Patent EA-001989-B1 (EA)
Title: PREPARATION OF [1S-[1a,2b,3b,4a(S*)]]-4-[7-[[1-(3-CHLORO-2-THIENYL) METHYL]PROPYLAMINO]-3H-IMIDAZO[4,5-b]PYRIDIN-3-yl]-N-ETHYL-2,3-DIHYDROXYCYCLOPENTANECARBOXAMIDE
Inventor: O'BRIEN MICHAEL K
IPC: C07D471/04
Filed: 1997-11-24
Abstract: 1. A method for preparing [1S-[1a,2b,3b,4a(S*)]-4-[7-[[1-(3-chloro-2-thienyl)methyl]propyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide (compound (I)), comprising reacting [1S-[1a,2b,3b,4a(S*)]]-4-[[3-amino-4-[[1-[(3-chloro-2-thienyl)methyl)propyl]amino]-2-pyridinyl]amino]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide (compound (IX)) with an orthoformate ester, formamidine acetate; or dimethylformamide dimethylacetal. 2. The method according to Claim 1 wherein said reacting is with formamidine acetate. 3. The method according to Claim 1 wherein said [1S-[1a,2b,3b,4a(S*)]]-4-[[3-amino-4-[[1-[(3-chloro-2-thienyl)methyl]propyl]amino]-2-pyridinyl]amino]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide (IX) is prepared by hydrolysis of [3aR-[3aa,4a,6a(R*),6aa]]-6-[[3-amino-4-[[1-[(3-chloro-2-thienyl)methyl]propyl]amino]-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (compound (VIII)). 4. The method according to Claim 3 wherein said hydrolysis takes place in the presence of aqueous hydrochloric acid. 5. A method according to Claim 3 additionally comprising recovering the [3aR-[3aa,4a,6a(R*),6aa]-6-[[4-[[1-(3-chloro-2-thienyl)-methyl]propyl]amino]-3-nitro-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (compound (VII)) with forming said [3aR-[3aa,4a,6a(R*),6aa]]-6-[[3-amino-4-[[1-[(3-chloro-2-thienyl)methyl]propyl]amino]-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (compound (VIII)). 6. The method according to Claim 5 wherein said reducing takes place in the presence of platinum on water wet carbon and ammonium formate, or in the presence of zinc and ammonium acetate, or in the presence of platinum on carbon in the presence of hydrogen. 7. The method according to Claim 5 additionally comprising reacting of (R)-2-chloro-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-3-nitro-4-pyridinamine (compound (V) with 2R,3S-isopropylidenedioxy-4R-amino-1S-ethylaminocarbonylcyclopentane (compound (VI) with forming of said [3aR-[3aa,4a,6a(R*),6aa]]-6-[[4-[[1-(3-chloro-2-thienyl)-methyl]propyl]amino]-3-nitro-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (compound (VII). 8. The method according to Claim 7 wherein said reacting takes place in the presence of toluene and an alkali metal carbonate. 9. The method according to Claim 7 additionally comprising replacing the hydroxyl moiety of (R)-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-2-hydroxy-3-nitro-4-pyridinamine (IV) with a chloro group with forming said (R)-2-chloro-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-3-nitro-4-pyridinamine (V). 10. The method according to Claim 9 wherein said replacing takes place in the presence of phosphorus oxychloride. 11. The method according to Claim 9 additionally comprising reacting 4-chloro-3-nitropyridin-2(1H)-one (compound (II)) with (R)-3-chloro-a-ethyl-2-thiopheneethanamine (compound (III)) to form said (R)-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-2-hydroxy-3-nitro-4-pyridinamine (IV). 12. The method according to Claim 11 wherein said reacting takes place in the presence of isopropanol and N,N-diisopropylethylamine. 13. The method according to Claim 11 additionally comprising reacting of 4-hydroxy-3-nitro-2(1H)-pyridone (compound XII) with phosphorus oxychloride to form said 4-chloro-3-nitropyridin-2(1H)-one (II). 14. A method for preparing [1S-[1a,2b,3b,4a(S*)]-4-[7-[[1-(3-chloro-2-thienyl)methyl]propyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide (I) in crystalline form comprising the steps of forming the free base of [1S-[1a,2b,3b,4a(S*)]]-4-[[3-amino-4-[[1-[(3-chloro-2-thienyl)methyl]propyl]amino]-2-pyridinyl]amino]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide (IX) from a dihydrochloride salt thereof, followed by reacting said free base with formamidine acetate, said steps being effected in a concatenated manner without a necessity for interim isolation and purification of said free base. 15. A method for preparing [1S-[1a,2b,3b,4a(S*)]-4-[7-[[1-(3-chloro-2-thienyl)methyl]propyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide (I) in crystalline form comprising reacting [1S[1a,2b,3b,4a(S*)]-4-[[3-amino-4-[[1-[3-chloro-2-thienyl)methyl]propyl]amino]-2-pyridinyl]amino]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide dihydrochloride with formamidine acetate. 16. A method for preparing the dihydrochloride salt of [1S-[1a,2b,3b,4a(S*)]]-4-[[3-amino-4-[[1-(3-chloro-2-thienyl)methyl]propyl]amino]-2-pyridinyl]amino-N-ethyl-2,3-dihydroxycyclopentanecarboxamide (compound (IX)) comprising the steps of reacting 4-chloro-3-nitropyridin-2(1H)-one (compound (II) with (R)-3-chloro-a-ethyl-2-thiopheneethanamine (compound (III)) to form (R)-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-2-hydroxy-3-nitro-4-pyridinamine (compound (IV)), followed by replacing the hydroxyl moiety of (R)-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-2-hydroxy-3-nitro-4-pyridinamine (IV) with a chloro group to form (R)-2-chloro-N-[1-[(3-chloro-2-thienyl)methyl)propyl]-3-nitro-4-pyridinamine (compound (V), followed by reacting (R)-2-chloro-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-3-nitro-4-pyridinamine (V) with 2R,3S-isopropylidenedioxy-4R-amino-1S-ethylaminocarbonylcyclopentane (compound (VI)) to form [3aR-[3aa,4a,6a(R*),6aa]-6-[[4-[[1-(3-chloro-2-thienyl)-methyl]propyl]amino]-3-nitro-2-pyridinyl]-amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (compound (VII)), followed by reducing [3aR-[3aa,4a,6a(R*),6aa]-6-[[4-[[1-(3-chloro-2-thienyl)-methyl]propyl]amino]-3-nitro-2-pyridinyl]amino-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (VII) to [3aR-[3aa,4a,6a(R*),6aa]]-6-[[3-amino-4-[[1-[(3-chloro-2-thienyl)methyl]propyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (compound (VIII)), followed by hydrolyzing [3aR-[3aa,4a,6a(R*),6aa]-6-[[3-amino-4-[[1-(3-chloro-2-thienyl)methyl]propyl]amino]-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (VIII), in the presence of hydrochloric acid, said steps being effected in a concatenated manner, without a necessity for interim isolation and purification of intermediate compounds [3aR-[3aa,4a,6a(R*),6aa]-6-[[3-amino-4-[[1-(3-chloro-2-thienyl)methyl]propyl]amino]-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (VIII), [3aR-[3aa,4a,6a(R*),6aa]-6-[[4-[[1-(3-chloro-2-thienyl)methyl]propyl]amino]-3-nitro-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (VII), (R)-2-chloro-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-3-nitro-4-pyridinamine (V) or (R)-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-2-hydroxy-3-nitro-4-pyridinamine (IV). 17. Method for preparing [1S-[1a,2b,3b,4a(S*)]]-4-[[3-amino-4-[[1-(3-chloro-2-thienyl)methyl]-propyl]amino]-2-pyridinyl]amino]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide (IX) comprising hydrolyzing [3aR-[3aa,4a,6a(R*),6aa]-6-[[3-amino-4-[[1-(3-chloro-2-thienyl)methyl]propyl]amino]-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (VIII). 18. A method for preparing [3aR-[3aa,4a,6a(R*),6aa]-6-[[3-amino-4-[[1-(3-chloro-2-thienyl)methyl]propyl]amino]-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (VIII) comprising reducing [3aR-[3aa,4a,6a(R*),6aa]]-6-[[4-[[1-(3-chloro-2-thienyl)methyl]propyl]amino]-3-nitro-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (VII) in the presence of platinum on water wet carbon and ammonium formate. 19. A method for preparing [3aR-[3aa,4a,6a(R*),6aa]-6-[[3-amino-4-[[1-(3-chloro-2-thienyl)methyl]propyl]amino]-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (VIII) comprising reducing [3aR-[3aa,4a,6a(R*),6aa]-6-[[4-[[1-(3-chloro-2-thienyl)methyl]propyl]amino]-3-nitro-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (VII) in the presence zinc and ammonium acetate. 20. A method for preparing [3aR-[3aa,4a,6a(R*),6aa]-6-[[3-amino-4-[[1-(3-chloro-2-thienyl)methyl]propyl]amino]-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (VIII) comprising reducing [3aR-[3aa,4a,6a(R*),6aa]-6-[[4-[[1-(3-chloro-2-thienyl)-methyl]propyl]amino]-3-nitro-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (VII) in the presence of in the presence of platinum on carbon and hydrogen. 21. A method for preparing [3aR-[3aa,4a,6a(R*),6aa]-6-[[4-[[1-(3-chloro-2-thienyl)-methyl]propyl]amino]-3-nitro-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (VII) comprising reacting (R)-2-chloro-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-3-nitro-4-pyridinamine (V) with 2R,3S-isopropylidenedioxy-4R-amino-1S-ethylaminocarbonylcyclopentane (VI) in the presence of an alkali metal carbonate. 22. A method for preparing (R)-2-chloro-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-3-nitro-4-pyridinamine (V) comprising replacing the hydroxyl moeity of (R)-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-2-hydroxy-3-nitro-4-pyridinamine (IV). 23. A method for preparing (R)-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-2-hydroxy-3-nitro-4-pyridinamine (IV) comprising reacting 4-chloro-3-nitropyridin-2(1H)-one (II) with (R)-3-chloro-a-ethyl-2-thiopheneethanamine (III). 24. A method for preparing 4-hydroxy-3-nitro-2(1H)-pyridone (XII) comprising hydrolyzing and decarboxylating 2-hydroxy-3-cyano-4-methoxypyridine (X) to give 2,4-dihydroxypyridine (XI), followed by nitration of said 2,4-dihydroxypyridine (XI). 25. A method according to Claim 24 wherein said hydrolyzing, decarboxylating and nitration are effected in a concatenated manner, without a necessity for interim isolation and purification of said 2,4