Process of making prostacyclin compounds with linker thiol and pegylated forms
A process provides for producing chiral prostacyclin derivatives of Formula (I) in high yield from meso anhydrides.
1. A process for the preparation of a compound of Formula I, or a pharmaceutically acceptable salt thereof:
the process comprising:
coupling a meso anhydride of Formula III with an ester compound of Formula IV in the presence of a chiral ligand, to provide a compound of Formula V:
coupling the compound of Formula V with a compound of Formula VI to form a thiol, hydrolyzing the thiol with a hydrolyzing agent to form a compound of Formula VIII;
deprotecting the compound of Formula VIII to form the compound of Formula II:
coupling the compound of Formula II with a PEG-maleimide compound to form the compound of Formula I;
wherein
X is O or CH 2 ;
Z is O or CH 2 ;
L is
p=0 or 1;
r=1-8;
t=1, 2 or 3;
w=1, 2, or 3;
PEG is a polyethylene glycol moiety;
R 1 represents an acid protective group; and
R 4 represents a thiol protecting group.
2. The process of claim 1 , wherein R 1 is a benzyl, tertiary-butyl, dimethoxy benzyl, nitrobenzyl or a dinitrobenzyl group.
3. The process of claim 1 , wherein the chiral ligand is a quinine or quinidine derivative.
4. The process of claim 3 , wherein the quinine or quinidine derivative is hydroquinine anthraquinone-1,4-diyl diether ((DHQ) 2 AQN), hydroquinidine anthraquinone-1,4-diyl diether ((DHQD) 2 AQN).
5. The process of claim 1 , wherein the hydrolyzing agent is trimethyltin hydroxide.
6. The process of claim 1 , wherein the compound of Formula VIII is deprotected using an acid.
7. The process of claim 6 , wherein the acid is trifluoroacetic acid.
8. A process for the preparation of a compound of Formula I, or a pharmaceutically acceptable salt thereof:
the process comprising: desymmeterizing a meso anhydride of structure III using an alcohol to provide an hemiester of Formula IX:
coupling the compound of Formula IX with a compound of Formula X,
deprotecting the product of the coupling of Formula IX with Formula X, to form the compound of Formula XI:
coupling the compound of Formula XI with a compound of Formula VI, to obtain a compound of Formula VII:
deprotecting the compound of Formula VII to form the compound of Formula II:
coupling the compound of Formula II with a polyethylene glycol maleimide compound to form the compound of Formula I;
wherein
X is O or CH 2 ;
Z is O or CH 2 ;
L is
L 1 is
p=0 or 1;
r=1-8;
w=1, 2, or 3;
t=1, 2 or 3;
R 1 represents an acid protective group;
R 2 represents a hydroxyl protective group;
R 4 represents a thiol protecting group; and
one of R 5 and R 6 represents H and the other represents a C 1-6 alkyl, allyl, or an aryl group.
9. The process of claim 8 , wherein R 1 is a benzyl, tertiary-butyl, dimethoxy benzyl, nitrobenzyl or a dinitrobenzyl group.
10. The process of claim 8 , wherein R 2 is a tetrahydropyranyl, benzyl, methoxybenzyl, nitrobenzyl, tertiary butyl dimethyl silyl or a tertiary methyl dimethyl silyl group.
11. The process of claim 8 , wherein the compound of Formula VII is deprotected using an acid.
12. The process of claim 11 , wherein the acid is trifluoroacetic acid.
13. A process for the preparation of a compound of Formula I, or a pharmaceutically acceptable salt thereof
the process comprising desymmeterizing a meso anhydride of Formula III using an alcohol to provide an hemiester of Formula IX:
coupling the compound of Formula IX with a compound of Formula VI, to provide a compound of Formula XII
coupling the compound of Formula XII with a compound of Formula X,
deprotecting the product of the coupling of Formula XII with Formula X, to form the compound of Formula II:
coupling the compound of Formula II with a polyethylene glycol maleimide compound to form the compound of Formula I;
wherein
X is O or CH 2 ;
Z is O or CH 2 ;
L is
L 1 is
p=0 or 1;
r=1-8;
w=1, 2, or 3;
t=1, 2 or 3;
R 1 represents an acid protective group;
R 2 represents a hydroxyl protective group,
R 4 represents a thiol protecting group; and
one of R 5 and R 6 represents H and the other represents a C 1-6 alkyl, allyl, or an aryl group,
R 7 represents an acid protective group.
14. The process of claim 13 , wherein R 1 is a benzyl, tertiary-butyl, dimethoxy benzyl, nitrobenzyl or a dinitrobenzyl group.
15. The process of claim 13 , wherein R 2 is a tetrahydropyranyl, benzyl, methoxybenzyl, nitrobenzyl, tertiary butyl dimethyl silyl or a tertiary methyl dimethyl silyl group.
16. The process of claim 13 , wherein R 7 is a C 1-6 alkyl group.
17. The process of claim 1 , wherein the purity of compound of Formula I is at least 90%.
18. The process of claim 1 , wherein the purity of compound of Formula II is at least 90%.
19. The process of claim 1 , wherein the polyethylene glycol maleimide compound is a 4-arm 20 KDa PEG maleimide.
20. The process of claim 1 , wherein X is O, w is 1, r is 6; and t is 2.
21. The process of claim 1 , wherein X is CH 2 , w is 2, r is 6; and t is 2.
22. A compound of Formula IB, prepared by the process of claim 1 :
23. A compound of Formula IIB, prepared by the process of claim 1 :