Prostaglandin synthesis and intermediates for use therein

• US 8,309,744 B2
• Filed: 04/07/2011
• Issued: 11/13/2012
• Est. Priority Date: 08/29/2008
• Status: Active Grant

• Current Assignee: Alphora Research Inc. (Eurofins Scientific SE)
• Original Assignee: Alphora Research Inc. (Eurofins Scientific SE)
• Inventors: Alberico, Dino, Clayton, Joshua, Gorin, Boris Ivanovich, Oudenes, Jan
• Primary Examiner(s): CHANDRAKUMAR, NIZAL S
• Application Number:
  US13/081,794
• Publication Number:
  US 20110184192A1
• Time in Patent Office: 586 Days
• Field of Search: 549/299, 549/465, 549/396, 562/503
• US Class Current: 549/299
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 405/00 Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
• CPC Class Codes: C07D 307/935 Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
• CPC Class Codes: C07D 311/94 condensed with rings other than six-membered or with ring systems containing such rings
• CPC Class Codes: C07D 493/04 Ortho-condensed systems

Abstract

Fused cyclopentane—4-substituted 3,5-dioxalane lactone compounds useful as an intermediate in the synthesis of prostaglandin analogs are provided. The compounds have the formula A:

wherein R represents an aryl group such as p-methoxyphenyl.

This compound can be reacted with a lower alkyl aluminum compound to open the dioxalane ring and reduce the lactone to lactol, without over-reducing to diol. The resulting compound can be functionalized to insert chemical side groups of target prostaglandins, adding the required α-side chain and then the required ω-side chain sequentially and independently of each other. The compounds and process are particularly suitable for preparing lubiprostone.

Claims

1. A fused cyclopentane—

4-substituted 3,5-dioxalane lactone compound useful as an intermediate in the synthesis of prostaglandin analogs, the compound having the formula A;

2. Compound A according to claim 1 wherein R represents a substituted phenyl group.

3. Compound A according to claim 1 wherein R represents p-methoxyphenyl.

4. A substituted cyclopentane lactone compound useful as an intermediate in the synthesis of prostaglandin analogs, the compound having the formula B:

5. Compound B according to claim 4 wherein R′

represents p-methoxybenzyl.

6. Compound C, ((Z)-benzyl 7-((1R,2R,3R)-2-((E)-4,4-difluoro-3-oxooct-1-enyl)-3-(4-methoxybenzyloxy)-5-oxocyclopentyl)hept-5-enoate), of formula: