Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid
AssigneeNovartis AG
InventorsDavid Hook, Thomas Ruch, Bernhard Riss, Bernhard Wietfeld, Gottfried Sedelmeier, Matthias Napp, Markus Bänziger, Steven Hawker, Lech Ciszewski, Liladhar M Waykole
Life of this patent
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Abstract
The present invention relates to pyrrolidin-2-ones according to the formula (1), or salts thereof, wherein R1 is hydrogen or a nitrogen protecting group, methods for their preparation and their use in the preparation of NEP-inhibitors, particularly in the preparation of N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester or salt thereof.
Claims30
A process for preparing a compound according to formula (1), or tautomer, or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group
- comprising the following steps:
- a) providing a compound according to formula (4), or tautomer, or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group and R4 is a CO-activating group,
- b) reacting the compound according to formula (4), or salt thereof, or tautomer, with a biphenylic compound to obtain a compound according to formula (5), or tautomer, or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group and
- c) reducing a compound according to formula (5), or tautomer, or salt thereof, to obtain a compound according to formula (1), or tautomer, or salt thereof.
A process for preparing a compound according to formula (1), or tautomer, or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group
- said process comprising reducing a compound according to formula (5), or tautomer, or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group
- to obtain the compound of formula (1), or tautomer, or salt thereof.
A process according to 1, wherein the configuration of the compounds of formulae (4), (5) and (1), or tautomers, or salts thereof, is according to formulae (4-a), (5-a) and (1-a), or tautomers thereof
- wherein R1 is hydrogen or a nitrogen protecting group and R4 is a CO-activating group.
A process for preparing a compound according to formula (1), or tautomer, or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group,
- comprising the following steps:
- a) providing a compound according to formula (7), or salt thereof,
- wherein R1 and R2 are independently, of each other, hydrogen or a nitrogen protecting group,
- b) reacting a compound according to formula (7), or salt thereof, in a Wittig reaction to obtain a compound according to formula (8), or salt thereof,
- wherein R1 and R2 are independently, of each other, hydrogen or a nitrogen protecting group and R5 is hydrogen or alkyl,
- c) reducing a compound according to formula (8), or salt thereof, to obtain a compound according to formula (9), or salt thereof,
- wherein R1 and R2 are independently, of each other, hydrogen or a nitrogen protecting group and R5 is hydrogen or alkyl,
- d) optionally removing the nitrogen protecting groups, thereby obtaining a compound according to formula (10) or a salt thereof
- wherein R5 is hydrogen or alkyl, and
- e) reacting the compound according to formula (10), or salt thereof, wherein R5 is hydrogen or alkyl, under ring-closing conditions to obtain a compound according to formula (1), or tautomer, or salt thereof.
A process for preparing a compound according to formula (1), or tautomer, or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group,
- comprising reacting a compound according to formula (11), or tautomer, or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group and R6 is a leaving group, with an activated biphenylic compound.
A process for preparing a compound according to formula (1), or tautomer, or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group,
- comprising the following steps:
- a) providing a compound according to formula (12), or tautomer, or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group,
- b) reacting compound (12), or tautomer, or salt thereof, with an activated biphenylic compound to obtain a compound according to formula (13), or tautomer, or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group, and
- c) reducing the compound according to formula (13), or tautomer, or salt thereof, to obtain the compound according formula (1), or tautomer, or salt thereof.
A process for preparing a compound according to formula (1), or tautomer, or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group,
- said process comprising reducing a compound according to formula (13), or tautomer, or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group,
- to obtain the compound according formula (1), or tautomer, or salt thereof.
A process for preparing a compound according to formula (1), or tautomer, or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group,
- comprising the following steps:
- a) providing a compound according to formula (14), or salt thereof,
- b) reacting the compound according to formula (14), or salt thereof, with 4-formyl biphenyl to obtain a compound according to formula (15), or salt thereof,
- c) hydrogenating compound (15), or salt thereof, to obtain a compound according to formula (16), or salt thereof,
- and
- d) reducing the compound according to formula (16), or salt thereof, to obtain a compound according to formula (1), or tautomer, or salt thereof,
- wherein in formulae (14) to (16) R1 is hydrogen or a nitrogen protecting group.
A process for preparing a compound according to formula (1), or tautomer, or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group,
- said process comprising reducing the compound according to formula (16), or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group,
- to obtain the compound according to formula (1), or tautomer, or salt thereof.
A process for preparing a compound according to formula (1), or tautomer, or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group,
- said process comprising hydrogenating the compound according to formula (15), or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group.
- to obtain the compound according to formula (1), or tautomer, or salt thereof.
A process for preparing a compound according to formula (1), or tautomer, or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group,
- said process comprising hydrogenating the compound according to formula (21), or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group,
- to obtain the compound according to formula (1), or tautomer, or salt thereof.
A process for preparing a compound according to formula (1), or tautomer, or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group,
- comprising the following steps:
- a) providing a compound according to formula (14), or salt thereof,
- b) reacting the compound according to formula (14), or salt thereof, with 4-formyl biphenyl to obtain a compound according to formula (15), or salt thereof,
- c) reducing the compound (15), or salt thereof, to obtain a compound according to formula (21), or tautomer, or salt thereof,
- and
- d) hydrogenating the compound according to formula (21), or salt thereof, to obtain a compound according to formula (1), or tautomer, or salt thereof,
- wherein in formulae (14), (15) and (16) R1 is hydrogen or a nitrogen protecting group.
A process for preparing a compound according to formula (1), or tautomer, or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group,
- comprising the following steps:
- a) providing a compound according to formula (14), or salt thereof,
- b) reacting the compound according to formula (14), or salt thereof, with 4-formyl biphenyl to obtain a compound according to formula (15), or salt thereof,
- c) hydrogenating the compound (15), or salt thereof, to obtain the compound according to formula (1), or tautomer, or salt thereof,
- wherein in formulae (14) and (15) R1 is hydrogen or a nitrogen protecting group.
A process for preparing a compound according to formula (1), or tautomer, or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group,
- comprising the following steps:
- a) providing a compound according to formula (6), or salt thereof,
- b) reacting the compound according to formula (6), or salt thereof, with an organometallic reagent derived from 4-methyl biphenyl to obtain a compound according to formula (22), or salt thereof,
- c) dehydrating the compound of formula (22), or salt thereof, to obtain the compound according to formula (21), or tautomer, or salt thereof,
- d) hydrogenating the compound (21), or salt thereof, to obtain the compound according to formula (1), or tautomer, or salt thereof,
- wherein in formulae (6), (22) and (21) R1 is hydrogen or a nitrogen protecting group.
Dependencies are inferred from the claim text.