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US 9,102,660 B2Granted
Process of making prostacyclin compounds with linker thiol and pegylated forms
AssigneeUnited Therapeutics Corporation
InventorsHitesh Batra, Liang Guo
Life of this patent
Estimating the term…
Abstract
A process provides for producing chiral prostacyclin derivatives of Formula (I) in high yield from meso anhydrides.
Claims23
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 CH2;
- Z is O or CH2;
- 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;
- R1 represents an acid protective group;
- and
- R4 represents a thiol protecting group.
14 more elements
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 CH2;
- Z is O or CH2;
- L is
- L1 is
- p=0 or 1;
- r=1-8;
- w=1, 2, or 3;
- t=1, 2 or 3;
- R1 represents an acid protective group;
- R2 represents a hydroxyl protective group;
- R4 represents a thiol protecting group;
- and
- one of R5 and R6 represents H and the other represents a C1-6 alkyl, allyl, or an aryl group.
18 more elements
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 CH2;
- Z is O or CH2;
- L is
- L1 is
- p=0 or 1;
- r=1-8;
- w=1, 2, or 3;
- t=1, 2 or 3;
- R1 represents an acid protective group;
- R2 represents a hydroxyl protective group,
- R4 represents a thiol protecting group;
- and
- one of R5 and R6 represents H and the other represents a C1-6 alkyl, allyl, or an aryl group,
- R7 represents an acid protective group.
17 more elements
Dependencies are inferred from the claim text.