07D 215/46 (2013.01) [B01J 8/0492 (2013.01); B01J 19/0013 (2013.01); B01J 19/0066 (2013.01); B01J 19/1862 (2013.01); B01J 19/245 (2013.01); B01J 2219/00033 (2013.01); B01J 2219/0004 (2013.01)]

19 Claims

1. A method for synthesizing hydroxychloroquine (HCQ), comprising

in a flow reactor,

i) reacting 5-iodopentan-2-one with 2-(ethylamino)ethan-1-ol to form 5-(ethyl(2-hydroxyethyl)amino)pentan-2-one; and

ii) converting 5-(ethyl(2-hydroxyethyl)amino)pentan-2-one to (E)-5-(ethyl(2-hydroxyethyl)amino)pentan-2-one oxime;

and

in a first continuous stirred tank reactor (CSTR)

iii) contacting (E)-5-(ethyl(2-hydroxyethyl)amino)pentan-2-one oxime with a catalyst to form 5-(ethyl(2-hydroxyethyl)amino)-2-aminopentane;

and

in a second CSTR,

iv) reacting the 5-(ethyl(2-hydroxyethyl)amino)-2-aminopentane with 4,7,-dichloroquinoline in the presence of a base to form HCQ.