Process and intermediates for the preparation of NEP inhibitors
AssigneeNovartis AG
InventorsBenjamin Martin, Francesca Mandrelli, Francesco Venturoni
Life of this patent
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Abstract
The present invention relates to a new chemical synthesis, intermediates and catalysts useful for the preparation of the neprilysin (NEP) inhibitor sacubitril. It further relates to new intermediate compounds and their use for said new chemical synthesis route.
Claims16
A compound of formula (1), or a salt thereof,
- wherein R1 is hydrogen or C1-C6-alkyl.
A compound of formula (2),
A compound of formula (7),
A process for the manufacture of a compound of formula (1),
- wherein R1 is hydrogen, or a salt thereof, comprising, oxidizing a compound of formula (2),
- in the presence of an oxidant.
A process for the manufacture of a compound of Formula (2),
- comprising, reacting a compound of formula (3),
- with methacrolein, or a reactive derivative thereof, in the presence of an organocatalyst suitable for a Michael reaction, wherein the organocatalyst is selected from the group consisting of those represented by the following formulae:
A process for the manufacture of a compound of formula (2),
- comprising, reacting of a compound of formula (7),
- with propionaldehyde, or a reactive derivative thereof, in the presence of an organocatalyst suitable for a Michael reaction, wherein the organocatalyst is selected from the group consisting of those represented by the following formulae:
A process for the manufacture of a compound of formula (7),
- comprising, reacting a compound of formula (3),
- with formaldehyde, or a reactive derivative thereof.
A process for the manufacture of a compound of formula (8),
- wherein R′ and R″ are independently of each other hydrogen or a nitrogen protecting group, and R1 is hydrogen or C1-C6-alkyl, comprising hydrogenating a compound of formula (1), or a salt thereof,
- wherein R1 is hydrogen or C1-C6-alkyl, in the presence of Raney Nickel and optionally including or followed by the introduction of a nitrogen protecting group;
- and
- wherein the obtained compound of formula (8) is optionally further reacted with succinic acid, or a derivative thereof to form a compound of formula (10),
- wherein R1 is hydrogen or C1-C6-alkyl, thereof.
Dependencies are inferred from the claim text.