SYNTHESIS ROUTES TO 2(S),4(S),5(S),7(S)-2,7-DIALKYL-4-HYDROXY-5-AMINO-8-ARYL-OCTANOYL AMIDES

1 . Process for the preparation of a compound according to formula (13) or its ring-closed form according to formula (2), or a mixture thereof,

wherein R 1 being selected from the group consisting of F, Cl, Br, I, C 1-6 halogenalkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyloxy, and C 1-6 alkoxy-C 1-6 alkyl;

R 2 being selected from the group consisting of F, Cl, BO, C 1-4 alkyl or C 1-4 alkoxy;

R 1 and R 2 may be linked together to form a ring structure;

R 3 and R 4 each independently being branched C 3-6 alkyl;

X stands for NHR 5 or OR 6 wherein

R 5 is C 1-12 cycloalkyl, C 1-12 alkyl, C 1-12 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkanoyloxy-C 1-6 alkyl, C 1-12 aminoalkyl, C 1-6 alkylamino-C 1-6 alkyl, C 1-6 dialkylamino-C 1-6 alkyl, C 1-6 alkanoylamino-C 1-6 alkyl, HO—(O)C—C 1-12 alkyl, C 1-6 alkyl-O—(O)C—C 1-6 alkyl, H 2 N—C(O)—C 1-12 alkyl, C 1-6 alkyl-HN—C(O)—C 1-6 alkyl, (C 1-6 alkyl) 2 -N—C(O)—C 1-6 alkyl; saturated, unsaturated, or partially saturated C 1-12 heterocyclyl bonded via a carbon atom, and which heterocyclyl is optionally substituted one or more times by C 1-6 alkyl, trifluoromethyl, nitro, amino, N-mono- or N,N-di-C 1-6 alkylated amino, C 1-6 alkanoyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkoxycarbonylamino, C 0-6 alkylcarbonylamino, C 1-6 alkylcarbonyloxy, C 1-12 aryl, N-mono or N,N-di-C 1-6 alkylated carbamoyl, optionally esterified carboxyl, cyano, halogen, halo-C 1-6 alkoxy halo-C 1-6 alkyl, C 1-12 heteroaryl, saturated, unsaturated or partially saturated C 1-6 heterocyclyl, hydroxyl, nitro;

and R 6 represents H, or optionally substituted C 1-12 alkyl, optionally substituted C 1-12 alkylaryl, or optionally substituted C 1-12 aryl;

R 7 represents H, or is an O-protecting group;

and wherein any two of R 7 , R 8 , or X are optionally linked together to form a ring structure;

R 8 denotes H; optionally substituted C 1-12 alkyl, optionally substituted C 1-12 alkylaryl, or optionally substituted C 1-12 aryl; optionally substituted C(O)C 1-6 alkyl; optionally substituted C(O)OC 1-6 alkyl; optionally substituted C(O)NHC 1-6 alkyl; or optionally substituted C(O)N(C 1-6 alkyl) 2 ; or R 8 denotes

—NHR 9 ,

—S(O) 2 R 9 ; SOR 9 ; S(O) 3 R 9 ; S(O) 2 N(R 9 );

—P(O)(R 9 ) 2

or R 8 stands for (R 9 ) 2 Y with Y being an anion such as acetate, or halogen;

and wherein each R 9 independently represents H, optionally substituted C 1-12 alkyl, optionally substituted C 1-12 alkylaryl, or optionally substituted C 1-12 aryl;

comprising the following steps,

a) reacting a compound according to formula (11), or its ring-closed form according to formula (4), or a mixture thereof,

wherein R 1 , R 2 , R 3 , R 4 , R 7 and X are each as described above for formula (2) and (13)

with a compound according to formula (5)

R 8 —NH 2   (5)

wherein R 8 is as described above for formula (2) and (13) which reaction results in a compound according to formula (7) or a compound according to formula (12) or a mixture thereof,

wherein R 1 , R 2 , R 3 , R 4 , R 7 , R 8 and X are each as described above for formula (2) and (13)

b) further reacting compound according to formula (7) or (12) or a mixture thereof, in the presence of a reducing reagent, and optionally in the presence of a catalyst,

and optionally in the presence of one or more additives,

which reaction results in the formation of compound according to formula (2) or formula (13) or a mixture thereof.

2 . A process according to claim 1 , wherein the compounds according to formula (7) or formula (12) are not isolated from the reaction mixture before carrying out step b).

3 . A process according to claim 1 , wherein step b) is performed in the presence of a catalyst and wherein said catalyst is a transition metal based catalyst.

4 . A process for the preparation of a compound according to formula (13) or its ring-closed form according to formula (2), or a mixture thereof, comprising reacting the compound according to formula (11), or its ring-closed form according to formula (4), or mixture thereof, with a compound according to formula (5) in the presence of a reducing agent and a catalyst.

5 . A process according to claim 4 , wherein the reducing agent is selected from the group of molecular hydrogen or a hydrogen donating compound; and wherein when the molecular hydrogen is used it is used in the presence of a transition metal catalyst and when a hydrogen donating compound is used it is used optionally in the presence of a catalyst.

6 . A process according to claim 4 wherein said catalyst is an enzyme, preferably an aminotransferase.

7 . A process according to claim 4 wherein compound according to formula (5) is also the reducing agent.

8 . Process according to claim 1 , wherein X in the compound according to formula (11), and also in resulting compounds according to formula (12), if it is formed, and the compound according to formula (13), respectively, stands for OR 6 and wherein R 6 is as described in claim 1 .

9 . Process according to claim 1 , wherein X in the compound according to formula (11), and also in resulting compounds according to formula (12), if it is formed, and the compound according to formula (13), respectively, stands for NHR 5 , and wherein R 5 is as described in claim 1 .

10 . Process for the preparation of a compound according to formula (13) or any pharmaceutically acceptable salt thereof, wherein X represent NHR 5 , wherein the process comprises a process according to claim 1 and wherein R 5 is as described in claim 1 .

11 . A compound according to formula (11)

wherein all the R-groups are defined as in claim 1 , and wherein X is selected from the group of OR 6 and NHR 5 , and wherein R 6 and R 5 are as described in claim 1 .

12 . A compound according to formula (12)

wherein all the R-groups are defined as in claim 1 and wherein X is selected from the group of OR 6 and NHR 6 , and wherein R 6 and R 5 are as described in claim 1 .

13 . A compound according to formula (7)

wherein R 1 , R 2 , R 3 , and R 4 , are defined as in claim 1 , and wherein R 8 denotes H; optionally substituted C 1-12 alkyl, optionally substituted C 1-12 alkylaryl, or optionally substituted C 1-12 aryl; optionally substituted C(O)C 1-6 alkyl; optionally substituted C(O)OC 1-6 alkyl; optionally substituted C(O)NHC 1-6 alkyl; or optionally substituted C(O)N(C 1-6 alkyl) 2 ; or R 8 denotes

—NHR 6 ,

—S(O) 2 R 9 ; SOR 9 ; S(O) 3 R 9 ; S(O) 2 N(R 9 );

—P(O)(R 9 ) 2 ;

or R 8 stands for (R 9 ) 2 Y with Y being an anion such as acetate, or halogen;

and wherein each R 9 independently represents H, optionally substituted C 1-12 alkyl,

optionally substituted C 1-12 alkylaryl, or optionally substituted C 1-12 aryl.

14 . Process according to claim 1 , wherein the compound according to formula (2) is further reacted with 3-amino-2,2-dimethylpropanamide to obtain a compound according to formula (13) with X═NHR 5 , or pharmaceutically acceptable salts thereof.

15 . Process according to claim 1 , wherein the compound according to formula (2) or formula (13) is further reacted to obtain 2(S),4(S),5(S),7(S)—N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)fenyl]-octanamide or any pharmaceutically acceptable salt thereof.