Process for stereoselective synthesis of prostacyclin...

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

2000-04-03

2002-08-27

Padmanabhan, Sreeni (Department: 1621)

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

Organic compounds

Oxygen containing

C568S338000, C560S121000, C562S503000

Reexamination Certificate

active

06441245

ABSTRACT:

FIELD OF THE INVENTION
The present application relates to a process for producing prostacyclin derivatives and novel intermediate compounds useful in the process.
BACKGROUND OF THE INVENTION
Prostacyclin derivatives are useful pharmaceutical compounds possessing activities such as platelet aggregation inhibition, gastric secretion reduction, lesion inhibition, 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.
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 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;
wherein n is 0, 1, 2, or 3;
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 an alcohol protecting group;
wherein R
7
is
(1) —C
p
H
2p
—CH
3
, wherein p is an integer from one 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 R4 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 one 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
5
:&bgr;-OH, wherein R
5
is hydrogen or methyl; 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 a complex is formed with the alkynyl group of the starting compound, which decomposes upon heating to form a tricyclic structure. More preferably, this cyclization is carried out by reacting Co
2
(CO)
8
with the above 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 CH
2
Cl
2
, toluene, isooctane, and heptane.
In the case of carrying out the cobalt-mediated cyclization with CH
2
Cl
2
, after reacting Co
2
(CO)
8
with the above compound of the formula:
in the presence of CH
2
Cl
2
to form a complex with the alkynyl group, preferably the CH
2
Cl
2
is removed in a subsequent step and replaced with CH
3
CN followed by heating in an inert gas atmosphere, such as argon, nitrogen, or carbon monoxide, which decomposes the complex to form the above 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 which catalyzes the transfer of CO through a Co-mediated complex formed with the above 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:
wherein n is 0, 1, 2 or 3;
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 an alcohol protecting group;
wherein R
7
is
(1) —C
p
H
2p
CH
3
, wherein p is an integer from one 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 one 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
5
:&bgr;-OH, wherein R
5
is hydrogen or methyl;
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 foregoing reaction:
wherein R
1
, is in each case an independently selected alcohol protecting group. Preferred alcohol protecting groups are tertiary butyl dimethyl sily (TBDMS) and tetra hydro pyranyl (THP).
The present invention also relates to the following novel intermediate compounds:
wherein X, Z, Y
1
, M
1
, L
1
, R
1
and R
7
are as defined above.


REFERENCES:
patent: 4306075 (1981-12-01), Aristoff
patent: 5153222 (1992-10-01), Tadepalli et al.
patent: 0 087 237 (1983-08-01), None
patent: WO 98/39337 (1998-09-01), None
J. J. F. Belch et al., Circulation, vol. 95, No. 9, “Randomized, Double-Blind, Placebo-Controlled Study Evaluating the efficacy and Safety of AS-013, a prostaglandin E1Prodrug, in Patients With Intermittent Claudication,” pp. 2298-2302 (1997).
N. A. Nelson, Journal of Medicinal Chemistry, vol. 17, No. 9, “Prostaglandin Nomenclature,” pp. 911-918 (1974).
S. Takano et al., Chemistry Letters, “Enantiodivergent Synthesis of Both Enantiomers of Sulcatol and Matsutake Alcohol from ®-Epichlorohydrin,” pp. 2017-2020 (1987).
D. J. Mathre et al., J. Org. Chem., vol. 56, “A Practical Enantioselective Synthesis of &agr;,&agr;-Diaryl-2-pyrrolidinemethanol, Preparation and Chemistry of the Corresponding Oxazaborolidines,” pp. 751-762 (1991).
B. L. Pagenkoph, Diss. Abstr. Int., vol. 57, No. 12, “Substrate and reagent control of diastereoselectivity in transition metal-mediated process: development of a catalytic pho

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