Fully-continuous synthesis method of cyproterone acetate

A fully-continuous synthesis method of cyproterone acetate, comprising:

• (a) dissolving 4-androstene-3,17-dione and an electron acceptor in a first organic solvent to obtain a first feed liquid;
• and dispersing a first catalyst in a buffer solution to obtain a second feed liquid, wherein the first catalyst is an enzyme;
• and
• pumping, by a first plunger pump, the first feed liquid and the second feed liquid into a first micromixer for mixing to obtain a first mixture, and conveying the first mixture to a dynamic tubular reactor and a first microreactor for 41-dehydrogenation reaction to obtain a first reaction solution;
• subjecting the first reaction solution to extraction with an extraction solvent in an extraction device followed by phase separation in a first online gravity separation column and upper phase removal to collect a first lower phase;
• concentrating the first lower phase in a first concentration device to obtain a first concentrate;
• and loading the first concentrate onto a first stainless steel column filled with Na2SO4 and SiO2 in a weight ratio of 1:1 for water and impurity removal to obtain an androstene-1,4-dien-3,17-dione (10)-containing mixed solution as a third feed liquid;
• (b) dissolving ethynylmagnesium bromide in a second organic solvent to obtain a fourth feed liquid;
• pumping, by a second plunger pump, the third feed liquid and the fourth feed liquid into a second micromixer for mixing to obtain a second mixture;
• conveying the second mixture to a second microreactor for alkynylation reaction to obtain a second reaction solution;
• and quenching the second reaction solution with an aqueous HCl solution in a third micromixer followed by extraction and phase separation in a second online gravity separation column to collect a second lower phase as a fifth feed liquid, wherein the second lower phase is a Δ1,4-dien-3-one propargyl alcohol (12)-containing mixed solution;
• (c) dissolving an acidic reagent in dichloroethane to obtain a sixth feed liquid;
• pumping, by a third plunger pump, the fifth feed liquid and the sixth feed liquid into a fourth micromixer for mixing to obtain a third mixture;
• conveying the third mixture to a third microreactor for Rupe rearrangement to obtain a third reaction solution;
• and conveying the third reaction solution to a fifth micromixer through a first back pressure regulator, quenching the third reaction solution with a first aqueous NaHCO3 solution in the fifth micromixer followed by extraction and phase separation in a third online gravity separation column to collect a third lower phase as a seventh feed liquid, wherein the third lower phase is a Δ1, 4, 16-trien-3,20-dione (9)-containing mixed solution;
• (d) dissolving a second catalyst and PhSiH3 in a third organic solvent to obtain an eighth feed liquid;
• pumping, by a fourth plunger pump, the seventh feed liquid, the eighth feed liquid and oxygen into a sixth micromixer for mixing to obtain a fourth mixture, wherein the oxygen is stored in an oxygen cylinder with flow rate regulated by a check valve and a gas flow meter;
• conveying the fourth mixture to a fourth microreactor for Mukaiyama hydration reaction followed by mixing with an ethanol solution of P(OEt)3 in a seventh micromixer to complete the Mukaiyama hydration reaction, so as to obtain a fourth reaction solution;
• quenching the fourth reaction solution with a first aqueous sodium chloride solution in an eighth micromixer followed by extraction and phase separation in a fourth online gravity separation column to collect a fourth lower phase;
• and mixing the fourth lower phase with a first N,N-dimethylformamide (DMF) solution in a ninth micromixer followed by concentration in a second concentration device to obtain a 17α-hydroxy-Δ1,4-dien-3,20-dione (8)-containing mixed solution as a ninth feed liquid;
• (e) dissolving tetrachloro-p-benzoquinone (TCBQ) in a fourth organic solvent to obtain a tenth feed liquid;
• pumping, by a fifth plunger pump, the ninth feed liquid and the tenth feed liquid into a tenth micromixer for mixing to obtain a fifth mixture;
• conveying the fifth mixture to a fifth microreactor for 46-dehydrogenation reaction to obtain a fifth reaction solution;
• quenching the fifth reaction solution with a first 1 wt. % aqueous NaOH solution in an eleventh micromixer followed by extraction with DCM and phase separation in a fifth online gravity separation column to obtain a fifth lower phase and a first upper phase;
• subjecting the first upper phase to secondary extraction with DCM followed by phase separation in a sixth online gravity separation column to collect a sixth lower phase;
• mixing the fifth lower phase and the sixth lower phase with a second aqueous sodium chloride solution in a twelfth micromixer followed by phase separation in a seventh online gravity separation column to collect a seventh lower phase;
• and concentrating the seventh lower phase in a third concentration device followed by loading onto a second stainless steel column filled with Na2SO4 and SiO2 in a weight ratio of 1:1 for moisture and impurity removal, so as to obtain a 17α-hydroxy-Δ1,4,6-trien-3,20-dione (13)-containing dichloromethane solution as an eleventh feed liquid;
• (f) dissolving a third catalyst, ethylene glycol and a water absorbent in dichloromethane to obtain a twelfth feed liquid;
• mixing the eleventh feed liquid with the twelfth feed liquid in a thirteenth micromixer to obtain a sixth mixture;
• conveying the sixth mixture to a sixth microreactor for ketal protection reaction to obtain a sixth reaction solution;
• conveying the sixth reaction solution to a fourteenth micromixer through a second back pressure regulator, and quenching the sixth reaction solution with a second aqueous NaHCO3 solution in the fourteenth micromixer followed by phase separation in an eighth online gravity separation column to collect an eighth lower phase;
• mixing the eighth lower phase with a second DMF solution in a fifteenth micromixer followed by concentration in a fourth concentration device to obtain a second concentrate;
• and loading the second concentrate onto a third stainless steel column filled with Na2SO4 and SiO2 in a weight ratio of 1:1 for moisture and impurity removal, so as to obtain a 17α-hydroxy-Δ1,4,6-trien-3-one-20-ketal (7)-containing mixed solution as a thirteenth feed liquid;
• (g) under a nitrogen atmosphere, dissolving trimethylsulfoxonium iodide (TMSOI) and a base in DMF followed by reaction at room temperature for 0.6-1.2 h to obtain a fourteenth feed liquid;
• mixing the thirteenth feed liquid with the fourteenth feed liquid in a sixteenth micromixer to obtain a seventh mixture;
• conveying the seventh mixture to a seventh microreactor for C1,C2 cyclopropanation reaction to obtain a seventh reaction solution;
• quenching the seventh reaction solution with a third aqueous sodium chloride solution in a seventeenth micromixer followed by extraction with dichloromethane and phase separation in a ninth online gravity separation column to obtain a ninth lower phase and a second upper phase;
• subjecting the second upper phase to secondary extraction with dichloromethane followed by phase separation in a tenth online gravity separation column to collect a tenth lower phase;
• and conveying the ninth lower phase and the tenth lower phase to a fifth concentration device for concentration, so as to obtain a 17α-hydroxy-1α,2α-cyclopropa-Δ4,6-dien-3-one-20-ketal (6)-containing mixed solution as a fifteenth feed liquid;
• (h) dissolving an oxidant in dichloromethane to obtain a sixteenth feed liquid;
• pumping, by a sixth plunger pump, the fifteenth feed liquid and the sixteenth feed liquid into an eighteenth micromixer for mixing to obtain an eighth mixture;
• conveying the eighth mixture to an eighth microreactor for C6, C7 epoxidation reaction to obtain an eighth reaction solution;
• conveying the eighth reaction solution to a nineteenth micromixer through a third back pressure regulator, and quenching the eighth reaction solution sequentially with an aqueous Na2S2O3 solution in the nineteenth micromixer and a second 1 wt. % aqueous NaOH solution in a twentieth micromixer to remove residual oxidant followed by phase separation in an eleventh online gravity separation column to obtain an eleventh lower phase and a third upper phase;
• subjecting the third upper phase to secondary extraction with dichloromethane followed by phase separation in a twelfth online gravity separation column to collect a twelfth lower phase;
• and conveying the eleventh lower phase and the twelfth lower phase to a sixth concentration device for concentration, so as to obtain a 17α-hydroxy-6α,7α-epoxy-1α,2α-cyclopropa-Δ4-en-3-one-20-ketal (14)-containing mixed solution as a seventeenth feed liquid;
• (i) dissolving N,N-dimethylacetamide hydrochloride (DMA·HCl) in DMF to obtain an eighteenth feed liquid;
• pumping, by a seventh plunger pump, the seventeenth feed liquid and the eighteenth feed liquid into a twenty-first micromixer for mixing to obtain a ninth mixture;
• conveying the ninth mixture to a ninth microreactor for C6, C7 epoxide ring-opening reaction, C6 chlorination, dehydration and deprotection cascade reaction to obtain a ninth reaction solution;
• conveying the ninth reaction solution to a twenty-second micromixer through a fourth back pressure regulator, and quenching the ninth reaction solution with a third 1 wt. % aqueous NaOH solution in the twenty-second micromixer followed by extraction with dichloromethane and phase separation in a thirteenth online gravity separation column to obtain a thirteenth lower phase and a fourth upper phase;
• subjecting the fourth upper phase to secondary extraction with dichloromethane followed by phase separation in a fourteenth online gravity separation column to collect a fourteenth lower phase;
• mixing the thirteenth lower phase and the fourteenth lower phase with a fourth aqueous sodium chloride solution in a twenty-third micromixer followed by phase separation in a fifteenth online gravity separation column to collect a fifteenth lower phase;
• and concentrating the fifteenth lower phase in a seventh concentration device followed by loading onto a fourth stainless steel column filled with Na2SO4 and SiO2 in a weight ratio of 1:1 for moisture and impurity removal, so as to obtain a 17α-hydroxy-1α,2α-cyclopropa-6-chloro-Δ4,6-dien-3,20-dione (5)-containing mixed solution as a nineteenth feed liquid;
• and
• (j) pumping, by an eighth plunger pump, the nineteenth feed liquid and an acetylation reagent into a twenty-fourth micromixer for mixing to obtain a tenth mixture;
• conveying the tenth mixture to a tenth microreactor containing an acid catalyst for acetylation reaction to obtain a tenth reaction solution;
• quenching the tenth reaction solution with a third aqueous NaHCO3 solution in a twenty-fifth micromixer followed by phase separation in a sixteenth online gravity separation column to collect a fifth upper phase, wherein the fifth upper phase is a cyproterone acetate (4)-containing mixed solution;
• and
• subjecting the fifth upper phase to chromatographic separation to obtain a pure cyproterone acetate product.