Intermediates of neutral endopeptidase inhibitors and preparation method thereof
AssigneeNovartis AG
InventorsDavid Hook, Jianguang Zhou, Yunzhong Li, Jie Ku
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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 a g-amino-d-biphenyl-a-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.
Claims17
A process for preparing a compound of formula (4), or salt thereof,
- wherein
- R1 is hydrogen or a nitrogen protecting group;
- and
- R4 is selected from hydroxyl, alkyl, aryl and arylalkyl;
- said process comprising
- reacting a compound of formula (3), or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group;
- first with a base and then with a compound of the formula CO2 or R4COY, wherein Y is halogen or —OR′ and wherein R4 and R′ are independently selected from alkyl, aryl and arylalkyl, to obtain the compound of formula (4), or salt thereof.
A process for preparing a compound of formula (1), or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group;
- said process comprising
- reacting a compound of formula (4), or salt thereof,
- wherein
- R1 is hydrogen or a nitrogen protecting group;
- and
- R4 is selected from hydroxyl, alkyl, aryl and arylalkyl;
- with a base and formaldehyde, optionally in the presence of a phase transfer catalyst, to obtain the compound of formula (1), or salt thereof.
A process for preparing a compound of formula (1), or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group;
- said process comprising the steps of
- (i) preparing a compound of formula (4), or salt thereof,
- wherein
- R1 is hydrogen or a nitrogen protecting group;
- and
- R4 is selected from hydroxyl, alkyl, aryl and arylalkyl;
- by reacting a compound of formula (3), or salt thereof,
- wherein R1 is hydrogen or a nitrogen protecting group;
- (i) first with a base and then with a compound of the formula CO2 or R4COY, wherein Y is halogen or —OR′ and wherein R4 and R′ are independently selected from alkyl, aryl and arylalkyl, to obtain the compound of formula (4), or salt thereof;
- and
- (ii) reacting the compound of formula (4), or salt thereof,
- wherein
- R1 is hydrogen or a nitrogen protecting group;
- and
- R4 is selected from hydroxyl, alkyl, aryl and arylalkyl;
- with a base and formaldehyde, optionally in the presence of a phase transfer catalyst, to obtain the compound of formula (1), or salt thereof.
A compound of formula (4), or salt thereof,
- wherein
- R1 is hydrogen or a nitrogen protecting group;
- and
- R4 is selected from hydroxyl, alkyl, aryl and arylalkyl.
Dependencies are inferred from the claim text.