1. A process for the preparation of any one of the compounds of formulae (Ia), (Ib) and (Ic) or a mixture thereof:
68
wherein R2 and R3 are selected, independently, from hydrogen, fluoro, chloro, SOq(C1-C6)alkyl wherein q is zero, one or two, ((C1-C6)alkyl)2amino-, CO2R7, CONR8R9, SO2NR10R11, aryl-(C0-C3)alkyl- or aryl-(C0-C3)alkyl-O, wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(C0-C3)alkyl- or heteroaryl-(C0-C3)alkyl-O, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur; X2(C0-C6)alkyl- and X2(C1-C6)alkoxy-(C0-C6)alkyl-, wherein X2 is absent or X2 is (C1-C6)alkylamino- or ((C1-C6)alkyl)2amino-, and wherein the (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties of said X2(C0-C6)alkyl- or X2(C1-C6)alkoxy-(C0-C6)alkyl- contains at least one carbon atom, and wherein from one to three of the carbon atoms of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl moieties of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- groups may be optionally substituted with from two to seven fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl-(C0-C3)alkyl- and said heteroaryl-(C0-C3)alkyl- may optionally be replaced by an oxygen, nitrogen or sulfur atom, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms, (C1-C6)alkoxy optionally substituted with from two to seven fluorine atoms, chloro, fluoro, ((C1-C6)alkyl)2amino-, CO2R7, CONR8R9, and SO2NR10R11;
or R2 and R3,together with the carbons to which they are attached, form a four to seven membered monocyclic, or a ten to fourteen membered bicyclic, carbocyclic ring that can be saturated or unsaturated, wherein from one to three of the non-fused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic rings that are not part of the benzo ring shown in formula (II), may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicyclic rings may optionally be substituted with one or more substituents, preferably from zero to two substituents for the monocyclic rings and from zero to three substituents for the bicyclic rings, that are selected, independently, from (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl-, wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; oxo, fluoro, chloro, ((C1-C6)alkyl)2amino-, CO2R7, CONR8R9, and SO2NR10R11;
each R7, R8, R9, R10, and R11 is selected, independently, from hydrogen and (C1-C6)alkyl, or R8 and R9, or R10 and R11 together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, morpholine, azetidine, piperazine, N(C1-C6)alkylpiperazine or thiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur is replaced with a sulfoxide or sulfone; and
each X is, independently, (C1-C6)alkylene;
R5 is C1-C6 alkyl or Si(R12)3
R1 is an electron withdrawing group selected from cyano, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, aryl, nitro, trifluoromethyl, and sulfonyl;
each R4 is independently H, C1-C6, H(L)3N, or a metal cation, including alkali metal cations of Na, K, Li, or Cs; or two R11 groups together form a C2-C3 alkylene bridge;
each L is independently H, C1-C6 alkyl, phenyl or benzyl; and
each R12 is independently C1-C6 alkyl or phenyl; comprising the step of
reacting a compound of formula (III)
69
wherein R1, R2, R3, and R5 are as set forth above; and X is iodo, bromo, chloro or OSO2R13, wherein R13 is (C1-C6)alkyl, Si((C1-C6)alkyl)3 or Si(phenyl)3, in the presence of a palladium catalyst and a base.
2. A process according to claim 1 wherein the palladium catalyst is formed from the combination of a palladium compound selected from the group consisting of palladium(II) acetate, palladium(II) chloride, bis-acetonitrile palladium(II) chloride, bis-benzonitrile palladium(II) chloride, palladium(II) bromide, tris(dibenzylideneacetone)dipalladium(0); and a phosphine ligand selected from dicyclohexylphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, tri-isopropylphosphine, tri-n-propylphosphine, tri-isobutylphosphine, tri-n-butylphosphine, tri-o-tolylphosphine, triphenylphosphine, 2-(dicyclohexylphosphino)-biphenyl, or 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl.
3. A process according to claim 1 wherein the palladium catalyst is formed from the combination of palladium(II) acetate and either tricyclohexylphosphine or tri-t-butylphosphine.
4. A process according to claim 1 wherein the base selected from sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide, sodium ethoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, lithium hydride and potassium hydride.
5. A process according to claim 1 wherein the base is either sodium tert-butoxide and sodium tert-pentoxide.
6. A process according to claim 1 wherein R1 is CN.
7. A process according to claim 1 further comprising the prior step of reacting a compound of formula (IV):
70
wherein R1 is an electron withdrawing group selected from cyano, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, aryl, nitro, trifluoromethyl, and sulfonyl; X is iodo, bromo, chloro or OSO2R13, wherein R13 is (C1-C6)alkyl, Si((C1-C6)alkyl)3 or Si(phenyl)3; with a compound of formula (V):
71
wherein R5 is C1-C6 alkyl or Si(R12)3; and R12 is C1-C6 alkyl or phenyl; in the presence of a base.
8. A process according to claim 7 wherein the base is selected from sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-pentoxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, and lithium hydride.
9. A process according to claim 7 wherein the base is selected from sodium tert-butoxide and sodium methoxide.
10. A process according to claim 7 wherein R1 is CN.
11. A process for the preparation of any one of compounds of the formulae (Ia), (Ib) and (Ic) or a mixture thereof:
72
wherein R2 and R3 are selected, independently, from hydrogen, fluoro, chloro, SOq(C1-C6)alkyl wherein q is zero, one or two, ((C1-C6)alkyl)2amino-, CO2R7, CONR8R9, SO2NR10R11, aryl-(C0-C3)alkyl- or aryl-(C0-C3)alkyl-O, wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(C0-C3)alkyl- or heteroaryl-(C0-C3)alkyl-O, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur; X2(C0-C6)alkyl- and X2(C1-C6)alkoxy-(C0-C6)alkyl-, wherein X2 is absent or X2 is (C1-C6)alkylamino- or ((C1-C6)alkyl)2amino-, and wherein the (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties of said X2(C0-C6)alkyl- or X2(C1-C6)alkoxy-(C0-C6)alkyl- contains at least one carbon atom, and wherein from one to three of the carbon atoms of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl moieties of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- groups may be optionally substituted with from two to seven fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl-(C0-C3)alkyl- and said heteroaryl-(C0-C3)alkyl- may optionally be replaced by an oxygen, nitrogen or sulfur atom, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms, (C1-C6)alkoxy optionally substituted with from two to seven fluorine atoms, chloro, fluoro, ((C1-C6)alkyl)2amino-, CO2R7, CONR8R9, and SO2NR10R11;
or R2 and R3 together with the carbons to which they are attached, form a four to seven membered monocyclic, or a ten to fourteen membered bicyclic, carbocyclic ring that can be saturated or unsaturated, wherein from one to three of the non-fused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic rings that are not part of the benzo ring shown in formula (II), may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicyclic rings may optionally be substituted with one or more substituents, preferably from zero to two substituents for the monocyclic rings and from zero to three substituents for the bicyclic rings, that are selected, independently, from (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl-, wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; oxo, fluoro, chloro, ((C1-C6)alkyl)2amino-, CO2R7, CONR8R9, and SO2NR10R11;
each R7, R8, R9, R10, and R11 is selected, independently, from hydrogen and (C1-C6)alkyl, or R8 and R9, or R10 and R11 together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, morpholine, azetidine, piperazine, N(C1-C6)alkylpiperazine or thiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur is replaced with a sulfoxide or sulfone; and
each X is, independently, (C1-C6)alkylene;
R5 is C1-C6 alkyl or Si(R12)3
R1 is an electron withdrawing group selected from cyano, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, aryl, nitro, trifluoromethyl, and sulfonyl;
each R4 is independently H, C1-C6, H(L)3N, or a metal cation, including alkali metal cations of Na, K, Li, or Cs; or two R11 groups together form a C2-C3 alkylene bridge;
each L is independently H, C1-C6 alkyl, phenyl or benzyl; and each R12 is independently C1-C6 alkyl or phenyl;
comprising the single step of reacting a compound of formula (IV)
73
wherein R1 is an electron withdrawing group selected from cyano, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, aryl, nitro, trifluoromethyl, and sulfonyl; and X is iodo, bromo, chloro or OSO2R13 wherein R13 is (C1-C6)alkyl, Si((C1-C6)alkyl)3 or Si(phenyl)3; with a compound of formula (V)
74
wherein R5 is defined above; in the presence of a base and a palladium catalyst.
12. A process according to claim 11 wherein the base is selected from the group consisting of sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-pentoxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, or lithium hydride.
13. A process according to claim 11 wherein the base is sodium tert-butoxide, sodium ethoxide or sodium methoxide.
14. A process according to claim 11 wherein the palladium catalyst is prepared by the addition of a palladium compound selected from palladium(II) acetate, palladium(II) chloride, bis-acetonitrile palladium(II) chloride, bis-benzonitrile palladium(II) chloride, palladium(II) bromide, tris(dibenzylideneacetone)dipalladium(0); and a phosphine ligand such as dicyclohexylphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, tri-isopropylphosphine, tri-n-propylphosphine, tri-isobutylphosphine, tri-n-butylphosphine, tri-o-tolylphosphine, triphenylphosphine, 2-(dicyclohexylphosphino)biphenyl, or 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl.
15. A process according to claim 11 wherein the palladium catalyst is prepared by the addition of palladium(II) acetate to either tricyclohexylphosphine or tri-t-butylphosphine.
16. A process according to claim 11 wherein R1 is CN.
17. A process according to claims 1, 7 or 11 wherein both R2 and R3 are H.
18. A process according to claims 1, 7 or 11 wherein one or both of R2 and R3 are (C1-C6)alkoxy, CF3, fluoro or C2F5.
19. A compound of any one of the formulae (Ia), (Ib) and (Ic):
75
or a mixture thereof;
wherein R2 and R3 are selected, independently, from hydrogen, fluoro, chloro, SOq(C1-C6)alkyl wherein q is zero, one or two, ((C1-C6)alkyl)2amino-, CO2R7, CONR8R9, SO2NR10R11, aryl-(C0-C3)alkyl- or aryl-(C0-C3)alkyl-O, wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(C0-C3)alkyl- or heteroaryl-(C0-C3)alkyl-O, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur; X2(C0-C6)alkyl- and X2(C1-C6)alkoxy-(C0-C6)alkyl-, wherein X2 is absent or X2 is (C1-C6)alkylamino- or ((C1-C6)alkyl)2amino-, and wherein the (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties of said X2(C0-C6)alkyl- or X2(C1-C6)alkoxy-(C0-C6)alkyl- contains at least one carbon atom, and wherein from one to three of the carbon atoms of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl moieties of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- groups may be optionally substituted with from two to seven fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl-(C0-C3)alkyl- and said heteroaryl-(C0-C3)alkyl- may optionally be replaced by an oxygen, nitrogen or sulfur atom, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms, (C1-C6)alkoxy optionally substituted with from two to seven fluorine atoms, chloro, fluoro, ((C1-C8)alkyl)2amino-, CO2R7, CONR8R9, and SO2NR10R11;
or R2 and R3, together with the carbons to which they are attached, form a four to seven membered monocyclic, or a ten to fourteen membered bicyclic, carbocyclic ring that can be saturated or unsaturated, wherein from one to three of the non-fused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic rings that are not part of the benzo ring shown in formula (II), may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicyclic rings may optionally be substituted with one or more substituents, preferably from zero to two substituents for the monocyclic rings and from zero to three substituents for the bicyclic rings, that are selected, independently, from (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl-, wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; oxo, fluoro, chloro, ((C1-C6)alkyl)2amino-, CO2R7, CONR8R9, and SO2NR10R11;
each R7, R8, R9, R10, and R11 is selected, independently, from hydrogen and (C1-C6)alkyl, or R8 and R9, or R10 and R11 together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, morpholine, azetidine, piperazine, N(C1-C6)alkylpiperazine or thiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur is replaced with a sulfoxide or sulfone; and
each X is, independently, (C1-C6)alkylene;
R5 is C1-C6 alkyl or Si(R12)3
R1 is an electron withdrawing group selected from cyano, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, aryl, nitro, trifluoromethyl, and sulfonyl;
each R4 is independently H, C1-C6, H(L)3N, or a metal cation, including alkali metal cations of Na, K, Li, or Cs; or two R11 groups together form a C2-C3 alkylene bridge;
each L is independently H, C1-C6 alkyl, phenyl or benzyl; and
each R12 is independently C1-C6 alkyl or phenyl.
20. A compound according to claim 19 wherein both R2 and R3 are H.
21. A compound according to claim 19 wherein one or both of R2 and R3 are (C1-C6)alkoxy, CF3, fluoro or C2F5.
22. A compound according to claim 19 wherein R1 is CN.
23. A compound according to claim 19 selected from:
3-(Hydroxy-methoxy-methylene)-5-trifluoromethyl-3H-indene-1-carbonitrile, sodium salt;
3-(Hydroxy-methoxy-methylene)-3H-indene-1-carbonitrile, sodium salt;
3-(Ethoxy-hydroxy-methylene)-3H-indene-1-carbonitrile, sodium salt;
3-(Ethoxy-hydroxy-methylene)-5,6-dimethoxy-3H-indene-1-carbonitrile, sodium salt;
3-(Hydroxy-ethoxy-methylene)-5-trifluoromethyl-3H-indene-1-carbonitrile, sodium salt;
3-(Ethoxy-hydroxy-methylene)-7-fluoro-3H-indene-1-carbonitrile, sodium salt;
3-(Ethoxy-hydroxy-methylene)-5-fluoro-3H-indene-1-carbonitrile, sodium salt;
3-1,3Dioxolan-2-ylidene-5-trifluoromethyl-3H-indene-1-carbonitrile;
3-1,3Dioxolan-2-ylidene-3H-indene-1-carbonitrile; and
3-Benzenesulfonyl-3H-indene-1-carboxylic acid ethyl ester.
24. A process for the preparation of compounds of formula (VII):
76
wherein R2 and R3 are selected, independently, from hydrogen, fluoro, chloro, SOq(C1-C6)alkyl wherein q is zero, one or two, ((C1-C6)alkyl)2amino-, CO2R7, CONR8R9, SO2NR10R11, aryl-(C0-C3)alkyl- or aryl-(C0-C3)alkyl-O, wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(C0-C3)alkyl- or heteroaryl-(C0-C3)alkyl-O, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur; X2(C0-C6)alkyl- and X2(C1-C6)alkoxy-(C0-C6)alkyl-, wherein X2 is absent or X2 is (C1-C6)alkylamino- or ((C1-C6)alkyl)2amino-, and wherein the (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties of said X2(C0-C6)alkyl- or X2(C1-C6)alkoxy-(C0-C6)alkyl- contains at least one carbon atom, and wherein from one to three of the carbon atoms of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl moieties of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- groups may be optionally substituted with from two to seven fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl-(C0-C3)alkyl- and said heteroaryl-(C0-C3)alkyl- may optionally be replaced by an oxygen, nitrogen or sulfur atom, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms, (C1-C6)alkoxy optionally substituted with from two to seven fluorine atoms, chloro, fluoro, ((C1-C6)alkyl)2amino-, CO2R7, CONR8R9, and SO2NR10R11;
or R2 and R3, together with the carbons to which they are attached, form a four to seven membered monocyclic, or a ten to fourteen membered bicyclic, carbocyclic ring that can be saturated or unsaturated, wherein from one to three of the non-fused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic rings that are not part of the benzo ring shown in formula (II), may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicyclic rings may optionally be substituted with one or more substituents, preferably from zero to two substituents for the monocyclic rings and from zero to three substituents for the bicyclic rings, that are selected, independently, from (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl-, wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; oxo, fluoro, chloro, ((C1-C6)alkyl)2amino-, CO2R7, CONR8R9, and SO2NR10R11;
each R7, R8, R9, R10, and R11 is selected, independently, from hydrogen and (C1-C6)alkyl, or R8 and R9, or R10 and R11 together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, morpholine, azetidine, piperazine, N(C1-C6)alkylpiperazine or thiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur is replaced with a sulfoxide or sulfone; and
each X is, independently, (C1-C6)alkylene;
R5 is C1-C6 alkyl or Si(R12)3 comprising the step of
subjecting any one of compounds of the formulae (Ia), (Ib) and (Ic):
77
or mixtures thereof, prepared according to the process of claim 6, to hydrogenolysis conditions.
25. A process according to claim 24 wherein the hydrogenolysis conditions comprise a hydrogenation catalyst selected from palladium on carbon, palladium hydroxide on carbon, platinum on carbon, platinum oxide, and platinum oxide on carbon; in the presence of an acid selected from sulfuric acid, hydrochloric acid, methane sulfonic acid, toluenesulfonic acid, trifluoroacetic acid, acetic acid, formic acid, phosphoric acid and perchloric acid.
26. A process according to claim 24 wherein the hydrogenolysis conditions comprise a hydrogenation catalyst selected from 5% palladium on carbon, 10% palladium on carbon or 5% platinum on carbon; in the presence of sulfuric acid, methane sulfonic acid, or a mixture of these two acids.
27. A process according to claim 24 wherein the single hydrogenation step is replaced by the two separate steps of
(a) subjecting any one of compounds of the formulae (Ia), (Ib) and (Ic):
78
or mixtures thereof, wherein R2, R3, R4 and R5 are as defined in claim 24; to hydrogenolysis conditions to obtain a compound of formula (IX):
79
wherein R2, R3 and R5 are as defined above;
(b) and then subjecting the compound of formula (IX) to reduction conditions to obtain a compound of formula (VII):
80
wherein R2, R3 and R5 are as defined above.
28. A process according to claim 27 wherein the hydrogenolysis conditions in step (a) for the reduction of the compounds of formulae (Ia), (Ib) and (Ic) or mixture thereof to one of formula (IX) comprise treatment with a hydrogenation catalyst selected from the group consisting of palladium on carbon, palladium hydroxide on carbon, platinum on carbon, platinum oxide, platinum oxide on carbon; in the presence of an acid selected from acetic acid, formic acid, benzoic acid, or salicylic acid.
29. A process according to claim 27 wherein the hydrogenolysis conditions in step (a) comprise treatment with a hydrogenolysis catalyst that is either 5% palladium on carbon, 10% palladium on carbon or 5% platinum on carbon; in the presence of either formic acid or acetic acid.
30. A process according to claim 27 wherein the reduction conditions in step (b) for reducing the nitrile compound of formula (IX) to one of formula (VII) comprise treatment with a hydrogenation catalyst selected from the group consisting of palladium on carbon, palladium hydroxide on carbon, platinum on carbon, platinum oxide, and platinum oxide on carbon; in the presence of an acid selected from sulfuric acid, hydrochloric acid, methane sulfonic acid, toluenesulfonic acid, trifluoroacetic acid, acetic acid, formic acid, phosphoric acid and perchloric acid.
31. A process according to claim 27 wherein the reduction conditions in step (b) comprise treatment with a hydrogenation catalyst that is 5% palladium on carbon, 10% palladium on carbon or 5% platinum on carbon; in the presence of any of sulfuric acid, methane sulfonic acid, or a combination thereof.
32. A compound of formula (IX):
81
wherein R2 and R3 are selected, independently, from hydrogen, fluoro, chloro, SOq(C1-C6)alkyl wherein q is zero, one or two, ((C1-C6)alkyl)2amino-, CO2R7, CONR8R9, SO2NR10R11, aryl-(C0-C3)alkyl- or aryl-(C0-C3)alkyl-O, wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(C0-C3)alkyl- or heteroaryl-(C0-C3)alkyl-O, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur; X2(C0-C6)alkyl- and X2(C1-C6)alkoxy-(C0-C6)alkyl-, wherein X2 is absent or X2 is (C1-C6)alkylamino- or ((C1-C6)alkyl)2amino-, and wherein the (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties of said X2(C0-C6)alkyl- or X2(C1-C6)alkoxy-(C0-C6)alkyl- contains at least one carbon atom, and wherein from one to three of the carbon atoms of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl moieties of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- groups may be optionally substituted with from two to seven fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl-(C0-C3)alkyl- and said heteroaryl-(C0-C3)alkyl- may optionally be replaced by an oxygen, nitrogen or sulfur atom, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms, (C1-C6)alkoxy optionally substituted with from two to seven fluorine atoms, chloro, fluoro, ((C1-C6)alkyl)2amino-, CO2R7, CONR8R9, and SO2NR10R11;
or R2 and R3,together with the carbons to which they are attached, form a four to seven membered monocyclic, or a ten to fourteen membered bicyclic, carbocyclic ring that can be saturated or unsaturated, wherein from one to three of the non-fused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic rings that are not part of the benzo ring shown in formula (II), may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicyclic rings may optionally be substituted with one or more substituents, preferably from zero to two substituents for the monocyclic rings and from zero to three substituents for the bicyclic rings, that are selected, independently, from (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl-, wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; oxo, fluoro, chloro, ((C1-C6)alkyl)2amino-, CO2R7, CONR8R9, and SO2NR10R11;
each R7, R8, R9, R10, and R11 is selected, independently, from hydrogen and (C1-C8)alkyl, or R8 and R9, or R10 and R11 together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, morpholine, azetidine, piperazine, N(C1-C6)alkylpiperazine or thiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur is replaced with a sulfoxide or sulfone; and each X is, independently, (C1-C6)alkylene;
R5 is C1-C6 alkyl or Si(R12)3; and
R12 is C1-C6 alkyl or phenyl.
33. A compound according to claim 32 wherein both R2 and R3 are H.
34. A compound according to claim 32 wherein one or both of R2and R3 are (C1-C6)alkoxy, CF3, fluoro or C2F5.
35. A compound according to claim 32 selected from:
3-Cyano-indan-1-carboxylic acid, ethyl ester;
6-Trifluoromethyl-3-cyano-indan-1-carboxylic acid, ethyl ester;
5,6-Dimethoxy 3-cyano-indan-1-carboxylic acid, ethyl ester;
4-Fluoro-3-cyano-indan-1-carboxylic acid, ethyl ester;
6-Fluoro-3-cyano-indan-1-carboxylic acid, ethyl ester; and
3-Benzenesulfonyl-3-Cyano-indan-1-carboxylic acid, ethyl ester.
36. A process for the preparation of a compound of formula (VIII):
82
wherein R2 and R3 are selected, independently, from hydrogen, fluoro, chloro, SOq(C1-C6)alkyl wherein q is zero, one or two, ((C1-C6)alkyl)2amino-, CO2R7, CONR8R9, SO2NR10R11, aryl-(C0-C3)alkyl- or aryl-(C0-C3)alkyl-O, wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(C0-C3)alkyl- or heteroaryl-(C0-C3)alkyl-O, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur; X2(C0-C6)alkyl- and X2(C1-C6)alkoxy-(C0-C6)alkyl-, wherein X2 is absent or X2 is (C1-C6)alkylamino- or ((C1-C6)alkyl)2amino-, and wherein the (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties of said X2(C0-C6)alkyl- or X2(C1-C6)alkoxy-(C0-C6)alkyl- contains at least one carbon atom, and wherein from one to three of the carbon atoms of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl moieties of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- groups may be optionally substituted with from two to seven fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl-(C0-C3)alkyl- and said heteroaryl-(C0-C3)alkyl- may optionally be replaced by an oxygen, nitrogen or sulfur atom, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms, (C1-C6)alkoxy optionally substituted with from two to seven fluorine atoms, chloro, fluoro, ((C1-C6)alkyl)2amino-, CO2R7, CONR8R9, and SO2NR10R11;
or R2 and R3, together with the carbons to which they are attached, form a four to seven membered monocyclic, or a ten to fourteen membered bicyclic, carbocyclic ring that can be saturated or unsaturated, wherein from one to three of the non-fused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic rings that are not part of the benzo ring shown in formula (II), may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicyclic rings may optionally be substituted with one or more substituents, preferably from zero to two substituents for the monocyclic rings and from zero to three substituents for the bicyclic rings, that are selected, independently, from (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl-, wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; oxo, fluoro, chloro, ((C1-C6)alkyl)2amino-, CO2R7, CONR8R9, and SO2NR10R11;
each R7, R8, R9, R10, and R11 is selected, independently, from hydrogen and (C1-C6)alkyl, or R8 and R9, or R10 and R11 together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, morpholine, azetidine, piperazine, N(C1-C6)alkylpiperazine or thiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur is replaced with a sulfoxide or sulfone; and
each X is, independently, (C1-C6)alkylene;
comprising the process according to claim 24 and the further step of subjecting a compound of formula (VII):
83
wherein R2 and R3 are as defined above and R5 is C1-C6 alkyl or Si(R12)3; to basic conditions to effect an amide cyclization.
37. A process according to claim 36 wherein the basic conditions comprise the treatment with a base selected from the group consisting of sodium tert-butoxide, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium tert-butoxide, potassium methoxide, potassium ethoxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, triethylamine, methylimidazole, lutidine, pyridine, methylmorpholine, ethylmorpholine, diisopropylethylamine and any combination of these bases.
38. A process according to claim 36 wherein the basic conditions comprise treatment with sodium tert-butoxide, sodium ethoxide or sodium methoxide.
39. A process for the preparation of compounds of formula (II):
84
wherein R6 is hydrogen; wherein R2 and R3 are selected, independently, from hydrogen, fluoro, chloro, SOq(C1-C6)alkyl wherein q is zero, one or two, ((C1-C6)alkyl)2amino-, CO2R7, CONR8R9, SO2NR10R11, aryl-(C0-C3)alkyl- or aryl-(C0-C3)alkyl-O, wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(C0-C3)alkyl- or heteroaryl-(C0-C3)alkyl-O, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur; X2(C0-C6)alkyl- and X2(C1-C6)alkoxy-(C0-C6)alkyl-, wherein X2 is absent or X2 is (C1-C6)alkylamino- or ((C1-C6)alkyl)2amino-, and wherein the (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties of said X2(C0-C6)alkyl- or X2(C1-C6)alkoxy-(C0-C6)alkyl- contains at least one carbon atom, and wherein from one to three of the carbon atoms of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl moieties of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- groups may be optionally substituted with from two to seven fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl-(C0-C3)alkyl- and said heteroaryl-(C0-C3)alkyl- may optionally be replaced by an oxygen, nitrogen or sulfur atom, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms, (C1-C6)alkoxy optionally substituted with from two to seven fluorine atoms, chloro, fluoro, ((C1-C6)alkyl)2amino-, CO2R7, CONR8R9, and SO2NR10R11;
or R2 and R3, together with the carbons to which they are attached, form a four to seven membered monocyclic, or a ten to fourteen membered bicyclic, carbocyclic ring that can be saturated or unsaturated, wherein from one to three of the non-fused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic rings that are not part of the benzo ring shown in formula (II), may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicyclic rings may optionally be substituted with one or more substituents, preferably from zero to two substituents for the monocyclic rings and from zero to three substituents for the bicyclic rings, that are selected, independently, from (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl-, wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; oxo, fluoro, chloro, ((C1-C6)alkyl)2amino-, CO2R7, CONR8R9, and SO2NR10R11;
each R7, R8, R9, R10, and R11 is selected, independently, from hydrogen and (C1-C6)alkyl, or R8 and R9, or R10 and R11 together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, morpholine, azetidine, piperazine, N(C1-C6)alkylpiperazine or thiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur is replaced with a sulfoxide or sulfone; and
each X is, independently, (C1-C6)alkylene;
comprising the process according to claim 36 and further comprising the step of reducing the carbonyl group of a compound of formula (VIII):
85
with a reducing agent.
40. A process according to claim 39 wherein the reducing agent is selected from the group consisting of borane tetrahydrofuran complex, diborane, borane dimethylsulfide complex, lithium aluminum hydride, and a combination of sodium borohydride and boron trifluoride.
41. A process according to claim 39 wherein the reducing agent is a combination of sodium borohydride and boron trifluoride.
42. A process for the preparation of a compound of formula (II):
86
wherein R6 is (C1-C6)alkyl, unconjugated (C3-C6)alkenyl, benzyl, (C1-C6)alkyl-CHO, (C1-C6)alkyl-(CO)(C1-C6)alkyl or CH2CH2O(C1-C4)alkyl;
R2 and R3 are selected, independently, from hydrogen, fluoro, chloro, SOq(C1-C6)alkyl wherein q is zero, one or two, ((C1-C6)alkyl)2amino-, CO2R4, CONR5R6, SO2NR7R8, aryl-(C0-C3)alkyl- or aryl-(C0-C3)alkyl-O, wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(C0-C3)alkyl- or heteroaryl-(C0-C3)alkyl-O, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur; X2(C0-C6)alkyl- and X2(C1-C6)alkoxy-(C0-C6)alkyl-, wherein X2 is absent or X2 is (C1-C6)alkylamino- or ((C1-C6)alkyl)2amino-, and wherein the (C0-C6)alkyl- or (C,-C6)alkoxy-(C0-C6)alkyl- moieties of said X2(C0-C6)alkyl- or X2(C1-C6)alkoxy-(C0-C6)alkyl- contains at least one carbon atom, and wherein from one to three of the carbon atoms of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl moieties of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- groups may be optionally substituted with from two to seven fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl-(C0-C3)alkyl- and said heteroaryl-(C0-C3)alkyl- may optionally be replaced by an oxygen, nitrogen or sulfur atom, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms, (C1-C6)alkoxy optionally substituted with from two to seven fluorine atoms, chloro, fluoro, ((C1-C6)alkyl)2amino-, CO2R4, CONR5R6, and SO2NR7R8;
or R2 and R3, together with the carbons to which they are attached, form a four to seven membered monocyclic, or a ten to fourteen membered bicyclic, carbocyclic ring that can be saturated or unsaturated, wherein from one to three of the non-fused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic rings that are not part of the benzo ring shown in formula (II), may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicyclic rings may optionally be substituted with one or more substituents, preferably from zero to two substituents for the monocyclic rings and from zero to three substituents for the bicyclic rings, that are selected, independently, from (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl-, wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; oxo, fluoro, chloro, ((C1-C6)alkyl)2amino-, CO2R4, CONR5R6, and SO2NR7R8;
each R4, R5, R6, R7, and R8 is selected, independently, from hydrogen and (C1-C6)alkyl, or R5 and R6, or R7 and R8 together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, morpholine, azetidine, piperazine, N(C1-C6)alkylpiperazine or thiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur is replaced with a sulfoxide or sulfone; and
each X is, independently, (C1-C6)alkylene.
comprising the step of reacting a compound of formula (II), made according to the process of claim 39, with a compound of formula R6,Y wherein Y is a leaving group such as chloro, bromo, iodo or mesylate, and R6 is as defined above.
43. A process for the preparation of compounds of formula (II):
87
wherein R6 is (C1-C5)alkyl, unconjugated (C3-C5)alkenyl, phenyl, (C1-C5)alkyl-CHO, (C1-C5)alkyl-(CO)(C1-C6)alkyl or CH2O(C1-C4)alkyl;
R2 and R3 are selected, independently, from hydrogen, fluoro, chloro, SOq(C1-C6)alkyl wherein q is zero, one or two, ((C1-C6)alkyl)2amino-, CO2R4, CONR5R6, SO2NR7R8, aryl-(C0-C3)alkyl- or aryl-(C0-C3)alkyl-O, wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(C0-C3)alkyl- or heteroaryl-(C0-C3)alkyl-O, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur; X2(C0-C6)alkyl- and X2(C1-C6)alkoxy-(C0-C6)alkyl-, wherein X2 is absent or X2 is (C1-C6)alkylamino- or ((C1-C6)alkyl)2amino-, and wherein the (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties of said X2(C0-C6)alkyl- or X2(C1-C6)alkoxy-(C0-C6)alkyl- contains at least one carbon atom, and wherein from one to three of the carbon atoms of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl moieties of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- groups may be optionally substituted with from two to seven fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl-(C0-C3)alkyl- and said heteroaryl-(C0-C3)alkyl- may optionally be replaced by an oxygen, nitrogen or sulfur atom, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms, (C1-C6)alkoxy optionally substituted with from two to seven fluorine atoms, chloro, fluoro, ((C1-C6)alkyl)2amino-, CO2R4, CONR5R6, and SO2NR7R8;
or R2 and R3, together with the carbons to which they are attached, form a four to seven membered monocyclic, or a ten to fourteen membered bicyclic, carbocyclic ring that can be saturated or unsaturated, wherein from one to three of the non-fused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic rings that are not part of the benzo ring shown in formula (II), may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicyclic rings may optionally be substituted with one or more substituents, preferably from zero to two substituents for the monocyclic rings and from zero to three substituents for the bicyclic rings, that are selected, independently, from (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl-, wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; oxo, fluoro, chloro, ((C1-C6)alkyl)2amino-, CO2R4, CONR5R6, and SO2NR7R8;
each R4, R5, R6, R7, and R8 is selected, independently, from hydrogen and (C1-C6)alkyl, or R5 and R6, or R7 and R8 together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, morpholine, azetidine, piperazine, N(C1-C6)alkylpiperazine or thiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur is replaced with a sulfoxide or sulfone; and
each X is, independently, (C1-C6)alkylene.
comprising reacting a compound of formula (II), prepared according to the process of claim 39, with a compound of formula R6CHO in the presence of a reducing agent.
44. A process according to claim 43 wherein the reducing agent is selected from the group consisting of sodium borohydride (NaBH4), sodium cyanoborohydride (NaBH3CN) and sodium triacetoxyborohydride (NaB(OAc)3H), boranes, aluminum-based reagents and trialkylsilanes.
45. A process for the preparation of the compounds of formula (XIV-Q):
88
wherein Q is a nitrogen protecting group,
(i) placing a protecting group, Q, on the nitrogen of a compound of formula (II) prepared according to the process of claim 39:
89
(ii) reacting the Q-group protected compound from step (i) with trifluoromethanesulfonic acid (CF3SO2OH) and nitric acid to obtain a compound of formula (XIII-Q):
90
and (iii) reducing the nitro groups of the compound XIII-Q to obtain a compound of formula (XIV-Q):
91
46. A process according to claim 45 wherein the nitrogen protecting group Q is selected from COCF3, COCCl3, COOCH2CCl3, COO(C1-C6)alkyl and COOCH2C6H5.
47. A process according to claim 45 wherein Q is a trifluoroacetyl or a t-butoxycarbonyl group.
48. A process according to claim 45 wherein step (ii) is carried out in a mixture of 4 or more equivalents of trifluoromethanesulfonic acid (CF3SO2OH) and 2 to 3 equivalents of nitric acid.
49. A process according to claim 45 wherein step (iii) is accomplished using hydrogen gas and a palladium catalyst such as palladium hydroxide, 5% palladium on carbon or 10% palladium on carbon.
50. A process for the preparation of a compound of formula (IA):
92
wherein R16 is H, (C1-C6)alkyl-, or (C1-C6)alkoxy-(C0-C6)alkyl-,
comprising the step of reacting a compound of formula (XIV-Q) made in accordance with the process according to claim 45:
93
wherein Q is a nitrogen protecting group, with a compound of formula (XXVIII):
94
wherein R20 and R21 are each independently (C1-C6)alkyl, and wherein R16 is defined above; and
(ii) removing the protecting group Q.
51. A process according to claim 50 wherein the nitrogen protecting group Q is trifluoroacetyl or a t-butoxycarbonyl group.
52. A process for the preparation of a compound of formula (IB):
95
wherein R16 and R17 are selected, independently, from H, (C1-C6)alkyl-, and (C1-C6)alkoxy-(C0-C6)alkyl-, comprising the steps of
(i) of reacting a compound of formula (XIV-Q) made in accordance with the process according to claim 45:
96
wherein Q is a nitrogen protecting group, with a compound of formula (XXVIII):
97
wherein R20 and R21 are each independently (C1-C6)alkyl, and wherein R16 is defined above; and
(ii) allowing the product of step (i) to react with a compound of the formula R17Z, wherein R17 is defined above, and Z is a leaving group, in the presence of a base;
(iii) removing the protecting group Q.
53. A process according to claim 52 wherein the leaving group Z is selected from the group consisting of halo, halosulfonate, mesylate and tosylate, and the base is an alkali metal hydride, hydroxide or carbonate.
54. A process for preparing a compound of formula (IC):
98
wherein R16 and R17 are selected, independently, from H, (C1-C6)alkyl-, and (C1-C6)alkoxy-(C0-C6)alkyl-, comprising the steps of
(i) allowing a compound of formula (XIV-Q) made in accordance with the process according to claim 45:
99
wherein Q is a nitrogen protecting group, to react with a compound of formula
100
wherein Y is an alkali metal or alkaline earth metal cation; or a compound of formula
101
wherein R16 and R17 are as defined above; and
(ii) removing the protecting group Q.
55. A process according to claim 54 wherein the protecting group Q is a trifluoroacetate group or a t-butoxycarbonyl group.
56. A process according to claim 54 wherein in step (i) the compound of formula (XIV-Q) is reacted with a compound of formula
102
wherein R16 and R17 are both H.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A method of causing a working fluid to flow from a first point to a second point, which comprises applying a driving pressure to the working fluid at the first point, wherein at least part of the driving pressure is provided by a driving fluid whose rate of flow comprises
(i) a hydrostatic component, and
(ii) an electroosmotic component.
2. A method according to claim 1 wherein the driving fluid and the working fluid are the same.
3. A method according to claim 1 wherein the working fluid comprises a fluid which
(i) is stored in a storage element at the first point, and
(ii) is displaced from the storage element by the driving fluid.
4. A method according to any one of the preceding claims wherein the driving fluid flow is produced by a process which comprises
(1) supplying a stream of fluid by hydrostatic pressure, and
(2) removing some of the fluid from the stream by electroosmotic flow.
5. A method according to any one of claims 1 to 4 wherein the driving fluid flow is produced by a process which comprises passing a mixture of first and second fluids under hydrostatic pressure through a channel in which electroosmotic flow is generated in the mixture.
6. A method according to any one of claims 1 to 4 wherein the driving fluid flow is produced by a process which comprises mixing
(i) the working fluid whose flow rate depends on a pressure which is partly or wholly hydrostatic, and
(ii) a second fluid whose flow rate, before said mixing, depends on a pressure which is partly or wholly hydrostatic,
wherein a mixture is created that passes through a channel in which electroosmotic flow is generated.
7. A method according to claim 6 wherein
(i) the working fluid
(a) is supplied from a first source at a hydrostatic pressure P1, and
(b) before it is mixed with the second fluid, passes through a first flow control element; and
(ii) the second fluid
(a) is supplied from a second source at a hydrostatic pressure P2, and
(b) passes through a second flow control element; and
wherein the first flow control element has a conductance k1, the second flow control element has a conductance k2, and the channel has a conductance k3; and 1k3k1 is greater than P1P2 and 1k3k2 is greater than P2P1.
8. A method according to any one of claims 1 to 4, wherein the electroosmotic component is produced by passing an electrokinetic fluid through a channel in which the electroosmotic flow is generated in the electrokinetic fluid, and at least part of the electrokinetic fluid is
(i) stored in a storage element, and
(ii) is displaced from the storage element, before passing through the channel, by a fluid under hydrostatic pressure.
9. A method according to any one of the preceding claims wherein at least part of the driving fluid passes through a flow control element.
10. A method according to any one of the preceding claims which comprises
(a) monitoring at least one variable by one or more of a pressure transducer, a flowmeter, a temperature sensor, a heat flux sensor, a displacement sensor, a load cell, a strain gauge, a conductivity sensor, a selective ion sensor, a pH sensor, a flow spectrophotometer, and a turbidity sensor, and
(b) changing, in response to said monitoring, an electrical potential which generates at least part of the electroosmotic component.
11. A method according to any one of the preceding claims wherein variations in the electroosmotic component at least partially compensate for variations in the hydrostatic component.
12. A method according to any one of preceding claims wherein the rate of flow of the working fluid at the second point is less than 50 microlitersminute.
13. A method according to any one of the preceding claims wherein the working fluid has at least one of the following characteristics:
(a) it comprises a liquid having an ionic strength of least 25 millimolar;
(b) it comprises a liquid having an ionic strength less than 0.5 millimolar;
(c) it comprises a liquid having a dynamic viscosity greater than 5 centipoise;
(d) it comprises a substantially pure organic liquid;
(e) it comprises a liquid having a dielectric constant less than 20;
(f) it comprises a liquid containing polyvalent ions;
(g) it comprises a liquid having a pH value less than 7; and
(h) it comprises a liquid having a pH value less than 4.
14. A method according to any one of preceding claims wherein the fluid from the second point passes into a chromatograph.
15. A method according to any one of preceding claims wherein apparatus operating under a first set of conditions causes the working fluid to flow from the first point to the second point and through an operable device during a first time period, and thereafter the same apparatus operating under a second set of conditions causes the working fluid to flow from the first point to the second point and through an operable device during a second time period, the working fluid during the first time period being different from the working fluid during the second time period andor the operating conditions of the operable device during the first time period being different from the operating conditions of the operable device during the second time period, andor the operable device during the first time period being different from the operable device during the second time period.
16. Apparatus suitable for use in a method as claimed in any one of preceding claims, the apparatus comprising
(1) a channel which includes an inlet and an outlet, and through which a fluid under pressure can flow from the inlet to the outlet;
(2) a porous solid dielectric material which is positioned within the channel between the inlet and the outlet; and
(3) electrodes which are positioned so that, when an electrokinetic fluid under pressure is flowing through the channel between the inlet and the outlet, the rate at which the fluid flows can be changed by changing an electric potential connected to the electrodes;
said apparatus having at least one of the following characteristics:
(a) it comprises a flow control element through which a fluid under pressure can flow before reaching the inlet;
(b) it comprises a flow control element through which a fluid under pressure can flow after leaving the outlet;
(c) it comprises an operable device which employs a pressurized fluid in its operation and is connected to
(i) the outlet, so that when pressurized fluid flows from the outlet, it passes through the device, or
(ii) a first outlet of a conduit having a second outlet connected to the channel and an inlet which can be connected to a source of pressurized fluid;
(d) it comprises a first source for a first fluid and a second source for a second fluid, both the first source and the second source being connected to the inlet so that pressurized fluid from the sources can pass through the inlet into the channel;
(e) it comprises a variable power supply connected to the electrodes;
(f) it comprises at least one sensor for monitoring a control signal, and a feedback control mechanism operatively connected to the sensor, whereby, when the apparatus includes a power supply connected to the electrodes, the feedback control mechanism modulates the electric potential supplied by the power supply;
(g) it comprises a conduit having (i) a first conduit outlet which is connected to the inlet, (ii) a second conduit outlet which can be connected to an operable device or a plurality of operable devices, and (iii) a conduit inlet which can be connected to a source of pressurized fluid, whereby, when pressurized fluid enters the conduit, a part of the pressurized fluid flows through the channel and the remainder of pressurized fluid flows through the device or devices;
(h) it comprises two or more said channels and a conduit having (i) a plurality of conduit inlets connected to an inlet or an outlet of each of said channels, and (ii) a conduit outlet which can be connected to an operable device or a plurality of operable devices;
(i) it comprises two or more said channels, the dielectric materials in the channels being different from each other;
(j) it comprises a pressure transducer through which a fluid under pressure can flow before reaching the inlet;
(k) it comprises a check valve through which a fluid under pressure can flow before reaching the inlet; and
(l) it comprises an accumulator through which a fluid under pressure can flow before reaching the inlet.
17. Apparatus according to claim 16 wherein the porous dielectric material comprises a fused silica capillary, silica particles, an organic polymer, or a product made by lithographic patterning, lithographic etching, direct injection molding, sol-gel processing, or electroforming.
18. Apparatus according to claim 16 or 17 which comprises a power supply having electrodes, the power supply having one or both of the following characteristics
(i) it is a variable power supply, and
(ii) its electrodes are connected to the channels through a bridge.
19. Apparatus according to any one of claims 16 to 18 which comprises at least one sensor for monitoring a control signal, and a feedback control mechanism operatively connected to the sensor, whereby, when the apparatus includes a power supply connected to the electrodes, the feedback control mechanism maintains the control signal within a predetermined range by modulating the electric potential supplied by the power supply, the sensor being one or more of a pressure transducer, a flowmeter, a temperature sensor, a heat flux sensor, a displacement sensor, a load cell, a strain gauge, a conductivity sensor, a selective ion sensor, a pH sensor, a flow spectrophotometer, and a turbidity sensor.
20. The use of electroosmotic flow to modify the rate at which a pressurized working fluid is delivered to an operable device which employs the pressurized fluid in its operation.
21. A flow controller system, comprising:
(a) a first conduit having:
(i) a first fluid inlet in fluid communication with a first fluid source at pressure P1;
(ii) a first fluid outlet at pressure P3 in fluid communication with the first fluid inlet, wherein P3<P1; and
(iii) a first flow element disposed between the first fluid inlet and a first node; and
(b) a second conduit having:
(i) a second fluid inlet in fluid communication with a second fluid source at pressure P2, wherein P3<P2;
(ii) a second fluid outlet in fluid communication with the second fluid inlet and, at the first node, with the first conduit;
(iii) a second flow element disposed between the second fluid inlet and the second fluid outlet; and
(iv) a third fluid outlet at pressure P4, wherein P4<P1 and P4<P2, the third fluid outlet being in fluid communication at a second node with the second flow element outlet
wherein 111, where 1 is the internal volume of the first node an 1 is the sum of apparent compressibilities within 1, 222 where 2 is the internal volume of the second node and 2 is the sum of apparent compressibilities within 2, the first flow element has a conductance of k1, the second flow element has a conductance of k2, and wherein 1k1>2k2.
22. A flow controller system, comprising:
(a) a first conduit having:
(i) a first fluid inlet in fluid communication with a first fluid source at pressure P1;
(ii) a first fluid outlet at pressure P3 in fluid communication with the first fluid inlet, wherein P3<P1; and
(iii) a first flow element disposed between the first fluid inlet and a first node; and
(b) a second conduit having:
(i) a second fluid inlet in fluid communication with a second fluid source at pressure P2, wherein P3<P2;
(ii) a second fluid outlet in fluid communication with the second fluid inlet and, at the first node, with the first conduit;
(iii) a second flow element disposed between the second fluid inlet and the second fluid outlet; and
(iv) a third fluid outlet at pressure P4, wherein P4<P1 and P4<P2, the third fluid outlet being in fluid communication at a second node at pressure PN2, with the second flow element outlet;
(c) a pressure transducer located at either the first or the second node; and
(d) an accumulator located at the opposite node as the pressure transducer;
wherein 111, where 1 is the internal volume of the first node and 1 is the sum of apparent compressibilities within 1, 222 where 2 is the internal volume of the second node and 2 is the sum of apparent compressibilities within 2, the first flow element has a conductance of k1, the second flow element has a conductance of k2, and wherein 1k1>2k2.
23. A flow controller system, comprising:
(a) a first conduit having:
(i) a first fluid inlet in fluid communication with a first fluid source at pressure P1;
(ii) a first fluid outlet at pressure P3 in fluid communication with the first fluid inlet, wherein P3<P1; and
(iii) a first flow element disposed between the first fluid inlet and a first node; and
(b) a second conduit having:
(i) a second fluid inlet in fluid communication with a second fluid source at pressured P2, wherein P3<P2;
(ii) a second fluid outlet in fluid communication with the second fluid inlet and, at the first node, with the first conduit;
(iii) a second flow element disposed between the second fluid inlet and a second fluid outlet; and
(iv) a third fluid outlet at pressure P4, wherein P4<P1 and P4<P2, the third fluid outlet being in fluid communication at a second node with the second flow element outlet;
(c) a pressure transducer located at either the first or the second node; and
(d) a check valve between the first and second nodes;
wherein 111, where 1 is the internal volume of the first node and 1 is the sum of apparent compressibilities within 1, 222 where 2 is the internal volume of the second node and 2 is the sum of apparent compressibilities within 2, the first flow element has a conductance of k1, the second flow element has a conductance of k2, and wherein 1k1>2k2.
24. A flow controller system, comprising:
(a) a first channel having:
(i) a first channel fluid inlet in fluid communication at a node with a first fluid source at pressure P1 and a second fluid source at pressure P2;
(ii) a first channel fluid outlet in fluid communication with the first channel fluid inlet and, at pressure P3, with a fluid terminus, wherein P3<P1 and P3<P2; and
(iii) a porous dielectric material disposed in the first channel;
(b) a second channel having:
(i) a second channel fluid inlet in fluid communication with the second fluid source;
(ii) a second channel fluid outlet in fluid communication with the second channel fluid inlet and, at the first node, with the first channel inlet and
(iii) a porous dielectric material disposed in the second channel; and
(c) a power supply in electrical communication with spaced electrodes for applying an electrical potential to the electrodes, the electrodes being positioned so that the channels are electrokinetically active when the power supply applies an electric potential to the electrodes;
wherein the electric potential generates an electroosmotically-driven flow component through at least one of the first and the second channels, wherein the electroosmotically-driven flow component modulates at least one pressure-driven flow component resulting from the P1P3 and the P2P3 pressure differentials.
25. A flow controller system, comprising:
(a) a first channel having:
(i) a first channel fluid inlet in fluid communication at a first node with a first fluid source at pressure P1 and a second fluid source at pressure P2;
(ii) a first channel fluid outlet in fluid communication with the first channel fluid inlet and, at pressure P3, with a fluid terminus, wherein P3<P1 and P3<P2; and
(iii) a porous dielectric material disposed in the first channel;
(b) a second channel having:
(i) a second channel fluid inlet in fluid communication with the second fluid source;
(ii) a second channel fluid outlet in fluid communication with the second channel fluid inlet and, at the first node, with the first channel; and
(iii) a porous dielectric material disposed in the second channel;
(c) a first power supply in electrical communication with a first set of spaced electrodes for applying a first electric potential to the first set of spaced electrodes, the first set of spaced electrodes being positioned so that the first channel is electrokinetically active when the first power supply applies an electric potential to the first set of spaced electrodes;
(d) a second power supply in electrical communication with a second set of spaced electrodes for applying a second electric potential to the second set of spaced electrodes, the second set of spaced electrodes being positioned so that the second channel is electrokinetically active when the second power supply applies an electric potential to the second set of spaced electrodes;
wherein the first electric potential generates a first electroosmotically-driven flow component through the first channel, the first electroosmotically-driven flow component modulating at least one pressure-driven flow component resulting from the P1P3 and the P2P3 pressure differentials and the second electric potential generates a second electroosmotically-driven flow component through the second channel, the second electroosmotically-driven flow component modulating at least one pressure-driven flow components resulting from the P1P3 and the P2P3 pressure differentials.
26. A flow controller system, comprising:
(a) a channel having:
(i) a fluid inlet in fluid communication at a node with a fluid source at pressure P1;
(ii) a fluid outlet in fluid communication with the fluid inlet and, at pressure P2, with a first fluid terminus, wherein P2<P1; and
(iii) a porous dielectric material disposed in the channel;
(b) a power supply in electrical communication with spaced electrodes for applying an electric potential to the spaced electrodes, the spaced electrodes being positioned so that the channel is electrokinetically active when the power supply applies an electric potential to the electrodes; and
(c) a first fluid storage element being disposed between the node and a second fluid terminus at pressure P3, wherein P3<P1, wherein the first fluid storage element has a first fluid storage element inlet in fluid communication at the node with the fluid source, and wherein the first fluid storage element also has a first fluid storage element outlet in fluid communication with the first fluid storage element inlet and the second fluid terminus;
wherein the electric potential generates an electroosmotically-driven flow component through the channel that modulates at least one pressure-driven flow component resulting from the P1P2 and the P1P3 pressure differentials.
27. A flow controller system, comprising:
(a) a channel having:
(i) a fluid inlet in liquid communication with a fluid source at pressure P1;
(ii) a fluid outlet in liquid communication with a first fluid terminus at pressure P2, wherein P2<P1; and
(iii) a porous dielectric material disposed in the channel;
(b) a power supply in electrical communication with spaced electrodes for applying an electric potential to the spaced electrodes, the spaced electrodes being positioned so that the channel is electrokinetically active when the power supply applies an electric potential to the electrodes; and
(c) a fluid storage element fluid disposed between the fluid source and the channel, the fluid storage element having a fluid storage element inlet in fluid communication with a fluid source, the fluid storage element also having a fluid storage element outlet in fluid communication with the fluid storage element inlet and the fluid inlet;
whereby the electric potential generates an electroosmotically-driven flow component through the channel that modulates a pressure-drive flow component resulting from the P1P2 pressure differential.
28. A method for controlling a flow of a fluid, comprising:
applying an electric potential to spaced electrodes in electrical communication with a channel, the channel having a porous dielectric material disposed therein, the channel also having a fluid inlet in fluid communication with a first fluid source at pressure P1 and a second fluid source at pressure P2, the channel also having a fluid outlet in fluid communication with the fluid inlet and, at pressure P3, with a terminus, wherein P3 <P1 and P3<P2, wherein the electric potential generates an electroosmotically-driven flow component through the channel that modulates at least one pressure-driven flow component resulting from the P1P3 and the P2P3 pressure differentials.
29. A method of controlling the flow of a fluid comprising:
(a) placing a first accumulator at a first node, wherein the first node is in a first conduit having: a first fluid inlet in fluid communication with a first fluid source at pressure P1, a first fluid outlet at pressure P3, wherein P3<P1, and a first flow element disposed between the first fluid inlet and the first fluid outlet;
(b) placing a second accumulator at a second node;
wherein, the second node is in a second conduit having: a second fluid inlet in fluid communication with a second fluid source at pressure P2, wherein P3<P2, a second fluid outlet in fluid communication with the first conduit at the first node, a second flow element disposed between the second fluid inlet and the second fluid outlet, and a third fluid outlet at pressure P4, wherein P4<P1 and P4<P2, the third fluid outlet being in fluid communication at the second node with the second fluid inlet.
30. A method of controlling a flow of a fluid, comprising:
applying an electric potential to spaced electrodes in electrical communication with a channel, the channel having a porous dielectric material disposed therein, the channel also having a fluid inlet in fluid communication at a node with a fluid source at pressure P1, the channel also having a fluid outlet in fluid communication with the fluid inlet and, at pressure P2, with a first fluid terminus, wherein P2<P1, and wherein a fluid storage element is disposed between the node and a second fluid terminus at pressure P3, wherein P3<P1, the fluid storage element having a fluid storage element inlet in fluid communication at the node with the fluid source, the fluid storage element also having a fluid storage element outlet in fluid communication with the fluid storage element inlet and the second fluid terminus, wherein the electric potential generates an electroosmotically-driven flow component through the channel that modulates at least one pressure-driven flow component resulting from the P1P2 and the P1P3 pressure differentials.
31. A method for controlling a flow of fluid, comprising:
applying an electric potential to spaced electrodes in electrical communication with a channel, the channel having a porous dielectric material disposed therein, the channel also having a fluid inlet in fluid communication at a node with a fluid source at pressure P1, the channel also having a fluid outlet in fluid communication with the fluid inlet and, at pressure P2, with a first fluid terminus, wherein P2<P1, and wherein a fluid storage element is disposed between the node and the fluid inlet, the fluid storage element having a fluid storage element inlet in fluid communication at the node with the fluid source, the fluid storage element also having a fluid storage element outlet in fluid communication with the fluid storage element inlet and the fluid inlet, wherein the electric potential generates an electroosmotically driven flow component through the channel that modulates a pressure-driven flow component resulting from the P1P2 pressure differential.