Process and intermediates

A process for the manufacture of the compound N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid or a salt thereof, or the compound N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula

• or a salt thereof, by:
• A) converting a compound of formula (I),
• wherein:
• Ra is selected from the group consisting of hydrogen, a carboxyl protecting group, and C1-C6-alkyl, into a compound of formula (VIII),
• wherein:
• Ra is selected from the group consisting of hydrogen and C1-C6-alkyl;
• and Re is selected from the group consisting of hydrogen and a nitrogen protecting group, by a process comprising any one of steps (i) to (vi):
• (i) reacting a compound of formula (I), or a salt thereof;
• wherein:
• Ra is hydrogen,
• with ammonia, a primary or secondary amine, or salts thereof, to provide a compound of formula (VIII), wherein Ra and Re are hydrogen, or a salt thereof;
• or
• (ii) converting a compound of formula (I), or a salt thereof;
• wherein:
• Ra is selected from the group consisting of hydrogen and C1-C6-alkyl, into the compound of formula (VIII), wherein Ra is selected from hydrogen and C1-C6-alkyl;
• and Re is hydrogen, or a salt thereof, by bringing it in contact with an (S)-selective ω-transaminase in the presence of an amine donor and a coenzyme, wherein the conversion rate from the compound of formula (I) to the compound of formula (VIII), is more than 50%;
• or
• (iii)
• a) reacting a compound of formula (I), or a salt thereof;
• wherein:
• Ra is selected from the group consisting of a carboxyl protecting group and C1-C6-alkyl, with an aminosulfinyl compound of formula (IX), or a salt thereof,
• wherein Rb is selected from the group consisting of C1-C6-alkyl, C6-C10-aryl, C6-C10-aryl-C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(═O)—, and S—(═O)2, and wherein each aryl or heterocyclyl group can be optionally substituted by one, two or three substituents independently selected from the group consisting of halo, C1-C7-alkyl, halo-C1-C7-alkyl, C1-C7-alkoxy, halo-C1-C7-alkoxy, and C1-C7-alkoxy-C1-C7-alkyl;
• to give a sulfinimide compound of the formula (X), or a salt thereof
• wherein:
• Rb is selected from the group consisting of C1-C6-alkyl, C6-C10-aryl, C6-C10-aryl-C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(═O)—, and S—(═O)2, and wherein each aryl or heterocyclyl group can be optionally substituted by one, two or three substituents independently selected from the group consisting halo, C1-C7-alkyl, halo-C1-C7-alkyl, and C1-C7-alkoxy, halo-C1-C7-alkoxy, and C1-C7-alkoxy-C1-C7-alkyl;
• and
• Ra is selected from a carboxyl protecting group and C1-C6-alkyl;
• b) reducing the obtained compound of formula (X), or a salt thereof, in the presence of a reducing agent to give a sulfinamide compound of the formula (XI), or a salt thereof
• wherein:
• Rb is selected from the group consisting of C1-C6-alkyl, C6-C10-aryl, C6-C10-aryl-C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, heterocyclyl or heterocyclyl-C1-C6-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(═O)— or S—(═O)2, and wherein each aryl or heterocyclyl group can be optionally substituted by one, two or three substituents independently selected from the group consisting of halo, C1-C7-alkyl, halo-C1-C7-alkyl, C1-C7-alkoxy, halo-C1-C7-alkoxy, and C1-C7-alkoxy-C1-C7-alkyl;
• and
• Ra is selected from a carboxyl protecting group and C1-C6-alkyl;
• c) reacting the obtained sulfinamide compound of formula (XI), or a salt thereof, by hydrolyzing the sulfonamide group in the presence of an acid to provide a compound of formula (VIII), or a salt thereof, wherein Ra is selected from the group consisting of a carboxyl protecting group and C1-C6-alkyl, and Re is hydrogen;
• and
• d) removing—if present—any carboxyl protecting group from the obtained compound of formula (VIII), or a salt thereof, to provide a compound of formula (VIII), or a salt thereof, wherein Ra is selected from the group consisting of hydrogen and C1-C6-alkyl;
• and Re is hydrogen;
• or
• (iv)
• a) reacting a compound of formula (I), or a salt thereof;
• wherein Ra is hydrogen,
• with hydroxylamine or a salt thereof to provide a compound of formula (XVII), or a salt thereof
• wherein Ra is hydrogen;
• b) subsequently cyclizing the obtained compound of formula (XVII) to give the corresponding compound of the formula (XVIII)
• c) reducing the obtained compound of formula (XVIII) in the presence of a reducing agent, to obtain the compound of formula (VIII), wherein Ra and Re are both hydrogen, or
• (v)
• a) reacting a compound of formula (I), or a salt thereof;
• wherein Ra is hydrogen,
• with ammonia or an ammonium salt, yielding a compound of the formula (XIX)
• b) reducing the obtained compound of formula (XIX), with a reducing agent, to give a lactam compound of formula (XX),
• c) reacting the obtained compound of formula (XX) under ring opening conditions, optionally in the presence of an C1-C7-alcohol, to provide the compound of formula (VIII), wherein Ra is selected from the group consisting of hydrogen and C1-C6-alkyl;
• and Re is hydrogen;
• or
• (vi)
• a) reacting a compound of formula (I), or a salt thereof;
• wherein Ra is selected from the group consisting of hydrogen, a carboxyl protecting group and C1-C6-alkyl;
• with an O-substituted hydroxylamine selected from
• or in each case a salt thereof,
• wherein:
• Rc and Rd are independently selected from the group consisting of C1-C6-alkyl, C6-C10-aryl, C6-C10-aryl-C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(═O)—, and S—(═O)2, and wherein each aryl or heterocyclyl group is optionally substituted by one, two or three substituents independently selected from the group consisting of halo, C1-C7-alkyl, halo-C1-C7-alkyl, C1-C7-alkoxy, halo-C1-C7-alkoxy, and C1-C7-alkoxy-C1-C7-alkyl;
• to provide a compound of formula (XVII***),
• wherein:
• Ra is selected from the group consisting of hydrogen, a carboxyl protecting group, and C1-C6-alkyl;
• and
• A is —O—C(═O)—Rc or —O-Rd;
• wherein,
• Rc and Rd are independently selected from the group consisting of C1-C6-alkyl, C6-C10-aryl, C6-C10-aryl-C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(═O)— or S—(═O)2, and wherein each aryl or heterocyclyl group can be optionally substituted by one, two or three substituents independently selected from the group consisting of halo, C1-C7-alkyl, halo-C1-C7-alkyl, C1-C7-alkoxy, halo-C1-C7-alkoxy, and C1-C7-alkoxy-C1-C7-alkyl,
• b) reducing the obtained compound of formula (XVII***), or a salt thereof to provide the compound of formula (VIII) or a salt thereof, wherein Ra is selected from the group consisting of hydrogen, a carboxyl protecting group and C1-C6-alkyl;
• and Re is hydrogen;
• and carboxyl protecting group and C1-C6-alkyl, preferably ethyl, and Re is hydrogen, and
• c) removing—if present—any carboxyl protecting group from the obtained compound of formula (VIII), or a salt thereof;
• and wherein all reaction variants (i) to (vi) are optionally followed by
• optionally reacting the obtained compound of formula (VIII), or a salt thereof, wherein Ra is selected from the group consisting of hydrogen and C1-C6-alkyl, and Re is hydrogen,
• with an agent introducing an amino protecting group, to provide the compound of formula (VIII), wherein Ra is selected from the group consisting of hydrogen and C1-C6-alkyl, and Re is a nitrogen protecting group, and/or
• optionally followed by reacting the compound of the formula (VIII) wherein Ra is hydrogen and Re is selected from hydrogen and a nitrogen protecting group, with a coupling reagent in the presence of an C1-C6-alkanol, to provide the compound of formula (VIII), wherein Ra is C1-C6-alkyl, and Re is a nitrogen protecting group;
• and
• B) converting the compound of formula (VIII) into the compound N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic-acid or a salt thereof, or the compound N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester or a salt thereof, by
• optionally removing—if present—any nitrogen protecting group Re,
• optionally reacting the obtained compound of formula (VIII) wherein Ra and Re are hydrogen with a coupling reagent in the presence of a C1-C6-alkanol, to provide the compound of formula (VIII), wherein Ra is C1-C6-alkyl, and Re is hydrogen, and
• reacting the compound of formula (VIII) wherein Ra is selected from the group consisting of hydrogen and C1-C6-alkyl, and Re is hydrogen, with succinic acid anhydride.