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US 6,294,680 B1Granted
Process for the production of semi synthetic statins via novel intermediates
AssigneePlus Chemicals SA
InventorsTon Rene Vries, Hans Wijnberg, Wijnand Sjourd Faber, Venetka Ivanova Kalkman-Agayn, Mieke Ivanova Sibeyn
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Abstract
A process has been provided to produce semi synthetic statins, as for instance simvastatin with a high yield, for another statin, preferably a naturally occurring statin, as for instance lovastatin. Also a number of novel intermediate compounds, prepared during said process, has been provided.
Claims41
A compound of formula II,
- wherein R1, and R2, are independently selected from the group consisting of a hydrogen atom, a hydroxyl, C1-10alkyl and C6-14aryl and C6-14arylC1-3alkyl, and wherein R3 is R9-C═O or hydrogen, and wherein each of R9, R4 and R5 are independently selected from the group consisting of:
- (1) C1-15alkyl, straight or branched,
- (2) C3-15cycloalkyl,
- (3) C2-15alkenyl, straight or branched,
- (4) C2-15alkynyl, straight or branched,
- (5) phenyl and
- (6) phenylC1-6,alkyl-
- and R9 may also be each of the definitions mentioned under (1) to (6) substituted with one or more of the substituents independently selected from the group consisting of halogen, C1-6alkyl, C1-6,alkoxy and C6-14aryl, and R4 and R5 may also be hydrogen or form with the nitrogen to which they are attached, a 5, 6 or 7 membered heterocycle moiety, and wherein R6 and R7 are also independently selected from the group consisting of:
- (1) a dioxane moiety,
- wherein R10 and R11 are independently selected from the group consisting of:
- (1) C1-15 alkyl, straight or branched,
- (2) C3-15cycloalkyl,
- (3) C2-15alkenyl, straight or branched,
- (4) C2-15,alkynyl, straight or branched,
- (5) phenyl, and
- (6) phenylC1-6alkyl-,
- all optionally substituted with one or more of the substituents independently selected from the group consisting of halogen C1-6alkyl, C1-6alkoxy or C6-14aryl,
- (7) hydrogen, with the proviso that R10 is not hydrogen,
- (8) R10 and R11 form an optionally substituted 5, 6, 7 or 8 membered cyclic moiety, in which one or more of the substituents;
- is selected from the group consisting of halogen and a lower alkyl in any combination,
- (2) a cyclic sulfate,
- (3) or a cyclic phosphate,
- in which R12 is selected from the group consisting of:
- (1) C1-15 alkyl, straight or branched,
- (2) C3-15cycloalkyl,
- (3) phenyl,
- (4) phenylC1-6alkyl-,
- (5) hydrogen,
- (6) primary amines, and
- (7) secondary amines, and with the proviso that when R3 is hydrogen, R6 and R7 may also form a
- (1) borylidene group,
- in which R8 is a phenyl optionally substituted by one to five substituents, halogen or lower alkyl in any combination, or (2) R6 and R7 are both hydrogen,
- and wherein the dotted lines at x, y and z represent possible double bonds, when any are present, being either x and z in combination or x, y or z alone or none;
- or a corresponding stereoisomer thereof.
31 more elements
A process to prepare simvastatin from lovastatin, comprising the following steps:
- a) ring opening of the lactone of lovastatin, by formation of an amide bond with n-butylamine, followed by dioxane forming with acetone or dimethoxypropane,
- b) α-methylation of the 2-methylbutyrate side chain of the compound formed in step a) with methyl iodide,
- c) removal of the dioxane moiety and of the amide group of the compound formed in step a) by hydrolysis, optionally followed by reaction with ammonium hydroxide to form ammonium salt of simvastatin,
- d) lactonization of the ammonium salt or sodium salt of simvastatin or by heating in toluene to form simvastatin, followed by crystallization.
1 more element
Dependencies are inferred from the claim text.