Full continuous-flow preparation method of (+)-biotin

A full continuous-flow preparation method of (+)-biotin (1) using a multi-stage micro-reaction system, the multi-stage micro-reaction system comprising a first micro-reaction unit, a second micro-reaction unit, a third micro-reaction unit, a fourth micro-reaction unit, a fifth micro-reaction unit, a sixth micro-reaction unit, a seventh micro-reaction unit, an eighth micro-reaction unit, and a ninth micro-reaction unit connected in series;

• and the full continuous-flow preparation method comprising:
• (S1) subjecting a cyclic anhydride (2) and a chiral biphenyl propylene glycol (3) to an asymmetric ring-opening reaction in the presence of an organic base (4) to produce a dicarboxylic acid monoester compound (5);
• (S2) subjecting the dicarboxylic acid monoester compound (5) and a borohydride (6) to a selective reduction reaction to produce a 5-hydroxymethyl-4-carboxylic acid compound (7);
• (S3) subjecting the 5-hydroxymethyl-4-carboxylic acid compound (7) and an inorganic mineral acid (8) to a cyclization reaction to produce (3aS, 6aR)-lactone (9);
• (S4) subjecting the (3aS, 6aR)-lactone (9) and a sulfenylating reagent (10) to sulfenylation to produce (3aS, 6aR)-thiolactone (11);
• (S5) subjecting the (3aS, 6aR)-thiolactone (11) and a zinc reagent (12) to Fukuyama coupling reaction in the presence of a palladium catalyst to produce a hydroxy valerate compound (13);
• (S6) subjecting the hydroxy valerate compound (13) to an elimination reaction in the presence of an inorganic mineral acid (14) to produce an alkenyl valerate compound (15);
• (S7) subjecting the alkenyl valerate compound (15) to a selective reduction reaction in the presence of a palladium-on-carbon (Pd/C) catalyst to produce a valerate ester (16);
• (S8) subjecting the valerate ester (16) to a hydrolysis reaction in the presence of an inorganic base (17) to produce a valeric acid salt (18);
• and
• (S9) subjecting the valeric acid salt (18) to a debenzylation reaction in the presence of an inorganic mineral acid (19) to produce a target product (+)-biotin (1).