Fully continuous chemical synthesis method of cyproterone acetate

Abstract

The invention belongs to the technical field of chemical medicines, and particularly relates to a full-continuous chemical synthesis method of cyproterone acetate. According to the method, 4-androstane-3, 17-diketone is taken as a starting raw material, and a full-continuous device consisting of a plurality of sequentially connected micro-mixers, micro-reactors, an online gravity separation device, an online solvent switching device, an online solvent concentration device, a solvent recovery device and the like is used; the cyproterone acetate product is synthesized through one-step enzyme catalysis reaction, nine-step chemical reaction and continuous operation, dichloromethane, dichloroethane and ethyl alcohol are recycled, and emission of three wastes is obviously reduced. According to the invention, the production efficiency and the process control accuracy can be greatly improved, and the stable product quality is ensured. And decoloring, recrystallizing, filtering and drying the obtained crude cyproterone acetate product to obtain a pure cyproterone acetate product with the purity of more than 99%.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical medicine, and particularly relates to a method for synthesizing cyproterone acetate. Background Art

[0002] Cyproterone acetate, commonly known as "Cyproterone", can strongly antagonize androgen receptors and reduce serum testosterone through its weak anti-gonadotropin effect. It was first used clinically as an anti-androgen in 1964. It is regarded as the only hormone that can cause complete androgen blockade through monotherapy, and is therefore used clinically to treat advanced prostate cancer, metastatic male breast cancer, and acne and hair loss caused by high androgen in women. This potent anti-androgen inhibitor has been included in the essential drug lists of 55 countries.

[0003] Several methods have been reported for the synthesis of cyproterone acetate, including Neumann et al. synthesizing compound 4 and its derivatives from Solasodine by an 18-step asymmetric synthesis (Gynecological Endocrinology, 11, 1997, 411-433). Manosroi et al. improved the 12-step, 14-step and 16-step synthesis strategies for synthesizing 4 from Solasodine (EP1359154A1). Kongkathip et al. reported that 16β-chloro (or bromo)-4 was obtained by 14-step stereoselective synthesis from commercially available 16-dehydropregnenolone acetate (Synthetic Communications, 33, 2003, 1695-1706). These synthetic routes have many steps (12-18 steps), with waste generated and safety issues in handling hazardous materials and / or highly reactive substances / intermediates to achieve complex selective transformations, and the overall efficiency of the reported batch methods is not ideal.

[0004] Flow chemistry has many advantages over batch synthesis in the synthesis of small organic molecules, especially in terms of environmental compatibility, safety, and synthetic efficiency, especially when considering scale-up. These advantages have begun to have an important impact on the entire chemical community. Summary of the invention

[0005] In view of the problems existing in the prior art, the object of the present invention is to provide a fully continuous chemical synthesis method of cyproterone acetate with high production efficiency, good product quality and fewer synthesis steps.

[0006] The present invention provides a fully continuous chemical synthesis method of cyproterone acetate, which uses androstenedione as a starting point, uses 3-sterone-Δ1-dehydrogenase mutant ReM2 and the like to catalyze androstenedione to synthesize androst-1,4-diene-3,17-dione, and then undergoes acetylation and Rupe rearrangement to obtain Δ1,4,16 -triene-3,20-dione, continued Δ 6 -dehydrogenation, C20-ketal, to obtain 17α-hydroxy-Δ 1,4,6 -triene-3,20-one (7), followed by cyclopropanation / epoxidation / ring opening / chlorination / dehydration / protection group removal cascade reaction and O-acetylation to obtain cyproterone acetate; specifically, a fully continuous device consisting of a plurality of sequentially connected micro-mixers, micro-reactors, online solvent switching and reagent recovery, low-boiling point reagent feeding and other equipment is used to achieve online extraction, online solvent switching, and online solvent concentration. The synthetic route is:

[0007]

[0008] The specific steps are as follows:

[0009] (a) dissolving 4-androstane-3,17-dione (11) and an electron acceptor in an organic solvent as feed liquid A; dispersing an enzyme catalyst in a buffer as feed liquid B; using a first plunger pump I to fully mix feed liquid A and feed liquid B in a first micromixer, and then entering a first dynamic tubular reactor and a second microreactor for Δ 1 -dehydrogenation reaction to generate a reaction liquid containing androsta-1,4-diene-3,17-dione (10), which then enters an extraction device, is extracted with an extraction solvent, and enters an online first gravity separation column I (Gravity Liquid / Liquid separator I) for stratification, and removes the upper layer of bacterial cell crushing liquid and part of the electron acceptor to obtain a lower layer of extraction solvent solution containing androsta-1,4-diene-3,17-dione (10); the solution enters an online solvent first concentration device I (Tube-in-tube) for concentration, and the obtained concentrated solution passes through a stainless steel column I filled with 1:1 Na2SO4 / SiO2 to capture water and impurities; thus, an extraction solvent solution containing the product (10) is obtained as a feed liquid C( Figure 3 ).

[0010] Further:

[0011] In step (a), the flow rate ratio of the mixed solution of the electron acceptor, 4-androstane-3,17-dione (11) and the enzyme catalyst to the first dynamic tubular reactor and the second microreactor is controlled so that the molar ratio of the electron acceptor, 4-androstane-3,17-dione (11) and the enzyme catalyst is (0.1-0.3):1:(1.0-5.0);

[0012] The electron acceptor is selected from any one of phenazine methyl sulfate, 2,6-dichlorophenol indophenol, resazurin, Worcester blue, methylene blue, coenzyme Q, vitamin K and menadione; preferably phenazine methyl sulfate;

[0013] The enzyme catalyst is derived from 3-sterone-Δ 1 -Dehydrogenase (Δ 1 -KstDs) and any of its mutants;

[0014] The organic solvent is any one of dichloromethane, 1,2-dichloroethane, methanol, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran and 1,4-dioxane;

[0015] The buffer is any one of a phosphate buffer, a glycine-sodium hydroxide buffer, a Tris-hydrochloric acid buffer, a phthalic acid-hydrochloric acid buffer and a glycine-hydrochloric acid buffer;

[0016] The extraction solvent is dichloromethane or dichloroethane;

[0017] The temperature in the first dynamic tubular reactor and the second microchannel reactor is controlled to be 20-45°C; the residence time of the mixed reaction materials in the first dynamic tubular reactor is 30-120 minutes. The residence time in the second microchannel reactor is 22-90 minutes;

[0018] The continuous quenching and extraction are completed in an extraction device with a residence time of 1-5 minutes;

[0019] Liquid-liquid separation is completed in the first gravity separation column I with a residence time of 3-20 minutes; solvent switching, solvent concentration and solvent recovery are completed in the first concentration device I with a residence time of 1-10 minutes.

[0020] (b) dissolving the reagent ethynyl magnesium bromide in an organic solvent as feed liquid D, and pumping it into a second micro mixer with feed liquid C by a second plunger pump II to be fully mixed, and the mixed reaction materials enter a third channel micro reactor for ethynylation reaction to generate a mixture containing Δ 1,4 -diene-3-one propargyl alcohol (12) extraction solvent / organic solvent reaction mixture; the mixture is mixed with HCl aqueous solution in a third micro mixer to quench, then extracted by an extraction device, and then enters the online second gravity separation column II for stratification to obtain a lower layer of extraction solvent solution containing the product (12) as feed liquid E ( Figure 4 ).

[0021] Further:

[0022] In step (b), the molar concentration of the reagent ethynylmagnesium bromide is 100-300mmol / L;

[0023] The organic solvent is selected from any one or two of tetrahydrofuran, N,N-dimethylacetamide, dimethyl sulfoxide, and hexamethylphosphoramide;

[0024] The temperature in the third microchannel reactor is controlled within the range of 20-45° C.; the residence time of the mixed reaction materials in the third microchannel reactor is 30-120 minutes.

[0025] (c) The acidic reagent is dissolved in dichloroethane as feed liquid F, which is pumped into the fourth micro mixer with feed liquid E by the third plunger pump III for thorough mixing. The mixed reaction materials enter the fourth micro reactor for Rupe rearrangement reaction to generate a Δ 1,4,16 The mixed solution is mixed with a NaHCO3 aqueous solution in a fifth mixer to be quenched, extracted by an extraction device, and then enters an online third gravity separation column III for stratification to obtain a lower layer of a dichloroethane solution containing the product 9 as feed liquid G ( Figure 4 ).

[0026] Further:

[0027] In step (c), the molar concentration of the acidic reagent is 50-200 mmol / L;

[0028] The acidic reagent is selected from any one of concentrated sulfuric acid, trifluoromethanesulfonic acid, Eaton's reagent (MeSO3H·P2O5), methanesulfonic acid, Amberlyst15 acidic resin, p-toluenesulfonic acid, aluminum chloride and acetic acid; preferably Eaton's reagent;

[0029] The temperature in the fourth microreactor is controlled within the range of 60-100° C.; the molar concentration of the acidic reagent is 1.5-3 equivalents of the molar concentration of compound 9; and the residence time of the mixed reaction materials in the third microreactor is 20-30 minutes.

[0030] (d) The catalyst and PhSiH3 are dissolved in an organic solvent as feed liquid H, which is pumped into the sixth mixer through the fourth plunger pump IV to mix with feed liquid G and oxygen (stored in an oxygen tank and the flow rate is adjusted by a flap-type bottle valve and a gas flow meter) and the mixed reaction materials enter the fifth microreactor for Mukaiyama hydration reaction, and continue to pass through the seventh micromixer to mix with P(OEt)3 dissolved in ethanol to complete the reaction, thereby generating a 17α-hydroxy-Δ 1,4The mixture is mixed with an aqueous sodium chloride solution in an eighth mixer to be quenched, and then extracted by an extraction device, and then enters an online fourth gravity separation column IV for stratification to obtain a lower layer of a dichloroethane / ethanol solution containing the product (8). The solution is mixed with an N,N-dimethylformamide solution in a ninth mixer and then enters an online second solvent concentration device II for concentration, thereby obtaining an N,N-dimethylformamide solution containing the product (8) as feed liquid I ( Figure 4 ).

[0031] Further:

[0032] In step (d), the molar concentration of the catalyst is 1-3 mol%;

[0033] The catalyst is selected from one of Mn(dpm)3, Co(acac)2, Fe(dpm)3, Fe(acac)3, Fe(acac)2, Co(acac)3, Cobalt acetate, Cobalt(II)bromide, Cobalt chloride and Cobalt iso-octoate;

[0034] The organic solvent is any one or two of dichloromethane, 1,2-dichloroethane, methanol, ethanol, and tetrahydrofuran;

[0035] The temperature in the fifth microreactor is controlled within the range of 25-35° C.; the residence time of the mixed reaction materials in the fifth microreactor is 10-15 minutes.

[0036] (e) Chloroquinone is dissolved in an organic solvent as feed liquid J, and is pumped into the tenth micro mixer together with feed liquid I by the fifth plunger pump V for mixing. The mixed reaction materials enter the sixth micro reactor for Δ 6 -dehydrogenation reaction, the mixed solution is mixed with 1% NaOH aqueous solution in the eleventh micro mixer for quenching, and the mixed solution is extracted with dichloromethane (or dichloromethane) and then enters the online fifth gravity separation column V for stratification to obtain the lower layer containing 17α-hydroxy-Δ 1,4,6-triene-3,20-dione (13) in a dichloromethane / N,N-dimethylformamide mixed solution, the upper layer solution and dichloromethane are extracted twice and then enter the sixth online gravity separation column VI for stratification to obtain a lower layer of dichloromethane solution containing the product (13). The two dichloromethane solutions containing the product (13) are mixed with a sodium chloride aqueous solution in the twelfth micro mixer and enter the seventh online gravity separation column VII for stratification to obtain a lower layer of dichloromethane solution containing the product (13). The solution enters the third concentration device III for concentration, and the concentrated reaction mixture passes through a second stainless steel column II filled with 1:1 Na2SO4 / SiO2 to capture moisture and impurities. At this point, a dichloromethane solution containing the product (13) is obtained as feed liquid K( Figure 5 ).

[0037] Further:

[0038] In step (e), the organic solvent is selected from one of dichloromethane, 1,2-dichloroethane, N,N-dimethylacetamide, dimethyl sulfoxide, dioxane and tert-butyl alcohol;

[0039] The temperature in the sixth microreactor is controlled within the range of 100-140° C.; the residence time of the mixed reaction materials in the sixth microreactor is 4-15 minutes.

[0040] (f) The catalyst / ethylene glycol / water absorbent is dissolved in dichloromethane as feed liquid L, and mixed with feed liquid K in the thirteenth micro mixer. The mixed reaction materials enter the seventh micro reactor for ketal protection reaction. The mixed liquid is mixed with NaHCO3 aqueous solution in the fourteenth micro mixer and quenched, and then enters the eighth online gravity separation column VIII for separation to obtain the lower layer containing 17α-hydroxy-Δ 1,4,6 -triene-3-one-20-ketal (7) in dichloromethane solution, the solution and N,N-dimethylformamide solution are mixed in a fifteenth mixer and then enter the fourth online solvent concentration device IV for concentration, and the concentrated reaction mixture passes through a third stainless steel column III filled with 1:1 Na2SO4 / SiO2 to capture moisture and impurities; thus, a dichloromethane / N,N-dimethylformamide mixed solution containing the product (7) is obtained as the feed liquid M( Figure 5 ).

[0041] Further:

[0042] In step (f), the water absorbent is selected from one of silica gel, molecular sieves, anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium chloride, and trimethyl orthoformate (TMOF);

[0043] The catalyst is selected from one of concentrated sulfuric acid, p-toluenesulfonic acid (TsOH), BF3·Et2O, TiCl4, Bi(NO3)3, LiBF4, Cu(BF4)2, RuCl3·H2O, CoCl2, InCl3, In(OTf)3, ZrCl4 and Zn(BF4)2;

[0044] The temperature in the seventh microreactor is controlled within the range of 40-100° C.; the residence time of the mixed reaction materials in the seventh microreactor is 15-20 minutes.

[0045] (g) Under nitrogen conditions, trimethyl sulfoxide iodide (TMSOI) and alkali are dissolved in N,N-dimethylformamide, and the mixed solution obtained after the reaction at room temperature for 0.6-1.2 hours is used as feed liquid N, and is mixed with feed liquid M in the sixteenth micro mixer. The mixed reaction materials enter the eighth micro reactor for C1, C2 cyclopropanation reaction. The mixed solution is mixed with sodium chloride aqueous solution in the seventeenth micro mixer to quench, and the mixed solution is extracted with an extraction solvent (such as dichloromethane) and then enters the online ninth gravity separation column IX for stratification to obtain a lower layer containing 17α-hydroxy-1α,2α-cyclopropane-Δ 4,6 -diene-3-one-20-ketal (6) in dichloromethane / N,N-dimethylformamide mixed solution, the upper layer solution and the extraction solvent are extracted twice and then enter the online tenth gravity separation column X for separation to obtain the lower layer extraction solvent / N,N-dimethylformamide solution containing 6. The two extraction solvent solutions containing 6 enter the fifth concentration device V for concentration to obtain the extraction solvent / N,N-dimethylformamide solution containing product 6 as feed liquid O( Figure 6 ).

[0046] Further:

[0047] In step (g), the base is selected from LiHMDS, NODX, t One of BuOK, LDA, MeONa and NaH.

[0048] The temperature in the eighth microreactor is controlled within the range of 25-40°C; the residence time of the mixed reaction materials in the eighth microreactor is 15-20 minutes. The molar concentration of trimethylsulfoxide iodide is 2-3 equivalents of material 7, and the molar concentration of the alkali is 1.5-3.0 equivalents of material 7.

[0049] (h) The oxidant is dissolved in dichloromethane as feed liquid P, and is pumped into the 18th micro mixer with the feed liquid O by the 6th plunger pump VI to mix, and the mixed reaction materials enter the 9th micro reactor for C6, C7 epoxidation reaction, and the mixed liquid is mixed with Na2S2O3 aqueous solution through the 19th micro mixer to quench the deoxybenzoic acid, and the reaction mixture is further mixed with 1% NaOH aqueous solution through the 20th micro mixer to quench the remaining oxidant, and then enters the 11th online gravity separation column XI for stratification to obtain the lower layer containing 17α-hydroxy-6α,7α-epoxy-1α,2α-cyclopropyl-Δ 4 -ene-3-one-20-ketal (14) in dichloromethane solution, the upper layer solution and dichloromethane are extracted twice and then enter the twelfth gravity separation column XII for stratification to obtain the lower layer dichloromethane solution containing the product (14). The two dichloromethane solutions containing the product (14) enter the sixth concentration device VI for concentration. At this point, the dichloromethane solution containing the product (14) is obtained as the feed liquid Q ( Figure 7 ).

[0050] Further:

[0051] In step (h), the oxidant is selected from any one of peroxyformic acid, peroxyacetic acid, peroxybenzoic acid, meta-chloroperbenzoic acid (m-CPBA), peroxytrifluoroacetic acid and hydrogen peroxide.

[0052] The temperature in the ninth microreactor is controlled within the range of 25-120° C.; the residence time of the mixed reaction materials in the ninth microreactor is 10-20 minutes.

[0053] (i) N,N-dimethylacetamide hydrochloride (DMA·HCl) is dissolved in N,N-dimethylformamide as feed liquid R, and is pumped into the twenty-first micro-mixer with feed liquid Q by the seventh plunger pump VII for mixing. The mixed reaction materials enter the tenth micro-reactor for C6, C7 epoxy ring-opening / C6 chlorination / dehydration / deprotection cascade reaction. The mixed liquid is mixed with 1% NaOH aqueous solution in the twenty-second mixer for quenching. The mixed liquid is extracted with dichloromethane and then enters the thirteenth online gravity separation column XIII for separation to obtain a lower layer containing 17α-hydroxy-1α,2α-cyclopropane-6-chloro-Δ 4,6-diene-3,20-one (5) in dichloromethane / N,N-dimethylformamide mixed solution, the upper layer solution and dichloromethane are extracted twice and then enter the online fourteenth gravity separation column XIV for stratification to obtain the lower layer dichloromethane / N,N-dimethylformamide mixed solution containing the product (5). The two dichloromethane / N,N-dimethylformamide mixed solutions containing the product (5) are mixed with sodium chloride aqueous solution in the twenty-third micro mixer and then enter the fifteenth gravity separation column XV for stratification to obtain the lower layer dichloromethane solution containing (5). The solution enters the seventh concentration device VII for concentration, and the concentrated reaction mixture passes through a fourth stainless steel column IV filled with 1:1 Na2SO4 / SiO2 to capture moisture and impurities. At this point, the dichloromethane solution containing the product (5) is obtained as the feed liquid S( Figure 7 ).

[0054] Further:

[0055] In step (i), the steroid C6, C7 epoxy ring-opening, C6 chlorination, dehydration and deprotection cascade reaction are achieved in one pot in the same system;

[0056] The temperature in the tenth microreactor is controlled within the range of 80-180° C.; the residence time of the mixed reaction materials in the tenth microreactor is 20-40 minutes.

[0057] (j) The acetylating agent is used as the feed liquid T, and is mixed with the feed liquid S by the eighth plunger pump VIII into the twenty-fourth micro-mixer, and the mixed reaction materials enter the eleventh micro-reactor for acetylation reaction. After the mixed solution is mixed and quenched with the NaHCO3 aqueous solution in the twenty-fifth micro-mixer, the reaction mixture enters the online sixteenth gravity separation column XVI for stratification to obtain the upper layer of the dichloromethane / isopropyl acetate mixed solution containing cyproterone acetate (4), and the pure cyproterone acetate (4) is obtained by chromatographic separation. Figure 7 ).

[0058] Further:

[0059] In step (j), the acetylating agent is selected from any one of acetic acid, acetic anhydride, acetyl chloride, trifluoroacetic anhydride and isopropenyl acetate;

[0060] The acid catalyst is selected from any one of concentrated sulfuric acid, trifluoromethanesulfonic acid, methanesulfonic acid, Amberlyst 15 acid resin, p-toluenesulfonic acid and acetic acid.

[0061] Further:

[0062] In the present invention, all micromixers are selected from any one of a T-type micromixer, a Y-type micromixer, a cross-type mixer, a coaxial flow micromixer and a flow focusing micromixer.

[0063] In the present invention, all microchannel reactors are tubular microchannel reactors or plate microchannel reactors.

[0064] In the present invention, the extraction solvent used in the extraction device is dichloromethane or dichloroethane.

[0065] In the present invention, all the concentrating devices are tube-in-tube concentrating devices.

[0066] In the present invention, all gravity separation columns adopt glass tube gravity liquid-liquid separation devices.

[0067] In the present invention, 3-sterone Δ 1 -Dehydrogenase mutant ReM2 enzyme or other 3-sterol Δ 1 -Dehydrogenase realizes continuous flow enzyme catalysis of steroid Δ 1 -Dehydrogenation reaction.

[0068] The present invention uses a dynamic tubular reactor (Nat Chem Eng 1, 522–531 (2024).) and a polytetrafluoroethylene reactor (reference patent application publication number: CN117695962A) to achieve continuous flow ReM2 biocatalytic substrate Δ 1 -Dehydrogenation to synthesize androst-1,4-diene-3,17-dione, solving the problem of steroid substrate blocking the pipeline.

[0069] In the present invention, each concentrator component is as follows Figure 1 As shown, it is composed of a feed liquid container or reactor, a solvent storage tank, a recovery tank, a nitrogen tank, a concentrator (with a jacket heating), a peristaltic pump, a hose (polytetrafluoroethylene coil, PTFE), a T-type connector and a mass flow meter (MFC). Two feed liquid tanks are connected by a T-type connector, and the peristaltic pump pumps the feed liquid into the polytetrafluoroethylene coil for mixing, and then enters the concentrator together with N2 through the T-type connector for heating and blowing and concentration. After the volatile solvent in the concentrator enters the condenser, it is condensed and enters the recovery tank to recover the evaporated solvent. After the feed liquid reaches the concentration multiple, the peristaltic pump transfers the feed liquid to the next operation stage.

[0070] In the present invention, the material of the first back-pressure valve and the second back-pressure valve is stainless steel or Hastelloy, the size of the connecting pipeline is 1.6mm-20mm, and the pressure condition range is 0.1-2.0MPa.

[0071] The present invention realizes efficient synthesis of cyproterone acetate by using microreactor technology by reasonably matching a micro mixer, a microreactor and a post-reaction online treatment device according to the synthesis process characteristics of cyproterone acetate. The continuous synthesis of cyproterone acetate is realized by a self-designed solvent switching system, which greatly improves production efficiency, saves the separation and extraction of synthetic intermediates, effectively reduces the generation of three wastes, reduces production costs, and has little pollution to the environment. Based on the innovative concept of the present invention, changes and modifications made to the embodiments, or equivalent structures or equivalent process changes made by the description and accompanying drawings of the present invention, directly or indirectly applying the above technical solutions to other related technical fields are all included in the scope of protection of the claims of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] Figure 1 A schematic diagram of the structure of the online concentration device of the present invention.

[0073] Figure 2 The overall flow chart of the fully continuous enzyme-chemical synthesis method of cyproterone acetate of the present invention is shown.

[0074] Figure 3 The diagram of module 1 of the present invention, PMS is phenazine methyl sulfate; OAR is a dynamic tubular reactor; PTFE is a polytetrafluoroethylene coil reactor; DCE is dichloroethane; DMF is N,N-dimethylformamide; BPR is a back pressure regulating valve.

[0075] Figure 4 A schematic representation of a module 2 according to the invention.

[0076] Figure 5 A schematic representation of a module 3 of the invention.

[0077] Figure 6 A schematic representation of a module 4 of the invention.

[0078] Figure 7 A schematic representation of a module 5 according to the invention.

[0079] Figure 8 The cyproterone acetate product of the present invention has a hydrogen nuclear magnetic resonance spectrum and a carbon nuclear magnetic resonance spectrum. DETAILED DESCRIPTION

[0080] The present invention is further described below through specific embodiments in conjunction with the accompanying drawings.

[0081] Example 1

[0082] (a) 4-androstane-3,17-dione (600 mM) and phenazine methyl sulfate (60 mM, 0.1 equiv.) were dissolved in N,N-dimethylformamide (50 mL, 0.1 mL / min) as feed A, and 50.0 mg / mL ReM2 enzyme catalyst was dispersed in Tri-HCl buffer (450 mL, 50 mM, pH 8.0, 0.9 mL / min) as feed B. The two streams of materials were mixed with O2 gas (0.6 mL / min) in the first micromixer by a plunger pump I and then introduced into the first dynamic tubular reactor and the second microreactor (V1 = 30 mL). The reaction was completed at 30°C within a retention time of 10 min, and the mixture was separated by an online gravity separation column I (retention time t R1-2 =10min) after stratification, the lower dichloroethane layer was taken (peristaltic pump controlled flow rate: V = 2mL / min), and it was concentrated into the first concentration device I together with dichloroethane / hexamethylphosphoric acid triamide (9:1, 0.5mL / min) by 5 times (V = 0.5mL / min, temperature T = 90°C, N2 flow rate 60mL / min). The concentrated reaction mixture was passed through a 1:1 Na2SO4 / SiO2 filled stainless steel column I (retention time t R1-4 =40min) to capture moisture and impurities, and obtain a dichloroethane solution containing product 10 as feed liquid C, with a total retention time of 82min.

[0083] (b) 0.5M ethynylmagnesium bromide (157.68mM, 0.5mL / min, 250mL) was dissolved in tetrahydrofuran, and the two streams of materials were pumped into the second micromixer by plunger pump II for mixing with liquid C, and then entered the third microreactor (V3 = 10mL). The reaction was completed after a retention time of 10min at 60°C to generate a dichloroethane / THF reaction mixture containing Δ1,4-diene-3-one propargyl alcohol (12). The mixture was mixed with HCl aqueous solution (0.3M, 1.0mL / min) in the third micromixer for quenching, and then extracted by an extraction device (t R3-1 =1min), and then passed through the second online gravity separation column II (R3-2=10min) for stratification, and then took the lower layer of dichloroethane (peristaltic pump controlled flow rate: V=1.0mL / min) to obtain the lower layer of dichloroethane solution containing product 12 as feed liquid E, with a total retention time of 21min.

[0084] (c) MeSO3H·P2O5 (172.4 mM, 0.5 mL / min, 250 mL) was dissolved in dichloroethane as feed liquid F, and the two streams of materials were pumped into the fourth micro mixer by plunger pump III for mixing, and then entered the fourth micro reactor (V4 = 37.5 mL), and retained for 25 min at 80 ° C and 5.0 bar back pressure conditions for Rupe rearrangement reaction. The reaction liquid was mixed with NaHCO3 aqueous solution in the fifth mixer for quenching (2.0 mL / min) and then entered the extraction device (t R4-1 =1min) extraction, and then passed through the third gravity separation column (t R4-2 =10min) after stratification, the lower dichloroethane layer was taken out (the flow rate was controlled by a peristaltic pump: V=1.5mL / min) to obtain a dichloroethane solution containing product 9 as feed liquid G, with a total retention time of 36min.

[0085] (d) 1.97 mM Co(acac)2 and 43.68 mM PhSiH3 were dissolved in anhydrous ethanol (1.5 mL / min, 750 mL) as feed liquid H. The two streams of materials were mixed with O2 gas (1.0 mL / min) through the sixth mixer by using a plunger pump IV and then pumped into the fifth microreactor for Mukaiyama hydration reaction (V5 = 37.5 mL). After being retained for 12.5 min at 35 ° C and 2.0 bar back pressure, the reaction was terminated by mixing with P(OEt)3 (65.52 mM, 0.5 mL / min, 250 mL) dissolved in ethanol in the seventh micromixer. The mixed solution was quenched by mixing with an aqueous solution of sodium chloride (1.0 mL / min) through the eighth mixer and then extracted by an extraction device (t R5-1 =1min), and then passed through the fourth gravity separation column IV (t R5-2 =10min) After stratification, the lower layer (peristaltic pump controls the flow rate: V = 3.5mL / min) containing 8 in dichloroethane / ethanol solution was taken out, which was mixed with N,N-dimethylformamide (0.5mL / min, 250mL) through the ninth mixer and then entered the second concentration device II (Tube-in-tube) for 7 times concentration (V = 0.5mL / min) (setting parameters: temperature T = 100°C; N2 flow rate 70mL / min). Thus, the feed solution I containing product 8 was obtained, with a total retention time of 24.5min.

[0086] (e) 123.12 mM tetrachlorobenzoquinone was dissolved in N,N-dimethylformamide (0.25 mL / min, 125 mL) feed liquid J, and feed liquid I (0.5 mL / min), and the two streams were pumped into the tenth micromixer by a plunger pump V and then into the sixth microreactor for mixing. 6-dehydrogenation reaction (V6 = 3.0 mL), the reaction was terminated after being kept at 140 ° C for 4 minutes, and after being mixed and quenched with 1% NaOH aqueous solution (2.0 mL / min, 1000 mL) in the eleventh micro mixer, it was mixed and extracted with dichloromethane (2.0 mL / min, 1000 mL) and then input (t R6-1 =1min) input into the fifth gravity separation column V(t R6-2 =10min) and then the lower layer was taken out (the flow rate was controlled by a peristaltic pump: V = 2.0mL / min) containing 17α-hydroxy-Δ 1,4,6 -triene-3,20-dione (13) dichloromethane / N,N-dimethylformamide solution (2.0 mL / min) enters the coil (20 mL, for buffer time), the upper layer solution (2.0 mL / min, 1000 mL) is extracted by the extraction device (t R6-3 =1min) after secondary extraction and input into the sixth gravity separation column VI (t R6-4 =10min) after stratification, the lower layer (peristaltic pump controls the flow rate: V = 2.0mL / min) containing DCM solution of 13 (2.0mL / min) is taken out, and the DCM solution of the first extract 13 is mixed with the sodium chloride aqueous solution in the twelfth micro mixer and passed through the extraction device (t R6-5 =1min) and then input into the seventh gravity separation column (t R6-6 =10min) after stratification, the lower layer (peristaltic pump controls the flow rate: V = 4.0mL / min) containing the dichloromethane solution of 13 is taken, which enters the third concentration device III for 8 times concentration (V = 0.5mL / min), the temperature is 70°C, and the N2 flow rate is 75mL / min. The concentrated reaction mixture passes through a stainless steel column II filled with 1:1 Na2SO4 / SiO2 to capture moisture and impurities. At this point, the dichloromethane solution containing the product 13 is obtained as feed solution K, with a total retention time of 105min.

[0087] (f) 4.26 mM p-toluenesulfonic acid / 191.7 mM ethylene glycol / 166.14 mM trimethyl orthoformate was dissolved in dichloromethane (0.5 mL / min, 250 mL), pumped into the thirteenth micro mixer with feed liquid K (0.5 mL / min) and then input into the seventh micro reactor (V7 = 20 mL), and the reaction was terminated after being retained at 90° C. and 4.0 bar back pressure for 20 min. The reaction mixture was subjected to online post-treatment [i.e., the reaction mixture was further quenched with NaHCO3 aqueous solution (2.0 mL / min, 1000 mL) through the fourteenth micro mixer and then extracted. Then, the mixture was passed through the eighth gravity separation column VIII (t R7-2 =10min) and then the lower layer was taken out (the flow rate was controlled by a peristaltic pump: V = 1.0mL / min) containing 17α-hydroxy-Δ 1,4,6-triene-3-one-20-ketal (7) in dichloromethane solution, which is mixed with DMF through the fifteenth mixer and enters the fourth concentration device IV for concentration 3 times (V = 0.5 mL / min, temperature T = 45 ° C; N2 flow rate F = 35 mL / min). The concentrated reaction mixture passes through a stainless steel column III filled with 1:1 Na2SO4 / SiO2 to capture moisture and impurities. At this point, a dichloromethane / N,N-dimethylformamide mixed solution containing product 7 is obtained as feed solution M, with a total retention time of 52 min.

[0088] (g) Under nitrogen conditions, 98 mM trimethyl sulfoxide iodide and 91.1 mM sodium methoxide were dissolved in N,N-dimethylformamide (0.5 mL / min, 250 mL) and reacted in advance at room temperature in an autoclave for 1 h. The obtained mixed solution was used as feed liquid N and entered the 16th micro mixer at a flow rate of 0.5 mL / min) to mix with feed liquid M. The mixed reaction materials entered the 8th micro reactor for C1, C2 cyclopropanation reaction (V8 = 10 mL). After the reaction was completed at 100° C. for 10 min, they entered the 17th micro mixer for extraction with NaCl aqueous solution (1.0 mL / min, 500 mL) and dichloromethane (2.0 mL / min, 1000 mL) and then entered the 9th gravity separation column IX (t R8-2 =10min) After separation, the lower layer (peristaltic pump controls the flow rate: V = 2.5mL / min) is taken out and the DCM solution containing 6 is put into Coil (10mL, used for buffering). The upper layer is extracted with dichloromethane (1.5mL / min, 750mL) for the second time and then input into the tenth gravity separation column X (t R8-4 =3min) and then the lower layer (peristaltic pump controls the flow rate: V = 1.5mL / min) containing DCM solution of 6 was taken out. The two streams of DCM solution containing 6 entered the fifth concentration device V and were concentrated 8 times (V = 0.5mL / min, temperature T = 75°C; N2 flow rate F = 70mL / min). At this point, a dichloromethane / N,N-dimethylformamide solution containing product 6 was obtained as feed solution O, with a total retention time of 46min.

[0089] (h) 94.9 mM m-CPBA was dissolved in dichloromethane (0.5 mL / min, 250 mL) and mixed with feed liquid O (0.5 mL / min) by plunger pump VI in the 18th micro mixer and then entered into the 9th micro reactor (V9 = 10 mL). The mixture was kept at 110 ° C. and 6.0 bar back pressure for 20 min and then reacted to achieve C6, C7 epoxidation reaction. The mixed solution was mixed with Na2S2O3 aqueous solution (1.0 mL / min, 500 mL) in the 19th micro mixer to quench the deoxybenzoic acid. The reaction mixture was further mixed with 1% NaOH aqueous solution (1.0 mL / min, 500 mL) in the 20th micro mixer to quench the remaining m-chloroperbenzoic acid and then extracted (t R9-1 =1min). Continue to pass through the eleventh gravity separation column XI (t R9-2 =10min) and then the lower layer was taken out (the flow rate was controlled by a peristaltic pump: V = 4.0mL / min) containing 17α-hydroxy-6α,7α-epoxy-1α,2α-cyclopropane-Δ 4 -ene-3-one-20-ketal (14) in dichloromethane solution, the upper layer was extracted with dichloromethane (2.0 mL / min, 1000 mL) and then input into the twelfth gravity separation column XII (t R9-4 =2min) after stratification, the lower layer (peristaltic pump controls the flow rate: V=2.0mL / min) is taken out of the dichloromethane solution containing 14. The two dichloromethane solutions containing 14 enter the sixth concentration device VI and are concentrated 6 times, with V=1.0mL / min, temperature T=60°C, and N2 flow rate F=60mL / min. At this point, a dichloromethane solution containing product 14 is obtained as feed solution Q, with a total retention time of 35min.

[0090] (i) 177.13 mM N,N-dimethylacetamide hydrochloride was dissolved in N,N-dimethylformamide (0.5 mL / min, 1000 mL) as feed liquid R, and the two streams of feed liquid Q were pumped into the twenty-first micro mixer by plunger pump VII for mixing, and then entered the tenth micro reactor for C6, C7 epoxy ring opening / C6 chlorination / dehydration / deprotection cascade reaction. The reaction was terminated after being retained for 35 min under the conditions of 180° C. and 16.0 bar back pressure. The mixture was extracted with 1% NaOH aqueous solution (1.0 mL / min, 500 mL) and dichloromethane (2.0 mL / min, 1000 mL) by the twenty-second mixer, and then entered the thirteenth gravity separation column XIII (t R10-2 =10min) and then the lower layer was taken out (the flow rate was controlled by a peristaltic pump: V = 3.0mL / min) containing 17α-hydroxy-1α,2α-cyclopropyl-6-chloro-Δ 4,6-diene-3,20-one (5) in a dichloromethane / N,N-dimethylformamide mixed solution, the upper layer was extracted with dichloromethane (2.0 mL / min, 1000 mL) and then input into the fourteenth gravity separation column XIV (t R10-4 =3min) after stratification, the lower layer was taken (peristaltic pump controlled flow rate: V = 2.0mL / min) of dichloromethane solution containing 5. The two dichloromethane solutions containing 5 were mixed with the sodium chloride aqueous solution in the 23rd micro mixer and then input into the 15th gravity separation column XV (t R10-6 =10min) After stratification, the lower layer (peristaltic pump controls the flow rate: V=5.0mL / min) containing the dichloromethane solution of 5 was taken out, which entered the seventh concentration device VII and concentrated 10 times (setting parameters: V=0.5mL / min, temperature T=100°C, N2 flow rate F=90mL / min. The concentrated reaction mixture was passed through a stainless steel column IV filled with 1:1 Na2SO4 / SiO2 to capture moisture and impurities. At this point, a dichloromethane solution containing the product 5 was obtained as the feed liquid S, with a total retention time of 102min.

[0091] (j) 1.5 mL / min isopropenyl acetate (750 mL) and feed liquid S (0.5 mL / min) were pumped into the twenty-fourth micro mixer by plunger pump VIII for mixing and then passed into the eleventh micro reactor XI (V11 = 30 mL) containing 3.5 g Amberlyst 15. The reaction was terminated after being kept at 40° C. for 15 min. The mixture was quenched with saturated NaHCO3 aqueous solution (1.0 mL / min, 500 mL) through the twenty-fifth micro mixer and then passed through the sixteenth gravity separation column XVI (t R11-2 =10min) after stratification, the lower layer (peristaltic pump controls the flow rate: V=2.0mL / min) containing 4 in dichloromethane / isopropyl acetate solution was taken out, with a total retention time of 27min.

[0092] Example 2

[0093] (a) 4-androstane-3,17-dione (600 mM) and methyl blue (60 mM, 0.1 equiv.) were dissolved in N,N-dimethylformamide (50 mL, 0.1 mL / min) as feed A, and 50.0 mg / mL ReM2 enzyme catalyst was dispersed in Tri-HCl buffer (450 mL, 50 mM, pH 8.0, 0.9 mL / min) as feed B. The two streams were mixed with O2 gas (0.6 mL / min) in the first micromixer by a plunger pump I and then introduced into the first dynamic tubular reactor and the second microreactor (V1 = 30 mL). The reaction was completed at 40°C within a retention time of 10 min, and the mixture was separated by an online gravity separation column I (retention time t R1-2=10min) after stratification, the lower dichloroethane layer was taken (peristaltic pump controlled flow rate: V = 2mL / min), and it was concentrated into the first concentration device I together with dichloroethane / hexamethylphosphoric acid triamide (9:1, 0.5mL / min) by 5 times (V = 0.5mL / min, temperature T = 90°C, N2 flow rate 60mL / min). The concentrated reaction mixture was passed through a 1:1 Na2SO4 / SiO2 filled stainless steel column I (retention time t R1-4 =40min) to capture moisture and impurities, and obtain a dichloroethane solution containing product 10 as feed liquid C, with a total retention time of 82min.

[0094] (b) 0.5M ethynylmagnesium bromide (157.68mM, 0.5mL / min, 250mL) was dissolved in tetrahydrofuran, and the two streams of materials were pumped into the second micromixer by plunger pump II to mix with liquid C, and then entered the third microreactor (V3 = 10mL). The reaction was completed at 50°C after a retention time of 10min to generate a dichloroethane / THF reaction mixture containing Δ1,4-diene-3-one propargyl alcohol (12). After being mixed and quenched with a hydrogen chloride aqueous solution (0.3M, 1.0mL / min) in the third micromixer, the mixture was extracted by an extraction device, and then passed through an online second gravity separation column II (t R3-2 =10min) after stratification, take the lower layer of dichloroethane (peristaltic pump controls the flow rate: V=1.0mL / min) to obtain the lower layer of dichloroethane solution containing product 12 as feed liquid E, with a total retention time of 21min.

[0095] (c) MeSO3H·P2O5 (172.4 mM, 0.5 mL / min, 250 mL) was dissolved in dichloroethane as feed liquid F, and the two streams of materials were pumped into the fourth micro mixer by plunger pump III for mixing, and then entered the fourth micro reactor (V4 = 37.5 mL), and retained for 25 min at 80 ° C and 5.0 bar back pressure conditions for Rupe rearrangement reaction. The reaction liquid was mixed with NaHCO3 aqueous solution in the fifth mixer for quenching (2.0 mL / min) and then entered the extraction device (t R4-1 =1min) extraction, and then passed through the third gravity separation column (t R4-2 =10min) after stratification, the lower dichloroethane layer was taken out (the flow rate was controlled by a peristaltic pump: V=1.5mL / min) to obtain a dichloroethane solution containing product 9 as feed liquid G, with a total retention time of 36min.

[0096] (d) 1.97 mM Co(acac)2 and 43.68 mM PhSiH3 were dissolved in anhydrous ethanol (1.5 mL / min, 750 mL) as feed liquid H. The two streams of materials were mixed with O2 gas (1.0 mL / min) through the sixth mixer by using a plunger pump IV and then pumped into the fifth microreactor for Mukaiyama hydration reaction (V5 = 37.5 mL). After being retained for 15 min at 35°C and 2.0 bar back pressure, the reaction was terminated by mixing with P(OEt)3 (65.52 mM, 0.5 mL / min, 250 mL) dissolved in ethanol in the seventh micromixer. The mixed solution was quenched by mixing with an aqueous solution of sodium chloride (1.0 mL / min) through the eighth mixer and then extracted by an extraction device (t R5-1 =1min), and then passed through the fourth gravity separation column IV (t R5-2 =10min) after stratification (peristaltic pump controls flow rate: V = 3.5mL / min) the lower layer of dichloroethane / ethanol solution containing 8 was taken out, and it was mixed with N,N-dimethylformamide (0.5mL / min, 250mL) through the ninth mixer and then entered the second concentration device II (Tube-in-tube) for 7 times concentration (V = 0.5mL / min) (setting parameters: temperature T = 100°C; N2 flow rate 70mL / min). Thus, the feed solution I containing product 8 was obtained, with a total retention time of 27min.

[0097] (e) 123.12 mM tetrachlorobenzoquinone was dissolved in N,N-dimethylformamide (0.25 mL / min, 125 mL) feed liquid J, and feed liquid I (0.5 mL / min), and the two streams were pumped into the tenth micromixer by a plunger pump V and then into the sixth microreactor for mixing. 6 -dehydrogenation reaction (V6 = 3.0 mL), the reaction was terminated after being kept at 120 ° C for 15 min, and after being mixed and quenched with 1% NaOH aqueous solution (2.0 mL / min, 1000 mL) in the eleventh micro mixer, it was mixed and extracted with dichloromethane (2.0 mL / min, 1000 mL) and then input (t R6-1 =1min) input into the fifth gravity separation column V(t R6-2 =10min) and then the lower layer was taken out (the flow rate was controlled by a peristaltic pump: V = 2.0mL / min) containing 17α-hydroxy-Δ 1,4,6 -triene-3,20-dione (13) dichloromethane / N,N-dimethylformamide solution (2.0 mL / min) enters the coil (20 mL, for buffer time), the upper layer solution (2.0 mL / min, 1000 mL) is extracted by the extraction device (t R6-3 =1min) after secondary extraction and input into the sixth gravity separation column VI (t R6-4=10min) after stratification, the lower layer (peristaltic pump controls the flow rate: V = 2.0mL / min) containing DCM solution of 13 (2.0mL / min) is taken out, and the DCM solution of the first extract 13 is mixed with the sodium chloride aqueous solution in the twelfth micro mixer and passed through the extraction device (t R6-5 =1min) and then input into the seventh gravity separation column (t R6-6 =10min) after stratification, the lower layer (peristaltic pump controls the flow rate: V = 4.0mL / min) containing the dichloromethane solution of 13 is taken, which enters the third concentration device III for 8 times concentration (V = 0.5mL / min), the temperature is 70°C, and the N2 flow rate is 75mL / min. The concentrated reaction mixture passes through a stainless steel column II filled with 1:1 Na2SO4 / SiO2 to capture moisture and impurities. At this point, a dichloromethane solution containing the product 13 is obtained as feed solution K, with a total retention time of 116min.

[0098] (f) 4.26 mM p-toluenesulfonic acid / 191.7 mM ethylene glycol / 166.14 mM trimethyl orthoformate was dissolved in dichloromethane (0.5 mL / min, 250 mL), pumped into the thirteenth micro mixer with feed liquid K (0.5 mL / min) and then input into the seventh micro reactor (V7 = 20 mL), and the reaction was terminated after being retained at 90°C and 6.0 bar back pressure for 10 min. The mixture was quenched with NaHCO3 aqueous solution (2.0 mL / min, 1000 mL) and then extracted. Then, the mixture was passed through the eighth gravity separation column VIII (t R7-2 =10min) and then the lower layer was taken out (the flow rate was controlled by a peristaltic pump: V = 1.0mL / min) containing 17α-hydroxy-Δ 1,4,6 -triene-3-one-20-ketal (7) in dichloromethane solution, which is mixed with DMF through the fifteenth mixer and enters the fourth concentration device IV for concentration 3 times (V=0.5mL / min, temperature T=45°C; N2 flow rate F=35mL / min). The concentrated reaction mixture passes through a stainless steel column III filled with 1:1 Na2SO4 / SiO2 to capture moisture and impurities. At this point, a dichloromethane / N,N-dimethylformamide mixed solution containing product 7 is obtained as feed solution M, with a total retention time of 42min.

[0099] (g) Under nitrogen conditions, 98 mM trimethyl sulfoxide iodide and 91.1 mM sodium methoxide were dissolved in N,N-dimethylformamide (0.5 mL / min, 250 mL) and reacted in advance at room temperature in an autoclave for 1 h. The obtained mixed solution was used as feed liquid N and entered the 16th micro mixer at a flow rate of 0.5 mL / min) to mix with feed liquid M. The mixed reaction materials entered the 8th micro reactor for C1, C2 cyclopropanation reaction (V8 = 10 mL). After the reaction was completed at 100° C. for 10 min, they entered the 17th micro mixer for extraction with NaCl aqueous solution (1.0 mL / min, 500 mL) and dichloromethane (2.0 mL / min, 1000 mL) and then entered the 9th gravity separation column IX (t R8-2 =10min) After separation, the lower layer (peristaltic pump controls the flow rate: V = 2.5mL / min) is taken out and the DCM solution containing 6 is put into Coil (10mL, used for buffering). The upper layer is extracted with dichloromethane (1.5mL / min, 750mL) for the second time and then input into the tenth gravity separation column X (t R8-4 =3min) and then the lower layer (peristaltic pump controls the flow rate: V = 1.5mL / min) containing DCM solution of 6 was taken out. The two streams of DCM solution containing 6 entered the fifth concentration device V and were concentrated 8 times (V = 0.5mL / min, temperature T = 75°C; N2 flow rate F = 70mL / min). At this point, a dichloromethane / N,N-dimethylformamide solution containing product 6 was obtained as feed solution O, with a total retention time of 46min.

[0100] (h) 94.9 mM m-chloroperbenzoic acid was dissolved in 1:1 dichloromethane / DMF (0.5 mL / min, 250 mL), and the two streams were mixed in the 18th micro mixer by plunger pump VI and then entered the 9th micro reactor (V9 = 10 mL). The mixture was kept at 110 ° C. and 6.0 bar back pressure for 20 min and then reacted to achieve C6, C7 epoxidation reaction. The mixed solution was mixed with Na2S2O3 aqueous solution (1.0 mL / min, 500 mL) through the 19th micro mixer to quench the deoxybenzoic acid. The reaction mixture was further mixed with 1% NaOH aqueous solution (1.0 mL / min, 500 mL) through the 20th micro mixer to quench the remaining m-chloroperbenzoic acid and then extracted (t R9-1 =1min). Continue to pass through the eleventh gravity separation column XI (t R9-2 =10min) and then the lower layer was taken out (the flow rate was controlled by a peristaltic pump: V = 4.0mL / min) containing 17α-hydroxy-6α,7α-epoxy-1α,2α-cyclopropane-Δ 4 -ene-3-one-20-ketal (14) in dichloromethane solution, the upper layer was extracted with dichloromethane (2.0 mL / min, 1000 mL) and then input into the twelfth gravity separation column XII (tR9-4 =2min) after stratification, the lower layer (peristaltic pump controls the flow rate: V=2.0mL / min) is taken out of the dichloromethane solution containing 14. The two dichloromethane solutions containing 14 enter the sixth concentration device VI and are concentrated 6 times, with V=1.0mL / min, temperature T=60°C, and N2 flow rate F=60mL / min. At this point, a dichloromethane solution containing product 14 is obtained as feed solution Q, with a total retention time of 35min.

[0101] (i) 177.13 mM N,N-dimethylacetamide hydrochloride was dissolved in N,N-dimethylformamide (0.5 mL / min, 1000 mL) as feed liquid R, and the two streams of feed liquid Q were pumped into the twenty-first micro mixer by plunger pump VII for mixing, and then entered the tenth micro reactor for C6, C7 epoxy ring opening / C6 chlorination / dehydration / deprotection cascade reaction. The reaction was terminated after being retained for 35 min under the conditions of 180° C. and 16.0 bar back pressure. The mixture was extracted with 1% NaOH aqueous solution (1.0 mL / min, 500 mL) and dichloromethane (2.0 mL / min, 1000 mL) by the twenty-second mixer, and then entered the thirteenth gravity separation column XIII (t R10-2 =10min) and then the lower layer was taken out (the flow rate was controlled by a peristaltic pump: V = 3.0mL / min) containing 17α-hydroxy-1α,2α-cyclopropyl-6-chloro-Δ 4,6 -diene-3,20-one (5) in a dichloromethane / N,N-dimethylformamide mixed solution, the upper layer was extracted with dichloromethane (2.0 mL / min, 1000 mL) and then input into the fourteenth gravity separation column XIV (t R10-4 =3min) after stratification, the lower layer was taken (peristaltic pump controlled flow rate: V = 2.0mL / min) of dichloromethane solution containing 5. The two dichloromethane solutions containing 5 were mixed with the sodium chloride aqueous solution in the 23rd micro mixer and then input into the 15th gravity separation column XV (t R10-6 =10min) After stratification, the lower layer (peristaltic pump controls the flow rate: V=5.0mL / min) containing the dichloromethane solution of 5 was taken out, which entered the seventh concentration device VII and concentrated 10 times (setting parameters: V=0.5mL / min, temperature T=100°C, N2 flow rate F=90mL / min. The concentrated reaction mixture was passed through a stainless steel column IV filled with 1:1 Na2SO4 / SiO2 to capture moisture and impurities. At this point, a dichloromethane solution containing the product 5 was obtained as the feed liquid S, with a total retention time of 102min.

[0102] (j) 1.5 mL / min isopropenyl acetate (750 mL) and feed liquid S (0.5 mL / min) were pumped into the twenty-fourth micro mixer by plunger pump VIII for mixing, and then introduced into the eleventh micro reactor XI (V11 = 30 mL) containing 3 g Amberlyst15. The reaction was terminated after being kept at 40° C. for 20 min. The mixture was quenched with saturated NaHCO3 aqueous solution (1.0 mL / min, 500 mL) through the twenty-fifth micro mixer and then passed through the sixteenth gravity separation column XVI (t R11-2 =10min) after stratification, take the lower layer (peristaltic pump controls the flow rate: V=2.0mL / min) containing cyproterone acetate 4 in dichloromethane / isopropyl acetate solution, with a total retention time of 32min.

[0103] Example 3

[0104] (a) 4-androstane-3,17-dione (600 mM) and 2,6-dichlorophenol indophenol (60 mM, 0.1 equiv.) were dissolved in N,N-dimethylformamide (50 mL, 0.1 mL / min) as feed A, and 60.0 mg / mL ReM2 enzyme catalyst was dissolved in Tri-HCl buffer (450 mL, 50 mM, pH 8.0, 0.9 mL / min) as feed B. The two streams were mixed with O2 gas (0.6 mL / min) in the first micromixer by a plunger pump I and then introduced into the first dynamic tubular reactor and the second microreactor (V1 = 30 mL). The reaction was completed at 35°C within a retention time of 6 min, and the mixture was separated by an online gravity separation column I (retention time t R1-2 =10min) after stratification, the lower dichloroethane layer was taken (peristaltic pump controlled flow rate: V = 2mL / min), and entered the first concentration device I for concentration 5 times (V = 0.5mL / min, temperature T = 90°C, N2 flow rate 60mL / min). The concentrated reaction mixture was passed through a 1:1 Na2SO4 / SiO2 filled stainless steel column I (retention time t R1-4 =40min) to capture moisture and impurities, and obtain a dichloroethane solution containing product 10 as feed liquid C, with a total retention time of 78min.

[0105] (b) 0.5M ethynylmagnesium bromide (157.68mM, 0.5mL / min, 250mL) was dissolved in tetrahydrofuran, and the two streams of materials were pumped into the second micromixer by plunger pump II to mix with liquid C, and then entered the third microreactor (V3 = 10mL). The reaction was completed at 50°C after a retention time of 10min to generate a dichloroethane / THF reaction mixture containing Δ1,4-diene-3-one propargyl alcohol (12). After being mixed and quenched with a hydrogen chloride aqueous solution (0.3M, 1.0mL / min) in the third micromixer, the mixture was extracted by an extraction device, and then passed through an online second gravity separation column II (tR3-2 =10min) after stratification, take the lower layer of dichloroethane (peristaltic pump controls the flow rate: V=1.0mL / min) to obtain the lower layer of dichloroethane solution containing product 12 as feed liquid E, with a total retention time of 21min.

[0106] (c) Eaton's reagent (172.4 mM, 0.5 mL / min, 250 mL) was dissolved in dichloroethane as feed liquid F, and the two streams of materials were pumped into the fourth micro mixer by plunger pump III for mixing, and then entered the fourth micro reactor (V4 = 37.5 mL), and retained for 30 min at 80 ° C and 6.0 bar back pressure conditions for Rupe rearrangement reaction. The reaction liquid was mixed with NaHCO3 aqueous solution in the fifth mixer for quenching (2.0 mL / min) and then entered the extraction device (t R4-1 =1min) extraction, and then passed through the third gravity separation column (t R4-2 =10min) and after stratification, the lower dichloroethane layer was taken out (the flow rate was controlled by a peristaltic pump: V=1.5mL / min) to obtain a dichloroethane solution containing the product 9 as feed liquid G, with a total retention time of 41min.

[0107] (d) 1.97 mM Co(acac)2 and 43.68 mM PhSiH3 were dissolved in anhydrous ethanol (1.5 mL / min, 750 mL) as feed liquid H. The two streams of materials were mixed with O2 gas (1.0 mL / min) through the sixth mixer by using a plunger pump IV and then pumped into the fifth microreactor for Mukaiyama hydration reaction (V5 = 37.5 mL). After being retained for 15 min at 35°C and 2.0 bar back pressure, the reaction was terminated by mixing with P(OEt)3 (65.52 mM, 0.5 mL / min, 250 mL) dissolved in ethanol in the seventh micromixer. The mixed solution was quenched by mixing with an aqueous solution of sodium chloride (1.0 mL / min) through the eighth mixer and then extracted by an extraction device (t R5-1 =1min), and then passed through the fourth gravity separation column IV (t R5-2 =10min) after stratification (peristaltic pump controls flow rate: V = 3.5mL / min) the lower layer of dichloroethane / ethanol solution containing 8 was taken out, and it was mixed with N,N-dimethylformamide (0.5mL / min, 250mL) through the ninth mixer and then entered the second concentration device II (Tube-in-tube) for 7 times concentration (V = 0.5mL / min) (setting parameters: temperature T = 100°C; N2 flow rate 70mL / min). Thus, the feed solution I containing product 8 was obtained, with a total retention time of 27min.

[0108] (e) 123.12 mM tetrachlorobenzoquinone was dissolved in N,N-dimethylformamide (0.25 mL / min, 125 mL) feed liquid J, and feed liquid I (0.5 mL / min), and the two streams were pumped into the tenth micromixer by a plunger pump V and then into the sixth microreactor for mixing. 6 -dehydrogenation reaction (V6 = 3.0 mL), the reaction was terminated after being kept at 120 ° C for 15 min, and after being mixed and quenched with 1% NaOH aqueous solution (2.0 mL / min, 1000 mL) in the eleventh micro mixer, it was mixed and extracted with dichloromethane (2.0 mL / min, 1000 mL) and then input (t R6-1 =1min) input into the fifth gravity separation column V(t R6-2 =10min) and then the lower layer was taken out (the flow rate was controlled by a peristaltic pump: V = 2.0mL / min) containing 17α-hydroxy-Δ 1,4,6 -triene-3,20-dione (13) dichloromethane / N,N-dimethylformamide solution (2.0 mL / min) enters the coil (20 mL, used for buffering), and the upper layer solution (2.0 mL / min, 1000 mL) is passed through the extraction device (t R6-3 =1min) after secondary extraction and input into the sixth gravity separation column VI (t R6-4 =10min) after stratification, the lower layer (peristaltic pump controls the flow rate: V = 2.0mL / min) containing dichloromethane solution of 13 (2.0mL / min) is taken out, and the dichloromethane solution of the first extract 13 is mixed with the sodium chloride aqueous solution in the twelfth micro mixer and passed through the extraction device (t R6-5 =1min) and then input into the seventh gravity separation column (t R6-6 =10min) after stratification, the lower layer (peristaltic pump controls the flow rate: V = 4.0mL / min) containing the dichloromethane solution of 13 is taken, which enters the third concentration device III for 8 times concentration (V = 0.5mL / min), the temperature is 70°C, and the N2 flow rate is 75mL / min. The concentrated reaction mixture passes through a stainless steel column II filled with 1:1 Na2SO4 / SiO2 to capture moisture and impurities. At this point, a dichloromethane solution containing the product 13 is obtained as feed solution K, with a total retention time of 116min.

[0109] (f) 4.26 mM p-toluenesulfonic acid / 191.7 mM ethylene glycol / 166.14 mM trimethyl orthoformate was dissolved in dichloromethane (0.5 mL / min, 250 mL), pumped into the thirteenth micro mixer with feed liquid K (0.5 mL / min) and then input into the seventh micro reactor (V7 = 20 mL), and the reaction was terminated after being retained at 80°C and 6.0 bar back pressure for 10 min. The mixture was quenched with NaHCO3 aqueous solution (2.0 mL / min, 1000 mL) and then extracted. Then, the mixture was passed through the eighth gravity separation column VIII (tR7-2 =10min) and then the lower layer was taken out (the flow rate was controlled by a peristaltic pump: V = 1.0mL / min) containing 17α-hydroxy-Δ 1,4,6 -triene-3-one-20-ketal (7) in dichloromethane solution, which is mixed with DMF through the fifteenth mixer and enters the fourth concentration device IV for concentration 3 times (V=0.5mL / min, temperature T=45°C; N2 flow rate F=35mL / min). The concentrated reaction mixture passes through a stainless steel column III filled with 1:1 Na2SO4 / SiO2 to capture moisture and impurities. At this point, a dichloromethane / N,N-dimethylformamide mixed solution containing product 7 is obtained as feed solution M, with a total retention time of 42min.

[0110] (g) Under nitrogen conditions, 98 mM trimethyl sulfoxide iodide and 91.1 mM sodium methoxide were dissolved in N,N-dimethylformamide (0.5 mL / min, 250 mL) and reacted in advance at room temperature in an autoclave for 1 h. The obtained mixed solution was used as feed liquid N and entered the 16th micro mixer at a flow rate of 0.5 mL / min) to mix with feed liquid M. The mixed reaction materials entered the 8th micro reactor for C1, C2 cyclopropanation reaction (V8 = 10 mL). After the reaction was completed at 120° C. for 7.5 min, they entered the 17th micro mixer for extraction with NaCl aqueous solution (1.0 mL / min, 500 mL) and dichloromethane (2.0 mL / min, 1000 mL) and then entered the 9th gravity separation column IX (t R8-2 =10min) After separation, the lower layer (peristaltic pump controls the flow rate: V = 2.5mL / min) is taken out and the DCM solution containing 6 is put into Coil (10mL, used for buffering). The upper layer is extracted with dichloromethane (1.5mL / min, 750mL) for the second time and then input into the tenth gravity separation column X (t R8-4 =3min) and then the lower layer (peristaltic pump controls the flow rate: V = 1.5mL / min) containing DCM solution of 6 was taken out. The two streams of DCM solution containing 6 entered the fifth concentration device V and were concentrated 8 times (V = 0.5mL / min, temperature T = 75°C; N2 flow rate F = 70mL / min). At this point, a dichloromethane / N,N-dimethylformamide solution containing product 6 was obtained as feed solution O, with a total retention time of 46min.

[0111] (h) 94.9 mM m-chloroperbenzoic acid was dissolved in 1:1 dichloromethane / DMF (0.5 mL / min, 250 mL), and the two streams were mixed in the 18th micro mixer by plunger pump VI and then entered the 9th micro reactor (V9 = 10 mL). The mixture was kept at 90 ° C. and 4.0 bar back pressure for 10 min and then reacted to achieve C6, C7 epoxidation reaction. The mixed solution was mixed with Na2S2O3 aqueous solution (1.0 mL / min, 500 mL) through the 19th micro mixer to quench the deoxybenzoic acid. The reaction mixture was further mixed with 1% NaOH aqueous solution (1.0 mL / min, 500 mL) through the 20th micro mixer to quench the remaining m-chloroperbenzoic acid and then extracted (t R9-1 =1min). Continue to pass through the eleventh gravity separation column XI (t R9-2 =10min) and then the lower layer was taken out (the flow rate was controlled by a peristaltic pump: V = 4.0mL / min) containing 17α-hydroxy-6α,7α-epoxy-1α,2α-cyclopropane-Δ 4 -ene-3-one-20-ketal (14) in dichloromethane solution, the upper layer was extracted with dichloromethane (2.0 mL / min, 1000 mL) and then input into the twelfth gravity separation column XII (t R9-4 =2min) after stratification, the lower layer (peristaltic pump controls the flow rate: V=2.0mL / min) is taken out of the dichloromethane solution containing 14. The two dichloromethane solutions containing 14 enter the sixth concentration device VI and are concentrated 6 times, with V=1.0mL / min, temperature T=60°C, and N2 flow rate F=60mL / min. At this point, a dichloromethane solution containing product 14 is obtained as feed solution Q, with a total retention time of 25min.

[0112] (i) 177.13 mM N,N-dimethylacetamide hydrochloride was dissolved in N,N-dimethylformamide (0.5 mL / min, 1000 mL) as feed liquid R, and the two streams of feed liquid Q were pumped into the twenty-first micro mixer by plunger pump VII for mixing, and then entered the tenth micro reactor for C6, C7 epoxy ring opening / C6 chlorination / dehydration / deprotection cascade reaction. The reaction was terminated after being retained for 40 min under the conditions of 170° C. and 8.0 bar back pressure. The mixture was extracted with 1% NaOH aqueous solution (1.0 mL / min, 500 mL) and dichloromethane (2.0 mL / min, 1000 mL) by the twenty-second mixer, and then entered the thirteenth gravity separation column XIII (t R10-2 =10min) and then the lower layer was taken out (the flow rate was controlled by a peristaltic pump: V = 3.0mL / min) containing 17α-hydroxy-1α,2α-cyclopropyl-6-chloro-Δ 4,6-diene-3,20-one (5) in a dichloromethane / N,N-dimethylformamide mixed solution, the upper layer was extracted with dichloromethane (2.0 mL / min, 1000 mL) and then input into the fourteenth gravity separation column XIV (t R10-4 =3min) after stratification, the lower layer was taken (peristaltic pump controlled flow rate: V = 2.0mL / min) of dichloromethane solution containing 5. The two dichloromethane solutions containing 5 were mixed with the sodium chloride aqueous solution in the 23rd micro mixer and then input into the 15th gravity separation column XV (t R10-6 =10min) After stratification, the lower layer (peristaltic pump controls the flow rate: V=5.0mL / min) containing dichloromethane solution of 5 was taken out, which entered the seventh concentration device VII and concentrated 10 times (setting parameters: V=0.5mL / min, temperature T=100°C, N2 flow rate F=90mL / min. The concentrated reaction mixture was passed through a stainless steel column IV filled with 1:1Na2SO4 / SiO2 to capture moisture and impurities. At this point, a dichloromethane solution containing product 5 was obtained as feed liquid S, with a total retention time of 107min.

[0113] (j) 1.5 mL / min isopropenyl acetate (750 mL) and feed liquid S (0.5 mL / min) were pumped into the twenty-fourth micro mixer by plunger pump VIII for mixing, and then introduced into the eleventh micro reactor XI (V11 = 30 mL) containing 2.5 g Amberlyst 15. The reaction was terminated after being kept at 40° C. for 25 min. The mixture was quenched with saturated NaHCO 3 aqueous solution (1.0 mL / min, 500 mL) through the twenty-fifth micro mixer and then passed through the sixteenth gravity separation column XVI (t R11-2 =10min) after stratification, take the lower layer (peristaltic pump controls the flow rate: V=2.0mL / min) containing cyproterone acetate 4 in dichloromethane / isopropyl acetate solution, with a total retention time of 37min.

[0114] Cyproterone acetate 4 is a white powder. Melting point: 206.5-207.5℃. 1H NMR (400 MHz, deuterated chloroform) δ 6.20 (d, J = 2.3 Hz, 1H), 6.15 (s, J = 1.0 Hz, 1H), 2.98 (ddd, J = 15.7, 10.9, 1.8 Hz, 1H), 2.37-2.25 (m, 1H), 2.05 (s, 3H), 2.04-1.94 (m, 3H), 1.93 (d, J = 2.9 Hz, 1H), 1.91-1.86 (m, 1H), 1.86-1.82 (m ,1H),1.83-1.76(m,1H),1.71(td,J=7.8,6.4Hz,1H),1.66-1.59(m,1H),1.55(dd,J=12.6,4.0Hz,1H),1. 52-1.37(m,2H),1.27(td,J=9.0,7.9,4.9Hz,1H),1.21(s,3H),0.87(dd,J=6.4,4.5Hz,1H),0.71(s,3H). 13 C NMR (101 MHz, deuterated chloroform) δ 203.8, 198.1, 170.6, 152.3, 136.6, 130.2, 120.4, 96.2, 48.7, 47.7, 47.2, 38.7, 38.3, 31.0, 30.3, 26.4, 26.1, 25.3, 23.2, 22.9, 21.2, 20.8, 14.2, 12.4. Fourier transform infrared spectrometer: nmax = 1740, 1718, 1651, 1370, 1351, 1257, 1245, 962, 898, 584 cm -1 .The charge-to-mass ratio detected by high-resolution mass spectrometry (electrospray ionization mode) was 417.1832, which is consistent with the theoretical molecular formula of cyproterone acetate C 24 H 30 ClO4 and the corresponding theoretical molecular weight is 417.1827. The specific rotation of the product measured at 25℃ and 20℃ are [α] D 25 =144.75 (c = 0.13, chloroform) and [α] D 20 =156.45 (c=1.0, acetone).

[0115] The present invention realizes efficient and rapid synthesis of cyproterone acetate by rationally matching a micro-mixer, a micro-reactor and a post-reaction online processing device according to the synthesis process characteristics of cyproterone acetate. The continuous synthesis of cyproterone acetate is realized by an independently designed solvent switching device, which greatly improves production efficiency, saves the separation and extraction of synthetic intermediates, effectively reduces the generation of three wastes, reduces production costs, and has little pollution to the environment. Based on the innovative concept of the present invention, changes and modifications made to the embodiments, or equivalent structures or equivalent process changes made by the description and drawings of the present invention, directly or indirectly applying the above technical scheme to other related technical fields are all included in the scope of protection of the claims of the present invention.

Claims

1. A fully continuous chemical synthesis method of cyproterone acetate, characterized in that: Starting from androstenedione, 3-sterone-Δ1-dehydrogenase mutant ReM2 was used to catalyze the synthesis of androstenedione into androst-1,4-diene-3,17-dione, which was then acetylated and Rupe rearranged to give Δ 1,4,16 -triene-3,20-dione, continued Δ 6 -dehydrogenation, C20-ketal, to obtain 17α-hydroxy-Δ 1,4,6 -triene-3,20-one (7), followed by cyclopropanation / epoxidation / ring opening / chlorination / dehydration / protection group removal cascade reaction and O-acetylation to obtain cyproterone acetate; specifically, a fully continuous device consisting of a plurality of sequentially connected micro-mixers, micro-reactors, online solvent switching and reagent recovery, and low-boiling point reagent feeding equipment is used to achieve online extraction, online solvent switching, and online solvent concentration. The synthetic route is: The specific steps are as follows: (a) dissolving 4-androstane-3,17-dione (11) and an electron acceptor in an organic solvent as feed liquid A; dispersing an enzyme catalyst in a buffer as feed liquid B; using a first plunger pump I to fully mix feed liquid A and feed liquid B in a first micromixer, and then entering a first dynamic tubular reactor and a second microreactor for Δ 1 -dehydrogenation reaction to generate a reaction liquid containing androsta-1,4-diene-3,17-dione (10), which then enters an extraction device, is extracted with an extraction solvent, and enters an online first gravity separation column I for stratification, and removes the upper layer of bacterial cell crushing liquid and part of the electron acceptor to obtain a lower layer of extraction solvent solution containing androsta-1,4-diene-3,17-dione (10); the solution enters an online solvent first concentration device I for concentration, and the obtained concentrated solution passes through a stainless steel column I filled with 1:1 Na2SO4 / SiO2 to capture water and impurities; thus, an extraction solvent solution containing the product (10) is obtained as feed liquid C; (b) dissolving the reagent ethynyl magnesium bromide in an organic solvent as feed liquid D, and pumping it into a second micro mixer with feed liquid C by a second plunger pump II to be fully mixed, and the mixed reaction materials enter a third channel micro reactor for ethynylation reaction to generate a mixture containing Δ 1,4 -diene-3-one propargyl alcohol (12) extraction solvent / organic solvent reaction mixture; the mixture is mixed with HCl aqueous solution in a third micro mixer to be quenched, extracted by an extraction device, and then enters an online second gravity separation column II for stratification to obtain a lower layer of extraction solvent solution containing the product (12) as feed liquid E; (c) The acidic reagent is dissolved in dichloroethane as feed liquid F, which is pumped into the fourth micro mixer with feed liquid E by the third plunger pump III for thorough mixing. The mixed reaction materials enter the fourth micro reactor for Rupe rearrangement reaction to generate a Δ 1,4,16 -triene-3,20-one (9) and dichloroethane reaction mixture; the mixture is mixed with NaHCO3 aqueous solution in a fifth mixer to be quenched, extracted by an extraction device, and then enters an online third gravity separation column III for stratification to obtain a dichloroethane solution containing product 9 in the lower layer as feed liquid G; (d) The catalyst and PhSiH3 are dissolved in an organic solvent as feed liquid H, which is pumped into the sixth mixer through the fourth plunger pump IV to mix with feed liquid G and oxygen (stored in an oxygen tank and the flow rate is adjusted by a flap-type bottle valve and a gas flow meter) and the mixed reaction materials enter the fifth microreactor for Mukaiyama hydration reaction, and continue to pass through the seventh micromixer to mix with P(OEt)3 dissolved in ethanol to complete the reaction, thereby generating a 17α-hydroxy-Δ 1,4 -diene-3,20-dione (8) in dichloroethane / ethanol reaction mixture; the mixture is mixed with sodium chloride aqueous solution in an eighth mixer to be quenched, then extracted in an extraction device, and then enters an online fourth gravity separation column IV for stratification to obtain a lower layer of dichloroethane / ethanol solution containing product (8), the solution is mixed with N,N-dimethylformamide solution in a ninth mixer and then enters an online second solvent concentrator II for concentration, so that an N,N-dimethylformamide solution containing product (8) is obtained as feed liquid I; (e) Dissolving chloranil in an organic solvent as feed liquid J is pumped into the tenth micromixer together with feed liquid I by a fifth plunger pump V for mixing, and the mixed reaction materials enter the sixth microreactor for Δ 6 -dehydrogenation reaction, the mixed solution is mixed with 1% NaOH aqueous solution in the eleventh micro mixer for quenching, and the mixed solution is extracted with dichloromethane (or dichloromethane) and then enters the online fifth gravity separation column V for stratification to obtain the lower layer containing 17α-hydroxy-Δ 1,4,6 -triene-3,20-dione (13) in dichloromethane / N,N-dimethylformamide mixed solution, the upper layer solution and dichloromethane are extracted twice and then enter the sixth online gravity separation column VI for stratification to obtain a lower layer of dichloromethane solution containing the product (13); the two streams of dichloromethane solution containing the product (13) are mixed with sodium chloride aqueous solution in the twelfth micro mixer and then enter the seventh online gravity separation column VII for stratification to obtain a lower layer of dichloromethane solution containing the product (13), the solution enters the third concentration device III for concentration, and the concentrated reaction mixture passes through a second stainless steel column II filled with 1:1 Na2SO4 / SiO2 to capture moisture and impurities; thus, a dichloromethane solution containing the product (13) is obtained as feed liquid K; (f) The catalyst / ethylene glycol / water absorbent is dissolved in dichloromethane as feed liquid L, and mixed with feed liquid K in the thirteenth micro mixer. The mixed reaction materials enter the seventh micro reactor for ketal protection reaction. The mixed liquid is mixed with NaHCO3 aqueous solution in the fourteenth micro mixer and quenched, and then enters the eighth online gravity separation column VIII for separation to obtain the lower layer containing 17α-hydroxy-Δ 1,4,6 -triene-3-one-20-ketal (7) in dichloromethane solution, the solution is mixed with N,N-dimethylformamide solution through a fifteenth mixer and then enters into an online solvent fourth concentration device IV for concentration, the concentrated reaction mixture passes through a third stainless steel column III filled with 1:1 Na2SO4 / SiO2 to capture moisture and impurities; thus, a dichloromethane / N,N-dimethylformamide mixed solution containing product (7) is obtained as feed liquid M; (g) Under nitrogen conditions, trimethyl sulfoxide iodide (TMSOI) and alkali are dissolved in N,N-dimethylformamide, and the mixed solution obtained after the reaction at room temperature for 0.6-1.2 hours is used as feed liquid N, and is mixed with feed liquid M in the sixteenth micro mixer. The mixed reaction materials enter the eighth micro reactor for C1, C2 cyclopropanation reaction. The mixed solution is mixed with sodium chloride aqueous solution in the seventeenth micro mixer to quench, and the mixed solution is extracted with an extraction solvent (such as dichloromethane) and then enters the online ninth gravity separation column IX for stratification to obtain a lower layer containing 17α-hydroxy-1α,2α-cyclopropane-Δ 4,6 -diene-3-one-20-ketal (6) in dichloromethane / N,N-dimethylformamide mixed solution, the upper layer solution and the extraction solvent are subjected to secondary extraction and then enter the online tenth gravity separation column X for separation to obtain the lower layer extraction solvent / N,N-dimethylformamide solution containing the product (6); the two extraction solvent solutions containing the product (6) enter the fifth concentration device V for concentration to obtain the extraction solvent / N,N-dimethylformamide solution containing the product (6) as the feed liquid O; (h) The oxidant is dissolved in dichloromethane as feed liquid P, and is pumped into the 18th micro mixer with the feed liquid O by the 6th plunger pump VI to mix, and the mixed reaction materials enter the 9th micro reactor for C6, C7 epoxidation reaction, and the mixed liquid is mixed with Na2S2O3 aqueous solution through the 19th micro mixer to quench the deoxybenzoic acid, and the reaction mixture is further mixed with 1% NaOH aqueous solution through the 20th micro mixer to quench the remaining oxidant, and then enters the 11th online gravity separation column XI for stratification to obtain the lower layer containing 17α-hydroxy-6α,7α-epoxy-1α,2α-cyclopropyl-Δ 4 -ene-3-one-20-ketal (14) in dichloromethane solution, the upper layer solution and dichloromethane are extracted twice and then enter the twelfth gravity separation column XII for stratification to obtain a lower layer of dichloromethane solution containing the product (14); the two dichloromethane solutions containing the product (14) enter the sixth concentration device VI for concentration; thus, a dichloromethane solution containing the product (14) is obtained as feed liquid Q; (i) N,N-dimethylacetamide hydrochloride (DMA·HCl) is dissolved in N,N-dimethylformamide as feed liquid R, and is pumped into the twenty-first micro-mixer with feed liquid Q by the seventh plunger pump VII for mixing. The mixed reaction materials enter the tenth micro-reactor for C6, C7 epoxy ring-opening / C6 chlorination / dehydration / deprotection cascade reaction. The mixed liquid is mixed with 1% NaOH aqueous solution in the twenty-second mixer for quenching. The mixed liquid is extracted with dichloromethane and then enters the thirteenth online gravity separation column XIII for separation to obtain a lower layer containing 17α-hydroxy-1α,2α-cyclopropane-6-chloro-Δ 4,6 -diene-3,20-one (5) in dichloromethane / N,N-dimethylformamide mixed solution, the upper layer solution and dichloromethane are extracted twice and then enter the online fourteenth gravity separation column XIV for stratification to obtain the lower layer dichloromethane / N,N-dimethylformamide mixed solution containing the product (5); the two streams of dichloromethane / N,N-dimethylformamide mixed solution containing the product (5) are mixed with sodium chloride aqueous solution in the twenty-third micro mixer and then enter the fifteenth gravity separation column XV for stratification to obtain the lower layer dichloromethane solution containing the product (5), the solution enters the seventh concentration device VII for concentration, and the concentrated reaction mixture passes through a fourth stainless steel column IV filled with 1:1 Na2SO4 / SiO2 to capture moisture and impurities; thus, the dichloromethane solution containing the product (5) is obtained as the feed liquid S; (j) The acetylation reagent is used as the feed liquid T, and is pumped into the twenty-fourth micro-mixer with the feed liquid S by the eighth plunger pump VIII to mix, and the mixed reaction materials enter the eleventh micro-reactor for acetylation reaction. After the mixed liquid is mixed with the NaHCO3 aqueous solution in the twenty-fifth micro-mixer for quenching, the reaction mixture enters the online sixteenth gravity separation column XVI for stratification to obtain the upper layer of the dichloromethane / isopropyl acetate mixed solution containing cyproterone acetate (4), and after chromatographic separation, the pure cyproterone acetate (4) is obtained.

2. The cyproterone acetate fully continuous chemical synthesis method according to claim 1, characterized in that: In step (a): Controlling the flow rate ratio of the mixed solution of the electron acceptor, 4-androstane-3,17-dione (11) and the enzyme catalyst to the first dynamic tubular reactor and the second microreactor so that the molar ratio of the electron acceptor, 4-androstane-3,17-dione (11) and the enzyme catalyst is (0.1-0.3):1:(1.0-5.0); The electron acceptor is selected from any one of phenazine methyl sulfate, 2,6-dichlorophenol indophenol, resazurin, Worcester blue, methylene blue, coenzyme Q, vitamin K and menadione; The enzyme catalyst is 3-sterone-Δ 1 -Dehydrogenase (Δ 1 -KstDs) and any of its mutants; The organic solvent is any one of dichloromethane, 1,2-dichloroethane, methanol, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran and 1,4-dioxane; The buffer is any one of a phosphate buffer, a glycine-sodium hydroxide buffer, a Tris-hydrochloric acid buffer, a phthalic acid-hydrochloric acid buffer and a glycine-hydrochloric acid buffer; The extraction solvent is dichloromethane or dichloroethane; The temperature in the first dynamic tubular reactor and the second microchannel reactor is controlled to be 20-45°C; the residence time of the mixed reaction materials in the first dynamic tubular reactor is 30-120 minutes; and the residence time in the second microchannel reactor is 22-90 minutes; The continuous quenching and extraction are completed in an extraction device with a residence time of 1-5 minutes; Liquid-liquid separation is completed in the first gravity separation column I with a residence time of 3-20 minutes; solvent switching, solvent concentration and solvent recovery are completed in the first concentration device I with a residence time of 1-10 minutes.

3. The cyproterone acetate fully continuous chemical synthesis method according to claim 2, characterized in that: In step (b): The molar concentration of the reagent ethynylmagnesium bromide is 100-300mmol / L; The organic solvent is selected from any one or two of tetrahydrofuran, N,N-dimethylacetamide, dimethyl sulfoxide, and hexamethylphosphoramide; The temperature in the third microchannel reactor is controlled within the range of 20-45°C; the residence time of the mixed reaction materials in the third microchannel reactor is 30-120 minutes; In step (c): The molar concentration of the acidic reagent is 50-200mmol / L; The acidic reagent is selected from any one of concentrated sulfuric acid, trifluoromethanesulfonic acid, Eaton's reagent, methanesulfonic acid, Amberlyst 15 acidic resin, p-toluenesulfonic acid, aluminum chloride and acetic acid; The temperature in the fourth microreactor is controlled within the range of 60-100° C.; the molar concentration of the acidic reagent is 1.5-3 equivalents of the molar concentration of compound 9; and the residence time of the mixed reaction materials in the third microreactor is 20-30 minutes.

4. The method for the fully continuous chemical synthesis of cyproterone acetate according to claim 3, characterized in that: In step (d): The molar concentration of the catalyst is 1-3 mol%; The catalyst is selected from one of Mn(dpm)3, Co(acac)2, Fe(dpm)3, Fe(acac)3, Fe(acac)2, Co(acac)3, Cobalt acetate, Cobalt(II)bromide, Cobalt chloride and Cobalt iso-octoate; The organic solvent is any one or two of dichloromethane, 1,2-dichloroethane, methanol, ethanol, and tetrahydrofuran; The temperature in the fifth microreactor is controlled within the range of 25-35°C; the residence time of the mixed reaction materials in the fifth microreactor is 10-15 minutes; In step (e): The organic solvent is selected from one of dichloromethane, 1,2-dichloroethane, N,N-dimethylacetamide, dimethyl sulfoxide, dioxane and tert-butyl alcohol; The temperature in the sixth microreactor is controlled within the range of 100-140° C.; the residence time of the mixed reaction materials in the sixth microreactor is 4-15 minutes; In step (f): The water absorbent is selected from one of silica gel, molecular sieve, anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium chloride, and trimethyl orthoformate (TMOF); The catalyst is selected from one of concentrated sulfuric acid, p-toluenesulfonic acid, BF3·Et2O, TiCl4, Bi(NO3)3, LiBF4, Cu(BF4)2, RuCl3·H2O, CoCl2, InCl3, In(OTf)3, ZrCl4 and Zn(BF4)2; The temperature in the seventh microreactor is controlled within the range of 40-100° C.; the residence time of the mixed reaction materials in the seventh microreactor is 15-20 minutes.

5. The method for the fully continuous chemical synthesis of cyproterone acetate according to claim 4, characterized in that: In step (g): The base is selected from LiHMDS, NODX, t One of BuOK, LDA, MeONa and NaH; The temperature in the eighth microreactor is controlled within the range of 25-40° C.; the residence time of the mixed reaction materials in the eighth microreactor is 15-20 minutes; The molar concentration of trimethyl sulfoxide iodide is 2-3 equivalents of material 7, and the molar concentration of the alkali is 1.5-3.0 equivalents of material 7; In step (h): The oxidant is selected from any one of peroxyformic acid, peracetic acid, peroxybenzoic acid, meta-chloroperbenzoic acid, peroxytrifluoroacetic acid and hydrogen peroxide; The temperature in the ninth microreactor is controlled within the range of 25-120° C.; the residence time of the mixed reaction materials in the ninth microreactor is 10-20 minutes; In step (i): The steroid C6, C7 epoxy ring opening, C6 chlorination, dehydration and deprotection cascade reaction are achieved in one pot in the same system; The temperature in the tenth microreactor is controlled within the range of 80-180° C.; the residence time of the mixed reaction materials in the tenth microreactor is 20-40 minutes; In step (j): The acetylating agent is selected from any one of acetic acid, acetic anhydride, acetyl chloride, trifluoroacetic anhydride and isopropenyl acetate; The acid catalyst is selected from any one of concentrated sulfuric acid, trifluoromethanesulfonic acid, methanesulfonic acid, Amberlyst 15 acid resin, p-toluenesulfonic acid and acetic acid.

6. The method for the fully continuous chemical synthesis of cyproterone acetate according to any one of claims 1 to 5, characterized in that: All micromixers are selected from any one of a T-type micromixer, a Y-type micromixer, a cross-type mixer, a coaxial flow micromixer and a flow focusing micromixer; All microchannel reactors are tubular microchannel reactors or plate microchannel reactors; All concentrators use tube-in-tube concentrators; All gravity separation columns use glass tube gravity liquid-liquid separation devices.

7. The method for the fully continuous chemical synthesis of cyproterone acetate according to any one of claims 1 to 5, characterized in that: Using 3-sterone Δ 1 -Dehydrogenase mutant ReM2 enzyme or other 3-sterol Δ 1 -Dehydrogenase realizes continuous flow enzyme catalysis of steroid Δ 1 -dehydrogenation reaction; and the dynamic tubular reactor and polytetrafluoroethylene reactor are used to realize the continuous flow ReM2 biocatalytic substrate Δ 1 -Dehydrogenation to synthesize androst-1,4-diene-3,17-dione, solving the problem of steroid substrate blocking the pipeline.

8. The method for the fully continuous chemical synthesis of cyproterone acetate according to any one of claims 1 to 5, characterized in that: The concentrating device is composed of a feed liquid container or reactor, a solvent storage tank, a recovery tank, a nitrogen tank, a concentrating tube, a peristaltic pump, a hose, a T-type connector and a mass flow meter (MFC); two feed liquid tanks are connected by a T-type connector; the peristaltic pump pumps the feed liquid into a polytetrafluoroethylene coil for mixing, and then enters the concentrating tube through the T-type connector together with N2 for heating and blowing and concentration. After the volatilized solvent in the concentrating tube enters the condenser, the condensate enters the recovery tank to recover the evaporated solvent. After the feed liquid reaches the concentration multiple, the peristaltic pump transfers the feed liquid to the next operation stage.

9. The method for the fully continuous chemical synthesis of cyproterone acetate according to any one of claims 1 to 5, characterized in that: The first back-pressure valve and the second back-pressure valve are made of stainless steel or Hastelloy, the size of the connecting pipeline is 1.6mm-20mm, and the pressure condition range is 0.1-2.0MPa.

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