Prostaglandin synthesis and intermediates for use therein

• US 7,928,252 B2
• Filed: 11/14/2008
• Issued: 04/19/2011
• Est. Priority Date: 08/29/2008
• Status: Expired due to Fees

• Current Assignee: Alphora Research Inc. (Eurofins Scientific SE)
• Original Assignee: Alphora Research Inc. (Eurofins Scientific SE)
• Inventors: Oudenes, Jan, Alberico, Dino, Gorin, Boris Ivanovich, Clayton, Joshua
• Primary Examiner(s): Chandrakumar; Nizal S
• Application Number:
  US12/271,374
• Publication Number:
  US 20100056807A1
• Time in Patent Office: 886 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 process of preparing a substituted cyclopentane lactone compound of formula B:

2. The process of claim 1 wherein the solvent is methylene chloride.

3. The process of claim 2 wherein the reducing agent is dialkylaluminum hydride.

4. The process of claim 3 wherein the reaction temperature is from −

40-−

50°

C.

5. The process of claim 4 wherein R in formula A represents p-methoxyphenyl.

6. The process of claim 5 wherein the compound of formula B is next reacted with (4-carboxybutyl)triphenylphosphonium bromide and sodium hexamethyl disilazane to cause opening of the lactone ring and condensation thereof to form a compound of the following formula C:

7. The process of claim 6 wherein the terminal carboxyl group of compound C so formed is protected with a benzyl group, and the protected compound C so formed is oxidized with pyridine-sulfur trioxide in the presence of N,N-diisopropylethylamine and in DMSO-methylene chloride solvent, to oxidize the primary alcohol group and the secondary alcohol group to aldehydic and keto functionalities respectively in a single reaction step, yielding a compound of formula D:

8. The process of claim 7 wherein the compound of formula D so formed is subsequently reacted with dimethyl-(2-oxo-3,3-difluoroheptyl)phosphonate of formula:

9. The process of claim 8 wherein the compound of formula E so formed is subjected to catalytic hydrogenation with hydrogen over Pd/C catalyst, to hydrogenate both carbon-carbon double bonds and produce lubiprostone of formula:

10. The process of claim 1 wherein the compound of formula B is prepared from Corey lactone diol by reaction thereof with anisaldehyde dimethyl acetal in the presence of trace amounts of acid.

11. A process of preparing lubiprostone, of formula:

12. The process of claim 11 wherein the metal catalyst is palladium, and the reaction is conducted at room temperature in solution in isopropanol.