A novel process for preparing 3,4-di(carbocyclyl or heterocyclyl)thiophenes comprising reacting a compound of Formula IV:

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.
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 xcex2-chlorovinylaldehyde. The xcex2-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 xcex2-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.
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:
R1 is selected from optionally substituted carbocyclyl and heterocyclyl;
R2 is selected from optionally substituted carbocyclyl and heterocyclyl;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8;
R4 and R5 are independently selected from hydrogen and optionally substituted alkyl; and
R6, R7 and R8 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:
R1 is selected from optionally substituted carbocyclyl and heterocyclyl;
R2 is selected from optionally substituted carbocyclyl and heterocyclyl;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8; and
R6, R7 and R8 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.
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 or amido functionality is selectively introduced to the ring at a position adjacent to the sulfur heteroatom while the other position of the ring adjacent to the sulfur heteroatom remains unsubstituted. Selection of the proper starting material for the cyclization reaction by which the thiophene is formed controls the regioselectivity of the resulting thiophene. The 3,4-di(carbocyclyl or heterocyclyl)thiophenes comprising the ester or amido functionality can then be used as a final product or can be further modified to yield other desirable thiophenes.
In accordance with a process of the present invention, a compound of Formula III:
is reacted with a compound selected from the group consisting of thioacetic acid, esters of thioacetic acid and amides of thioacetic acid to form a compound of Formula IV:
wherein:
R1 is selected from optionally substituted carbocyclyl and heterocyclyl;
R2 is selected from optionally substituted carbocyclyl and heterocyclyl;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8;
R4 and R5 are independently selected from hydrogen and optionally substituted alkyl; and
R6, R7 and R8 are independently selected from hydrogen, hydrocarbyl and heterosubstituted hydrocarbyl.
The compound of Formula III preferably is reacted with HSCH2C(O)R3 to form the compound of Formula IV,
wherein:
R1 is selected from optionally substituted cycloalkyl, cycloalkenyl, aryl and heteroaryl;
R2 is selected from optionally substituted cycloalkyl, cycloalkenyl, aryl and heteroaryl;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8;
R4 and R5 are independently selected from optionally substituted alkyl; and
R6, R7 and R8 are independently selected from hydrogen and optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, arylalkyl and heterocyclylalkyl, wherein said alkyl may have one or more carbon atoms that are optionally replaced with oxygen atoms.
In another embodiment, the compound of Formula III is reacted with HSCH2C(O)R3 to form the compound of Formula IV wherein:
R1 is selected from optionally substituted aryl and 5- or 6-membered ring heteroaryl;
R2 is selected from optionally substituted aryl and 5- or 6-membered ring heteroaryl;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8;
R4 and R5 are independently selected from optionally substituted alkyl; and
R6, R7 and R8 are independently selected from hydrogen and optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, arylalkyl and heterocyclylalkyl, wherein said alkyl may have one or more carbon atoms that are optionally replaced with oxygen atoms.
In still another embodiment, the compound of Formula III is reacted with HSCH2C(O)R3 to form the compound of Formula IV wherein:
R1 is selected from optionally substituted phenyl, pyridinyl, pyrimidinyl, thienyl or furyl;
R2 is selected from optionally substituted phenyl, pyridinyl, pyrimidinyl, thienyl or furyl;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8;
R4 and R5 are independently selected from optionally substituted alkyl; and
R6, R7 and R8 are independently selected from hydrogen and optionally substituted lower alkyl, lower alkenyl, 3-6 member ring cycloalkyl, 3-6 member ring cycloalkenyl, phenyl, (phenyl)-lower alkyl and (5- or 6-member heteroaryl)-lower alkyl, wherein said alkyl may have one or more carbon atoms that are optionally replaced with oxygen atoms.
In still another embodiment, the compound of Formula III is reacted with HSCH2C(O)R3 to form the compound of Formula IV wherein:
one of R1 and R2 is phenyl, pyridinyl, pyrimidinyl, thienyl or furyl optionally substituted with one, two or three radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, phenylamino, nitro, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, halo, alkoxy and alkylthio;
the other of R1 and R2 is phenyl optionally substituted with one, two or three radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, phenylamino, nitro, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, halo, alkoxy and alkylthio;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8;
R4 and R5 are independently selected from optionally substituted alkyl; and
R6, R7 and R8 are independently selected from hydrogen and optionally substituted alkyl, alkenyl, alkynyl, 3-6 member ring cycloalkyl, 3-6 member ring cycloalkenyl, 5- or 6-member ring aryl, 5- or 6-member ring heteroaryl, phenylalkyl and (5- or 6-member heteroaryl)alkyl.
In still another embodiment, the compound of Formula III is reacted with HSCH2C(O)R3 to form the compound of Formula IV wherein:
one of R1 and R2 is phenyl, pyridinyl, or pyrimidinyl optionally substituted with one, two or three radicals selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, lower alkylsulfonyl, aminosulfonyl, halo, lower alkoxy and lower alkylthio;
the other of R1 and R2 is phenyl optionally substituted with one, two or three radicals selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, lower alkylsulfonyl, aminosulfonyl, halo, lower alkoxy and lower alkylthio;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8;
R4 and R5 are independently selected from optionally substituted alkyl; and
R6, R7 and R8 are independently selected from hydrogen and optionally substituted lower alkyl, lower alkenyl, 3-6 member ring cycloalkyl, phenyl, 5- or 6-member ring heteroaryl, (phenyl)-lower alkyl, and (5- or 6-member ring heteroaryl)-lower alkyl.
In still another embodiment, the compound of Formula III is reacted with HSCH2C(O)R3 to form the compound of Formula IV wherein:
one of R1 and R2 is phenyl, pyridinyl, or pyrimidinyl optionally substituted with one, two or three radicals selected from C1-2-alkyl, C1-2-haloalkyl, cyano, carboxyl, C1-2-alkoxycarbonyl, hydroxyl, C1-2-hydroxyalkyl, C1-2-haloalkoxy, amino, C1-2-alkylamino, phenylamino, nitro, C1-2-alkoxy-C1-2-alkyl, C1-2-alkylsulfinyl, C1-2-alkylsulfonyl, aminosulfonyl, halo, C1-2-alkoxy and C1-2-alkylthio;
the other of R1 and R2 is phenyl optionally substituted with one, two or three radicals selected from C1-2-alkyl, C1-2-haloalkyl, cyano, carboxyl, C1-2-alkoxycarbonyl, hydroxyl, C1-2-hydroxyalkyl, C1-2-haloalkoxy, amino, C1-2-alkylamino, phenylamino, nitro, C1-2-alkoxy-C1-2-alkyl, C1-2-alkylsulfinyl, C1-2-alkylsulfonyl, aminosulfonyl, halo, C1-2-alkoxy and C1-2-alkylthio;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8;
R4 and R5 are independently selected from optionally substituted C1-4-alkyl; and
R6, R7 and R8 are independently selected from hydrogen and optionally substituted C1-3-alkyl, C1-3-alkenyl, 3-6 member ring cycloalkyl, phenyl, 5- or 6-member ring heteroaryl, (phenyl)C1-3-alkyl, (5- or 6-member ring heteroaryl)C1-3-alkyl.
In still another embodiment, the compound of Formula III is reacted with HSCH2C(O)R3 to form the compound of Formula IV wherein:
one of R1 and R2 is phenyl or pyridinyl optionally substituted with one, two or three radicals selected from methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, methylamino, phenylamino, nitro, methoxymethyl, methylsulfinyl, methylsulfonyl, aminosulfonyl, fluoro, chloro, bromo, methoxy and methylthio;
the other of R1 and R2 is phenyl optionally substituted with one, two or three radicals selected from methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, methylamino, phenylamino, nitro, methoxymethyl, methylsulfinyl, methylsulfonyl, aminosulfonyl, fluoro, chloro, bromo, methoxy and methylthio;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8;
R4 and R5 are independently selected from optionally substituted methyl and ethyl; and
R6, R7 and R8 are independently selected from hydrogen and optionally substituted methyl, ethyl, propyl, t-butyl, ethenyl, propenyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, phenyl, pyridinyl, pyrimidinyl, and benzyl.
In still another embodiment, the compound of Formula III is reacted with HSCH2C(O)R3 to form the compound of Formula IV wherein:
one of R1 and R2 is phenyl or pyridinyl optionally substituted with one, two or three radicals selected from halo, cyano, C1-2-alkyl, C1-2-haloalkyl, C1-2-alkoxy, C1-2-haloalkoxy, C1-2-alkylsulfonyl, aminosulfonyl;
the other of R1 and R2 is phenyl optionally substituted with one, two or three radicals selected from halo, cyano, C1-2-alkyl, C1-2-haloalkyl, C1-2-alkoxy, C1-2-haloalkoxy, C1-2-alkylsulfonyl, aminosulfonyl;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8;
R4 and R5 are methyl; and
R6, R7 and R8 are independently selected from hydrogen and optionally substituted C1-3-alkyl, C1-3-alkenyl, 3-6 member ring cycloalkyl, phenyl, 5- or 6-member ring heteroaryl, (phenyl)C1-3-alkyl, and (5- or 6-member ring heteroaryl)C1-3-alkyl.
In still another embodiment, the compound of Formula III is reacted with HSCH2C(O)R3 to form the compound of Formula IV wherein:
R1 is phenyl or pyridinyl optionally substituted with one, two or three radicals selected from methyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, cyano, methylsulfonyl, aminosulfonyl, fluoro, chloro, bromo, and methoxy;
R2 is phenyl optionally substituted with one, two or three radicals selected from methyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, cyano, methylsulfonyl, aminosulfonyl, fluoro, chloro, bromo, and methoxy;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8;
R4 and R5 are methyl; and
R6, R7 and R8 are independently selected from hydrogen and optionally substituted methyl, ethyl, propyl and benzyl.
The reaction of the compound of Formula III with the thioacetic acid, ester of thioacetic acid or amide of thioacetic acid generally is conducted in solution, typically in an organic solvent. The organic solvent may be any suitable solvent such as, for example, a solvent selected from the group consisting of toluene, alcohols and halogenated hydrocarbons. Suitable halogenated hydrocarbons include, but are not limited to, haloalkyls such as 1,2-dichloroethane. The reaction can be carried out over a range of concentrations. In one embodiment, for example, the compound of Formula III is initially present at a concentration of about 1 gram per about 2 to 20 mL of the appropriate solvent. The thioacetic acid, ester of thioacetic acid or amide of thioacetic acid typically is initially present in excess. Preferably, the molar equivalents of thioacetic acid, ester of thioacetic acid or amide of thioacetic acid initially present is at least about 5 to 10 times greater than the molar equivalents of the compound of Formula III initially present. The temperature of the reaction is not critical, but productivity is enhanced by operation at elevated temperature. For example, the reaction advantageously may be carried out by reacting the compound of Formula III with the compound selected from thioacetic acid, esters of thioacetic acid and amides of thioacetic acid in a suitable solvent under reflux conditions. When the reaction is carried out under reflux conditions, it generally is completed within about 4 to 24 hours. The compound of Formula IV is then isolated by removal of solvent and used in the next step of the process. The compounds of Formula IV are novel compounds and have substantial value as intermediates for the preparation of the compounds of Formula V discussed below.
The compound of Formula III can be prepared by any suitable method. In one illustrative process, the compound of Formula III is prepared by reacting an ethanone of Formula I:
with an acetal of Formula II:
wherein R1, R2, R4 and R5 are as defined for the compound of Formula III, and R9 and R10 are optionally substituted alkyl.
The reaction of the ethanone of Formula I with the acetal of Formula II generally is conducted in solution, typically in an organic solvent. The organic solvent may be any suitable solvent, preferably one having a boiling point greater than about 90xc2x0 C. such as toluene. The reaction can be carried out over a range of concentrations. In one embodiment, for example, the ethanone of Formula I is initially present at a concentration of about 1 gram per about 2 to 20 mL of the appropriate solvent. The acetal of Formula II typically is initially present in excess. Preferably, the molar equivalents of the acetal of Formula II initially present is at least about 1 to 5 times greater than the molar equivalents of the compound of Formula I initially present. The temperature of the reaction is not critical, but productivity is enhanced by operation at elevated temperature. For example, the reaction advantageously may be carried out by reacting the ethanone of Formula I with the acetal of Formula II in a suitable solvent under reflux conditions. When the reaction is carried out under reflux conditions, it generally is completed within about 4 to 24 hours. The compound of Formula II is then isolated by removal of solvent and trituration with hexanes or other appropriate solvents and used in the preparation of the compound of Formula III. The compounds of Formula III are novel compounds and have substantial value as intermediates for the preparation of the compounds of Formula IV.
The ethanones of Formula I can be prepared in accordance with methods disclosed in the technical literature. By way of illustration and not limitation, where the ethanone of Formula I is a deoxybenzoin, such deoxybenzoins can be prepared with specific aromatic ring substitution, for example, through Friedel-Crafts acylation in the manner discussed in C. F. Allen et al., Org. Synth. 1943, II, 156; alkylation of cyanohydrins in the manner discussed in Dembech P. et al., Tetrahedron 1990, 46, 2999-3006; coupling of organometallic precursors in the manner discussed in S.-H. Kim et al., Tetrahedron Lett 1999, 40, 4931-4934; or any other suitable method.
In another embodiment of the invention, (a) an ethanone of Formula I is reacted with an acetal of Formula II to yield a compound of Formula III, and (b) the compound of Formula III is reacted with a compound selected from thioacetic acid, esters of thioacetic acid and amides of thioacetic acid to yield a compound of Formula IV without first isolating the compound of Formula III in purified form. Alternatively, as previously noted, the compound of Formula III can be isolated in substantially purified form before it is reacted with the compound selected from the group consisting thioacetic acid, esters of thioacetic acid and amides of thioacetic acid.
The compound of Formula IV:
is then reacted with a ring cyclizing reagent to form a compound of Formula V:
wherein:
R1 is selected from optionally substituted carbocyclyl and heterocyclyl;
R2 is selected from optionally substituted carbocyclyl and heterocyclyl;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8; and
R6, R7 and R8 are independently selected from hydrogen, hydrocarbyl and heterosubstituted hydrocarbyl.
In another embodiment, the compound of Formula IV is reacted with a ring cyclizing reagent to form a compound of Formula V wherein:
R1 is selected from optionally substituted cycloalkyl, cycloalkenyl, aryl and heteroaryl;
R2 is selected from optionally substituted cycloalkyl, cycloalkenyl, aryl and heteroaryl;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8; and
R6, R7 and R8 are independently selected from hydrogen and optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, arylalkyl and heterocyclylalkyl, wherein said alkyl may have one or more carbon atoms that are optionally replaced with oxygen atoms.
In still another embodiment, the compound of Formula IV is reacted with a ring cyclizing reagent to form a compound of Formula V wherein:
R1 is selected from optionally substituted aryl and 5- or 6-membered ring heteroaryl;
R2 is selected from optionally substituted aryl and 5- or 6-membered ring heteroaryl;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8; and
R6, R7 and R8 are independently selected from hydrogen and optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, arylalkyl and heterocyclylalkyl, wherein said alkyl may have one or more carbon atoms that are optionally replaced with oxygen atoms.
In still another embodiment, the compound of Formula IV is reacted with a ring cyclizing reagent to form a compound of Formula V wherein:
R1 is selected from optionally substituted phenyl, pyridinyl, pyrimidinyl, thienyl or furyl;
R2 is selected from optionally substituted phenyl, pyridinyl, pyrimidinyl, thienyl or furyl;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8; and
R6, R7 and R8 are independently selected from hydrogen and optionally substituted lower alkyl, lower alkenyl, 3-6 member ring cycloalkyl, 3-6 member ring cycloalkenyl, phenyl, (phenyl)-lower alkyl and (5- or 6-member heteroaryl)-lower alkyl, wherein said alkyl may have one or more carbon atoms that are optionally replaced with oxygen atoms.
In still another embodiment, the compound of Formula IV is reacted with a ring cyclizing reagent to form a compound of Formula V wherein:
one of R1 and R2 is phenyl, pyridinyl, pyrimidinyl, thienyl or furyl optionally substituted with one, two or three radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, phenylamino, nitro, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, halo, alkoxy and alkylthio;
the other of R1 and R2 is phenyl optionally substituted with one, two or three radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, phenylamino, nitro, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, halo, alkoxy and alkylthio;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8; and
R6, R7 and R8 are independently selected from hydrogen and optionally substituted alkyl, alkenyl, alkynyl, 3-6 member ring cycloalkyl, 3-6 member ring cycloalkenyl, 5- or 6-member ring aryl, 5- or 6-member ring heteroaryl, phenylalkyl and (5- or 6-member heteroaryl)alkyl.
In still another embodiment, the compound of Formula IV is reacted with a ring cyclizing reagent to form a compound of Formula V wherein:
one of R1 and R2 is phenyl, pyridinyl, or pyrimidinyl optionally substituted with one, two or three radicals selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, lower alkylsulfonyl, aminosulfonyl, halo, lower alkoxy and lower alkylthio;
the other of R1 and R2 is phenyl optionally substituted with one, two or three radicals selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, lower alkylsulfonyl, aminosulfonyl, halo, lower alkoxy and lower alkylthio;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8; and
R6, R7 and R8 are independently selected from hydrogen and optionally substituted lower alkyl, lower alkenyl, 3-6 member ring cycloalkyl, phenyl, 5- or 6-member ring heteroaryl, (phenyl)-lower alkyl, and (5- or 6-member ring heteroaryl)-lower alkyl.
In still another embodiment, the compound of Formula IV is reacted with a ring cyclizing reagent to form a compound of Formula V wherein:
one of R1 and R2 is phenyl, pyridinyl, or pyrimidinyl optionally substituted with one, two or three radicals selected from C1-2-alkyl, C1-2-haloalkyl, cyano, carboxyl, C1-2-alkoxycarbonyl, hydroxyl, C1-2-hydroxyalkyl, C1-2-haloalkoxy, amino, C1-2-alkylamino, phenylamino, nitro, C1-2-alkoxy-C1-2-alkyl, C1-2-alkylsulfinyl, C1-2-alkylsulfonyl, aminosulfonyl, halo, C1-2-alkoxy and C1-2-alkylthio;
the other of R1 and R2 is phenyl optionally substituted with one, two or three radicals selected from C1-2-alkyl, C1-2-haloalkyl, cyano, carboxyl, C1-2-alkoxycarbonyl, hydroxyl, C1-2-hydroxyalkyl, C1-2-haloalkoxy, amino, C1-2-alkylamino, phenylamino, nitro, C1-2-alkoxy-C1-2-alkyl, C1-2-alkylsulfinyl, C1-2-alkylsulfonyl, aminosulfonyl, halo, C1-2-alkoxy and C1-2-alkylthio;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8;
R4 and R5 are independently selected from optionally substituted C1-4-alkyl; and
R6, R7 and R8 are independently selected from hydrogen and optionally substituted C1-3-alkyl, C1-3-alkenyl, 3-6 member ring cycloalkyl, phenyl, 5- or 6-member ring heteroaryl, (phenyl)C1-3-alkyl, (5- or 6-member ring heteroaryl)C1-3-alkyl.
In still another embodiment, the compound of Formula IV is reacted with a ring cyclizing reagent to form a compound of Formula V wherein:
one of R1 and R2 is phenyl or pyridinyl optionally substituted with one, two or three radicals selected from methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, methylamino, phenylamino, nitro, methoxymethyl, methylsulfinyl, methylsulfonyl, aminosulfonyl, fluoro, chloro, bromo, methoxy and methylthio;
the other of R1 and R2 is phenyl optionally substituted with one, two or three radicals selected from methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, methylamino, phenylamino, nitro, methoxymethyl, methylsulfinyl, methylsulfonyl, aminosulfonyl, fluoro, chloro, bromo, methoxy and methylthio;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8; and
R6, R7 and R8 are independently selected from hydrogen and optionally substituted methyl, ethyl, propyl, t-butyl, ethenyl, propenyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, phenyl, pyridinyl, pyrimidinyl, and benzyl.
In still another embodiment, the compound of Formula IV is reacted with a ring cyclizing reagent to form a compound of Formula V wherein:
one of R1 and R2 is phenyl or pyridinyl optionally substituted with one, two or three radicals selected from halo, cyano, C1-2-alkyl, C1-2-haloalkyl, C1-2-alkoxy, C1-2-haloalkoxy, C1-2-alkylsulfonyl, aminosulfonyl;
the other of R1 and R2 is phenyl optionally substituted with one, two or three radicals selected from halo, cyano, C1-2-alkyl, C1-2-haloalkyl, C1-2-alkoxy, C1-2-haloalkoxy, C1-2-alkylsulfonyl, aminosulfonyl;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8; and
R6, R7 and R8 are independently selected from hydrogen and optionally substituted C1-3-alkyl, C1-3-alkenyl, 3-6 member ring cycloalkyl, phenyl, 5- or 6-member ring heteroaryl, (phenyl)C1-3-alkyl, and (5- or 6-member ring heteroaryl)C1-3-alkyl.
In still another embodiment, the compound of Formula IV is reacted with a ring cyclizing reagent to form a compound of Formula V wherein:
R1 is phenyl or pyridinyl optionally substituted with one, two or three radicals selected from methyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, cyano, methylsulfonyl, aminosulfonyl, fluoro, chloro, bromo, and methoxy;
R2 is phenyl optionally substituted with one, two or three radicals selected from methyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, cyano, methylsulfonyl, aminosulfonyl, fluoro, chloro, bromo, and methoxy;
R3 is selected from xe2x80x94OR6 and xe2x80x94NR7R8; and
R6, R7 and R8 are independently selected from hydrogen and optionally substituted methyl, ethyl, propyl and benzyl.
The reaction of the compound of Formula IV with the cyclizing reagent generally is conducted in solution, typically in an organic solvent. The organic solvent may be any suitable solvent such as a solvent selected from the group consisting of alcohols, such as methanol, and ethereal solvents. Suitable ring cyclizing reagents include, but are not limited to, alkoxides, particularly alkoxide bases. Typical alkoxide bases useful as ring cyclizing reagents include alkali metal alkoxides such as sodium methoxide and potassium tert-butoxide. The reaction advantageously may be carried out by reacting the compound of Formula IV with an alkoxide base, preferably an alkali metal alkoxide such as sodium methoxide, in an alcohol solvent, preferably methanol. The reaction can be carried out over a range of concentrations. In one embodiment, for example, the compound of Formula IV is initially present at a concentration of about 1 to 10 g per mL solvent. The cyclizing reagent typically is initially present in excess. Preferably, the molar equivalents of the cyclizing reagent initially present is at least about 3 to 5 times greater than the molar equivalents of the compound of Formula IV initially present. The temperature of the reaction is not critical, but productivity is enhanced by operation at elevated temperature up to the reflux temperature of the reaction solvent. When the reaction is carried out in methanol with sodium methoxide as the cyclizing agent, it generally is completed within about two hours. Michael addition of the methylthioglycolate in refluxing 1,2-dichloroethane, for example, affords a mixture of E and Z vinylogous thioesters as well as some of the desired thiophenes. Removal of the solvent and replacement with, for example, methanol, followed by the addition of, for example, sodium methoxide affords the 3,4-diarylthiophenes after about 1 to 16 hours of mixing.
The compound of Formula V is then isolated by crystallization, distillation, chromatography, or other suitable method and functionalized as desired. The compounds of Formula V are novel compounds and have substantial value as final products or as intermediates for the preparation of thiophene derivatives and analogs of compounds of Formula V. The regioselective placement of the single ester or amido functionality relative to the 3,4-di(carbocyclyl or heterocyclyl)moieties of the thiophene permits the direct use of the thiophene in subsequent ring modification reactions without the need for separation of isomeric mixtures as typically required in conventional processes.
In one embodiment, (a) the compound of Formula V is prepared by reacting a compound of Formula IV with a ring cyclizing reagent; and (b) the compound of Formula IV is prepared 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, as previously discussed.
In another embodiment (a) the compound of Formula V is prepared by reacting a compound of Formula IV with a ring cyclizing reagent; (b) the compound of Formula IV is prepared 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, as previously discussed; and (c) the compound of Formula III is prepared by reacting an ethanone of Formula I with an acetal of Formula II, as previously discussed.
In still another embodiment, (a) an ethanone of Formula I is reacted with an acetal of Formula II to prepare a compound of Formula III, (b) the compound of formula III is reacted with a compound selected from thioacetic acid, esters of thioacetic acid and amides of thioacetic acid to prepare a compound of formula IV, as previously discussed, and (c) the compound of Formula V is prepared by reacting a compound of Formula IV with a ring cyclizing reagent, without first isolating one or both of the compounds of Formulae III and IV in purified form for use in the next step of the process. Alternatively, the compounds of Formulae III and IV each can be isolated in substantially purified form before they are used in the next step of the reaction.
In one embodiment of specific interest, the present invention comprises a process for the regioselective preparation of 3,4-diphenylthiophenes. In general, a deoxybenzoin comprising two differently substituted phenyl moieties is prepared. For example, one phenyl moiety is substituted with one or more functional groups and the other phenyl moiety is unsubstituted. Alternatively, each phenyl moiety is substituted with one or more functional groups, but has a different substitution pattern than the other phenyl moiety. A Michael acceptor is introduced into the primary carbon chain of the deoxybenzoin to yield a deoxybenzoin comprising at least two double bonds conjugated with the same or different electron withdrawing groups. This deoxybenzoin is reacted with thioacetic acid or an ester or amide of thioacetic acid to yield a Michael addition product in a nucleophilic addition reaction. Finally, the Michael addition product is cyclized to yield a 3,4-diphenylthiophene that can be further functionalized if desired.
Scheme I-A illustrates a preferred embodiment of the overall process described above:
In one embodiment of particular interest, the present invention comprises a process for the regioselective preparation of 3,4-di(carbocyclyl or heterocyclyl)thiophenes wherein the thiophene is substituted at the 3- or 4-position with a phenyl group comprising a methylsulfonyl or aminosulfonyl group. Preferably, the thiophene is substituted at the 3- or 4-position with a 4-methylsulfonylphenyl, 4-aminosulfonylphenyl, (3-fluoro-4-methylsulfonyl)phenyl, or (3-fluoro-4-aminosulfonyl)phenyl group.
The present process can be used to prepare compounds of Formula V that are encompassed within, or that can be used as intermediates in the preparation of, a group of compounds of particular interest having Formula VI:
wherein:
RW is cyclohexyl, pyridinyl, or phenyl, wherein said cyclohexyl, pyridinyl, and phenyl may be optionally substituted with one, two or three radicals selected from C1-2-alkyl, C1-2-haloalkyl, cyano, carboxyl, C1-2-alkoxycarbonyl, hydroxyl, C1-2-hydroxyalkyl, C1-2-haloalkoxy, amino, C1-2-alkylamino, phenylamino, nitro, C1-2-alkoxy-C1-2-alkyl, C1-2-alkylsulfinyl, halo, C1-2-alkoxy and C1-3-alkylthio;
RX is a radical selected from hydrido, halo, C1-2-alkyl, C2-3-alkenyl, C2-3-alkynyl, oxo, cyano, carboxyl, cyano-C1-3-alkyl, heterocyclyloxy, C1-3-alkoxy, C1-3-alkylthio, alkylcarbonyl, cycloalkyl, phenyl, C1-3-haloalkyl, heterocyclyl, cycloalkenyl, phenyl-C1-3-alkyl, heterocyclyl-C1-3-alkyl, C1-3-alkylthio-C1-3-alkyl, C1-3-hydroxyalkyl, C1-3-alkoxycarbonyl, phenylcarbonyl, phenyl-C1-3-alkylcarbonyl, phenyl-C2-3-alkenyl, C1-3-alkoxy-C1-3-alkyl, phenylthio-C1-3-alkyl, phenyloxyalkyl, alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C1-3-alkyl, C1-3-alkylaminocarbonyl, N-phenylaminocarbonyl, N-(C1-3-alkyl)-N-phenylaminocarbonyl, C1-3-alkylaminocarbonyl-C1-3-alkyl, carboxy-C1-3-alkyl, C1-3-alkylamino, N-arylamino, N-aralkylamino, N-(C1-3-alkyl)-N-aralkylamino, N-(C1-3-alkyl)-N-arylamino, amino-C1-3-alkyl, C1-3-alkylaminoalkyl, N-phenylamino-C1-3-alkyl, N-phenyl-C1-3-alkylaminoalkyl, N-(C1-3-alkyl)-N-(phenyl-C1-3-alkyl)amino-C1-3-alkyl, N-(C1-3-alkyl)-N-phenylamino-C1-3-alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-C1-3-alkylthio, C1-3-alkylsulfinyl, C1-3-alkylsulfonyl, aminosulfonyl, C1-3-alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl, and N-(C1-3-alkyl)-N-phenylaminosulfonyl; and
RY is methyl or amino; and
RZ is hydrogen or fluoro; or
a pharmaceutically-acceptable salt, tautomer or prodrug thereof.
In another embodiment, the compounds of Formula V prepared in accordance with the present process are encompassed within, or can be used as intermediates in the preparation of, compounds of Formula VI wherein:
RW is cyclohexyl, pyridinyl, or phenyl, wherein said cyclohexyl, pyridinyl, and phenyl may be optionally substituted with one, two or three radicals selected from C1-2-alkyl, C1-2-haloalkyl, cyano, carboxyl, C1-2-alkoxycarbonyl, hydroxyl, C1-2-hydroxyalkyl, C1-2-haloalkoxy, amino, C1-2-alkylamino, phenylamino, nitro, C1-2-alkoxy-C1-2-alkyl, C1-2-alkylsulfinyl, halo, C1-2-alkoxy and C1-3-alkylthio;
RX is a radical selected from hydrido, halo, C1-2-alkyl, C2-3-alkenyl, C2-3-alkynyl, oxo, cyano, carboxyl, cyano-C1-3-alkyl, (5- or 6-member ring heterocyclyl)oxy, C1-3-alkoxy, C1-3-alkylthio, C1-3-alkylcarbonyl, C3-6-cycloalkyl, phenyl, C1-3-haloalkyl, 5- or 6-member ring heterocyclyl, C3-6-cycloalkenyl, phenyl-C1-3-alkyl, (5- or 6-member ring heterocyclyl)-C1-3-alkyl, C1-3-alkylthio-C1-3-alkyl, C1-3-hydroxyalkyl, C1-3-alkoxycarbonyl, phenylcarbonyl, phenyl-C1-3-alkylcarbonyl, phenyl-C2-3-alkenyl, C1-3-alkoxy-C1-3-alkyl, phenylthio-C1-3-alkyl, phenyloxy-C1-3-alkyl, C1-3-alkoxyphenyl-C1-3-alkoxy-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyl, aminocarbonyl, aminocarbonyl-C1-3-alkyl, C1-3-alkylaminocarbonyl, N-phenylaminocarbonyl, N-(C1-3-alkyl)-N-phenylaminocarbonyl, C1-3-alkylaminocarbonyl-C1-3-alkyl, carboxy-C1-3-alkyl, C1-3-alkylamino, N-phenylamino, N-(phenyl-C1-3-alkyl)amino, N-(C1-3-alkyl)-N-(phenyl-C1-3-alkyl)amino, N-(C1-3-alkyl)-N-phenylamino, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, N-phenylamino-C1-3-alkyl, N-phenyl-C1-3-alkylamino-C1-3-alkyl, N-(C1-3-alkyl)-N-phenyl-C1-3-alkylamino-C1-3-alkyl, N-(C1-3-alkyl)-N-phenylamino-C1-3-alkyl, phenyloxy, phenyl-C1-3-alkoxy, phenylthio, phenyl-C1-3-alkylthio, C1-3-alkylsulfinyl, C1-3-alkylsulfonyl, aminosulfonyl, C1-3-alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl, and N-(C1-3-alkyl)-N-phenylaminosulfonyl; and
RY is methyl or amino; and
RZ is hydrogen or fluoro; or
a pharmaceutically-acceptable salt, tautomer or prodrug thereof.
In still another embodiment, the compounds of Formula V prepared in accordance with the present process are encompassed within, or can be used as intermediates in the preparation of, compounds of Formula VI wherein RW is cyclohexyl, pyridinyl, or phenyl, wherein said cyclohexyl, pyridinyl, and phenyl may be optionally substituted with one, two or three radicals selected from methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, methylamino, phenylamino, nitro, methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy and methylthio.
In still another embodiment, the compounds of Formula V prepared in accordance with the present process are encompassed within, or can be used as intermediates in the preparation of, compounds of Formula VI wherein RX is a radical selected from hydrido, fluoro, chloro, bromo, methyl, oxo, cyano, carboxyl, cyanomethyl, methoxy, methylthio, methylcarbonyl, phenyl, trifluoromethyl, difluoromethyl, phenylmethyl, methylthiomethyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, phenylcarbonyl, phenylmethylcarbonyl, methoxymethyl, phenylthiomethyl, phenyloxymethyl, methoxyphenylmethoxymethyl, methoxycarbonylmethyl, aminocarbonyl, aminocarbonylmethyl, methylaminocarbonyl, N-phenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, methylaminocarbonylmethyl, carboxymethyl, methylamino, N-phenylamino, N-(phenylmethyl)amino, N-methyl-N-(phenylmethyl)amino, N-methyl-N-phenylamino, aminomethyl, methylaminomethyl, N-phenylaminomethyl, N-phenylmethylaminomethyl, N-methyl-N-phenylmethylaminomethyl, N-methyl-N-phenylaminomethyl, phenyloxy, phenylmethoxy, phenylthio, phenylmethylthio, methylsulfinyl, methylsulfonyl, aminosulfonyl, methylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl, and N-methyl-N-phenylaminosulfonyl.
In still another embodiment, the compounds of Formula V prepared in accordance with the present process are encompassed within, or can be used as intermediates in the preparation of, compounds of Formula VI wherein:
RW is cyclohexyl or phenyl, wherein said cyclohexyl and phenyl may be optionally substituted with one, two or three radicals selected from methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, methylamino, phenylamino, nitro, methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy and methylthio; and
RX is a radical selected from hydrido, fluoro, chloro, bromo, methyl, oxo, cyano, carboxyl, cyanomethyl, methoxy, methylthio, methylcarbonyl, phenyl, trifluoromethyl, difluoromethyl, phenylmethyl, methylthiomethyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, phenylcarbonyl, phenylmethylcarbonyl, methoxymethyl, phenylthiomethyl, phenyloxymethyl, methoxyphenylmethoxymethyl, methoxycarbonylmethyl, aminocarbonyl, aminocarbonylmethyl, methylaminocarbonyl, N-phenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, methylaminocarbonylmethyl, carboxymethyl, methylamino, N-phenylamino, N-(phenylmethyl)amino, N-methyl-N-(phenylmethyl)amino, N-methyl-N-phenylamino, aminomethyl, methylaminomethyl, N-phenylaminomethyl, N-phenylmethylaminomethyl, N-methyl-N-phenylmethylaminomethyl, N-methyl-N-phenylaminomethyl, phenyloxy, phenylmethoxy, phenylthio, phenylmethylthio, methylsulfinyl, methylsulfonyl, aminosulfonyl, methylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl, and N-methyl-N-phenylaminosulfonyl.
In still another embodiment, the compounds of Formula V prepared in accordance with the present process are encompassed within, or can be used as intermediates in the preparation of, compounds of Formula VIA:
wherein RW, RX, RY and RY are as defined above.
In still another embodiment, the compounds of Formula V prepared in accordance with the present process are encompassed within, or can be used as intermediates in the preparation of, compounds of Formula VIA wherein:
RW is cyclohexyl or phenyl, wherein said cyclohexyl and phenyl may be optionally substituted with one, two or three radicals selected from halo, cyano, C1-2-alkyl, C1-2-haloalkyl, C1-2-alkoxy, and C1-2-haloalkoxy; and
RX is a radical selected from hydrido, halogen, C1-2-alkyl, C1-3-alkoxy, C1-3-alkylcarbonyl, C1-3-haloalkyl, C1-3-hydroxyalkyl, and C1-3-alkoxycarbonyl.
In still another embodiment, the compounds of Formula V prepared in accordance with the present process are encompassed within, or can be used as intermediates in the preparation of, compounds of Formula VIA wherein:
RW is cyclohexyl or phenyl, wherein said cyclohexyl and phenyl may be optionally substituted with one, two or three radicals selected from methyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, cyano, fluoro, chloro, bromo, iodo and methoxy; and
RX is a radical selected from hydrido, chloro, fluoro, bromo, cyano, methyl, methoxy, methylcarbonyl, trifluoromethyl, difluoromethyl, hydroxymethyl, and methoxycarbonyl.
In still another embodiment, the compounds of Formula V prepared in accordance with the present process are used as intermediates in the preparation of a compound selected from the group consisting of the following compounds:
3-phenyl-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(3-chlorophenyl)-4-[3-fluoro-4-(methylsulfonyl) phenyl]thiophene;
3-(4-chlorophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(3-bromophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(4-bromophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(3-fluorophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(4-fluorophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(3-methylphenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(4-methylphenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(3-cyanophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(4-cyanophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(3-trifluoromethylphenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(4-trifluoromethylphenyl)-4-[3-fluoro-4 (methylsulfonyl)phenyl]thiophene;
3-(3-trifluoromethoxyphenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(4-trifluoromethoxyphenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(3,4-dichlorophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(3,4-dibromophenyl)-4-[3-fluoro-4-(methylsulfonyl) phenyl]thiophene;
3-(3,4-difluorophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(3,5-dichlorophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(3,5-dibromophenyl)-4-[3-fluoro-4-(methylsulfonyl) phenyl]thiophene;
3-(3,5-difluorophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(3,4-dimethylphenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(3,5-dimethylphenyl)-4-[3-fluoro-4-(methylsulfonyl) phenyl]thiophene;
3-(3-methyl-4-chlorophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(4-methyl-3-chlorophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(3-methyl-4-fluorophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(4-methyl-3-fluorophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(3-methyl-4-bromophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(4-methyl-3-bromophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(3-methyl-4-trifluoromethylphenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(4-methyl-3-trifluoromethylphenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(3-methyl-4-trifluoromethoxyphenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(4-methyl-3-trifluoromethoxyphenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(3-cyano-4-methylphenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(4-cyano-3-methylphenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(3-chloro-4-methoxyphenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(4-chloro-3-methoxyphenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(2-methylpyridin-6-yl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(2-methylthiazol-4-yl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(4-methylthiazol-2-yl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(2-methylpyridin-3-yl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(2-methylpyridin-3-yl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(3-pyridinyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-(5-methylpyridin-3-yl)-4-[3-fluoro-4-(methylsulfonyl) phenyl]thiophene;
3-(2-methylpyridin-3-yl)-4-[3-fluoro-4-(methylsulfonyl) phenyl]thiophene;
3-cyclohexyl-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
3-cyclopentyl-4-[3-fluoro-4-(methylsulfonyl)phenyl]thiophene;
2-fluoro-4-[4-phenyl-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3-chlorophenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(4-chlorophenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3-bromophenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(4-bromophenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3-fluorophenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(4-fluorophenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3-methylphenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(4-methylphenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3-cyanophenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(4-cyanophenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3-trifluoromethylphenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(4-trifluoromethylphenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3-trifluoromethoxyphenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(4-trifluoromethoxyphenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3,4-dichlorophenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3,4-dibromophenyl)-3-thiophenyl]benezenesulfonamide
2-fluoro-4-[4-(3,4-difluorophenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3,5-dichlorophenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3,5-dibromophenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3,5-difluorophenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3,4-dimethylphenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3,5-dimethylphenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3-methyl-4-chlorophenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(4-methyl-3-chlorophenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3-methyl-4-fluorophenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(4-methyl-3-fluorophenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3-methyl-4-bromophenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(4-methyl-3-bromophenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3-methyl-4-trifluoromethylphenyl)-3-thiophenyl]benezene-sulfonamide;
2-fluoro-4-[4-(4-methyl-3-trifluoromethylphenyl)-3-thiophenyl]benezene-sulfonamide;
2-fluoro-4-[4-(3-methyl-4-trifluoromethoxyphenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(4-methyl-3-trifluoromethoxyphenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3-cyano-4-methylphenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(4-cyano-3-methylphenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3-chloro-4-methoxyphenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(4-chloro-3-methoxyphenyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(2-methylpyridin-6-yl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(2-methylthiazol-4-yl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(4-methylthiazol-2-yl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(2-methylpyridin-3-yl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(2-methylpyridin-3-yl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(3-pyridinyl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(5-methylpyridin-3-yl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-(2-methylpyridin-3-yl)-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-cyclohexyl-3-thiophenyl]benezenesulfonamide;
2-fluoro-4-[4-cyclopentyl-3-thiophenyl]benezenesulfonamide;
and the pharmaceutically-acceptable salts, tautomers and prodrugs thereof.
The term xe2x80x9chydridoxe2x80x9d denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (xe2x80x94CH2xe2x80x94) radical.
Where the term xe2x80x9calkylxe2x80x9d is used, either alone or within other terms such as xe2x80x9chaloalkylxe2x80x9d and xe2x80x9calkylsulfonylxe2x80x9d, it embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are xe2x80x9clower alkylxe2x80x9d radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like. Even more preferred are lower alkyl radicals having one to three carbon atoms.
The term xe2x80x9calkenylxe2x80x9d embraces linear or branched radicals having at least one carbonxe2x80x94carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkenyl radicals are xe2x80x9clower alkenylxe2x80x9d radicals having two to about six carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.
The term xe2x80x9calkynylxe2x80x9d denotes linear or branched radicals having two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkynyl radicals are xe2x80x9clower alkynylxe2x80x9d radicals having two to about ten carbon atoms. Most preferred are lower alkynyl radicals having two to about six carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.
The terms xe2x80x9calkenylxe2x80x9d and xe2x80x9clower alkenylxe2x80x9d, embrace radicals having xe2x80x9ccisxe2x80x9d and xe2x80x9ctransxe2x80x9d orientations, or alternatively, xe2x80x9cExe2x80x9d and xe2x80x9cZxe2x80x9d orientations.
The term xe2x80x9chaloxe2x80x9d means halogens such as fluorine, chlorine, bromine or iodine atoms. The term xe2x80x9chaloalkylxe2x80x9d embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. xe2x80x9cLower haloalkylxe2x80x9d embraces radicals having one to six carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. xe2x80x9cPerfluoroalkylxe2x80x9d means alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.
The term xe2x80x9chydroxyalkylxe2x80x9d embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are xe2x80x9clower hydroxyalkylxe2x80x9d radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals having one to three carbon atoms.
The term xe2x80x9ccyanoalkylxe2x80x9d embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one cyano radicals. More preferred cyanoalkyl radicals are xe2x80x9clower cyanoalkylxe2x80x9d radicals having one to six carbon atoms and one cyano radical. Even more preferred are lower cyanoalkyl radicals having one to three carbon atoms. Examples of such radicals include cyanomethyl.
The term xe2x80x9calkoxyxe2x80x9d embraces linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are xe2x80x9clower alkoxyxe2x80x9d radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Even more preferred are lower alkoxy radicals having one to three carbon atoms. The xe2x80x9calkoxyxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide xe2x80x9chaloalkoxyxe2x80x9d radicals. Even more preferred are lower haloalkoxy radicals having one to three carbon atoms. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
The term xe2x80x9carylxe2x80x9d, alone or in combination, means a carbocyclic aromatic system containing one or two rings wherein such rings may be attached together in a pendent manner or may be fused. The term xe2x80x9carylxe2x80x9d embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. More preferred aryl is phenyl. Said xe2x80x9carylxe2x80x9d group may have one to three substituents such as lower alkyl, hydroxy, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino.
The term xe2x80x9cheterocyclylxe2x80x9d or xe2x80x9cheterocycloxe2x80x9d embraces saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocylic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl]; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Examples of unsaturated heterocyclic radicals, also termed xe2x80x9cheteroarylxe2x80x9d radicals, include unsaturated 5 to 6 membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl]; unsaturated 3 to 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]; unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said xe2x80x9cheterocyclylxe2x80x9d group may have 1 to 3 substituents such as lower alkyl, hydroxy, oxo, amino and lower alkylamino.
Preferred heterocyclic radicals include five to ten membered fused or unfused radicals. More preferred examples of heteroaryl radicals include benzofuryl, 2,3-dihydrobenzofuryl, benzothienyl, indolyl, dihydroindolyl, chromanyl, benzopyran, thiochromanyl, benzothiopyran, benzodioxolyl, benzodioxanyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl. Even more preferred heteroaryl radicals are 5- or 6-membered heteroaryl, containing one or two heteroatoms selected from sulfur nitrogen and oxygen, selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl.
The term xe2x80x9csulfonylxe2x80x9d, whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals xe2x80x94SO2xe2x80x94. xe2x80x9cAlkylsulfonylxe2x80x9d embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are xe2x80x9clower alkylsulfonylxe2x80x9d radicals having one to six carbon atoms. Even more preferred are lower alkylsulfonyl radicals having one to three carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. xe2x80x9cHaloalkylsulfonylxe2x80x9d embraces haloalkyl radicals attached to a sulfonyl radical, where haloalkyl is defined as above. More preferred haloalkylsulfonyl radicals are xe2x80x9clower haloalkylsulfonylxe2x80x9d radicals having one to six carbon atoms. Even more preferred are lower haloalkylsulfonyl radicals having one to three carbon atoms. Examples of such lower haloalkylsulfonyl radicals include trifluoromethylsulfonyl. The term xe2x80x9carylalkylsulfonylxe2x80x9d embraces aryl radicals as defined above, attached to an alkylsulfonyl radical. Examples of such radicals include benzylsulfonyl and phenylethylsulfonyl. The term xe2x80x9cheterocyclosulfonylxe2x80x9d embraces heterocyclo radicals as defined above, attached to a sulfonyl radical. More preferred heterocyclosulfonyl radicals contain 5-7 membered heterocyclo radicals containing one or two heteroatoms. Examples of such radicals include tetrahydropyrrolylsulfonyl morpholinylsulfonyl and azepinylsulfonyl.
The terms xe2x80x9csulfamyl,xe2x80x9d xe2x80x9caminosulfonylxe2x80x9d and xe2x80x9csulfonamidyl,xe2x80x9d whether alone or used with terms such as xe2x80x9cN-alkylaminosulfonylxe2x80x9d, xe2x80x9cN-arylaminosulfonylxe2x80x9d, xe2x80x9cN,N-dialkylaminosulfonylxe2x80x9d and xe2x80x9cN-alkyl-N-arylaminosulfonylxe2x80x9d, denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide (xe2x80x94SO2NH2). The term xe2x80x9calkylaminosulfonylxe2x80x9d includes xe2x80x9cN-alkylaminosulfonylxe2x80x9d and xe2x80x9cN,N-dialkylaminosulfonylxe2x80x9d where sulfamyl radicals are substituted, respectively, with one alkyl radical, or two alkyl radicals. More preferred alkylaminosulfonyl radicals are xe2x80x9clower alkylaminosulfonylxe2x80x9d radicals having one to six carbon atoms. Even more preferred are lower alkylaminosulfonyl radicals having one to three carbon atoms. Examples of such lower alkylaminosulfonyl radicals include N-methylaminosulfonyl, N-ethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl. The terms xe2x80x9cN-arylaminosulfonylxe2x80x9d and xe2x80x9cN-alkyl-N-arylaminosulfonylxe2x80x9d denote sulfamyl radicals substituted, respectively, with one aryl radical, or one alkyl and one aryl radical. More preferred N-alkyl-N-arylaminosulfonyl radicals are xe2x80x9clower N-alkyl-N-arylsulfonylxe2x80x9d radicals having alkyl radicals of one to six carbon atoms. Even more preferred are lower N-alkyl-N-arylsulfonyl radicals having one to three carbon atoms. Examples of such lower N-alkyl-N-aryl-aminosulfonyl radicals include N-methyl-N-phenylaminosulfonyl and N-ethyl-N-phenylaminosulfonyl. Examples of such N-aryl-aminosulfonyl radicals include N-phenylaminosulfonyl. The term xe2x80x9carylalkylaminosulfonylxe2x80x9d embraces aralkyl radicals as described above, attached to an aminosulfonyl radical. More preferred are lower arylalkylaminosulfonyl radicals having one to three carbon atoms. The term xe2x80x9cheterocyclylaminosulfonylxe2x80x9d embraces heterocyclyl radicals as described above, attached to an aminosulfonyl radical.
The terms xe2x80x9ccarboxyxe2x80x9d or xe2x80x9ccarboxylxe2x80x9d, whether used alone or with other terms, such as xe2x80x9ccarboxyalkylxe2x80x9d, denotes xe2x80x94CO2H. The term xe2x80x9ccarboxyalkylxe2x80x9d embraces radicals having a carboxy radical as defined above, attached to an alkyl radical.
The term xe2x80x9ccarbonylxe2x80x9d, whether used alone or with other terms, such as xe2x80x9calkylcarbonylxe2x80x9d, denotes xe2x80x94(Cxe2x95x90O)xe2x80x94.
The term xe2x80x9cacylxe2x80x9d denotes a radical provided by the residue after removal of hydroxyl from an organic acid. Examples of such acyl radicals include alkanoyl and aroyl radicals. Examples of such lower alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl.
The term xe2x80x9caroylxe2x80x9d embraces aryl radicals with a carbonyl radical as defined above. Examples of aroyl include benzoyl, naphthoyl, and the like and the aryl in said aroyl may be additionally substituted.
The term xe2x80x9calkylcarbonylxe2x80x9d embraces radicals having a carbonyl radical substituted with an alkyl radical. More preferred alkylcarbonyl radicals are xe2x80x9clower alkylcarbonylxe2x80x9d radicals having one to six carbon atoms. Even more preferred are lower alkylcarbonyl radicals having one to three carbon atoms. Examples of such radicals include methylcarbonyl and ethylcarbonyl. The term xe2x80x9chaloalkylcarbonylxe2x80x9d embraces radicals having a carbonyl radical substituted with an haloalkyl radical. More preferred haloalkylcarbonyl radicals are xe2x80x9clower haloalkylcarbonylxe2x80x9d radicals having one to six carbon atoms. Even more preferred are lower haloalkylcarbonyl radicals having one to three carbon atoms. Examples of such radicals include trifluoromethylcarbonyl.
The term xe2x80x9carylcarbonylxe2x80x9d embraces radicals having a carbonyl radical substituted with an aryl radical. More preferred arylcarbonyl radicals include phenylcarbonyl. The term xe2x80x9cheteroarylcarbonylxe2x80x9d embraces radicals having a carbonyl radical substituted with a heteroaryl radical. Even more preferred are 5- or 6-membered heteroarylcarbonyl radicals. The term xe2x80x9carylalkylcarbonylxe2x80x9d embraces radicals having a carbonyl radical substituted with an arylalkyl radical. More preferred radicals are phenyl-C1-C3-alkylcarbonyl, including benzylcarbonyl. The term xe2x80x9cheteroarylalkylcarbonylxe2x80x9d embraces radicals having a carbonyl radical substituted with a heteroarylalkyl radical. Even more preferred are lower heteroarylalkylcarbonyl radicals having 5-6-membered heteroaryl radicals attached to alkyl portions having one to three carbon atoms.
The term xe2x80x9calkoxycarbonylxe2x80x9d means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. Preferably, xe2x80x9clower alkoxycarbonylxe2x80x9d embraces alkoxy radicals having one to six carbon atoms. Examples of such xe2x80x9clower alkoxycarbonylxe2x80x9d ester radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. Even more preferred are lower alkoxycarbonyl radicals having alkoxy portions of one to three carbon atoms.
The term xe2x80x9caminocarbonylxe2x80x9d when used by itself or with other terms such as xe2x80x9caminocarbonylalkylxe2x80x9d, xe2x80x9cN-alkylaminocarbonylxe2x80x9d, xe2x80x9cN-arylaminocarbonylxe2x80x9d, xe2x80x9cN,N-dialkylaminocarbonylxe2x80x9d, xe2x80x9cN-alkyl-N-arylaminocarbonylxe2x80x9d, xe2x80x9cN-alkyl-N-hydroxyaminocarbonylxe2x80x9d and xe2x80x9cN-alkyl-N-hydroxyaminocarbonylalkylxe2x80x9d, denotes an amide group of the formula xe2x80x94C(xe2x95x90O)NH2. The terms xe2x80x9cN-alkylaminocarbonylxe2x80x9d and xe2x80x9cN,N-dialkylaminocarbonylxe2x80x9d denote aminocarbonyl radicals which have been substituted with one alkyl radical and with two alkyl radicals, respectively. More preferred are xe2x80x9clower alkylaminocarbonylxe2x80x9d having lower alkyl radicals as described above attached to an aminocarbonyl radical. The terms xe2x80x9cN-arylaminocarbonylxe2x80x9d and xe2x80x9cN-alkyl-N-arylaminocarbonylxe2x80x9d denote aminocarbonyl radicals substituted, respectively, with one aryl radical, or one alkyl and one aryl radical. The term xe2x80x9cN-cycloalkylaminocarbonylxe2x80x9d denoted aminocarbonyl radicals which have been substituted with at least one cycloalkyl radical. More preferred are xe2x80x9clower cycloalkylaminocarbonylxe2x80x9d having lower cycloalkyl radicals of three to seven carbon atoms, attached to an aminocarbonyl radical.
The term xe2x80x9caminoalkylxe2x80x9d embraces alkyl radicals substituted with amino radicals. The term xe2x80x9calkylaminoalkylxe2x80x9d embraces aminoalkyl radicals having the nitrogen atom substituted with an alkyl radical. Even more preferred are lower alkylaminoalkyl radicals having one to three carbon atoms. The term xe2x80x9cheterocyclylalkylxe2x80x9d embraces heterocyclic-substituted alkyl radicals. More preferred heterocyclylalkyl radicals are xe2x80x9c5- or 6-membered heteroarylalkylxe2x80x9d radicals having alkyl portions of one to six carbon atoms and a 5- or 6-membered heteroaryl radical. Even more preferred are lower heteroarylalkyl radicals having alkyl portions of one to three carbon atoms. Examples include such radicals as pyridylmethyl and thienylmethyl.
The term xe2x80x9caralkylxe2x80x9d embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are xe2x80x9clower aralkylxe2x80x9d radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Even more preferred are lower aralkyl radicals phenyl attached to alkyl portions having one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term xe2x80x9carylalkenylxe2x80x9d embraces aryl-substituted alkenyl radicals. Preferable arylalkenyl radicals are xe2x80x9clower arylalkenylxe2x80x9d radicals having aryl radicals attached to alkenyl radicals having two to six carbon atoms. Examples of such radicals include phenylethenyl. The aryl in said arylalkenyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term xe2x80x9carylalkynylxe2x80x9d embraces aryl-substituted alkynyl radicals. Preferable arylalkynyl radicals are xe2x80x9clower arylalkynylxe2x80x9d radicals having aryl radicals attached to alkynyl radicals having two to six carbon atoms. Examples of such radicals include phenylethynyl. The aryl in said aralkyl, arylalkenyl and arylalkynyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The terms benzyl and phenylmethyl are interchangeable.
The term xe2x80x9calkylthioxe2x80x9d embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower alkylthio radicals having one to three carbon atoms. An example of xe2x80x9calkylthioxe2x80x9d is methylthio, (CH3xe2x80x94Sxe2x80x94). The term xe2x80x9chaloalkylthioxe2x80x9d embraces radicals containing a haloalkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower haloalkylthio radicals having one to three carbon atoms. An example of xe2x80x9chaloalkylthioxe2x80x9d is trifluoromethylthio.
The term xe2x80x9calkylsulfinylxe2x80x9d embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent xe2x80x94S(xe2x95x90O)xe2x80x94 atom. More preferred are lower alkylsulfinyl radicals having one to three carbon atoms. The term xe2x80x9carylsulfinylxe2x80x9d embraces radicals containing an aryl radical, attached to a divalent xe2x80x94S(xe2x95x90O)xe2x80x94 atom. Even more preferred are optionally substituted phenylsulfinyl radicals. The term xe2x80x9chaloalkylsulfinylxe2x80x9d embraces radicals containing a haloalkyl radical, of one to ten carbon atoms, attached to a divalent xe2x80x94S(xe2x95x90O)xe2x80x94 atom. Even more preferred are lower haloalkylsulfinyl radicals having one to three carbon atoms.
The terms xe2x80x9cN-alkylaminoxe2x80x9d and xe2x80x9cN,N-dialkylaminoxe2x80x9d denote amino groups which have been substituted with one alkyl radical and with two alkyl radicals, respectively. More preferred alkylamino radicals are xe2x80x9clower alkylaminoxe2x80x9d radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. Even more preferred are lower alkylamino radicals having one to three carbon atoms. Suitable xe2x80x9calkylaminoxe2x80x9d may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like. The term xe2x80x9carylaminoxe2x80x9d denotes amino groups which have been substituted with one or two aryl radicals, such as N-phenylamino. The xe2x80x9carylaminoxe2x80x9d radicals may be further substituted on the aryl ring portion of the radical. The term xe2x80x9cheteroarylaminoxe2x80x9d denotes amino groups which have been substituted with one or two heteroaryl radicals, such as N-thienylamino. The xe2x80x9cheteroarylaminoxe2x80x9d radicals may be further substituted on the heteroaryl ring portion of the radical. The term xe2x80x9caralkylaminoxe2x80x9d denotes amino groups which have been substituted with one or two aralkyl radicals. More preferred are phenyl-C1-C3-alkylamino radicals, such as N-benzylamino. The xe2x80x9caralkylaminoxe2x80x9d radicals may be further substituted on the aryl ring portion of the radical. The terms xe2x80x9cN-alkyl-N-arylaminoxe2x80x9d and xe2x80x9cN-aralkyl-N-alkylaminoxe2x80x9d denote amino groups which have been substituted with one aralkyl and one alkyl radical, or one aryl and one alkyl radical, respectively, to an amino group.
The term xe2x80x9carylthioxe2x80x9d embraces aryl radicals of six to ten carbon atoms, attached to a divalent sulfur atom. An example of xe2x80x9carylthioxe2x80x9d is phenylthio. The term xe2x80x9caralkylthioxe2x80x9d embraces aralkyl radicals as described above, attached to a divalent sulfur atom. More preferred are phenyl-C1-C3-alkylthio radicals. An example of xe2x80x9caralkylthioxe2x80x9d is benzylthio. The term xe2x80x9caralkylsulfonylxe2x80x9d embraces aralkyl radicals as described above, attached to a divalent sulfonyl radical. More preferred are phenyl-C1-C3-alkylsulfonyl radicals.
The term xe2x80x9caryloxyxe2x80x9d embraces optionally substituted aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy. The term xe2x80x9caralkoxyxe2x80x9d embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are xe2x80x9clower aralkoxyxe2x80x9d radicals having optionally substituted phenyl radicals attached to lower alkoxy radical as described above.
The intermediates, thiophene compounds and functionalized thiophene compounds discussed above can be synthesized, for example, according to the procedures set forth below, or by appropriate modification of these general synthetic procedures. The substituents of the compounds shown in the following procedures have the same definition as the substituents at the corresponding position in the compounds of Formulae I-VI, except where further noted.
One approach for the preparation of optionally substituted 3,4-diarylthiophenes 4 is outlined in Scheme I. Diphenyl ethanones 1 (wherein each phenyl moiety may be substituted with one or more functional groups) and an acetal (shown here as an acetal of dimethyl-formamide) are refluxed together in a suitable solvent such as toluene. Upon removal of the solvent and excess acetal, the enamine 2 is obtained. The enamine 2 is refluxed in a suitable solvent (such as 1,2 dichloroethane) with an ester of thioacetic acid (or alternatively thioacetic acid or an amide of thioacetic acid) which affords the mixture of Michael addition products 3. The solvent is removed at reduced pressure. The residue is then taken up in an alcoholic solvent and a ring cyclizing reagent, such as the corresponding sodium alkoxide, is added. Upon mixing at room temperature the desired tri-substituted thiophenes 4 were obtained after purification.
As outlined in Scheme II, standard organic laboratory procedures can be employed to manipulate the ester group of thiophene 4 into a number of different functional groups such as alcohols, alkyls, alkenes, alkynes, amides, cyanos, etc. Alternatively, the ester group can be saponified and the resulting carboxylic acid 6 removed through a copper-mediated decarboxylation affording the 3,4-substituted diphenylthiophene 7.
Alternatively, as outlined in Scheme III the remaining thiophene-ring hydrogen of thiophene 4 can be converted to a halogen or nitro group to form thiophene 8. The ester group of thiophene 8 then can be manipulated as described above to provide a variety of functional groups, such as for thiophenes 9 and 10.
The following example contains a detailed description of the methods of preparation of compounds of Formulae I-VI. The detailed description falls within the scope, and serves to exemplify, the previously-described processes which form part of the invention. The detailed description is presented for illustrative purposes only and is not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are in Degrees centigrade unless otherwise indicated. All compounds showed NMR spectra consistent with their assigned structures.
The following abbreviations are used:
HClxe2x80x94hydrochloric acid
DMSOxe2x80x94dimethylsulfoxide
DMSOd6xe2x80x94deuterated dimethylsulfoxide
CDCl3xe2x80x94deuterated chloroform
MgSO4xe2x80x94magnesium sulfate
NaHCO3xe2x80x94sodium bicarbonate
KHSO4xe2x80x94potassium hydrogen sulfate
DMFxe2x80x94dimethylformamide
NaOHxe2x80x94sodium hydroxide
BOCxe2x80x94tert butyloxycarbonyl
CD3ODxe2x80x94deuterated methanol
EtOHxe2x80x94ethanol
LiOHxe2x80x94lithium hydroxide
CH2Cl2xe2x80x94methylene chloride
hxe2x80x94hour
hrxe2x80x94hour
minxe2x80x94minutes
THFxe2x80x94tetrahydrofuran
TLCxe2x80x94thin layer chromatography
Et3Nxe2x80x94triethylamine
DBUxe2x80x941,8-diazabicyclo[5.4.0]undec-7-ene
DMAPxe2x80x944-dimethylaminopyridine

Regioselective synthesis of 3,4-di(carbocyclyl or heterocyclyl)thiophenes

Abstract: with a ring cyclizing reagent to form the compound of Formula V to yield a compound of Formula V:

Abstract: wherein R1, R2 and R3 are as defined in the specification.


A tandem thrust bearing arrangement associated with a rotating shaft which is subjected to an axial load having spaced first and second annular members or thrust runners fixed to the shaft and first and second thrust bearings associated with the respective annular members and means axially movable with respect to the shaft supporting one of the thrust bearings which activates pivotable means applying load to the other thrust bearing.

The use of thrust bearings to carry the imposed load on a substantially vertical shaft is well known in the art. As imposed loads on the shaft are increased, it becomes necessary to construct large thrust bearings. Thus, housings in which the shaft is journeyed must be larger to house the shaft-thrust bearing assembly.
One solution to the problem of providing a relatively compact shaft-thrust bearing assembly is taught in the U.S. Pat. No. 4,033,647 granted July 5, 1977 to John A. Beavers. The Beavers patent teaches a tandem thrust bearing assembly in which a second thrust bearing carries load in excess of the load which can be carried by a first thrust bearing.


A method of nullifying digital certificates for nullifying, by means of a communications apparatus, a digital certificate for use by a communications counterpart of the communications apparatus in authenticating includes the step of causing the communications apparatus to transfer to the communications counterpart, when determining based on a normal certificate being a valid digital certificate received from the communications counterpart or information received via a communications path based on the normal certificate that the normal certificate is to be nullified, a certificate for nullifying being a digital certificate for nullifying.

Conventionally, connecting multiple communications apparatuses, each having its own communications function, via a network for communicating, and building various systems are performed. As an example, there is a so-called electronic-commerce system such that an order for a product is transmitted from a computer such as a PC (Personal Computer) that functions as a client apparatus and accepts the order in a server apparatus that communicates with the client apparatus via the Internet. Moreover, a system is being proposed such that various electronic apparatuses are provided with a function of a client apparatus or a server apparatus so as to be connected via an network, and are remotely controlled by mutual communications.
In building such systems, it is important to confirm when communicating whether a communications counterpart is appropriate, or whether information being transmitted has not been tampered with. Moreover, especially in the Internet, as often information goes through computers that are unrelated before reaching the communications counterpart, when transmitting secret information, there is also a demand for making sure that the contents are not viewed secretly. Then, a protocol such as SSL (Secure Sockets Layer), for example, as a communications protocol to respond to such demand is being developed and widely used. Using this protocol to communicate combines public-key encrypting methods and common-key encrypting methods for authenticating the communications counterpart as well as preventing tampering and tapping by encrypting information. Moreover, even at the communications-counterpart side, a communications-originating apparatus that requests for communications is authenticated.
As technologies related to authentication using such SSL and public-key encrypting, there are those described in Patent Documents 1 and 2:
Patent Document 1
JP2002-353959A
Patent Document 2
JP2002-251492A
Now, a communications procedure for mutually authenticating according to this SSL is described focusing on the authentication process portion. FIG. 27 is a diagram illustrating a flow of a process of executing in each apparatus when communications apparatuses A and B mutually authenticate according to the SSL, along with information used for the process.
As illustrated in FIG. 27, when mutually authenticating according to the SSL, there is a need to first have a root-key certificate, a private key, and a public-key certificate stored in both of the communications apparatuses. This private key is a private key issued to each apparatus by a CA (Certificate Authority), while the public-key certificate is one such that the public key corresponding to the private key is appended with a digital signature by the CA so as to be set as a digital certificate. Moreover, the root-key certificate is one such that a root key corresponding to a root-private key used in the digital signature is appended with a digital signature so as to be set as a digital certificate.
FIGS. 28A and 28B illustrate these relationships.
As illustrated in FIG. 28A, a public key A is configured from a main body of the key for decrypting text encrypted using a private key A, and bibliographical information which includes such information as issuer (CA) of the public key and validity. Then, in order to indicate that the main body of the key and the bibliographical information are not tampered with, a hash value obtained by hashing the public key A is encrypted using a root-private key so as to be applied to a client common key as a digital signature. Moreover, at that time, information identifying the root-private key used in the digital signature is added as signature-key information to the bibliographical information of the public key A. Then, the public-key certificate having this digital signature applied is a common-key certificate A.
When using this common-key certificate A for authenticating, the digital signature contained therein is decrypted using a main body of a root key being a public key corresponding to the root-private key. It is understood when this decrypting is performed successfully that the digital signature is certainly applied by the CA. Moreover, it is understood when the hash value obtained by hashing the public key A portion and a hash value obtained by decrypting matches that the key itself is also neither damaged nor tampered with. Furthermore, it is understood when it is possible to successfully decrypt the received data using this public key A that the data is transmitted from the owner of the private key A.
Now, while it is necessary to store in advance a root key for performing authentication, as illustrated in FIG. 28B, this root key is stored as a root-key certificate having applied a digital signature by the CA. This root-key certificate is in a self-signature format enabled to decrypt the digital signature with a public key contained therein. Then, when using the root key, the main body of the key contained in the root-key certificate is used to decrypt the digital signature so as to compare with the hash value obtained by hashing the root key. When there is a match, it is possible to confirm that the root key is not corrupted, for instance.
Now the flowcharts in FIG. 27 are described. It is noted that in this diagram, an arrow between the two flow charts represents transferring of data such that the transmitting side performs a transferring process at a step from which the arrow originates, while the receiving side once the information is received performs a process of a step to which the arrow points. Moreover, when a process of each of the steps is not successfully completed, at that time a response of having failed authentication is returned so as to suspend the process. The same holds when a response of having failed authentication is received from the counterpart, or upon time-out of the process.
Now, with a communications apparatus A requesting for communications with a communications apparatus B, when performing this request, the CPU of the communications apparatus A executing a required control program starts a process of the flowchart illustrated on the left-hand side of FIG. 27. Then, in step S11, a request for connection is transmitted to the communications apparatus B.
On the other hand, the CPU of the communications apparatus B once receiving this request for connection executing a required control program starts a process of the flowchart illustrated on the right-hand side of FIG. 27. Then, in step S21 a first random number is generated for encrypting using a private key B. Then, in step S22, the encrypted first random number and a public-key certificate B are transmitted to the communications apparatus A.
At the communications apparatus A side, when receiving this, in step S12 the validity of the public-key certificate B is confirmed using a root-key certificate.
Then once confirmed, in step S13 the first random number is decrypted using a public key B contained in the received public-key certificate B. When the decrypting here is successful, confirming that the first random number is certainly received from a subject to which the public-key certificate is issued is enabled. Then, when the confirming as described above is enabled, information indicating success of authentication is transmitted to the communications apparatus B.
Moreover, at the communications apparatus B side, upon receiving this information, in step S23, transmission of a public-key certificate for authentication is requested to the communications apparatus A.
Then, at the communications apparatus A, based on the above request for transmission, in step S14, a second random number and a common-key seed are generated. A common-key seed may be generated based on data transacted in previous communications, for example. Then, in step S15 the second random number is encrypted using a private key A, the common-key seed is encrypted using the public key B, and in step S16 these are transmitted with a public-key certificate A to the server apparatus. Encrypting the common-key seed is performed for the purpose of making sure that the common-key seed is not known to apparatuses other than the communications counterpart.
Then, in the next step S17, a common key for use in encrypting subsequent communications is generated from the common-key seed generated in step S14.
At the communications apparatus B side, when receiving this, in step S24 the validity of the public-key certificate A is confirmed using the root-key certificate. Then once confirmed, in step S25, the second random number is decrypted using a public key A contained in the public-key certificate A received. When the decrypting here is successful, confirming that the second random number is certainly received from a subject to which the public-key certificate A is issued is enabled.
Subsequently, in step S26 the common-key seed is decrypted using a private key B. It can be said that, in the process thus far, the common-key seed common to the communications apparatus A side and the communications apparatus B side are shared. Then, the common-key seed does not become known to apparatuses other than the communications apparatus A having generated the seed and the communications apparatus B having the private key B. Once the process described thus far succeeds, also at the communications apparatus B side in step S27 a common key for use in encrypting subsequent communications is generated from the common-key seed obtained by decrypting.
Then, once the process of step S17 at the communications apparatus A side and the process of step S27 at the communications apparatus B side are terminated, success of authentication and encrypting method for use in subsequent communications are mutually confirmed for terminating the process regarding authentication assuming that the generated common key is used to conduct the subsequent communications using the encrypting method confirmed as described above. It is noted that the confirming as described above includes a response from the communications apparatus B that authentication has succeeded. The process as described above enables mutually establishing communications so as to subsequently use the common key generated in step S17 or S27 and to encrypt data according to the common-key encrypting method for conducting communications.
Performing such process as described above enables securely sharing a common key upon the communications apparatus A and communications apparatus B mutually authenticating their counterparts, and establishing a path for communicating securely.
It is noted that in the process as described above, it is not mandatory to encrypt the second random number with the private key A and to transmit the public-key certificate A to the communications apparatus B. In this way, while it is not possible for the communications apparatus B to authenticate the communications apparatus A, this process is sufficient when it suffices for the communications apparatus A to only authenticate the communications apparatus B. Then in this case, it is necessary to have only the root-key certificate stored in the communications apparatus A so that neither the private key A nor the public-key certificate A are needed. Moreover, it is not necessary to have the root-key certificate stored in the communications apparatus B.
Now, when using such authentication process for identifying a subject for providing a service such as remote control, a certificate, etc., required for authentication process is to be stored in a subject apparatus for providing the service (an apparatus at the user side). Then, an apparatus providing the service, based on information provided in the certificate, etc., determining whether a communications counterpart is an apparatus suitable as a subject for providing the service is performed. Moreover, if the information provided in the certificate, etc. is not sufficient, obtaining an equipment-number information for use in the determining as described above, after establishing a communications path, is performed.
Moreover, a certain apparatus being a subject for providing the service for a predetermined period may no longer be a subject for providing the service upon dissolving an agreement. In such a case, nullifying a certificate of the apparatus which is no longer a subject for providing the service is required.
As a technologies related to such nullifying, technologies as described in Patent Documents 3 and 4 are known.
Then, in the Patent Document 3, a technology is described in which an Issuing Authority (IA) for providing an authentication service such as a public-key registration based on a request from a Registration Authority (RA), upon receiving from the RA as described above a request for nullifying a public-key certificate of the RA itself, retrieves a public-key certificate of an user that is registered from the RA so as to nullify the public-key certificate of the user. Moreover, in Patent Document 4, a technology is described in which a pubic-key authentication apparatus analyzes a request for nullifying a public-key certificate that is received from an attribute-authentication apparatus to extract a public-key certificate to be nullified so as to nullify the extracted public-key certificate in a database.
Patent Document 3
JP2002-247028A
Patent Document 4
JP2002-058049A
However, with the techniques as described in these Patent Documents 3 and 4, nullifying of the public-key certificate of the user is provided for performing only at the side managing the certificate, or the side providing the service. In other words, a process of deleting user information and certificate identification number regarding the public-key certificate for nullifying is provided for so that while the fact that the public-key certificate is nullified is communicated to the user, no action is performed on the public-key certificate, etc. which has been stored in the apparatus at the user side so as to leave the public-key certificate, etc. as it is.
Therefore, in the apparatus at the user side, the common-key certificate at the time of being provided the service remains to be stored. Therefore, there was a problem such that there is the potential that a certificate or a key may leak out, get copied, or be abused. Such item as the certificate is being set up as a nullified one at the service provider side. However, it is not preferable for these items to leak out unlimitedly as the certificate itself is within its validity period and is no different from a valid certificate or key from in terms of the respective forms unless there are particular circumstances such as having dissolved an agreement in tandem with expiration of the validity period.
Moreover, there was a problem such that as the apparatus at the user side is still in a state of being able to attempt accessing an apparatus at the service providing side, a process load arises with the apparatus at the service providing side to determine that this access is out of scope of providing the service so as to reject communicating. This kind of process load becomes greater when the user-side apparatus has a function of automatically accessing the service providing side once every certain time period. As a method of reducing this process load, while a CRL (a Certificate Revocation List) may be registered so as to make impossible communications according to the SSL with the out-of-scope apparatus, even such method does not completely eliminate the process load as, long as there is an access.
Then, as it is not desirable to spare processing power for dealing with apparatuses which are out of scope for providing the service, there was a demand for reducing such process load as much as possible.

Method of nullifying digital certificate, apparatus for nullifying digital certificate, and system, program, and recoring medium for nullifying digital certificate