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US 6,610,887 B2Granted
Methods of preparing didesmethylsibutramine and other sibutramine derivatives
AssigneeSepracor Inc.
InventorsChris Hugh Senanayake, Zhengxu Han, Dhileepkumar Krishnamurthy, Derek Pflum
Life of this patent
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Abstract
This invention encompasses novel methods of preparing sibutramine and sibutramine derivatives, and stereomerically pure sibutramine derivatives in particular. Examples of sibutramine derivatives include, but are not limited to, sibutramine metabolites such as desmethylsibutramine and didesmethylsibutramine. The invention further encompasses novel compounds useful in the synthesis of sibutramine derivatives.
Claims25
A method of preparing a compound of Formula 1:
- or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof, wherein R1 is substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle;
- and R2 and R3 together form a cyclic structure or each of R2 and R3 is independently substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, which comprises contacting a compound of Formula 2:
- wherein X is independently a polymer bound alkyl, aryl or heteroalkyl;
- substituted or unsubstituted alkyl;
- substituted or unsubstituted aralkyl;
- substituted or unsubstituted heteroalkyl;
- substituted or unsubstituted aryl;
- substituted or unsubstituted ether;
- substituted or unsubstituted ester;
- substituted or unsubstituted ketone;
- substituted or unsubstituted phosphonate;
- substituted or unsubstituted phosphonic acid ester;
- substituted or unsubstituted phosphinoyl;
- substituted or unsubstituted sulfide;
- substituted or unsubstituted sulfone;
- substituted or unsubstituted sulfinyl imine;
- substituted or unsubstituted heterocycle;
- or —NR4R5, wherein R4 and R5 together with the nitrogen atom to which they are attached form a heterocycle or each of R4 and R5 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted ether, substituted or unsubstituted sulfide, or substituted or unsubstituted heterocycle;
- with a reagent capable of cleaving a nitrogen-sulfur bond under conditions suitable for the formation of the compound of Formula 1.
16 more elements
A method of preparing a compound of Formula 2:
- which comprises contacting a compound of Formula 3:
- with a Lewis acid or a base and a compound of the formula R1M, wherein X is independently a polymer bound alkyl, aryl or heteroalkyl;
- substituted or unsubstituted alkyl;
- substituted or unsubstituted aralkyl;
- substituted or unsubstituted heteroalkyl;
- substituted or unsubstituted aryl;
- substituted or unsubstituted ether;
- substituted or unsubstituted ester;
- substituted or unsubstituted ketone;
- substituted or unsubstituted phosphonate;
- substituted or unsubstituted phosphonic acid ester;
- substituted or unsubstituted phosphinoyl;
- substituted or unsubstituted sulfide;
- substituted or unsubstituted sulfone;
- substituted or unsubstituted sulfinyl imine;
- substituted or unsubstituted heterocycle;
- or —NR4R5, wherein R4 and R5 together with the nitrogen atom to which they are attached form a heterocycle or each of R4 and R5 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted ether, substituted or unsubstituted sulfide, or substituted or unsubstituted heterocycle;
- and M is CdZ, BaZ, Na, K, MgZ, ZnZ, Li, MnZ, CuZ, TiZ3, or In, and Z is Cl, Br, I, aryl, aralkyl, alkoxy, or heterocycle under conditions suitable for the formation of the compound of Formula 2.
15 more elements
A method of preparing a compound of Formula 3:
- which comprises contacting a compound of Formula 4:
- with a compound of Formula 5:
- wherein X is independently a polymer bound alkyl, aryl or heteroalkyl;
- substituted or unsubstituted alkyl;
- substituted or unsubstituted aralkyl;
- substituted or unsubstituted heteroalkyl;
- substituted or unsubstituted aryl;
- substituted or unsubstituted ether;
- substituted or unsubstituted ester;
- substituted or unsubstituted ketone;
- substituted or unsubstituted phosphonate;
- substituted or unsubstituted phosphonic acid ester;
- substituted or unsubstituted phosphinoyl;
- substituted or unsubstituted sulfide;
- substituted or unsubstituted sulfone;
- substituted or unsubstituted sulfinyl imine;
- substituted or unsubstituted heterocycle;
- or —NR4R5, wherein R4 and R5, together with the nitrogen atom to which they are attached form a heterocycle or each of R4 and R5 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted ether, substituted or unsubstituted sulfide, or substituted or unsubstituted heterocycle;
- under conditions suitable for the formation of the compound of Formula 3.
16 more elements
A compound of Formula 2:
- or a salt, solvate, clathrate, hydrate, or prodrug thereof, wherein each of X is independently a polymer bound alkyl, aryl or heteroalkyl;
- substituted or unsubstituted alkyl;
- substituted or unsubstituted aralkyl;
- substituted or unsubstituted heteroalkyl;
- substituted or unsubstituted aryl;
- substituted or unsubstituted ether;
- substituted or unsubstituted ester;
- substituted or unsubstituted ketone;
- substituted or unsubstituted phosphonate;
- substituted or unsubstituted phosphonic acid ester;
- substituted or unsubstituted phosphinoyl;
- substituted or unsubstituted sulfide;
- substituted or unsubstituted sulfone;
- substituted or unsubstituted sulfinyl imine;
- substituted or unsubstituted heterocycle;
- or —NR4R5, wherein R4 and R5 together with the nitrogen atom to which they are attached form a heterocycle or each of R4 and R5 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted ether, substituted or unsubstituted sulfide, or substituted or unsubstituted heterocycle;
- and R1 is independently substituted or unsubstituted alkyl;
- substituted or unsubstituted aralkyl;
- substituted or unsubstituted heteroalkyl;
- substituted or unsubstituted aryl;
- and R2 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted aryl.
18 more elements
A compound of Formula 3:
- or a salt, solvate, clathrate, hydrate, or prodrug thereof, wherein X is substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted aryl.
Dependencies are inferred from the claim text.