Patent EA-003645-B1 (EA)
Title: Process for preparing n6-substituted deaza-adenosine derivatives
Inventor: RODRIGUEZ WALTER
IPC: C07D471/04
Filed: 1999-12-14
Abstract: 1. A process for preparing a 2-halo-3-nitro-4-aminopyridine compound of formula wherein X is a straight or branched chain alkylene, cycloalkylene or cycloalkenylene group; X2 is Cl of F; Y is NR4, O or S; a = 0 or l; and Z is of the formula wherein Z1 is N, CR5, (CH)m-CR5 or (CH)m-N, m being 1 or 2; and Z2 is N, NR6, O or S, n being 0 or 1; R4, R5 and R6 are independently H, alkyl, aryl or heterocyclyl ; and Ra and Rb are independently H, OH, alkyl, hydroxyalkyl, alkylmercaptyl, thioalkyl,alkoxy, alkoxyalkyl, amino, alkylamino, hydroxyalkyl, carboxyl, acyl, halogen, carbamoyl, alkylcarbamoyl, aryl or heterocyclyl, comprising reacting a 2,4-dihalo-3-nitropyridine compound of formula wherein X1 is F and X2 is Cl or F, with an amine of formula H, N-X- (Y)a-Z. 2. The process of claim 1 wherein both X1 and X2 are F. 3. The process of claim 1 wherein X is a straight or branched chain alkylene; a = 0; R4, R5 and R6 are independently H or alkyl; and Z is wherein Z1 is N, CR5, (CH)mCR5 or (CH)m-N, m being 1 or 2; and Z2 is N. NR6, O or S, n being 0 or 1. 4. The process of claim 1 wherein H2N-X- (Y)a-Z is (R)-1-(3-chlorothien-2-yl)-2-aminobutane. 5. The process of claim 1, further comprising the step of reacting the 2-halo-3-nitro-4- aminopyridine compound with a protected dihydroxyaminocyclopentane compound of formula to form a 2,4-diamino-3-nitropyridine compound of formula wherein T is or R3O-CH2; Q is CH2 or O; R1, R2 and R3 are independently H, alkyl, aryl or heterocyclyl ; and R7 and R8 are independently hydrogen, alkyl, aralkyl, carbamoyl, alkyl carbamoyl, dialkyl-carbamoyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl, or R7 and R8 together form , where Rc is hydrogen or alkyl, , where Rd and Re are independently hydrogen, alkyl, or together with the carbon atom they are attached to form a 1,1- cycloalkyl group. 6. The process of claim 5 wherein Q is CH2; R1 and R2 are independently H or alkyl; T is and R7 and R8 are alkyl, or together form , where Rd and Re are independently hydrogen or alkyl, or together with the carbon atom they are attached to form a 1,1- cycloalkyl group. 7. The process of claim 5, further comprising the step of reducing the 2,4-diamino-3-nitropyridine compound to form a 2,3,4-triaminopyridine compound of formula 8. The process of claim 7, further comprising the step of removing the groups R7 and R8. 9. The process of claim 8, further comprising the step of reacting the 2,3,4-triaminopyridine compound with an orthoformate ester, formamidine acetate or dimethylformamide dimethyl acetal to form a compound of formula 10. A process for preparing (R)-N-[1-[(3-chlorothien-2-yl) methyl] propyl]-2-halo-3-nitro-4-pyridinamine comprising (a) reacting a 2,4-dihalo-3-nitropyridine, wherein halo is Cl or F, with (R)-1-(3-chlorothien-2-yl)-2-aminobutane, hydrochloride. 11. The process of claim 10, further comprising the step of (b) reacting the (R)-N-[1-[ (3-chlorothien-2-yl) methyl] propyl]-2-halo-3-nitro-4-pyridinamine with 3aR-[3aalpha, 4alpha, 6a, 6aalpha]-6-amino-N-ethyl tetrahydro-3,3-di-methyl-2,4-dioxabicyclo [3.3.0]octan-8-carboxamide, benzoate to form [3aR-[3aalpha, 4alpha, 6a (R*), 6aalpha]]-6-[4-[[1-[(3-chlorothien-2-yl) methyl] propyl] amino]-3-nitropyrid-2-ylamino] N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide. 12. The process of claim 11, further comprising the step of (c) reducing the [3aR[3aalpha, 4alpha, 6a(R*), 6aalpha]]-6-[4-[[1-[(3-chlorothien-2-yl) methyl]propyl] amino]-3-nitropyrid-2-ylamino]N-ethyl tetrahydro-2,2-di-methyl-4H-cyclopenta-1,3-dioxole-4-carboxamide to form [3aR[3aalpha, 4alpha, 6a(R*), 6aalpha]]-6-[4-[[1-[(3-chloro-thien-2-yl) methyl] propyl] amino]-3-aminopyrid-2-ylamino] N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide. 13. The process of claim 12, further comprising the step of (d) hydrolyzing the [3aR [3aalpha, 4alpha, 6a(R*), 6aalpha]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl]amino]-3-aminopyrid-2-ylamino] N-ethyltetrahydro-2,2-di-methyl-4H-cyclopenta-1,3-dioxole-4-carboxamide to form [1S-[1alpha, 2beta, 3beta, 4alpha(S*)]]-4-[3-amino-4-[[1-[3-chlorothien-2-yl)methyl]propyl]amino]pyrid-2-ylamino]N-ethyl 2,3-dihydroxycyclopentane carboxamide dihydrochloride hydrate. 14. The process of claim 13, further comprising the step of recovering the [1S-[1alpha,2beta, 3beta, 4alpha (S*)]]-4-[3-amino-4-[[1-[3-chlorothien-2-yl)methyl]propyl]amino]pyrid-2-ylamino]N-ethyl dihydroxycyclopentane carboxamide dihydrochloride hydrate. 15. The process of claim 14, further comprising the step of reacting the [1S-[1alpha, 2beta, 3beta, 4alpha (S*)]]-4-[3-amino-4-[[1-[3-chlorothien-2-yl)methyl]propyl]amino]pyrid-2-ylamino]N-ethyl dihydroxycyclopentane carboxamide dihydrochloride hydrate with an orthoformate ester, formamidine acetate or dimethylform-amide dimethyl acetal to form [1S-[1alpha, 2beta, 3beta, 4alpha(S*)]]-4-[7-[[1-[(3-chlorothien-2-yl) methyl] propyl] amino]-3H-imidazo [4,5-b] pyrid-3-yl] N-ethyl 2,3-dihydroxycyclopentane carboxamide. 16. The process of claim 13, wherein said steps (a)-(d) are effected in a concatenated manner without isolation of the intermediate compounds (R)-N-[1-[(3-chlorothien-2-yl) methyl] propyl]-2-halo-3-nitro-4-pyridinamine, [3aR-[3aalpha, 4alpha, 6a (R*), 6aalpha]]-6-[4-[[1-[(3-chlorothien-2-yl) methyl] propyl] amino]-3-nitropyrid-2-ylamino] N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide and [3aR-[3aalpha, 4alpha, 6a(R*),6aalpha]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl]amino]-3-aminopyrid-2-ylamino] N-ethyl. 17. The process of claim 16 wherein the 2,4-dihalo-3-nitropyridine is 2,4-difluoro-3-nitropyridine or a mixture of 2,4-difluoro-3-nitropyridine and 2-chloro-4-fluoro-3-nitropyridine. 18. The process of claim 16 further comprising the step of converting 2,4-dichloro-3-nitropyridine to a mixture of 2,4-difluoro-3-nitropyridine and 2-chloro-4-fluoro-3-nitropyridine.