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Details for Patent: 6,441,245

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Details for Patent: 6,441,245

Title: Process for stereoselective synthesis of prostacyclin derivatives
Abstract:An improved method is described for making 9-deoxy-PGF.sub.1 -type compounds. In contrast to the prior art, the method is stereoselective and requires fewer steps than the known methods for making these compounds.
Inventor(s): Moriarty; Robert M. (Oak Park, IL), Penmasta; Raju (Bolingbrook, IL), Guo; Liang (Chicago, IL), Rao; Munagala S. (Westmont, IL), Staszewski; James P. (Naperville, IL)
Assignee: United Therapeutics Corporation (Washington, DC)
Filing Date:Apr 03, 2000
Application Number:09/541,521
Claims:1. A process for making 9-deoxy-PGF.sub.1 -type compounds comprising cyclizing a starting compound of the formula: ##STR25##

into a compound of the following formula: ##STR26##

by cobalt mediated cyclization wherein the starting compound is reacted with CO.sub.2 (CO).sub.8,

wherein Z is O, S, CH.sub.2, or NR.sub.8 in which R.sub.8 is H, alkyl or aryl; X is H, CN, OR.sub.9, or COOR.sub.9 in which R.sub.9 is alkyl, THP or TBDMS; wherein n is 0, 1, 2, or 3; wherein Y.sub.1 is trans-CH.dbd.CH--, cis-CH.dbd.CH--, --CH.sub.2 (CH.sub.2).sub.m --, or --C.ident.C--; m is 1,2, or 3; wherein R.sub.1 is an alcohol protecting group; wherein R.sub.7 is (1) --C.sub.p H.sub.2p --CH.sub.3, wherein p is an integer from one to 5, inclusive, (2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R.sub.7 is phenoxy or substituted phenoxy, only when R.sub.3 and R.sub.4 are hydrogen or methyl, being the same or different, (3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoxy, with the proviso that not more than two substituents are other than alkyl, (4) cis-CH.dbd.CH--CH.sub.2 --CH.sub.3, (5) --(CH.sub.2).sub.2 --CH(OH)--CH.sub.3, or (6) --(CH.sub.2).sub.3 --CH.dbd.C(CH.sub.3).sub.2 ; wherein --C(L.sub.1)--R.sub.7 taken together is (1) (C.sub.4 -C.sub.7)cycloalkyl optionally substituted by one to 3 (C.sub.1 -C.sub.5) alkyl; (2) 2-(2-furyl)ethyl, (3) 2-(3-thienyl)ethoxy, or (4) 3-thienyloxymethyl; wherein M.sub.1 is .alpha.-OH:.beta.-R.sub.5 or .alpha.-R.sub.5 :.beta.-OH or .alpha.-OR.sub.1 :.beta.-R.sub.5 or .alpha.-R.sub.5 :.beta.-OR.sub.1, wherein R.sub.5 is hydrogen or methyl and R.sub.1 is an alcohol protecting group; and wherein L.sub.1 is .alpha.-R.sub.3 :.beta.-R.sub.4, .alpha.-R.sub.4 :.beta.-R.sub.3, or a mixture of .alpha.-R.sub.3 :.beta.-R.sub.4 and .alpha.-R.sub.4 :.beta.-R.sub.3, wherein R.sub.3 and R.sub.4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R.sub.3 and R.sub.4 is fluoro only when the other is hydrogen or fluoro.

2. The process as claimed in claim 1, wherein the cyclization is a cobalt-mediated cyclization.

3. The process as claimed in claim 2, wherein the starting compound is reacted with Co.sub.2 (CO).sub.8 in a non-reactive solvent to form a complex, followed by heating to form the tricyclic compound.

4. The process as claimed in claim 3, wherein the non-reactive solvent during the complex-forming step is CH.sub.2 Cl.sub.2 and the non-reactive solvent during the heating step is CH.sub.3 CN.

5. The process as claimed in claim 3, wherein the non-reactive solvent during the complex-forming step is toluene and the non-reactive solvent during the heating step is toluene.

6. A stereoselective process of making a 9-deoxy-PGF.sub.1 -type compound, comprising the following reaction: ##STR27## wherein R.sub.1 is an alcohol protecting group; wherein n is 0, 1, 2, or 3; wherein Y.sub.1 is trans-CH.dbd.CH--, cis-CH.dbd.CH--, --CH.sub.2 (CH.sub.2).sub.m --, or --C.ident.C--; m is 1,2, or 3; wherein R.sub.7 is (1) --C.sub.p H.sub.2p --CH.sub.3, wherein p is an integer from one to 5, inclusive, (2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R.sub.7 is phenoxy or substituted phenoxy, only when R.sub.3 and R.sub.4 are hydrogen or methyl, being the same or different, (3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoxy, with the proviso that not more than two substituents are other than alkyl, (4) cis-CH.dbd.CH--CH.sub.2 --CH.sub.3, (5) --(CH.sub.2).sub.2 --CH(OH)--CH.sub.3, or (6) --(CH.sub.2).sub.3 --CH.dbd.C(CH.sub.3).sub.2 ; wherein --C(L.sub.1)--R.sub.7 taken together is (1) (C.sub.4 -C.sub.7)cycloalkyl optionally substituted by one to 3 (C.sub.1 -C.sub.5) alkyl; (2) 2-(2-furyl)ethyl, (3) 2-(3-thienyl)ethoxy, or (4) 3-thienyloxymethyl; wherein M.sub.1 is .alpha.-OH:.beta.-R.sub.5 or .alpha.-R.sub.5 :.beta.-OH, wherein R.sub.5 is hydrogen or methyl; wherein L.sub.1 is .alpha.-R.sub.3 :.beta.-R.sub.4, .alpha.-R.sub.4 :.beta.-R.sub.3, or a mixture of .alpha.-R.sub.3 :.beta.-R.sub.4 and .alpha.-R.sub.4 :.beta.-R.sub.3, wherein R.sub.3 and R.sub.4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R.sub.3 and R.sub.4 is fluoro only when the other is hydrogen or fluoro.

7. The process as claimed in claim 6, further comprising the following steps: ##STR28##

wherein R.sub.1 is an independently selected alcohol protecting group, m is 1, 2, or 3 and n is 0, 1, 2, or 3.

8. The process as claimed in claim 7, comprising the following steps: ##STR29## ##STR30## ##STR31##

9. The process as claimed in claim 8, wherein m is 1 and n is 0.

10. A compound of the formula ##STR32## wherein Z is O, S, CH.sub.2, or NR.sub.8 in which R.sub.8 is H, alkyl or aryl; wherein X is H, CN, OR.sub.9, or COOR.sub.9 in which R.sub.9 is alkyl, THP or TBDMS; wherein R.sub.1 is an alcohol protecting group; wherein n is 0, 1, 2, or 3; wherein Y.sub.1 is trans-CH.dbd.CH--, cis-CH.dbd.CH--, --CH.sub.2 (CH.sub.2).sub.m --, or --C.ident.C--; m is 1, 2, or 3; wherein R.sub.7 is (1) --C.sub.p H.sub.2p --CH.sub.3, wherein p is an integer from one to 5, inclusive, (2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R.sub.7 is phenoxy or substituted phenoxy, only when R.sub.3 and R.sub.4 are hydrogen or methyl, being the same or different, (3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoxy, with the proviso that not more than two substituents are other than alkyl, (4) cis-CH.dbd.CH--CH.sub.2 --CH.sub.3, (5) --(CH.sub.2).sub.2 --CH(OH)--CH.sub.3, or (6) --(CH.sub.2).sub.3 --CH.dbd.C(CH.sub.3).sub.2 ; wherein --C(L.sub.1)--R.sub.7 taken together is (1) (C.sub.4 -C.sub.7)cycloalkyl optionally substituted by one to 3 (C.sub.1 -C.sub.5)alkyl; (2) 2-(2-furyl)ethyl, (3) 2-(3-thienyl)ethoxy, or (4) 3-thienyloxymethyl; wherein M.sub.1 is .alpha.-OH:.beta.-R.sub.5 or .alpha.-R.sub.5 :.beta.-OH, wherein R.sub.5 is hydrogen or methyl; wherein L.sub.1 is .alpha.-R.sub.3 :.beta.-R.sub.4, .alpha.-R.sub.4 :.beta.-R.sub.3, or a mixture of .alpha.-R.sub.3 :.beta.-R.sub.4 and .alpha.-R.sub.4 :.beta.-R.sub.3, wherein R.sub.3 and R.sub.4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R.sub.3 and R.sub.4 is fluoro only when the other is hydrogen or fluoro.
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