US 12,459,883 B2
Substituted hydroxystilbene compounds and derivatives synthesis and uses thereof
Colin Charles Duke, Randwick (AU); Rujee Kyokajee Duke, Randwick (AU); and Van Hoan Tran, Guilford (AU)
Assigned to Kynan Duke IP, LLC, Greensboro, NC (US)
Appl. No. 17/788,698
Filed by Kynan Duke IP, LLC, Greensboro, NC (US)
PCT Filed Dec. 23, 2020, PCT No. PCT/AU2020/051431
§ 371(c)(1), (2) Date Jun. 23, 2022,
PCT Pub. No. WO2021/127743, PCT Pub. Date Jul. 1, 2021.
Claims priority of application No. 2019904976 (AU), filed on Dec. 23, 2019.
Prior Publication US 2023/0159421 A1, May 25, 2023
Int. Cl. C07D 263/58 (2006.01); A61P 17/00 (2006.01); A61P 17/06 (2006.01); A61P 29/00 (2006.01); A61P 35/00 (2006.01); C07C 41/26 (2006.01); C07C 43/23 (2006.01); C07C 51/367 (2006.01); C07C 65/28 (2006.01); C07C 201/12 (2006.01); C07C 209/04 (2006.01); C07C 217/80 (2006.01); C07C 217/82 (2006.01); C07C 225/06 (2006.01); C07C 231/12 (2006.01); C07C 231/14 (2006.01); C07C 233/01 (2006.01); C07C 235/74 (2006.01); C07C 237/04 (2006.01); C07C 277/08 (2006.01); C07C 279/18 (2006.01); C07C 303/40 (2006.01); C07C 311/08 (2006.01); C07D 235/26 (2006.01)
CPC C07C 43/23 (2013.01) [A61P 17/00 (2018.01); A61P 17/06 (2018.01); A61P 29/00 (2018.01); A61P 35/00 (2018.01); C07C 41/26 (2013.01); C07C 51/367 (2013.01); C07C 65/28 (2013.01); C07C 201/12 (2013.01); C07C 209/04 (2013.01); C07C 217/80 (2013.01); C07C 217/82 (2013.01); C07C 225/06 (2013.01); C07C 231/12 (2013.01); C07C 231/14 (2013.01); C07C 233/01 (2013.01); C07C 235/74 (2013.01); C07C 237/04 (2013.01); C07C 277/08 (2013.01); C07C 279/18 (2013.01); C07C 303/40 (2013.01); C07C 311/08 (2013.01); C07D 235/26 (2013.01); C07D 263/58 (2013.01)] 33 Claims
 
1. A process of synthesising a compound of formula (I):

OG Complex Work Unit Chemistry
wherein:
R1a is independently allyl, crotyl, prenyl, benzyl or 2-alkenyl;
R1b is independently CF3, OR2 or NHR3;
R1c is H;
R1d is independently OH, O-protecting group, NHR3 or NO2;
R1e is independently C1-C6 alkyl, OH, OR2, NO2, NHR3, NMeR3 or SR2;
R1f is independently H, OH, O-protecting group, NO2, NHR3, N(OH)(CO)CH3, NHC═NH(NH2) or COOH;
R1g is independently H, C1-C6 alkyl or OH;
R1b and R1d are not the same;
no more than one of R1f or R1g can be H;
R2 is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or trifluoromethyl;
protecting group is selected from the group consisting of COMe, t-BuSi(CH3)2, 2-(trimethylsilyl) ethoxymethyl (SEM), CH(OEt)CH3, tetrahydropyranyl and C(OEt)(CH3)2;
R3 is independently H, CH3, (CO)H, (CO)Me, SO2Me, CH2COOH, CH2COOR2, CO(CH2)nNH2, CONH2, CO(CH2)nCOOH or COCOOR4, where n is 0, 1 or 2; and
R4 is C1-C6 alkyl;
or R1e and R1f form a five-membered heterocyclic ring containing a carbonyl group when R1e is independently OH, NH2 or NHMe and R1f is NH2, such that the nitrogen of R1f is bridged with the carbonyl group to the oxygen or nitrogen of R1e and R1g is H;
the process comprising:
i) a step of coupling a compound of formula (II) (Module A) with a compound of formula (III) (Module B) to afford a compound of formula (IV) (Module C):

OG Complex Work Unit Chemistry
wherein,
in Formula II (Module A):
R2b is independently CF3, OR2 or NH2;
R2c is H;
R2d is independently O-protecting group or NO2;
X is a halide or a hydroxyl group, wherein the halide is selected from the group consisting of F, Cl, Br, I, and At; and
R2 is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or trifluoromethyl;
in Formula III (Module B):
R3e is independently C1-C6 alkyl, OR2, NO2 or SR2;
R3f is independently H, O-protecting group, NO2 or COOR2;
R3g is independently H, C1-C6 alkyl, OH or OR2;
no more than one of R3f or R3g can be H;
R2 is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or trifluoromethyl; and
R4 is C1-C6 alkyl;
or R3e and R3f form a five-membered heterocyclic ring containing a carbonyl group when R3e is OH, NH2 or NHMe and R3f is NH2, such that the nitrogen of R3f is bridged with the carbonyl group to the oxygen or nitrogen of R3e and R3g is H;
in Formula IV (Module C):
R4b is independently CF3, OR2 or NH2;
R4c is H;
R4d is independently O-protecting group or NO2;
R4e is independently C1-C6 alkyl, OR2, NO2 or SR2;
R4f is independently H, O-protecting group, NO2 or COOH;
R4g is independently H, C1-C6 alkyl, OH or OR2;
no more than one of R4f or R4g can be H;
R2 is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or trifluoromethyl; and
X is a halide or a hydroxyl group, wherein the halide is selected from the group consisting of F, Cl, Br, I, and At;
or R4e and R4f form a five-membered heterocyclic ring containing a carbonyl group when R4e is OH, NH2 or NHMe and R4f is NH2, such that the nitrogen of R4f is bridged with the carbonyl group to the oxygen or nitrogen of R4e and R4g is H;
wherein the protecting group is selected from the group consisting of COMe, t-BuSi(CH3)2, 2-(trimethylsilyl) ethoxymethyl (SEM), CH(OEt)CH3, tetrahydropyranyl, or C(OEt)(CH3)2.