Synthesis routes for prostaglandins and prostaglandin intermediates using metathesis
Inventors
Yiannikouros, George Petros • Kalaritis, Panos • Gamage, Chaminda Priyapushpa • Arefyev, Denis Viktorovich
Assignees
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Publication Number
US-10100028-B2
Publication Date
2018-10-16
Expiration Date
Abstract
Methods of synthesizing prostaglandins, prostaglandin analogs and their synthetic intermediates are described. The methods can comprise metal-catalyzed metathesis reactions. Also provided are synthetic intermediates that can be used in the synthesis of the prostaglandins and prostaglandin analogs.
Core Innovation
The invention relates to methods for preparing synthetic intermediates of a prostaglandin or prostaglandin analog. A compound of Formula (VI) is reacted with a transition metal catalyst to perform a ring closing metathesis reaction to form a lactone, thereby preparing a synthetic intermediate of Formula (VII). The method optionally includes reducing a carbon-carbon double bond in the formed lactone via catalytic hydrogenation.
The synthetic intermediates include compounds defined by substituent-variable Formulae (XI), (XII), and related Formulae (II) to (IV), with m and n independently an integer between 0 and 10 and R1 independently H or a hydroxyl protecting group. R2, R3, R4, and R5 are independently selected from H, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl, and R is selected from aldehyde, acyl, nitroalkyl, aminoalkyl, thioalkyl, vinyl, and alkyl or alkenyl.
The disclosure further describes hydroxyl protecting groups including silyl ethers such as TBDMS, TMS, TES, and TBDPS, alkyl and aryl ether protecting groups, benzyl protecting groups, and carbonates or esters. It also states that some intermediates are crystalline compounds and that purification may be achieved via crystallinity versus chromatographic purification for some intermediates.
The intermediates are described as transformable to prostaglandins or prostaglandin analogs via enantioselective carbonyl reduction, hydroxyl deprotection, and/or lactone ring opening, and can also serve as prodrugs with in vivo lactone opening.
Claims Coverage
The claim coverage centers on one independent claim directed to preparing a synthetic intermediate of a prostaglandin or prostaglandin analog via ring closing metathesis of a defined Formula (VI) to produce a lactone intermediate of Formula (VII), with optional catalytic hydrogenation. Dependent claims refine the catalyst, lactone ring size, hydroxyl deprotection, lactone ring opening, and nitro-to-aldehyde conversion.
Ring closing metathesis to form a lactone intermediate
Reacting a compound of Formula (VI) with a transition metal catalyst to perform a ring closing metathesis reaction to form a lactone, thereby preparing a synthetic intermediate of a prostaglandin or prostaglandin analog as a compound of Formula (VII).
Optional catalytic hydrogenation of a carbon-carbon double bond
Optionally reducing a carbon-carbon double bond in the formed lactone via catalytic hydrogenation.
Specified transition metal catalyst for ring closing metathesis
Using the transition metal catalyst benzylidene-bis(tricyclohexylphosphine) dichlororuthenium.
Nine- or ten-membered lactone constraint
Forming a lactone that is either a nine-membered lactone or a ten-membered lactone.
Hydroxyl protecting group removal from Formula (VII) to Formula (VIII)
Removing one or more hydroxyl protecting groups from a compound of Formula (VII) to yield a compound of Formula (VIII).
Lactone ring opening to form a ring-opened prostaglandin or prostaglandin analog
Reacting the lactone ring of a compound of Formula (VII) with a selected nucleophile to form a ring-opened product that is a prostaglandin or prostaglandin analog.
Nitro-to-aldehyde conversion using titanium trichloride and sodium acetate
Contacting a nitro group-containing compound of Formula (VII) with titanium trichloride and sodium acetate to provide an aldehyde of a specified formula.
Overall, the claims focus on forming a prostaglandin or prostaglandin-analog lactone by transition metal-catalyzed ring closing metathesis from Formula (VI), optionally followed by catalytic hydrogenation. Dependent features further specify catalyst identity and lactone ring size, and add hydroxyl deprotection, lactone ring opening with defined nucleophile sets, and nitro-to-aldehyde conversion using titanium trichloride and sodium acetate.
Stated Advantages
Intermediates can serve as prodrugs with in vivo lactone opening.
Some intermediates are provided as crystalline compounds and purification may be achieved via crystallinity versus chromatographic purification for some intermediates.
Scalability/crystallization advantage is discussed.
Documented Applications
Intermediates can be transformed to prostaglandins or prostaglandin analogs via enantioselective carbonyl reduction, hydroxyl deprotection, and/or lactone ring opening.
Use of the described intermediates as prodrugs, where lactone opening can occur in vivo.
Example preparation of Formula (III) via intermolecular metathesis of allylcyclopentenones is documented.
Preparing synthetic intermediates of a prostaglandin or prostaglandin analog, including intermediates corresponding to compounds of Formula (VII) and related downstream intermediates derived therefrom.
Preparation of fluorinated prostaglandin analogs.
Preparation of unoprostone isopropyl ester.
Preparation of dinoprost.
Preparation of travoprost.
Preparation of chloroprostenol.
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