New process for the preparation of intermediates useful for the manufacture nep inhibitors
AssigneeNovartis AG
InventorsDavid Hook, Bernhard Riss, Jianguang Zhou, Yunzhong Li, Erhard Bappert
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Abstract
The invention relates to a new process for producing useful intermediates for the manufacture of NEP inhibitors or prodrugs thereof, in particular NEP inhibitors comprising -amino- -biphenyl- -methylalkanoic acid, or acid ester, backbone, such as N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester or salt thereof.
Claims16
A process for preparing a compound of formula (4), or salt thereof,
- wherein
- R1 is hydrogen or a nitrogen protecting group;
- said process comprising
- reacting a compound of formula (1), or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group;
- with a transition metal catalyst, optionally in the presence of a base,
- to obtain the compound of formula (4), or salt thereof.
A process for preparing a compound according to formula (5),
- or salt thereof,
- wherein R1 and R2 are, independently of each other, hydrogen or a nitrogen protecting group, and R3 is a carboxyl group or an ester group, preferably a carboxyl group, comprising reacting a compound of formula (4)
- or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group, with a lactam ring opening agent to obtain the compound of formula (5).
A process for preparing a compound according to formula (2),
- or salt thereof,
- wherein R1 and R2 are, independently of each other, hydrogen or a nitrogen protecting group, and R3 is a carboxyl group or an ester group, preferably a carboxyl group, comprising reducing a compound according to formula (5),
- or salt thereof,
- wherein R1 and R2 are, independently of each other, hydrogen or a nitrogen protecting group, and R3 is a carboxyl group or an ester group, preferably a carboxyl group, to obtain the compound of formula (2).
A process for preparing a compound of formula (4), or salt thereof,
- wherein
- R1 is hydrogen or a nitrogen protecting group;
- said process comprising
- i) reacting a compound of formula (3), or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group;
- with a selenide in the presence of a base,
- to obtain a compound of formula (6), or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group;
- and
- R is aryl;
- and
- ii) treating the compound of formula (6) with an oxidizing agent, to obtain the compound of formula (4).
A process for preparing a compound according to formula (3),
- or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group,
- comprising reducing a compound according to formula (4),
- or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group,
- to obtain the compound of formula (3).
A compound of formula (4), or salt thereof,
- wherein
- R1 is hydrogen or a nitrogen protecting group, for example BOC.
A compound according to formula (5),
- or salt thereof,
- wherein R1 and R2 are, independently of each other, hydrogen or a nitrogen protecting group, such as BOC;
- and
- R3 is a carboxyl group or an ester group, preferably a carboxyl group.
A compound of formula (6), or salt thereof,
- or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group;
- and
- R is aryl.
Dependencies are inferred from the claim text.