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US 8,138,344 B2Granted
Process for the preparation of rapamycin derivatives
AssigneeNovartis AG
InventorsMurat Acemoglu, Sabine Pfeffer
Life of this patent
Estimating the term…
Abstract
Processes for the production of a 32-deoxorapamycin from a 32-iodo- or 32-hydroxyrapamycin, wherein the hydroxy group is substituted by the residue of an arylthionocarbonate or an arylthiocarbamate, in the presence of tris(trimethylsilyl)-silan and α,α′-azo-isobutyronitril in organic solvent; and 32-deoxorapamycin in the form of a crystalline solvate.
Claims6
A process for the production of a compound of formula I:
- wherein
- R1 is alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, benzyl, alkoxybenzyl or chlorobenzyl,
- R2 is a compound of formula II or III:
- wherein
- R3 is selected from H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl and alkylsilyl;
- R4 is H, methyl or together with R3 forms C2-6 alkylene;
- R5 is R6O—CH2—, wherein
- R6 is selected from H, alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl, formyl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl and carbalkoxyalkyl;
- Y is selected from O, (H, OH), and (H, OR9), wherein
- R9 is selected from C1-4alkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl, formyl or aryl;
- and,
- X is H,
- the process comprising
- A) treating a compound of formula IV:
- wherein R1, R2 and Y are as defined above and wherein R′ is a the residue of an arylthionocarbonate or arylthionocarbamate which arylthionocarbonate or arylthionocarbamate is bound to the C-atom in position 32 of the ring structure via the —O— group, and wherein reactive groups are in unprotected or protected form, with tris(trimethylsilyl)-silan and α,α′-azo-isobutyronitril in organic solvent;
- B) optionally splitting off protective groups, if present;
- C) isolating a compound of formula I wherein R1, R2 and Y are as defined above;
- and
- D) optionally converting a compound of formula I wherein R1 is alkyl into a compound of formula I wherein R1 is as defined above but not alkyl.
16 more elements
A process for the production of a compound of formula VI:
- wherein
- R1 is alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroalkynyl, benzyl, alkoxybenzyl or chlorobenzyl,
- R2 is selected from a compound of formula
- wherein:
- R3 is selected from H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl and alkylsilyl;
- R4 is H, methyl or together with R3 forms C2-6 alkylene;
- R5 is R6O—CH2—, wherein
- R6 is selected from H, alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl, formyl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl and carbalkoxyalkyl;
- Y is selected from 0 (H, OH), and (H, OR9), wherein R9 is selected from C1-4-alkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl, formyl or aryl;
- and,
- R′ is a residue of an arylthionocarbonate or arylthionocarbamate, which arylthionocarbonate or arylthionocarbamate is bound to the C-atom in position 32 of the ring structure via the —O— atom, in protected form,
- comprising treating a compound of formula I,
- wherein X is hydroxy, and R1, R2 and Y are as defined above,
- with an arylthionocarbonate where compound I is in a protected form;
- or, where the compound of formula I is in a reactive form:
- an arylthionocarbamate:
- an arylthionocarbamate of the formula VIII:
- wherein Hal is halogen, and ARYL is C6-18aryloxy or an arylic 5 or 6 membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, S with the proviso that the heterocyclyl comprises at least one N, which heterocyclyl is bound to the C═S group in a the compound of formula VII:
- via a heterocyclic nitrogen atom;
- or,
- an arylthionocarbamate of formula IX:
- wherein each ARYL′ is independently arylic heterocyclyl as defined above under ARYL;
- in organic solvent in the presence of a base and optionally in the presence of a condensation agent, selected from the group consisting of succinimide, N-hydroxysuccinimide, and 4-dimethylaminopyridine;
- and
- isolating compound of formula VI.
22 more elements
32-Deoxorapamycin, in crystalline form in the form of an acetone solvate.
32-Deoxorapamycin, in crystalline form in the form of a propylene glycol solvate.
32-Deoxorapamycin in crystalline form in the form of a hydrate.
Dependencies are inferred from the claim text.