Methods of O-demethylation

1. A process for the preparation of a compound of formula I,

or a pharmaceutically acceptable salt thereof;

wherein:

W and Z independently represent CHR 3 or S, provided that at least one of W and Z represents CHR 3 ;

R 1 represents hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 cycloalkyl (which latter four groups are optionally substituted by one or more substituents selected from the list consisting of halogen atoms, phenyl groups and C 3-12 cycloalkyl groups);

R 2 represents hydrogen, a halogen atom, —OR 4 , —OC(O)R 4 , —N(R 4 ) 2 , C 1-12 alkyl, C 2-12 alkenyl or C 2-12 alkynyl (which latter three groups are optionally substituted by one or more halogen atoms);

each R 3 independently represents hydrogen, —CN, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 cycloalkyl (which latter four groups are optionally substituted by one or more substituents selected from the list consisting of halogen atoms, —OR 5 groups and 5 to 10-membered heteroaryl groups);

R 4 independently represents hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl (which latter three groups are optionally substituted by one or more halogen atoms or phenyl groups);

R 5 represents hydrogen or C 1-6 alkyl, optionally substituted by one or more halogen atoms; and

represents a single or double bond;

which process comprises contacting a compound of formula II,

or a salt thereof,

wherein R 1a , R 2a , W a and Z a are defined according to R 1 , R 2 , W and Z, respectively, with an alkali metal borohydride and an additional alkali metal salt.

2. The process of claim 1 , wherein: (i) R 1 represents methyl, ethyl, propyl, butyl, benzyl or —CH 2 -cyclopropyl; or (ii) R 3 represents C 1-6 alkyl optionally substituted by one or more substituents selected from the group consisting of halogen atom, —OR 5 groups, 5-membered heteroaryl groups.

3. The process of claim 1 , wherein W and Z independently represent CHR 3 , and optionally, wherein W represents CHR 3 and Z represents CH 2 .

4. The process of claim 2 , wherein R 3 represents C 1-6 alkyl optionally substituted by one or more substituents selected from the list consisting of —OH and thiophenyl.

5. The process of claim 4 , wherein R 3 represents:

wherein represents the point of attachment of R 3 to the rest of the compound of formula I.

6. The process of claim 1 , wherein:

(i) wherein R 2 represents —OR 4 ; —OC(O)R 4 ; or a methoxy group;

(ii) the alkali metal borohydride and the additional alkali metal salt each comprise the same alkali metal; or

(iii) the alkali metal borohydride is a compound of formula III,

wherein each R 6 independently represents C 1-12 alkyl, and X + represents an alkali metal cation.

7. The process of in claim 6 , wherein the alkali metal borohydride is an alkali metal tri-sec-butylborohydride or an alkali metal trisiamylborohydride; and optionally, wherein (i) the alkali metal borohydride is lithium tri-sec-butylborohydride or (ii) the amount of alkali metal borohydride present is from about 1 to about 10 equivalents relative to the compound of formula II.

8. The process of claim 7 , wherein: (i) the amount of alkali metal borohydride present is from about 2 to about 5 equivalents relative to the compound of formula II; or (ii) the additional alkali metal salt is lithium bromide; and optionally, wherein the additional alkali metal salt contains from about 1 to about 6 equivalents of alkali metal cations relative to the compound of formula II.

9. The process of claim 1 , wherein: (i) the additional alkali metal salt is lithium bromide; or (ii) wherein the additional alkali metal salt is an alkali metal halide.

10. The process of claim 1 , wherein the additional alkali metal salt contains from about 1.5 to about 3 equivalents of alkali metal cations relative to the compound of formula II and optionally, wherein: the reaction is performed in a solvent system comprising 2-methyltetrahydrofuran.

11. The process of claim 1 , wherein: (a) wherein the reaction is performed at a temperature of up to about 150° C.; or (b) the compound of formula I is buprenorphine and the process comprises contacting 3-O-methyl-buprenorphine with:

(i) an alkali metal borohydride selected from the group consisting of lithium tri-sec-butylborohydride, sodium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, and mixtures thereof; and

(ii) an additional alkali metal halide.

12. The process of claim 1 , wherein the process further comprises adding an oxidant after the compound of formula I has been formed and optionally, wherein the oxidant is an amine N-oxide, and/or the amine N-oxide is selected from the list consisting of trimethylamine N-oxide and N-methylmorpholine N-oxide.

13. The process of claim 12 , wherein the amount of oxidant added is from about 1 to about 10 equivalents relative to the total amount of alkali metal borohydride added to the reaction mixture.

14. The process of claim 13 , wherein the amount of oxidant added is from about 3 to about 7 equivalents relative to the alkali metal borohydride.

15. The process of claim 1 , wherein the compound of formula II is formed by a process comprising reacting a compound of formula IV,

or a salt thereof,

wherein R 2b , W b and Z b are defined according to R 2 , W and Z, respectively, with a compound of formula V,

R 7 —Y  V

wherein:

R 7 represents C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl or C 3-12 cycloalkyl, which groups are optionally substituted by one or more substituents selected from the list consisting of halogen atoms, phenyl groups and C 3-12 cycloalkyl groups; and

Y represents a suitable leaving group and optionally,

wherein (i) wherein: R 7 represents methyl, ethyl, propyl, butyl, benzyl or —CH 2 -cyclopropyl; and Y represents chloro, bromo, iodo, mesylate or tosylate; or (ii) the reaction between the compound of formula IV and the compound of formula V is conducted in the presence of an inorganic base.

16. The process of claim 15 , wherein the compound of formula IV is 3-O-methyl-norbuprenorphine, and the compound of formula II is 3-O-methyl-buprenorphine.

17. A process for preparing a pharmaceutically acceptable salt of a compound of formula I, as defined in claim 1 , which process comprises the steps of:

(i) preparing a compound of formula I in accordance with a process as claimed in claim 1 ;

(ii) optionally isolating and/or purifying the compound of formula I obtained from that process;

(iii) bringing into association the compound of formula I so formed with an acid;

(iv) optionally wherein the product of step (iii) is converted into a different salt.

18. A process for preparing a pharmaceutical formulation comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined in claim 1 , which process comprises the steps of:

(i) preparing a compound of formula I (or pharmaceutically acceptable salt thereof) in accordance with the process of claim 1 ;

(ii) optionally isolating and/or purifying the compound of formula I (or pharmaceutically acceptable salt thereof) obtained from that process; and

(iii) bringing into association the compound of formula I so formed (or pharmaceutically acceptable salt thereof) with one or more pharmaceutically acceptable excipients, adjuvants, diluents or carriers.

19. A process for the preparation of buprenorphine, or a pharmaceutically acceptable salt thereof, wherein the process comprises the steps of:

(i) contacting 3-O-methyl-buprenorphine with an alkali metal borohydride; and

(ii) adding an oxidant to the mixture obtained in (i).