Process for the synthesis of buprenorphine

A process for the synthesis of the opioid receptor antagonist Buprenorphine (5R,6R,7R,9R,13S,14S)-17-Cyclopropylmethyl-7-[(S)-3,3-dimethyl-2-hydroxybutan-2-yl]-6-methoxy-4,5-epoxy-6,14-ethanomorphinan-3-ol, or a pharmaceutical acceptable salt thereof, comprising the steps of

• a) reacting a thebaine-derivative according to the formula I and a dienophile to yield the reaction product II
• wherein, R1, R2 and R3 are independently selected from the group consisting of H or C1-C3 alkyl and wherein the bridge between the 14 and the 6 position consists of one double or only single bonds;
• b) contacting the reaction product II and a Grignard-reagent R4—Mg—X to yield the corresponding alkylated reaction product according to the following formula III
• wherein R4 is selected from the group consisting of C1-C6-Alkyl and X is selected from the group consisting of I, Cl, F and Br;
• c) reacting the compound according to formula III and a halo-cyanide to yield the corresponding cyanamide according to formula IV
• d) cleaving the cyanamide-moiety and the phenolic-oxygen-moiety to yield the deprotected intermediate according to formula VI
• e) derivatization of compound VI in the presence of a cyclopropyl-methylene-halogen and optionally hydrogenation of the bridge between C6 and C14 positions to comprise single bonds only to yield Buprenorphine, a Buprenorphine derivative according to compound VII or a Buprenorphine salt
• wherein
• at least one of the cleavages in step d) is performed in the presence of an alkali or alkaline earth sulfide.