US 12,122,759 B2
Method for the synthesis of cyclic depsipeptides
Dirk Heimbach, Düsseldorf (DE); Satoshi Omura, Tokyo (JP); Toshiaki Sunazuka, Chiba (JP); Tomoyasu Hirose, Asao-ku (JP); Yoshihiko Noguchi, Tokyo (JP); Johannes Köbberling, Neuss (DE); Zhijie Wu, Zhejiang (CN); Shuibiao Fu, Zhejiang (CN); Wei Wu, Zhejiang (CN); Jinfeng Qiu, Zhejiang (CN); Liu He, Zhejiang (CN); and Xudong Wei, Zhejiang (CN)
Assigned to ELANCO ANIMAL HEALTH GMBH, Monheim am Rhein (DE); and THE KITASATO INSTITUTE, Tokyo (JP)
Appl. No. 16/762,068
Filed by ELANCO ANIMAL HEALTH GMBH, Monheim am Rhein (DE); and THE KITASATO INSTITUTE, Tokyo (JP)
PCT Filed Nov. 6, 2018, PCT No. PCT/EP2018/080333
§ 371(c)(1), (2) Date May 6, 2020,
PCT Pub. No. WO2019/091975, PCT Pub. Date May 16, 2019.
Claims priority of application No. 17200415 (EP), filed on Nov. 7, 2017; and application No. 201811254536.0 (CN), filed on Oct. 25, 2018.
Prior Publication US 2021/0130315 A1, May 6, 2021
Int. Cl. C07D 325/00 (2006.01); A61K 38/15 (2006.01)
CPC C07D 325/00 (2013.01) [A61K 38/15 (2013.01)] 13 Claims
 
1. A method of synthesizing a depsipeptide of formula (IIa) from formula (IV) and formula (III):

OG Complex Work Unit Chemistry
wherein PG2 is an amine protecting group and PG3 is a carboxylic acid protecting group, and
by:
deprotecting the amine group that is protected by PG2 in the formula (IV) in the presence of a base to obtain a deprotected amine group;
deprotecting the carboxylic acid that is protected by the group PG3 in the formula (III) in the presence of an acid to obtain a deprotected carboxylic acid group; and
condensing the deprotected amine group and the carboxylic acid group to obtain the depsipeptide of formula (IIa);
and further synthesizing a cyclic depsipeptide of formula (I) from the depsipeptide of formula (IIa):

OG Complex Work Unit Chemistry
wherein Y is an amine protecting group and X is a carboxylic acid protecting group;
wherein
R2 and R8, are independently hydrogen, straight-chain or branched C1-C8-alkyl, straight-chain or branched halogenated C1-C8 alkyl, hydroxy-C1-C6-alkyl, C1-C4-alkanoyloxy-C1-C6-alkyl, C1-C4-alkoxy-C1-C6-alkyl, aryl-C1-C4-alkyloxy-C1-C6-alkyl, mercapto-C1-C6-alkyl, C1-C4-alkylthio-C1-C6-alkyl, C1-C4-alkylsulphinyl-C1-C6-alkyl, C1-C4-alkylsulphonyl-C1-C6-alkyl, carboxy-C1-C6-alkyl, C1-C4-alkoxycarbonyl-C1-C6-alkyl, C1-C4-arylalkoxycarbonyl-C1-C6-alkyl, carbamoyl-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C4-alkylamino-C1-C6-alkyl, C1-C4-dialkylamino-C1-C6-alkyl, guanidino-C1-C6-alkyl, C1-C4-alkoxycarbonylamino-C1-C6-alkyl, 9-fluorenylmethoxycarbonyl(Fmoc)amino-C1-C6-alkyl, C2-C8-alkenyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C4-alkyl, benzyl, substituted benzyl, phenyl, or phenyl-C1-C4-alkyl which may optionally be substituted by halogen;
wherein x is 1, y is 1, R1, R4, R7 and R10 are each methyl, R6 and R12 are each methyl, R5 and R11 are each independently a straight-chain or branched C1-C4-alkyl or a straight-chain or branched halogenated C1-C4-alkyl, and R3 and R9 are each independently benzyl or substituted benzyl;
wherein synthesizing a cyclic depsipeptide of formula (I) from the depsipeptide of formula (IIa) comprises:
deprotecting the amine group that is protected by Y in the presence of an acid to obtain a deprotected amine group;
deprotecting the carboxylic acid that is protected by X via hydrogenolysis to obtain a deprotected carboxylic acid group; and
condensing the deprotected amine group and the deprotected carboxylic acid group by a coupling agent to obtain the cyclic depsipeptide of formula (I),
wherein the coupling agent is BOP ((Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate), EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide), DEPBT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one), HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate), HBTU (2-(1H-benzotriazol-1-yl)-1, 1,3,3-tetramethyluronium hexafluorophosphate) or Propylphosphonic anhydride (2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide, PPACA).