New processes and intermediates for nep inhibitor synthesis

A process for producing a compound of formula (1-a)

• preferably of formula (1-a-R)
• wherein R1 is hydrogen or C1-C6-alkyl, preferably ethyl,
• comprising reacting a compound of formula (2-a)
• preferably of formula (2-a-R)
• wherein R1 is hydrogen or C1-C6-alkyl, preferably ethyl,
• with a compound of formula (3)
• wherein the reaction of compound of formula (2-a) with the compound of formula (3) is performed in the presence of a catalyst, preferably a metal complex catalyst.

A process for producing a compound of formula (1-b)

• preferably a compound of formula (1-b-R)
• comprising hydrogenation of a compound of formula (1-a)
• preferably a compound of formula (1-a-R)
• optionally in the presence of a nitrogen protecting agent, preferably di-tert-butyl dicarbonate, wherein in the above formulas R′ and R″ are independently of each other hydrogen or a nitrogen protecting group, preferably R″ is hydrogen and R′ is a nitrogen protecting group, preferably tert-butyloxycarbonyl, and wherein R1 is hydrogen or C1-C6-alkyl, preferably ethyl.

A process for producing a compound of formula (6)

• wherein R′ and R″ are independently of each other hydrogen or a nitrogen protecting group, preferably R′ and R″ are both hydrogen, and R1 is hydrogen or C1-C6-alkyl, preferably ethyl, preferably a compound of formula (6-R)
• said process comprising
• taking a compound of formula (1-b)
• wherein R′ and R″ are independently of each other hydrogen or a nitrogen protecting group, preferably R″ is hydrogen and R′ is a nitrogen protecting, preferably group tert-butyloxycarbonyl, and R1 is hydrogen or C1-C6-alkyl, preferably ethyl,
• preferably a compound of formula (1-b-R)
• optionally treating the compound of formula (1-b) with an OH-activating agent to obtain a compound of formula (1-d)
• wherein R′ and R″ are independently of each other hydrogen or a nitrogen protecting group, preferably R″ is hydrogen and R′ is a nitrogen protecting group, preferably tert-butyloxycarbonyl,
• R1 is hydrogen or C1-C6-alkyl, preferably ethyl, and
• R4 is an OH-activating group, preferably selected from C1-C6-carbonyl, C1-C6-alkoxycarbonyl and sulphonyl,
• preferably a compound of formula (1-d-R)
• and
• subjecting the compound of formula (1-d)
• wherein R′ and R″ are independently of each other hydrogen or a nitrogen protecting group, preferably R″ is hydrogen and R′ is a nitrogen protecting group, preferably tert-butyloxycarbonyl, R1 is hydrogen or C1-C6-alkyl, preferably ethyl, and
• R4 is hydrogen or a OH-activating group, preferably selected from C1-C6-carbonyl, C1-C6-alkoxycarbonyl and sulphonyl,
• preferably a compound of formula (1-d-R)
• to a hydrogenation reaction to obtain the compound of formula (6), preferably of formula (6-R).

Use of a compound of formula (1)

• wherein R1 is hydrogen or C1-C6-alkyl, preferably ethyl,
• R3 is —NR′R″, or —NO2 and R′ and R″ are independently of each other hydrogen or a nitrogen protecting group, preferably R3 is —NHR′ and R′ is tert-butyloxycarbonyl, and
• R4 is selected from hydrogen, C1-C6-carbonyl, C1-C6-alkoxycarbonyl and a sulphonyl group, preferably hydrogen,
• in the preparation of a compound of formula (8)
• wherein R1 is hydrogen or C1-C6-alkyl, preferably ethyl,
• preferably in the preparation of N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid, or salts thereof, or N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester or salts thereof.