The invention relates to a new process for producing NEP inhibitors or prodrugs thereof, in particular NEP inhibitors comprising a γ-amino-δ-biphenyl-α-methylalkanoic acid, or acid ester, backbone. In detail, the new processes, according to the present invention, are ultimately related to the synthesis of intermediates to prepare the above NEP inhibitors, namely compounds according to formula (1), 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 carboxyl group or alkyl ester.
1. A compound of formula (4)
or a salt thereof,
wherein R1 is hydrogen or a nitrogen protecting group, having a configuration according to formula (4-a),
2. A compound of formula (5), or a salt thereof,
wherein R1 is hydrogen or a nitrogen protecting group, of formulae (5-a), (5-b) or (5-c),
3. A compound of formula (6), or a tautomer thereof,
or a salt thereof,
wherein R1 is hydrogen or a nitrogen protecting group, having a configuration according to formula (6-a),
4. A compound of formula (7), or a salt thereof,
wherein R1 is hydrogen or a nitrogen protecting group and, R6 and R7 are, independently, an alkyl group, an aryl group, an arylalkyl group, a cycloalkyl group or together R6 and R7 form a cycle, together with the nitrogen to which they are attached, which cycle may be saturated or unsaturated and may optionally contain one or more heteroatoms, including nitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, ring atoms, having a configuration according to formula (7-a), (7-b) or (7-c),
5. A compound of formula (9-a), or a salt thereof,
wherein R1 is hydrogen or a nitrogen protecting group and, R6 and R7 are, independently, an alkyl group or together are an alkylene group, having a configuration according to formula (9-a) (9-b) or (9-c),
6. A compound of formula (10), or a salt thereof,
wherein R1 is hydrogen or a nitrogen protecting group, R6 and R7 are, independently, an alkyl group, an aryl group, an arylalkyl group, a cycloalkyl group or together R6 and R7 form a cycle, together with the nitrogen to which they are attached, which cycle may be saturated or unsaturated and may optionally contain one or more heteroatoms, including nitrogen, oxygen or sulphur, whereby the cycle contains 3 to 8, ring atoms, Z − is a halide, an alkyl sulphate or a sulfonyl ester and R10 is hydrogen, alkyl or aryl; having a configuration according to formula (10-a), (10-b) or (10-c),
7. A compound of formula (11)
or a salt thereof, wherein R1 is hydrogen or a nitrogen protecting group and R4 is an OH-activating group, having a configuration according to formula (11-a), (11-b) or (11-c),
8. A compound of formula (16)
or a salt thereof,
wherein R1 is hydrogen or a nitrogen protecting group, Y is O or S and each R9, is, independently, alkyl, aryl, arylalkyl or acetyl
having a configuration according to formula (16-a),