Micro-electrolysis reactor for ultra fast, oxidant free, C—C coupling reaction and synthesis of daclatasvir analogs thereof

A continuous flow process for preparation of daclatasvir of Formula I, comprising the steps of:

• a) introducing a solution of a haloarene of Formula 1 and a Ni catalyst of Formula 2 in an aprotic solvent to a continuous micro-electro-flow reactor and maintaining a reaction mixture in the reactor for about 1-200 minutes at a temperature of about 25-80° C. and at a pressure of about 0-5 bar to obtain compounds of Formula 3a-3h;
• wherein compounds of Formula 1 are independently selected from the group:
• bromobenzene (1a);
• chlorobenzene (1a′);
• 1-bromo-4-methylbenzene (1b);
• 1-chloro-4-methylbenzene (1b′);
• 1-bromo-3-methylbenzene (1c);
• 1-chloro-3-methylbenzene (1c′);
• 1-bromonaphthalene (1d);
• 1-chloronaphthalene (1d′);
• 2-bromonaphthalene (1e);
• 2-chloronaphthalene (1e′);
• 4-bromo-1,1′-biphenyl (1f);
• 4-chloro-1,1′-biphenyl (1f′);
• 2-(4-bromophenyl)-2-methyl-1,3-dioxolane (1g);
• 1-(4-bromophenyl) ethanone (1h);
• b) continuous flow bromination of the compound of Formula 3h obtained in step a) by reacting with a brominating agent in an aprotic solvent while maintaining a reaction mixture in the reactor for about 10-200 minutes at a temperature of about 30-50° C. and at a pressure of about 1-10 bar to obtain a compound of Formula 4;
• c) reaction of the compound of formula 4 obtained in step b) with N-protected-L-proline in an aprotic solvent while maintaining a reaction mixture in the reactor for about 1-5 minutes at a temperature of about 30-80° C. and at a pressure of about 1-10 bar to obtain a compound of formula 5;
• d) reaction of the compound of formula 5 obtained in step c) with a regent while maintaining a reaction mixture in the reactor for about 1-5 minutes at a temperature of about 130-180° C. and at a pressure of about 10-30 bar to obtain a compound of formula 6;
• e) deprotection of the compound of formula 6 obtained in step d) by reacting it with aqueous HCl in a protic solvent while maintaining a reaction mixture in the reactor for about 1-5 minutes at a temperature of about 20-40° C. and at a pressure of about 1-10 bar to obtain a compound of formula 7;
• f) coupling of the compound of formula 7 or its pharmaceutically acceptable salt obtained in step e) with N-Moc-L-valine while maintaining a reaction mixture in the reactor for about 20-100 minutes at a temperature of about 20-40° C. and at a pressure of about 1-10 bar to obtain daclatasvir of formula I.