Crystalline (2S,4R)-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid and uses thereof
In one aspect, the invention relates to a crystalline form of the structure: or a pharmaceutically acceptable salt thereof, having neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising this crystalline form; methods of using this crystalline form and its soluble form (I); and processes for preparing soluble (I) and crystalline (I′) forms.
1. A process for preparing (2S,4R)-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid (I), the process comprising:
(a) coupling benzyl (2S,4R)-4-amino-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-2-methylpentanoate hydrochloride with 3-((4-methoxybenzyl)oxy)isoxazole-5-carboxylic acid in a solvent in approximately a 1:1 molar ratio to give benzyl (2S,4R)-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-((4-methoxybenzyl)oxy)isoxazole-5-carboxamido)-2-methylpentanoate; and
(b) deprotecting benzyl (2S,4R)-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-((4-methoxybenzyl)oxy)isoxazole-5-carboxamido)-2-methylpentanoate to form (2S,4R)-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid (I).
2. The process of claim 1 , wherein (a) further comprises a peptide coupling agent and a base in approximately a 1:3:1:1 molar ratio of coupling agent to base to benzyl (2S,4R)-4-amino-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-2-methylpentanoate hydrochloride to 3-((4-methoxybenzyl)oxy)isoxazole-5-carboxylic acid.
3. The process of claim 2 , wherein the coupling agent is 2-(6-chloro-1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) and the base is N,N-diisopropylethylamine.
4. The process of claim 1 , wherein (b) is performed with a palladium catalyst and hydrogen gas.
5. The process of claim 1 , wherein (a) further comprises a peptide coupling agent.
6. The process of claim 5 , wherein the peptide coupling agent is selected from O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, O-(6-chlorobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, and O-[(ethoxycarbonyl)cyanomethylenamino]-N,N,N′,N′-tetra methyluronium tetrafluoroborate.
7. The process of claim 6 , wherein the peptide coupling agent is selected from O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, and O-(6-chlorobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate.
8. The process of claim 7 , wherein the peptide coupling agent is O-(6-chlorobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate.
9. The process of claim 1 , wherein (a) further comprises a base.
10. The process of claim 9 , wherein the base is N,N-diisopropylethylamine.
11. The process of claim 1 , wherein the solvent of (a) is tetrahydrofuran.
12. The process of claim 1 , wherein the deprotecting of (b) comprises adding a palladium catalyst.
13. The process of claim 1 , wherein the deprotecting of (b) comprises adding hydrogen.
14. The process of claim 1 , wherein the deprotecting of (b) comprises adding ethanol.
15. The process of claim 12 , further comprising removing the palladium catalyst following the deprotecting of (b).
16. The process of claim 15 , further comprising adding an oxidizing agent following the removing of the palladium catalyst.
17. The process of claim 16 , wherein the oxidizing agent is hydrogen peroxide.
18. The process of claim 8 , wherein (a) further comprises N,N-diisopropylethylamine.
19. The process of claim 18 , wherein the deprotecting of (b) comprises adding a palladium catalyst and hydrogen.
20. The process of claim 1 , further comprising isolating (2S,4R)-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid (I).