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US 6,713,615 B2Granted
Process for producing erythromycin derivative
AssigneeTaisho Pharmaceutical Co., Ltd.
InventorsMasato Kashimura, Hiroaki Kamiyama, Takeshi Kuwada, Nobuyuki Suzuki, Takashi Adachi
Life of this patent
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Abstract
There is provided a preparation process useful for an efficient synthesis of 6-O-substituted ketolide derivatives by combining a characterized step of introduction of a substituent at the 6-position by selective cleavage of a C—O bond of the cyclic acetal at the 9-position side via 6,9-cyclic acetal 5-O-desosaminyl erythronolide derivative, a step of conversion into carbonyl groups at the 9- and 3-positions, and a step of 11,12-cyclic carbamation to lead to 6-O-substituted ketolide derivatives.
Claims7
A process for preparing Compound (V) defined below, which comprises the steps of:
- (A) providing Compound (I) of the formula:
- wherein R1 and R2, which may be the same or different, are a hydrogen atom, formula —CO—RA wherein RA is a C1-3 alkyl group, C1-3 alkyl group substituted with 1-3 halogen atoms, C1-3 alkoxy group, phenyl group, phenyloxy group, benzyloxy group, or phenyl group substituted with 1-3 substituents selected from the group consisting of C1-3 alkyl group, C1-3 alkoxy group, nitro group, cyano group, halogen atom, acetyl group, phenyl group and hydroxy group, or a silyl group substituted with 2-3 substituents selected from the group consisting of C1-4 alkyl group, phenyl group and benzyl group,
- by reaction of erythromycin with ethylene carbonate, subsequent reduction of ketone in 9-position, and optional protection of hydroxy groups in 2′- and/or 4”-positions,
- (B) reacting Compound (I) with a compound of the formula:
- wherein A is CH═CH or C≡C;
- R5 and R6, which may be the same or different, are a C1-7 alkyl group, and optionally protecting a resulting 3-hydroxy group, to obtain Compound (II) of the formula:
- wherein R3 is the same as R1 defined above;
- R2 and A are as defined above,
- (C) reacting Compound (II) with a compound of the formula:
- X—R4 (2)
- wherein X is a halogen atom;
- R4 is the formula:
- wherein R7 and R8 are a hydrogen atom or, alternatively, they form a benzene nucleus together with the adjacent carbon atoms, or the formula:
- wherein Ar is a pyridyl group, quinolyl group or aryl group,
- to obtain Compound (III) of the formula:
- wherein A, R2, R3 and R4 are as defined above,
- (D) reacting Compound (III) with a compound of the formula:
- wherein R9 is a hydrogen atom, chlorine atom, linear or branched C1-4 alkyl group, C1-3 alkoxy group, phenyl or benzyl group;
- R10 and R11, which may be the same or different, are a chlorine atom, linear or branched C1-4 alkyl group, C1-3 alkoxy group, phenl group or benzyl group, to obtain Compound (IV) of the formula:
- wherein A, R2, R3 and R4 are as defined above, and
- (E) subjecting Compound (IV) to carbonylation at 9-position, carboxylation at 3-position, 11,12-cyclic carbamation and deprotection of 2′-hydroxy group, to obtain Compound (V) of the formula:
- wherein A and R4 are as defined above.
19 more elements
A compound of the formula:
- wherein A is CH═CH or C≡C;
- R2 and R3, which may be the same or different, are a hydrogen atom, formula —CO—RA wherein RA is a C1-3 alkyl group, C1-3 alkyl group substituted with 1-3 halogen atoms, C1-3 alkoxy group, phenyl group, phenyloxy group, benzyloxy group, or phenyl group substituted with 1-3 substituents selected from the group consisting of C1-3 lower alkyl group, C1-3 alkoxy group, nitro group, cyano group, halogen atom, acetyl group, phenyl group and hydroxy group, or a silyl group substituted with 2-3 substituents selected from the group consisting of C1-4 alkyl group, phenyl group and benzyl group.
A compound of the formula:
- wherein A is CH═CH or C≡C;
- R2 and R3, which may be the same or different, are a hydrogen atom, formula —CO—RA wherein RA is a C1-3 alkyl group, C1-3 alkyl group substituted with 1-3 halogen atoms, C1-3 alkoxy group, phenyl group, phenyloxy group, benzyloxy group, or phenyl group substituted with 1-3 substituents selected from the group consisting of C1-3 lower alkyl group, C1-3 alkoxy group, nitro group, cyano group, halogen atom, acetyl group, phenyl group and hydroxy group, or a silyl group substituted with 2-3 substituents selected from the group consisting of C1-4 alkyl group, phenyl group and benzyl group;
- R4 is the formula:
- wherein R7 and R8 are a hydrogen atom or, alternatively, they form a benzene nucleus together with adjacent carbon atoms, or the formula:
- wherein Ar is a pyridyl group, quinolyl group or aryl group.
2 more elements
A process for preparing a decladinosylated 6,9-cyclic acetal erythromycin derivative defined below, which comprises the step of reacting Compound (I) of the formula:
- wherein R1 and R2, which may be the same or different, are a hydrogen atom, residue —CO—RA in which RA is a C1-3 alkyl group, C1-3 alkyl group substituted with 1-3 halogen atoms, C1-3 alkoxy group, phenyl group, phenyloxy group, benzyloxy group, or phenyl group substituted with 1-3 substituents selected from the group consisting of C1-3 alkyl group, C1-3 alkoxy group, nitro group, cyano group, halogen atom, acetyl group, phenyl group and hydroxy group, or a silyl group substituted with 2-3 substituents selected from the group consisting of C1-4 alkyl group, phenyl group and benzyl group, with a compound of the formula:
- wherein A is CH═CH or C≡C;
- R5 and R6, which may be the same or different, are a C1-7 alkyl group,
- to obtain the decladinosylated 6,9-cyclic acetal erythromycin derivative of the formula:
- wherein R3 is the same as R1 defined above;
- R2 and A are as defined above.
3 more elements
Dependencies are inferred from the claim text.