Process and intermediates

A compound of formula (XVI), or a salt thereof

• preferably of formula (XVI-a)
• wherein
• R6 is —O—Ra, and R7 is selected from
• —S(═O)—Rb
• —OH
• A, wherein A is —O—C(═O)—Rc or —O-Rd
• wherein Ra is selected from hydrogen, a carboxyl protecting group, and C1-C6-alkyl, preferably ethyl, and
• Rb, Rc and Rd are independently selected from 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 halo, C1-C7-alkyl, halo-C1-C7-alkyl, and C1-C7-alkoxy, halo-C1-C7-alkoxy, and C1-C7-alkoxy-C1-C7-alkyl, or
• R6 and R7 together represent —O— or form a bond.

A process for the manufacture of a compound of formula (I), or a salt thereof;

• preferably of formula (I-a), or a salt thereof;
• wherein Ra is selected from hydrogen, a carboxyl protecting group and C1-C6-alkyl, preferably ethyl,
• comprising reacting a compound of formula (II), or a salt thereof
• preferably of formula (II-a), or a salt thereof;
• wherein Ra and R* are, independently of each other, selected from hydrogen, a carboxyl protecting group, and C1-C6-alkyl, preferably ethyl,
• under—if required—deprotection reaction conditions, followed by decarboxylation reaction conditions, and optionally by introduction of a moiety Ra selected from a carboxyl protecting group and C1-C6-alkyl, to provide the compound of formula (I).

A process for the manufacture of a compound of formula (I), or a salt thereof;

• preferably of formula (I-a), or a salt thereof;
• wherein Ra is selected from hydrogen, a carboxyl protecting group and C1-C6-alkyl, preferably ethyl,
• comprising reacting an activated dianionic derivate of the compound of formula (V), or a salt thereof
• with a compound of formula (XIV), or a salt thereof
• preferably of formula (XIV-a)
• wherein Rf is selected from
• —O—R* wherein R* is selected from a carboxyl protecting group and C1-C6-alkyl, preferably methyl,
• —N(CH3)-O(CH3),
• morpholinyl, and
• imidazolinyl,
• in the presence of a base, and
• followed by a decarboxylation reaction,
• to obtain compound of formula (I), or a salt thereof wherein Ra is hydrogen,
• optionally followed by reacting the obtained compound of formula (I), or a salt thereof, wherein Ra is hydrogen, with an agent introducing a carboxyl protecting group, to provide the compound of formula (I), wherein Ra is a carboxyl protecting group, and/or
• optionally followed by reacting the compound of the formula (I), or a salt thereof, wherein Ra is hydrogen, with a coupling reagent in the presence of an C1-C6-alkanol, especially ethanol, to provide the compound of formula (I), wherein Ra is C1-C6-alkyl, preferably ethyl.

A process for the manufacture of a compound of formula (VIII), or a salt thereof

• preferably of formula (VIII-a), or a salt thereof
• more preferably of formula (VIII-aa), or a salt thereof
• wherein Ra is selected from hydrogen and C1-C6-alkyl, preferably ethyl, and
• Re is selected from hydrogen and a nitrogen protecting group,
• by a process comprising
• (i) reacting a compound of formula (I), or a salt thereof;
• preferably of formula (I-a), 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), preferably to the compound of formula (VIII-a), more preferably of formula (VIII-aa), wherein Ra and Re are hydrogen, or a salt thereof, or
• (ii) converting a compound of formula (I), or a salt thereof;
• preferably of formula (I-a), or a salt thereof;
• wherein Ra is selected from hydrogen and C1-C6-alkyl, preferably hydrogen,
• into the compound of formula (VIII), preferably to the compound of formula (VIII-a), more preferably of formula (VIII-aa), wherein Ra is selected from hydrogen and C1-C6-alkyl, preferably hydrogen, 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), preferably the conversion rate from the compound of formula (I-a) to the compound of formula (VIII-a), more preferably of formula (VIII-aa), is more than 50%, or
• (iii)
• a) reacting a compound of formula (I), or a salt thereof;
• preferably of formula (I-a), or a salt thereof;
• wherein Ra is selected from a carboxyl protecting group and C1-C6-alkyl, preferably ethyl, with an aminosulfinyl compound of formula (IX), or a salt thereof,
• especially of formula (IX-a),
• wherein Rb is selected from 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 halo, C1-C7-alkyl, halo-C1-C7-alkyl, and 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
• preferably of formula (X-a),
• wherein Rb is selected from 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 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, preferably ethyl,
• 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
• preferably of formula (XI-a), or a salt thereof
• more preferably of formula (XI-aa), or a salt thereof
• wherein Rb is selected from 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 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, preferably ethyl,
• 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 a carboxyl protecting group and C1-C6-alkyl, preferably ethyl, 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 hydrogen and C1-C6-alkyl, preferably ethyl, and Re is hydrogen
• or
• (iv)
• a) reacting a compound of formula (I), or a salt thereof;
• preferably of formula (I-a), 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
• preferably of formula (XVII-a),
• wherein Ra is hydrogen,
• b) subsequently cyclizing the obtained compound of formula (XVII) to give the corresponding compound of the formula (XVIII)
• preferably of formula (XVIII-a)
• 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;
• preferably of formula (I-a), or a salt thereof;
• wherein Ra is hydrogen,
• with ammonia or an ammonium salt, yielding a compound of the formula (XIX)
• preferably of formula (XIX-a)
• b) reducing the obtained compound of formula (XIX), especially (XIX-a), with a reducing agent, to give a lactam compound of formula (XX),
• preferably of formula (XX-a)
• more preferably of formula (XX-aa), and
• 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 hydrogen and C1-C6-alkyl, preferably ethyl, and Re is hydrogen, or
• (vi)
• a) reacting a compound of formula (I), or a salt thereof;
• preferably of formula (I-a), or a salt thereof;
• wherein Ra is selected from hydrogen, a carboxyl protecting group and C1-C6-alkyl, preferably ethyl,
• with an O-substituted hydroxylamine selected from
• or in each case a salt thereof.
• wherein Rc and Rd are independently selected from 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 halo, C1-C7-alkyl, halo-C1-C7-alkyl, and C1-C7-alkoxy, halo-C1-C7-alkoxy, and C1-C7-alkoxy-C1-C7-alkyl,
• to provide a compound of formula (XVII***),
• preferably of formula (XVII-a),
• wherein Ra is selected from hydrogen, a carboxyl protecting group, and C1-C6-alkyl, preferably ethyl, and
• A is —O—C(═O)—Rc or —O-Rd,
• wherein Rc and Rd are independently selected from 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 halo, C1-C7-alkyl, halo-C1-C7-alkyl, and 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 hydrogen, a 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 hydrogen or C1-C6-alkyl, preferably ethyl, and Re is hydrogen, with an agent introducing an amino protecting group, to provide the compound of formula (VIII), wherein Ra is selected from hydrogen and C1-C6-alkyl, preferably ethyl, 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, especially ethanol, to provide the compound of formula (VIII), wherein Ra is C1-C6-alkyl, preferably ethyl, and Re is a nitrogen protecting group.