Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-20
2003-07-29
Rotman, Alan L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06600052
ABSTRACT:
FIELD OF THE INVENTION
This invention is in the field of processes for the preparation of thiophene compounds. The invention particularly relates to processes for the regioselective preparation of 3,4-di(carbocyclyl or heterocyclyl)thiophenes, particularly 3,4-di(aryl or heteroaryl)thiophenes.
BACKGROUND OF THE INVENTION
Selected 3,4-di(aryl or heteroaryl)thiophene compounds have been disclosed in the literature as inhibitors of the cyclooxygenase-II enzyme. K. R Gans et al.,
Pharmacol. Exp. Ther.
1990, 254, 180. These thiophene compounds are useful as antiinflammatory and analgesic pharmaceutical agents. See, for example, WO94/15932. Conventional processes for the preparation of such thiophenes generally are not regioselective and require separation of isomeric mixtures to obtain the desired thiophene. Accordingly, there has been increased interest in improved processes for the preparation of 3,4-di(aryl or heteroaryl)thiophene compounds and improved processes for the preparation of intermediate compounds used in the preparation of such 3,4-di(aryl or heteroaryl)thiophenes.
One conventional method of preparing 3,4-diarylthiophenes is through a Hinsberg synthesis by the condensation of dithioglycolate esters with arylsubstituted benzoins. O. Hinsberg, Ber. 1910, 43, 901. This method, however, is not regioselective. When a thiophene possessing a specific regiochemistry is desired, the desired thiophene typically is obtained through (a) unselective base saponification of a single ester, (b) separation of the resulting isomers to obtain the desired isomer, and (c) manipulation of the desired isomer to introduce the necessary functional group or groups. S. R. Bertenshaw et al.,
Bioorg. Med. Chem. Lett.
1995, 5, 2919-2922; and J. Nakayama et al.,
Tetrahedron Lett.
1985, 26, 1981. This approach is illustrated in Comparative Scheme A below:
Another method for introducing a desired functional group to the thiophene ring requires electrophilic substitution of the thiophene. Regioselectivity of the resulting thiophene using the electrophilic substitution method can be achieved through introduction of differential electronic donating and withdrawing groups on the aromatic rings. This approach, however, is limited in scope and does not allow for the preparation of certain desirable substitutions of the thiophene ring. J. Y. Gauthier et. al.,
Bioorg. Med. Chem. Lett.
1996, 6, 87.
Scheme XIII of WO94/15932 discloses a non-regioselective method for the preparation of 3,4-diarylthiophenes wherein a thioacetylketone is coupled with a haloacetophenone to form a dione which is then converted to the thiophene in a modified McMurray synthesis.
WO95/00501 discloses a method for the preparation of 2,3-disubstituted thiophenes. In Method A of WO95/00501, a ketone is reacted with the Vilsmeier reagent (dimethylformamide-phosphorus oxychloride) to form a &bgr;-chlorovinylaldehyde. The &bgr;-chlorovinylaldehyde is then converted to a 2,3-disubstituted thiophene in accordance with the method of Weissenfels, Z.
Chem.,
1973, 13, 57. Regiochemistry of the thiophene can be controlled by selection of the desired ketone starting material. U.S. Pat. No. 4,820,827 discloses a similar conversion.
E. Dominguez et al.,
Synlett,
1995, 955-956, describes the preparation and use of a vinylogous amide as a starting compound for the synthesis of diarylpyrimidines.
R. Sanmartin et al.,
Tetrahedron
1994, 50, 2255-2264, describes the preparation and use of a vinylogous amide as a starting compound for the synthesis of &bgr;-aminoketones.
J. T. Gupton et al.,
Tetrahedron
1998, 54, 5075-5088, describes the preparation and use of a vinylogous amide as a starting compound for the synthesis of diarylpyrroles.
E. Dominguez et al.,
J. Org. Chem.
1996, 61, 5435-5439, describes the preparation and use of a vinylogous amide as a starting compound for the synthesis of diarylisoxazoles.
Accordingly, an improved process for the preparation of 3,4-di(carbocyclyl or heterocyclyl)thiophenes would be desirable, particularly a process that permits the regioselective preparation of a broad range of thiophenes and that is not dependent on the electronic nature of carbocyclyl or heterocyclyl rings attached to the thiophene ring.
SUMMARY OF THE INVENTION
The present invention is directed to an improved processes for the regioselective preparation of 3,4-di(carbocyclyl or heterocyclyl)thiophenes. In one aspect, the invention comprises a process for the preparation of a compound of Formula IV:
by reacting a compound of Formula III:
with a compound selected from the group consisting of thioacetic acid, esters of thioacetic acid and amides of thioacetic acid to form the compound of Formula IV,
wherein:
R
1
is selected from optionally substituted carbocyclyl and heterocyclyl;
R
2
is selected from optionally substituted carbocyclyl and heterocyclyl;
R
3
is selected from —OR
6
and —NR
7
R
8
;
R
4
and R
5
are independently selected from hydrogen and optionally substituted alkyl; and
R
6
, R
7
and R
8
are independently selected from hydrogen, hydrocarbyl and heterosubstituted hydrocarbyl.
In another aspect, the present invention comprises a process for the preparation of a compound of Formula V:
by reacting a compound of Formula IV:
with a ring cyclizing reagent to form the compound of Formula V,
wherein:
R
1
is selected from optionally substituted carbocyclyl and heterocyclyl;
R
2
is selected from optionally substituted carbocyclyl and heterocyclyl;
R
3
is selected from —OR
6
and —NR
7
R
8
; and
R
6
, R
7
and R
8
are independently selected from hydrogen, hydrocarbyl and heterosubstituted hydrocarbyl.
In another aspect, the present invention comprises a process for the regioselective preparation of 3,4-diphenylthiophenes comprising (a) reacting a deoxybenzoin with thioacetic acid or an ester or amide of thioacetic acid to form a Michael addition product, wherein (i) the deoxybenzoin comprises at least two double bonds conjugated with the same or different electron withdrawing groups, (ii) the dexoybenzoin comprises two phenyl moieties that are differently substituted, and (iii) the reaction is a nucleophilic addition reaction, and (b) cyclizing the Michael addition product to form a 3,4-diphenylthiophene.
In another aspect, the present invention comprises a process for the regioselective preparation of 3,4-diphenylthiophenes comprising (a) preparing a deoxybenzoin comprising (i) at least two double bonds conjugated with the same or different electron withdrawing groups and (ii) two phenyl moieties that are differently substituted, (b) reacting the deoxybenzoin with thioacetic acid or an ester or amide of thioacetic acid to form a Michael addition product, wherein the reaction is a nucleophilic addition reaction, and (c) cyclizing the Michael addition product to form a 3,4-diphenylthiophene.
In another aspect, the present invention comprises a process for the regioselective preparation of 3,4-diphenylthiophenes comprising (a) preparing a deoxybenzoin comprising two phenyl moieties that are differently substituted, (b) introducing a Michael acceptor into the primary carbon chain of the deoxybenzoin to provide a deoxybenzoin comprising at least two double bonds conjugated with the same or different electron withdrawing groups, (c) reacting the deoxybenzoin with thioacetic acid or an ester or amide of thioacetic acid to form a Michael addition product, wherein the reaction is a nucleophilic addition reaction, and (d) cyclizing the Michael addition product to form a 3,4-diphenylthiophene.
DESCRIPTION OF THE INVENTION
The present invention comprises processes for the regioselective preparation of 3,4-di(carbocyclyl or heterocyclyl)thiophenes, particularly processes that do not depend on the electronic nature of a carbocyclyl or heterocyclyl ring attached to the thiophene ring, as well as processes for the preparation of intermediate compounds useful in the the regioselective preparation of 3,4-di(carbocyclyl or heterocyclyl)thiophenes. The novel processes result in the formation of a thiophene ring wherein a single ester
Brown David L.
Ludwig Cindy L.
Pharmacia Corporation
Rotman Alan L.
Shameem Golam M. M.
LandOfFree
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