Process for stereoselective synthesis of prostacyclin...

Details Process for stereoselective synthesis of prostacyclin... Process for stereoselective synthesis of prostacyclin...

2001-01-05

2004-03-02

Richter, Johann (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C568S807000, C568S808000, C544S154000, C544S171000, C544S176000, C544S376000, C546S203000, C546S309000, C548S250000, C560S028000, C560S056000, C052S446000

Reexamination Certificate

active

06700025

ABSTRACT:

FIELD OF THE INVENTION
The present application relates to a shortened process for producing prostacyclin derivatives and novel intermediate compounds useful in the process. The present application also relates to stereoselectively produced compounds prepared by the inventive process. Furthermore, the prostacyclins produced in this process are pure diastereomers, i.e., >99%.
BACKGROUND OF THE INVENTION
Prostacyclin derivatives are useful pharmaceutical compounds possessing activities such as platelet aggregation inhibition, gastric secretion reduction, lesion inhibition, vasodilation and bronchodilation.
For convenience, the novel prostacyclin derivatives will be referred to by the trivial, art-recognized system of nomenclature described by N. A. Nelson, J. Med. Chem. 17:911 (1974) for prostaglandins. Accordingly, all of the novel prostacyclin derivatives herein will be named as 9-deoxy-PGF
1
-type compounds.
U.S. Pat. No. 4,306,075 discloses methods for making prostacyclin derivatives. However, these and other known processes involve a large number of steps. It is an object of the present invention to provide an improved method of preparing prostacyclin derivatives involving fewer steps.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing 9-deoxy-PGF
1
-type compounds by a process that is stereoselective and requires fewer steps than the prior art. The invention also relates to novel intermediates prepared during the synthesis of the 9-deoxy-PGF
1
-type compounds. Furthermore, the invention relates to 9-deoxy-PGF
1
-type compounds prepared by the inventive process.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In one embodiment, the present invention relates to an improved stereoselective method for making 9-deoxy-PGF
1
-type compounds comprising converting a compound of the formula:
into a compound of the following formula:
wherein Y
1
is trans-CH═CH—, cis-CH═CH—, —CH
2
(CH
2
)
m
—, or —C≡C—; m is 1,2, or 3;
wherein R
1
is H or an alcohol protecting group;
wherein R
7
is
(1) —C
p
H
2p
—CH
3
, wherein p is an integer from 1 to 5, inclusive,
(2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C
1
-C
3
)alkyl, or (C
1
-C
3
)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R
7
is phenoxy or substituted phenoxy, only when R
3
and R
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
1
-C
3
)alkyl, or (C
1
-C
3
)alkoxy, with the proviso that not more than two substituents are other than alkyl,
(4) cis-CH═CH—CH
2
—CH
3
,
(5) —(CH)
2
—CH(OH)—CH
3
, or
(6) —(CH)
3
—CH═C(CH
3
)
2
;
wherein —C(L
1
)—R
7
taken together is
(1) (C
4
-C
7
)cycloalkyl optionally substituted by 1 to 3 (C
1
-C
5
)alkyl;
(2) 2-(2-furyl)ethyl,
(3) 2-(3-thienyl)ethoxy, or
(4) 3-thienyloxymethyl;
wherein M
1
is &agr;-OH:&bgr;-R
5
or &agr;-R:&bgr;-OH or &agr;-OR
1
:&bgr;-R
5
or &agr;-R
5
:&bgr;-OR
1
, wherein R
5
is hydrogen or methyl and R
1
is an alcohol protecting group; and
wherein L
1
is &agr;-R
3
:&bgr;-R
4
, &agr;-R
4
:&bgr;-R
3
, or a mixture of &agr;-R
3
:&bgr;-R
4
and &agr;-R
4
:&bgr;-R
3
, wherein R
3
and R
4
are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R
3
and R
4
is fluoro only when the other is hydrogen or fluoro.
Preferably, the above conversion is carried out through cobalt-mediated cyclization, in which the enyne undergoes intramolecular cyclization accompanied by a carbon monoxide insertion to form the tricyclic structure shown below.
More preferably, this cyclization is carried out by reacting Co
2
(CO)
8
with a compound of the formula:
using a suitable non-reactive solvent. Preferably, the non-reactive solvent is a chlorinated solvent, a hydrocarbon solvent, or an aromatic solvent. More preferably, the non-reactive solvent is selected from the group consisting of 1,2-DME (1,2-dimethoxyethane), CH
2
Cl
2
, toluene, isooctane, and heptane.
In the case of carrying out the cobalt-mediated cyclization with 1,2-DME after reacting Co
2
(CO)
8
with the compound of the formula:
to form a complex with the alkynyl group, preferably the solvent is removed in a subsequent step after intramolecular cyclization occurs to form the tricyclic compound.
Although Co
2
(CO)
8
contributes a carbonyl during the reaction, it is not necessary to react equal amounts of the starting compound of the above formula and Co
2
(CO)
8
. It is also possible to use the Co
2
(CO)
8
in a catalytic way, by introducing a relatively small amount of Co
2
(CO)
8
and also introducing CO into the reaction mixture (e.g., by bubbling CO into the reaction mixture) in the presence of light or heat which causes the transfer of CO through a Co-mediated complex formed with the compound of the formula:
In another preferred embodiment, the present invention relates to an improved stereoselective method for making 9-deoxy-PGF
1
-type compounds comprising the following reaction with heat or light:
wherein Y
1
is trans-CH═CH—, cis-CH═CH—, —CH
2
(CH)
m
—, or —C≡C—; m is 1,2, or 3;
wherein R
1
is an alcohol protecting group;
wherein R
7
is
(1) —C
p
H
2p
—CH
3
, wherein p is an integer from 1 to 5, inclusive,
(2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C
1
-C
3
)alkyl, or (C
1
-C
3
)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R
7
is phenoxy or substituted phenoxy, only when R
3
and R
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
1
-C
3
)alkyl, or (C
1
-C
3
)alkoxy, with the proviso that not more than two substituents are other than alkyl,
(4) cis-CH═CH—CH
2
—CH
3
,
(5) —(CH
2
)
2
—CH(OH)—CH
3
, or
(6) —(CH
2
)
3
—CH═C(CH
3
)
2
;
wherein —C(L
1
)—R
7
taken together is
(1) (C
4
-C
7
)cycloalkyl optionally substituted by 1 to 3 (C
1
-C
5
)alkyl;
(2) 2-(2-furyl)ethyl,
(3) 2-(3-thienyl)ethoxy, or
(4) 3-thienyloxymethyl;
M
1
is &agr;-OH:&bgr;-R
5
or &agr;-R
5
:&bgr;-OH or &agr;-OR
1
:&bgr;-R
5
or &agr;-R
5
:&bgr;-OR
1
, wherein R
5
is hydrogen or methyl and R
1
is an alcohol protecting group;
wherein L
1
is &agr;-R
3
:&bgr;-R
4
, &agr;-R
4
:&bgr;-R
3
, or a mixture of &agr;-R
3
:&bgr;-R
4
and &agr;-R
4
:&bgr;-R
3
, wherein R
3
and R
4
are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R
3
and R
4
is fluoro only when the other is hydrogen or fluoro.
The present invention also relates to a method of making the following compounds utilizing the following reaction scheme:
wherein R
1
is in each case an independently selected alcohol protecting group. Preferred alcohol protecting groups are tertiary butyl dimethyl silyl (TBDMS) and tetra hydro pyranyl (THP), trimethylsilyl (TMS), TES or any bulky groups.
The present invention also relates to the following novel intermediate compounds:
wherein Y
1
, M
1
, L
1
, R
1
and R
7
are as defined above.
The present invention also relates to a stereoselectively produced compound according to the following formula:
wherein Z is O, S, CH
2
, or NR
8
in which R
8
is H, alkyl or aryl;
X is H, CN, OR
9
, or COOR
9
in which R
9
is alkyl, THP or TBDMS;
n is 0, 1, 2, or 3;
Y
1
, M
1
, L
1
, and R
7
are as defined above and the compound is produced according to the inventive stereoselective synthesis. The produced compounds are diastereomerically pure.
In a preferred embodiment of the stereoselectively produced isomeric compound, Z is O, n is 1, X is COOH, Y
1
is —CH
2
CH
2
—M
1
is &agr;-OH:&bgr;-R
5
, wherein R
3
is hydrogen, L
1
is &agr;-R
3
:&bgr;-R
4
, wherein R
3
and R
4
are hydrogen and R
7
is propyl. The stereoselectively produced isomeric compound is diastereomerically pure.
“Diastereom

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