Method for the synthesis of cyclic depsipeptides
AssigneesElanco Animal Health GmbH, The Kitasato Institute
InventorsDirk HEIMBACH, Satoshi OMURA, Toshiaki SUNAZUKA, Tomoyasu HIROSE, Yoshuhiko NOGUCHI, Johannes KÖBBERLING, Zhijie WU, Shuibiao FU, Wei WU, Jinfeng QIU, Liu HE, Xudong WEI
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Abstract
The present invention relates to a method for the synthesis of cyclic depsipeptides, in particular emodepside, from the open form.
Claims34
A method of synthesizing a cyclic depsipeptide of formula (1) from a depsipeptide of formula (II):
- wherein B is an amine protecting group and A is a carboxylic acid protecting group,
- whereby x and y are, independently of each other, 0, 1 or 2, provided that x+y≥1, and
- each R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 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 radicals from the group consisting of halogen;
- the method comprising:
- deprotecting the amine group that is protected by B to obtain a deprotected amine group;
- deprotecting the carboxylic acid that is protected by A to obtain a deprotected carboxylic acid group;
- and
- condensing the deprotected amine group and the deprotected carboxylic acid group to obtain the cyclic depsipeptide of formula (I).
A method for the synthesis of cyclic depsipeptides according to the general formula (1) from depsipeptides according to the general formula (IIc):
- comprising
- providing a mixture of compound (IIc) and a base in a solvent having an ET(30)-value of ≥30 and ≤43;
- adding by slow addition of a solution of a coupling agent in the solvent to form the cyclic depsipeptide (I)
- whereby x and y are independently 0, 1 or 2, provided that x+y≥1, and
- each R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 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 radicals from the group consisting of halogen.
A linear or cyclic depsipeptide selected from the group consisting of one of the general formulas (II-1) to (II-14b) or (I-1) to (1-9) or a pharmaceutically or veterinarily acceptable salt thereof:
- wherein in formulas (II-11a) to (II-14b) and (I-1) to (I-9), respectively:
- -LINK- is selected from:
- and R13 is SO2NH(CH3), SO2NH2, OC(O)CH3, CF3 or one the following lactone structures:
Dependencies are inferred from the claim text.