Improved synthesis of buprenorphine, analogues and intermediates
OwnerAaron GREGSON, Peter John SCAMMELLSinventors
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Abstract
The present invention relates to methods for preparing buprenorphine, analogues, and intermediates. More particularly, the present invention relates to an improved synthesis of a key intermediate toward buprenorphine.
Claims24
A method of preparing a compound of formula Pg-O-IIIA-Pg*,
- comprising mixing a compound of formula Pg-O-II-Pg*,
- with a tert-butylmagnesium compound and one or more additives in a solvent system to provide the compound of formula Pg-O-IIIA-Pg*;
- wherein each Pg and Pg* is a hydroxy-protecting group and Pg and Pg* the same or different;
- wherein each Pg and Pg* is selected from the group consisting of:
- benzyl (Bn), methoxymethyl (MOM), tetrahydropyranyl (THP), tert-butyl (tBu), allyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl (Piv), and benzoyl (Bz).
The method according to any one of the preceding claims, wherein the one or more additives are selected from the group consisting of:
- a non-cyclic polyether, a cyclic polyether, a Lewis acid, and a combination thereof, for example wherein the non-cyclic polyether is a glyme.
The method according to any one of the preceding claims, wherein the one or more additives are added to the solvent system in a stochiometry with respect to the compound Pg-O-II-Pg* of from 1 equivalent to 8 equivalents, such as from 2 equivalents to 7 equivalents, such as from 3 equivalents to 6 equivalents, for example 4 equivalents.
The method according to any one of the preceding claims, wherein the method comprises the steps:
- a. adding the tert-butylmagnesium compound to a first solvent system to provide a solution of the tert-butylmagnesium compound;
- b. adding Compound Pg-O-II-Pg* to a second solvent system to provide a solution of Pg-O-II-Pg*;
- and
- c. adding the solution of Pg-O-II-Pg* over a time period to the solution of the tert-butylmagnesium compound;
- or adding the solution of the tert-butylmagnesium compound over a time period to the solution of Pg-O-II-Pg*.
The method according to any one of the preceding claims, wherein the time period is from 10 to 80 minutes per mL of solution of BnO-II-Bn, for example 20 minutes for 0.5 mL solution of BnO-II-Bn.
The method according to any one of the preceding claims, wherein BnO-II-Bn and the tert-butylmagnesium compound are mixed and allowed to react for at least 1 hour after mixing, such as from 1 hour to 24 hours after mixing.
The method according to any one of the preceding claims, wherein the tert-butylmagnesium compound is selected from the group consisting of:
- a tert-butylmagnesium halide and di-tert-butylmagnesium, for example wherein the tert-butylmagnesium compound is tert-butylmagnesium chloride.
The method according to any one of the preceding claims, wherein the tert-butylmagnesium compound is added to the solvent system in a stochiometry with respect to the compound BnO-II-Bn of from 2 equivalents to 12 equivalents, such as from 2 equivalents to 11 equivalents, such as from 2 equivalents to 10 equivalents, such as from 3 equivalents to 9 equivalents, such as from 4 equivalents to 8 equivalents, such as from 5 equivalents to 9 equivalents, such as from 6 to 7 equivalents, for example 6 equivalents or for example 8 equivalents.
The method according to any one of the preceding claims, wherein the solvent system, the first solvent system, and/or the second solvent system comprises a solvent having a dielectric constant of from 1 to 6, such as from 1 to 5.
The method according to any one of the preceding claims, wherein the method comprises mixing Compound BnO-II-Bn with tert-butylmagnesium chloride and diglyme in a solvent system at a temperature within the range of from 5° C. to 60° C. and allowed to react at 15° C. to 60° C. for at least 1 hour after mixing to provide Compound BnO-IIIA-Bn.
A method of preparing a compound of formula Pg-O-IIIA-Pg*,
- comprising mixing a compound of formula Pg-O-II-Pg*,
- with 4 to 8 equivalents of a tert-butylmagnesium compound and 3 to 6 equivalents of diglyme in a solvent system comprising cyclopentyl methyl ether (CPME) to provide the compound of formula Pg-O-IIIA-Pg*;
- wherein each Pg and Pg* is a hydroxy-protecting group and Pg and Pg* the same or different;
- wherein each Pg and Pg* is selected from the group consisting of:
- benzyl (Bn), methoxymethyl (MOM), tetrahydropyranyl (THP), tert-butyl (tBu), allyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl (Piv), and benzoyl (Bz).
A method for isolating a compound of formula Pg-O-IIIA-Pg* from a reaction mixture in a reaction container, the method comprising:
- a. adding an alcoholic solvent, such as ethanol to the reaction mixture;
- b. heating the reaction mixture to at least 60° C., for example to the boiling point of the alcoholic solvent, for a predefined amount of time;
- c. cooling the reaction mixture to from 40 to 55° C., optionally over the course of at least 30 minutes, forming a solid comprising the compound;
- d. further cooling the reaction mixture to from 0 to 30° C. and stirring the mixture for a predefined amount of time;
- e. adding further of the alcoholic solvent to the reaction mixture;
- and
- f. collecting the solid comprising the compound by filtration and optionally drying the solid in vacuo.
A method for preparing buprenorphine, or a salt thereof, comprising the method as defined in any one of the preceding claims.
Dependencies are inferred from the claim text.