Method of preparing buprenorphine
View Patent ↗An improved process for preparing buprenorphine and a method for increasing the yield of buprenorphine or a derivative thereof.
1. A process for the preparation of a compound of formula (Ib),
wherein:
R 10 is a straight-chain, branched or cyclic C 1 -C 20 alkyl;
R 11 is C(R 13 )(R 14 )(OH) or a protected C(═O)(R 15 );
R 12 is H or CN;
R 13 is a straight-chain, branched or cyclic C 1 -C 20 -alkyl;
R 14 is a straight-chain, branched or cyclic C 1 -C 20 -alkyl; and
R 15 is a straight-chain, branched or cyclic C 1 -C 20 -alkyl
is a double bond or a single bond;
the process comprising:
i. reacting a compound of formula (Ia) with a thiolate in a suitable polar aprotic solvent, wherein the thiolate is selected from the group consisting of an optionally substituted C 1 -C 20 -alkylthiolate, an optionally substituted C 6 -C 20 -arylthiolate or an optionally substituted C 7 -C 30 -arylalkylthiolate; and
ii. treating the reaction mixture of step (i) with a protonating agent to give the compound of formula (Ib).
2. A process according to claim 1 , wherein the thiolate is a C 10 -C 20 -alkylthiolate.
3. A process according to claim 2 , wherein the C 10 -C 20 -alkylthiolate is a dodecanethiolate salt.
4. A process according to claim 1 , wherein the thiolate is prepared from a thiol and a base which is capable of deprotonating the thiol.
5. A process according to claim 4 , wherein the base is selected from the group consisting of alkali metal alkoxides, alkali metal hydroxides, alkali metal hydrides, organolithium reagents and alkali metal amides.
6. A process according to claim 1 , wherein the polar aprotic solvent is selected from the group consisting of dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, sulfolane, hexamethylphosphoramide and combinations thereof.
7. A process according to claim 1 , wherein the reaction of step (i) may be conducted at a temperature in the range of about 100° C. to about 130° C.