A fully continuous flow production method for (+)-biotin

Abstract

The present invention discloses a fully continuous flow preparation method for (+)-biotin. The method comprises: performing an asymmetric ring-opening reaction on a cyclic anhydride and a biphenyl chiral propylene glycol, performing a selective reduction reaction on the product with a borohydride, and then performing a cyclization reaction with an inorganic mineral acid to obtain (3a S ,6a R ) lactone; (3a S ,6a R ) The lactone undergoes a thiolation reaction with a thio reagent, the product then undergoes a Fukuyama coupling reaction with a zinc reagent in the presence of a palladium catalyst, the product undergoes an elimination reaction in the presence of an inorganic mineral acid to obtain an alkenyl valerate compound; the alkenyl valerate compound is reduced in the presence of a palladium / carbon catalyst to obtain a valerate ester; a hydrolysis reaction is performed to obtain a valerate salt; and the valerate salt undergoes a debenzylation reaction in the presence of an inorganic mineral acid. The process of the present invention is carried out continuously, the total time is greatly shortened, the total yield is increased to 48.7%, the degree of automation is high, the time-space yield is high, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of fine chemicals, and particularly relates to a fully continuous flow manufacturing method for (+)-biotin. Background Art

[0002] The structure of (+)-biotin (also known as vitamin H or coenzyme R) is shown in formula (1)

[0003]

[0004] Chemically known as (3aS,4S,6aR)-hexahydro-2-oxo-1H-thieno[3,4-d]imidazole-4-n-pentanoic acid, (+)-biotin is a water-soluble B vitamin primarily involved in the metabolism of carbohydrates, lipids, proteins, and nucleic acids. Deficiency symptoms in humans include dermatitis, nausea, vomiting, depression, and weight loss; in animals, deficiency symptoms include dandruff, ulcers, low littering rates, high embryonic mortality, and, in severe cases, even death. Supplementation with appropriate amounts of (+)-biotin can alleviate or eliminate these symptoms, leading to its widespread use in medicine, food additives, and feed additives.

[0005] (+)-biotin has a long synthetic route and many steps. Existing preparation methods are all traditional batch reactor methods, i.e., multi-step batch reactor synthesis. Multiple building-up reactions from starting materials to the target product are progressively carried out. After the single-step reaction is completed in the batch reactor, the corresponding separation and purification steps are carried out. The resulting intermediate is then subjected to the next step reaction in the batch reactor, followed by corresponding separation, purification, and other operations, and this process is repeated until the target product (+)-biotin is obtained. Each reaction, including its corresponding separation, purification, and other post-processing, is carried out independently in each step, resulting in problems such as large process losses, low yields, complex operations, low process efficiency, low degree of automation, many operators, and high labor intensity. In addition, limitations such as the molecular mixing performance and poor heat and mass transfer of traditional batch reactors themselves can also cause outstanding problems such as long batch reactor synthesis reaction times, large safety hazards, high material consumption (i.e., high unit consumption), and high energy consumption. Therefore, based on the problems existing in the existing preparation methods, it is an urgent problem for technical personnel in this field to develop a continuous preparation method with short reaction time, low energy consumption, low material consumption, high process efficiency and inherent safety. Summary of the Invention

[0006] The present invention aims to overcome the deficiencies of the prior art and to provide a fully continuous flow method for producing (+)-biotin. The method greatly shortens the total preparation time, significantly improves the degree of automation and time-space efficiency of the process, greatly increases the total yield of the target product, significantly reduces material and energy consumption, greatly improves safety, and facilitates industrial application.

[0007] The present invention provides a fully continuous flow method for producing (+)-biotin (1). The reaction is carried out in a multi-stage micro-reaction system connected in series. Each micro-reaction system includes a connected micro-reaction mixer and a microchannel reactor. The specific steps of the preparation are as follows:

[0008] S1: a cyclic anhydride (2) and a biphenyl chiral propylene glycol (3) are subjected to an asymmetric ring-opening reaction in the presence of an organic base (4) to obtain a first product, a dicarboxylic acid monoester compound (5);

[0009] S2: subjecting the first product, the dicarboxylic acid monoester compound (5) produced in step S1, to a selective reduction reaction with a borohydride (6) to produce a second product, a 5-hydroxymethyl-4-carboxylic acid compound (7);

[0010] S3: The second product 5-hydroxymethyl-4-carboxylic acid compound (7) generated in step S2 is subjected to a cyclization reaction with an inorganic mineral acid (8) to obtain a third product (3aS, 6aR) lactone (9);

[0011] S4: The third product (3aS, 6aR) lactone (9) generated in step S3 is subjected to a thiolation reaction with a thiolation reagent (10) to obtain a fourth product (3aS, 6aR) thiolactone (11);

[0012] S5: The fourth product (3aS, 6aR) thiolactone (11) generated in step S4 is subjected to a Fukuyama coupling reaction with a zinc reagent (12) under the catalysis of a palladium catalyst to obtain a fifth product, a hydroxyvalerate compound (13);

[0013] S6: subjecting the fifth product, the hydroxyvalerate compound (13), produced in step S5, to an elimination reaction under the catalysis of an inorganic mineral acid (14) to produce a sixth product, the alkenylvalerate compound (15);

[0014] S7: subjecting the sixth product, alkenyl valerate compound (15), produced in step S6, to a hydrogenation reduction reaction in the presence of a palladium / carbon catalyst to produce a seventh product, valerate compound (16);

[0015] S8: hydrolyzing the seventh product valerate (16) generated in step S7 under the action of an inorganic base (17) to obtain the eighth product valerate (18);

[0016] S9: The eighth product valerate (18) generated in step S8 is subjected to a debenzylation reaction under the action of an inorganic mineral acid (19) to obtain the target product (+)-biotin (1);

[0017] Among them, steps S1, S2, S3, S4, S5, S6, S7, S8 and S9 are performed continuously in sequence without interruption; step S2 is performed after S1, step S3 is performed after S2, step S4 is performed after S3, step S5 is performed after S4, step S6 is performed after S5, step S7 is performed after S6, step S8 is performed after S7, and step S9 is performed after S8.

[0018] In step S1, the structural formula of the cyclic anhydride (2) is:

[0019]

[0020] In step S1, the biphenyl chiral propylene glycol (3) is (S)-1,1-diphenyl-1,2-propylene glycol, and its structural formula is:

[0021]

[0022] In the formula, R1 is hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy; R2 is hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy.

[0023] In step S1, the biphenyl chiral propylene glycol (3) has a high diastereoselective reaction effect, mild reaction conditions, simple operation, high chemical yield and optical purity, and this type of chiral propylene glycol is easy to synthesize, has a wide range of raw material sources, and is easy to recycle.

[0024] In step S1, the organic base (4) is an organic tertiary amine (denoted as NR3R4R5), selected from one of triethylamine, tripropylamine, triisobutylamine, tri-n-butylamine, tripentylamine, trihexylamine, triheptylamine, trioctylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 4-dimethylaminopyridine, and 1,8-diazabicycloundec-7-ene (DBU), or a mixture of multiple thereof; preferably, the organic base (4) is tri-n-butylamine, which has a wide source and low cost.

[0025] In step S1, the cyclic anhydride (2) and the biphenyl chiral propylene glycol (3) undergo an asymmetric ring-opening reaction in the presence of an organic base (4) to convert into a first product, a dicarboxylic acid monoester compound (5), which includes two diastereomers of formula (5a) and (5b), and their structural formulas are as follows:

[0026]

[0027] As a preferred technical solution, in step S1, the asymmetric ring-opening reaction of the cyclic anhydride (2) and the biphenyl chiral propylene glycol (3) in the presence of an organic base (4) is carried out in a first microchannel reactor; the solution of the cyclic anhydride (2) enters a fluid inlet of the first micromixer, the solution of the biphenyl chiral propylene glycol (3) and the organic base (4) enters another fluid inlet of the first micromixer, and the outlet of the first micromixer is directly connected to a fluid inlet of the first microchannel reactor; the solution of the cyclic anhydride (2) and the solution of the biphenyl chiral propylene glycol (3) and the organic base (4) are mixed in the first micromixer and then directly enter the first microchannel reactor for continuous asymmetric ring-opening reaction.

[0028] As a preferred technical solution, in step S1, the molar ratio of the cyclic anhydride (2), the biphenyl chiral propylene glycol (3) and the organic base (4) is controlled within the range of 1:(0.8-3.0):(0.8-3.0), and the reaction can be successfully completed; more preferably, the molar ratio of the cyclic anhydride (2), the biphenyl chiral propylene glycol (3) and the organic base (4) is controlled to be 1:(0.90-2.5):(0.90-2.5), which is the best material ratio, not only can the reaction be successfully completed, but also save materials.

[0029] As a preferred technical solution, the solvent used to prepare the solution of the cyclic anhydride (2) and the solution of the biphenyl chiral propylene glycol (3) and the organic base (4) in step S1 is selected from one of benzene, toluene, xylene, anisole, fluorobenzene, chlorobenzene, bromobenzene, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, ethyl ether, n-hexane, cyclohexane, acetonitrile, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, N-alkylpyridinium salt, 1,3-dialkylimidazolium salt, or a mixed solvent of multiple thereof; more preferably, tetrahydrofuran or toluene is used to prepare the solutions of the reactants in step S1 to obtain a better reaction effect.

[0030] As a preferred technical solution, in step S1, the first micromixer is any one of a static mixer, a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer, and a flow-focusing micromixer.

[0031] As a preferred technical solution, in step S1, the temperature in the first micro mixer is controlled within the range of -20 to 80°C.

[0032] As a preferred technical solution, in step S1, the temperature in the first microchannel reactor is controlled within the range of -20 to 80°C, and the reaction can be completed smoothly; more preferably, the temperature in the first microchannel reactor is controlled within the range of -15 to 60°C, the reaction effect is good, and the energy consumption is lower.

[0033] As a preferred technical solution, in step S1, the first microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 100 microns to 10 mm; more preferably, the inner diameter of the tubular microchannel reactor is 120 microns to 5.35 mm; the plate microchannel reactor includes a first heat exchange layer, a reaction layer and a second heat exchange layer arranged in sequence from top to bottom; the reaction layer is provided with a reaction fluid channel; the hydraulic diameter of the reaction fluid channel is 100 microns to 10 mm; more preferably, the hydraulic diameter of the reaction fluid channel is 120 microns to 5.35 mm.

[0034] As a preferred technical solution, in step S1, the first microchannel reactor is an oscillating microchannel reactor; more preferably, the oscillating microchannel reactor is a Coflore Agitated Cell Reactor (AM Technology, UK).

[0035] As a preferred technical solution, in step S1, the total flow rate of the two reaction liquids entering the first micromixer is controlled so that the residence time of the mixed reaction materials flowing out of the first micromixer in the first microchannel reactor is in the range of 1 to 40 minutes, and the reaction can be successfully completed.

[0036] In step S2, the borohydride (6) is selected from any one of lithium borohydride, sodium borohydride, potassium borohydride, and calcium borohydride; preferably, the borohydride (6) is lithium borohydride, which has stable chemical properties, better reaction effect, and is cheap and easy to obtain.

[0037] In step S2, the first product dicarboxylic acid monoester compound (5) generated in step S1 is subjected to a selective reduction reaction with a borohydride (6) to be converted into a second product 5-hydroxymethyl-4-carboxylic acid compound (7).

[0038] As a preferred technical solution, the selective reduction reaction of the first product dicarboxylic acid monoester compound (5) and the borohydride (6) in step S2 is carried out in a second microchannel reactor; the outlet of the first microchannel reactor is connected to a fluid inlet of a second micromixer, the reaction liquid flowing out of the first microchannel reactor directly enters the fluid inlet of the second micromixer, the borohydride (6) solution enters another fluid inlet of the second micromixer, and the outlet of the second micromixer is directly connected to a fluid inlet of the second microchannel reactor; the reaction liquid flowing out of the first microchannel reactor and the borohydride (6) solution are mixed in the second micromixer and then directly enter the second microchannel reactor for continuous selective reduction reaction.

[0039] As a preferred technical solution, in step S2, the solvent used to prepare the borohydride (6) solution is selected from one of benzene, toluene, xylene, anisole, fluorobenzene, chlorobenzene, bromobenzene, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, ethyl ether, n-hexane, cyclohexane, acetonitrile, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, cyclopentane, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, N-alkylpyridinium salt, 1,3-dialkylimidazolium salt, or a mixed solvent of multiple thereof; more preferably, the organic solvent is tetrahydrofuran or toluene, which is more widely available and has lower cost.

[0040] As a preferred technical solution, in step S2, the second micromixer is any one of a static mixer, a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer, and a flow-focusing micromixer.

[0041] As a preferred technical solution, in step S2, the molar ratio of the borohydride (6) to the first product dicarboxylic acid monoester compound (5) is controlled within the range of (1 to 8):1, and the reaction can be successfully completed; more preferably, the molar ratio of the borohydride (6) to the first product dicarboxylic acid monoester compound (5) generated in step S1 is controlled to be (1.02 to 5.0):1, which is even better, not only allowing the reaction to be successfully completed, but also saving materials.

[0042] As a preferred technical solution, in step S2, the temperature in the second micro mixer is controlled within the range of 0 to 100°C.

[0043] As a preferred technical solution, in step S2, the temperature in the second microchannel reactor is controlled within the range of 0 to 100°C, and the reaction can be completed smoothly; more preferably, the temperature in the second microchannel reactor is controlled within the range of 0 to 80°C, which has a better reaction effect and lower energy consumption.

[0044] As a preferred technical solution, in step S2, the second microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 100 microns to 10 mm; more preferably, the inner diameter of the tubular microchannel reactor is 120 microns to 5.35 mm; the plate microchannel reactor includes a first heat exchange layer, a reaction layer and a second heat exchange layer arranged in sequence from top to bottom; the reaction layer is provided with a reaction fluid channel; the hydraulic diameter of the reaction fluid channel is 100 microns to 10 mm; more preferably, the hydraulic diameter of the reaction fluid channel is 120 microns to 5.35 mm.

[0045] As a preferred technical solution, in step S2, the outlet of the second microchannel reactor is connected to a fluid inlet of the second A micromixer, and water is introduced into the other fluid inlet of the second A micromixer. The reaction mixture flowing out of the second microchannel reactor is mixed with water in the second A micromixer, and then enters the first continuous liquid-liquid extractor. After extraction with ethyl acetate or toluene, the organic phase flows out from the organic phase outlet of the first continuous liquid-liquid extractor, and the aqueous phase flows out from the aqueous phase outlet of the first continuous liquid-liquid extractor. The organic phase can be collected to recover the biphenyl chiral propylene glycol (3) for reuse.

[0046] In step S3, the second product 5-hydroxymethyl-4-carboxylic acid compound (7) generated in step S2 is subjected to a cyclization reaction with an inorganic mineral acid (8) solution to be converted into a third product (3aS, 6aR) lactone (9). The structural formula of the third product (3aS, 6aR) lactone (9) is:

[0047]

[0048] As a preferred technical solution, the second product 5-hydroxymethyl-4-carboxylic acid compound (7) in step S2 is subjected to a continuous cyclization reaction with an inorganic mineral acid (8) in a third microchannel reactor; the aqueous phase outlet of the first continuous liquid-liquid extractor is connected to a fluid inlet of a third micromixer, the reaction liquid flowing out of the aqueous phase outlet of the first continuous liquid-liquid extractor directly enters the fluid inlet of the third micromixer, the inorganic mineral acid (8) solution enters another fluid inlet of the third micromixer, and the outlet of the third micromixer is directly connected to a fluid inlet of the third microchannel reactor; the reaction liquid flowing out of the second microchannel reactor and the inorganic mineral acid (8) solution are mixed in the third micromixer and then directly enter the third microchannel reactor for a continuous cyclization reaction.

[0049] In step S3, the inorganic mineral acid (8) is selected from any one of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; preferably, the inorganic mineral acid (8) is hydrochloric acid, which has a better reaction effect.

[0050] In step S3, the inorganic mineral acid (8) solution is a solution prepared by dissolving the inorganic mineral acid (8) in water.

[0051] As a preferred technical solution, in step S3, the third micromixer is any one of a static mixer, a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer, and a flow-focusing micromixer.

[0052] As a preferred technical solution, in step S3, the molar ratio of the inorganic mineral acid (8) to the second product 5-hydroxymethyl-4-carboxylic acid compound (7) is controlled within the range of (1 to 50):1, and the reaction can be successfully completed; more preferably, the molar ratio of the inorganic mineral acid (8) to the cyclic anhydride (2) in step S1 is (1 to 30):1, which is even better, not only allowing the reaction to be successfully completed, but also saving materials.

[0053] As a preferred technical solution, in step S3, the temperature in the third micro mixer is controlled within the range of -10 to 120°C.

[0054] As a preferred technical solution, in step S3, the temperature in the third microchannel reactor is controlled within the range of 10 to 150°C, and the reaction can be completed smoothly; more preferably, the temperature in the third microchannel reactor is controlled within the range of 20 to 120°C, the reaction effect is better, and the energy consumption is lower.

[0055] As a preferred technical solution, in step S3, the third microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 100 microns to 10 mm; more preferably, the inner diameter of the tubular microchannel reactor is 120 microns to 5.35 mm; the plate microchannel reactor includes a first heat exchange layer, a reaction layer and a second heat exchange layer arranged in sequence from top to bottom; the reaction layer is provided with a reaction fluid channel; the hydraulic diameter of the reaction fluid channel is 100 microns to 10 mm; more preferably, the hydraulic diameter of the reaction fluid channel is 120 microns to 5.35 mm.

[0056] As a preferred technical solution, in step S3, the outlet of the third microchannel reactor is connected to a fluid inlet of the second continuous liquid-liquid extractor. The reaction mixture flowing out of the third microchannel reactor then enters the second continuous liquid-liquid extractor. After extraction with ethyl acetate or toluene, the organic phase flows out of the organic phase outlet of the second continuous liquid-liquid extractor, and the aqueous phase flows out of the aqueous phase outlet of the second continuous liquid-liquid extractor. The organic phase outlet of the second continuous liquid-liquid extractor is connected to the inlet of the first continuous concentrator, and the reaction liquid flowing out of the organic phase outlet of the second continuous liquid-liquid extractor enters the first continuous concentrator for continuous concentration.

[0057] In step S4, the structural formula of the thiolation reagent (10) is:

[0058]

[0059] In formula (10), R6 is a C1-C6 alkyl group or a C3-C6 cycloalkyl group, X is oxygen or sulfur, and Q is potassium or sodium.

[0060] In step S4, (3aS, 6aR) lactone (9) undergoes a thiolation reaction with a thiolation reagent (10) to convert into a fourth product (3aS, 6aR) thiolactone (11). The structural formula of the fourth product (3aS, 6aR) thiolactone (11) is:

[0061]

[0062] As a preferred technical solution, the thiolation reaction of (3aS, 6aR) lactone (9) and the thiolation reagent (10) in step S4 is carried out in a fourth microchannel reactor; the outlet of the first continuous concentrator is connected to a fluid inlet of the fourth micromixer, the reaction liquid flowing out of the outlet of the first continuous concentrator directly enters the fluid inlet of the fourth micromixer, the solution of the thiolation reagent (10) enters another fluid inlet of the fourth micromixer, the outlet of the fourth micromixer is directly connected to a fluid inlet of the fourth microchannel reactor, and the outlet of the fourth microchannel reactor is connected to the inlet of the first back-pressure valve; the reaction liquid flowing out of the outlet of the first continuous concentrator and the solution of the thiolation reagent (10) are mixed in the fourth micromixer and then directly enter the fourth microchannel reactor for continuous thiolation reaction; the reaction liquid flowing out of the fourth microchannel reactor then enters the first back-pressure valve.

[0063] As a preferred technical solution, in step S4, the solvent used to prepare the solution of the thio reagent (10) is any one of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-methylpyrrolidone, sulfolane, dichlorosolvent, etc.; more preferably, the organic solvent is N,N-dimethylformamide or N,N-dimethylacetamide.

[0064] As a preferred technical solution, in step S4, the fourth micromixer is any one of a static mixer, a T-type micromixer, a Y-type micromixer, a coaxial flow micrometer, and a flow-focusing micromixer.

[0065] As a preferred technical solution, in step S4, the molar ratio of the thio reagent (10) to the third product (3aS, 6aR) lactone (9) is controlled within the range of (0.8-5.0):1.

[0066] As a preferred technical solution, in step S4, the temperature in the fourth micromixer is controlled within the range of 60-250°C; more preferably, the temperature in the fourth micromixer is controlled within the range of 80-180°C.

[0067] As a preferred technical solution, in step S4, the temperature in the fourth microchannel reactor is controlled within the range of 60 to 250°C; more preferably, the temperature in the fourth microchannel reactor is controlled within the range of 90 to 185°C.

[0068] As a preferred technical solution, in step S4, the fourth microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 100 microns to 10 mm; more preferably, the inner diameter of the tubular microchannel reactor is 120 microns to 5.35 mm; the plate microchannel reactor includes a first heat exchange layer, a reaction layer and a second heat exchange layer arranged in sequence from top to bottom; the reaction layer is provided with a reaction fluid channel; the hydraulic diameter of the reaction fluid channel is 100 microns to 10 mm; more preferably, the hydraulic diameter of the reaction fluid channel is 120 microns to 5.35 mm.

[0069] As a preferred technical solution, in step S4, the residence time of the mixed reaction materials in the fourth microchannel reactor is controlled to be 1 to 30 minutes; more preferably, the residence time of the mixed reaction materials in the fourth microchannel reactor is controlled to be 2 to 27 minutes.

[0070] As a preferred technical solution, in step S4, the back pressure value of the first back pressure valve is set within the range of 0.1 to 2 MPa; more preferably, the back pressure value of the first back pressure valve is set within the range of 0.2 to 1.5 MPa.

[0071] In step S5, the structural formula of the zinc reagent (12) is:

[0072]

[0073] In the formula, Y is a halogen, which is any one of fluorine, chlorine, bromine or iodine; R7 is a C1-C6 alkyl, a C3-C6 cycloalkyl, a monosubstituted or polysubstituted aryl or arylalkyl; preferably, Y is bromine or iodine, and R7 is any one of methyl, ethyl or propyl.

[0074] In step S5, (3aS, 6aR) thiolactone (11) and zinc reagent (12) undergo a Fukuyama coupling reaction under the catalysis of a palladium catalyst to convert into a fifth product hydroxyvalerate compound (13). The structural formula of the fifth product hydroxyvalerate compound (13) is:

[0075]

[0076] As a preferred technical solution, in step S5, the Fukuyama coupling reaction of (3aS, 6aR) thiolactone (11) and zinc reagent (12) is carried out in a fifth microchannel reactor; the outlet of the first back-pressure valve is connected to a fluid inlet of the fifth micromixer, the reaction liquid flowing out of the outlet of the first back-pressure valve enters the fluid inlet of the fifth micromixer, and the zinc reagent solution containing palladium catalyst enters another fluid inlet of the fifth micromixer; the outlet of the fifth micromixer is connected to a fluid inlet of the fifth microchannel reactor, and the reaction liquid flowing out of the outlet of the first back-pressure valve enters the fluid inlet of the fifth micromixer. The reaction liquid flowing out of the mixer directly enters the fluid inlet of the fifth microchannel reactor, the zinc reagent (12) solution containing the palladium catalyst enters the other fluid inlet of the fifth micromixer, and the outlet of the fifth microchannel reactor is connected to the inlet of the second back-pressure valve; the reaction liquid flowing out of the first back-pressure valve and the zinc reagent solution containing the palladium catalyst are mixed in the fifth micromixer to form a reaction mixture which then directly enters the fifth microchannel reactor for continuous Fukuyama coupling reaction; the reaction mixture flowing out of the fifth microchannel reactor then directly enters the second back-pressure valve.

[0077] As a preferred technical solution, in step S5, the palladium catalyst is any one of palladium acetate, bis(triphenylphosphine)palladium dichloride, palladium / carbon, nanopalladium and palladium hydroxide / carbon.

[0078] As a preferred technical solution, in step S5, the solvent used to prepare the zinc reagent solution containing the palladium catalyst is any one of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-methylpyrrolidone, sulfolane, dichlorosolvent, etc.; more preferably, the organic solvent is N,N-dimethylformamide or N,N-dimethylacetamide.

[0079] As a preferred technical solution, in step S5, the molar ratio of (3aS, 6aR) thiolactone (11) to the palladium catalyst is controlled to be 1: (0.001-0.500).

[0080] As a preferred technical solution, in step S5, the fifth micromixer is any one of a static mixer, a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer, and a flow-focusing micromixer.

[0081] As a preferred technical solution, in step S5, the molar ratio of (3aS, 6aR) thiolactone (11) to zinc reagent (12) is controlled within the range of 1: (1.0 to 8.0).

[0082] As a preferred technical solution, in step S5, the temperature in the fifth micromixer is controlled within the range of 5 to 160°C; more preferably, the temperature in the fifth micromixer is controlled within the range of 30 to 155°C.

[0083] As a preferred technical solution, in step S5, the temperature in the fifth microchannel reactor is controlled within the range of 5 to 160°C; more preferably, the temperature in the fifth microchannel reactor is controlled within the range of 30 to 155°C.

[0084] As a preferred technical solution, in step S5, the fifth microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 100 microns to 10 mm; more preferably, the inner diameter of the tubular microchannel reactor is 120 microns to 5.35 mm; the plate microchannel reactor includes a first heat exchange layer, a reaction layer and a second heat exchange layer arranged in sequence from top to bottom; the reaction layer is provided with a reaction fluid channel; the hydraulic diameter of the reaction fluid channel is 100 microns to 10 mm; more preferably, the hydraulic diameter of the reaction fluid channel is 120 microns to 5.35 mm.

[0085] As a preferred technical solution, in step S5, the residence time of the mixed reaction material in the fifth microchannel reactor is controlled to be 0.5 to 30 minutes; more preferably, the residence time of the mixed reaction material in the fifth microchannel reactor is controlled to be 1 to 27 minutes.

[0086] As a preferred technical solution, in step S6, the fifth product hydroxyvalerate compound (13) undergoes an elimination reaction under the action of an inorganic mineral acid (14) solution to convert it into a sixth product alkenyl valerate compound (15). The structural formula of the sixth product alkenyl valerate compound (15) is:

[0087]

[0088] In step S6, the inorganic mineral acid (14) is any one of sulfuric acid, hydrochloric acid, boric acid, phosphoric acid, carbonic acid and nitric acid.

[0089] As a preferred technical solution, in step S6, the elimination reaction of the fifth product hydroxyvalerate compound (13) under the action of the inorganic mineral acid (14) solution is carried out in the sixth microchannel reactor; the outlet of the second back pressure valve is connected to a fluid inlet of the sixth micromixer, and the reaction liquid flowing out of the outlet of the second back pressure valve directly enters the fluid inlet of the sixth micromixer, and the inorganic mineral acid (14) solution enters another fluid inlet of the sixth micromixer; the outlet of the sixth micromixer is directly connected to a fluid inlet of the sixth microchannel reactor, and the reaction mixture flowing out of the sixth micromixer directly enters the fluid inlet of the sixth microchannel reactor; the reaction mixture flowing out of the outlet of the second back pressure valve and the inorganic mineral acid (14) solution are mixed in the sixth micromixer and then directly enter the sixth microchannel reactor for continuous elimination reaction.

[0090] As a preferred technical solution, in step S6, the outlet of the sixth microchannel reactor is connected to a fluid inlet of the first continuous liquid-liquid separator, and the reaction mixture flowing out of the sixth microchannel reactor directly enters the first continuous liquid-liquid separator, the aqueous phase flows out from the aqueous phase outlet of the first continuous liquid-liquid separator, and the organic phase flows out from the organic phase outlet of the first continuous liquid-liquid separator.

[0091] As a preferred technical solution, in step S6, the inorganic mineral acid (14) solution is a solution prepared by dissolving the inorganic mineral acid (14) in water.

[0092] As a preferred technical solution, in step S6, the seventh micromixer is any one of a static mixer, a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer, and a flow-focusing micromixer.

[0093] As a preferred technical solution, in step S6, the temperature in the sixth micromixer is controlled within the range of 5 to 100°C; more preferably, the temperature in the sixth micromixer is controlled within the range of 10 to 90°C.

[0094] As a preferred technical solution, in step S6, the molar ratio of the fifth product hydroxyvalerate compound (13) to the inorganic mineral acid (14) is controlled within the range of 1: (1 to 50).

[0095] As a preferred technical solution, in step S6, the sixth microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 100 microns to 10 mm; more preferably, the inner diameter of the tubular microchannel reactor is 120 microns to 5.35 mm; the plate microchannel reactor includes a first heat exchange layer, a reaction layer and a second heat exchange layer arranged in sequence from top to bottom; the reaction layer is provided with a reaction fluid channel; the hydraulic diameter of the reaction fluid channel is 100 microns to 10 mm; more preferably, the hydraulic diameter of the reaction fluid channel is 120 microns to 5.35 mm.

[0096] As a preferred technical solution, in step S6, the residence time of the mixed reaction material in the sixth microchannel reactor is controlled to be 0.5 to 30 minutes; more preferably, the residence time of the mixed reaction material in the sixth microchannel reactor is controlled to be 1 to 27 minutes.

[0097] As a preferred technical solution, in step S6, the temperature inside the sixth microchannel reactor is controlled within the range of 5 to 100°C; more preferably, the temperature inside the sixth microchannel reactor is controlled within the range of 10 to 90°C.

[0098] In step S7, the sixth product, alkenyl valerate compound (15), is hydrogenated and reduced in the presence of a palladium / carbon catalyst to convert it into a seventh product, valerate (16). The structural formula of the seventh product, valerate (16), is:

[0099]

[0100] As a preferred technical solution, in step S7, the hydrogenation reduction reaction of the sixth product, alkenyl valerate compound (15), under the action of palladium / carbon catalyst is carried out in a seventh microchannel reactor; the organic phase outlet of the first continuous liquid-liquid separator is connected to a fluid inlet of the seventh micromixer, and the reaction liquid flowing out of the organic phase outlet of the first continuous liquid-liquid separator directly enters the fluid inlet of the seventh micromixer, and the hydrogen enters another fluid inlet of the seventh micromixer; the outlet of the seventh micromixer is directly connected to a fluid inlet of the seventh microchannel reactor, and the reaction mixture flowing out of the seventh micromixer directly enters the seventh microchannel reactor; the reaction liquid flowing out of the organic phase outlet of the first continuous liquid-liquid separator and the hydrogen are mixed in the seventh micromixer and then tightly Then it directly enters the seventh microchannel reactor for continuous hydrogenation reduction reaction; the outlet of the seventh microchannel reactor is connected to a buffer tank, the bottom of the buffer tank is equipped with a liquid outlet with a valve, the top of the buffer tank has a first interface connected to the nitrogen pipeline, a second interface connected to the outlet of the seventh microchannel reactor, and a third interface connected to the back pressure valve; the first interface is connected to nitrogen for providing pressure to the buffer tank, and the pressure of the connected nitrogen is adjustable in the range of 0.1 to 2.0 MPa. The third interface is connected to the third back pressure valve; the back pressure range of the third back pressure valve is 0.1 to 1.5 MPa; the pressure value of the connected nitrogen is 0.2 to 1.0 MPa greater than the back pressure value set by the third back pressure valve; the second interface is connected to the outlet of the seventh microchannel reactor.

[0101] As a preferred technical solution, in step S7, the palladium / carbon catalyst is a palladium-carbon (Pd / C) catalyst with a loading of 0.5 to 30% or a palladium-carbon (Pd(OH)2 / C) catalyst with a loading of 0.5 to 30%; more preferably, the palladium / carbon catalyst is a mixture formed by mixing a palladium-carbon (Pd / C) catalyst with a loading of 0.5 to 30% or a palladium-carbon (Pd(OH)2 / C) catalyst with an inert solid medium particle (such as quartz sand, diatomaceous earth, glass beads, silica gel, etc.).

[0102] As a preferred technical solution, in step S7, the molar ratio of the sixth product alkenyl valerate compound (15) to hydrogen is controlled within the range of 1: (0.8 to 50.0).

[0103] As a preferred technical solution, in step S7, the temperature in the seventh micro-mixer is controlled at 10-120°C.

[0104] As a preferred technical solution, in step S7, the temperature in the seventh microchannel reactor is controlled within the range of 15 to 120° C.;

[0105] As a preferred technical solution, in step S7, the residence time of the mixed reaction materials in the seventh microchannel reactor is controlled to be in the range of 0.1 to 30 minutes.

[0106] As a preferred technical solution, in step S7, the seventh micromixer is any one of a static mixer, a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer or a flow-focusing micromixer.

[0107] As a preferred technical solution, in step S7, the seventh microchannel reactor is a micro fixed bed reactor filled with palladium / carbon catalyst; the inner diameter of the micro fixed bed reactor is 1 mm to 100 mm, more preferably 1.5 mm to 70 mm.

[0108] In step S8, the seventh product, valerate (16), is hydrolyzed in the presence of an inorganic base (17) solution to convert it into an eighth product, valerate (18). The eighth product, valerate (18), has the structural formula:

[0109]

[0110] Wherein Z is a sodium or potassium ion.

[0111] As a preferred technical solution, in step S8, the hydrolysis reaction of the seventh product valerate (16) under the action of the inorganic base (17) solution is carried out in the eighth microchannel reactor; the reaction liquid in the buffer tank is transported to a fluid inlet of the eighth micromixer, and the inorganic base (17) solution enters another fluid inlet of the eighth micromixer; the outlet of the eighth micromixer is directly connected to a fluid inlet of the eighth microchannel reactor, and the reaction mixture flowing out of the eighth micromixer directly enters the eighth microchannel reactor for continuous hydrolysis reaction.

[0112] As a preferred technical solution, in step S8, the inorganic base (17) is any one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and lithium carbonate; and the inorganic base (17) solution is a solution prepared by dissolving the inorganic base (17) in water.

[0113] As a preferred technical solution, in step S8, the outlet of the eighth microchannel reactor is connected to a fluid inlet of the second continuous liquid-liquid separator, and the reaction mixture flowing out of the eighth microchannel reactor directly enters the second continuous liquid-liquid separator, the aqueous phase flows out from an aqueous phase outlet of the second continuous liquid-liquid separator, and the organic phase flows out from the organic phase outlet of the second continuous liquid-liquid separator.

[0114] As a preferred technical solution, in step S8, the eighth micromixer is any one of a static mixer, a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer or a flow-focusing micromixer.

[0115] As a preferred technical solution, in step S8, the molar ratio of valerate (16) to inorganic base (17) is controlled to be 1: (0.75-30).

[0116] As a preferred technical solution, in step S8, the temperature in the eighth micro-mixer is controlled within the range of 2 to 120°C.

[0117] As a preferred technical solution, in step S8, the temperature in the eighth microchannel reactor is controlled within the range of 15 to 150°C.

[0118] As a preferred technical solution, in step S8, the eighth microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 100 microns to 50 mm, more preferably 120 microns to 30 mm; the hydraulic diameter of the reaction fluid channel of the plate microchannel reactor is 100 microns to 50 mm, more preferably 120 microns to 30 mm.

[0119] As a preferred technical solution, in step S8, the residence time of the mixed reaction materials in the eighth microchannel reactor is controlled to be within the range of 0.1 to 30 minutes.

[0120] In step S9, the eighth product valerate (18) undergoes a debenzylation reaction in the presence of an inorganic mineral acid (19) solution to be converted into the target product (+)-biotin (1).

[0121] As a preferred technical solution, in step S8, the debenzylation reaction of the eighth product valerate (18) under the action of an inorganic mineral acid (19) solution is carried out in a ninth microchannel reactor; the reaction liquid flowing out of the aqueous phase outlet of the second continuous liquid-liquid separator enters a fluid inlet of a ninth micromixer, and the inorganic mineral acid (19) solution enters another fluid inlet of the ninth micromixer; the outlet of the ninth micromixer is connected to a fluid inlet of a ninth microchannel reactor, and the reaction mixture flowing out of the ninth micromixer directly enters the ninth microchannel reactor for a continuous debenzylation reaction.

[0122] As a preferred technical solution, in step S9, the inorganic mineral acid (19) is hydrogen bromide or hydrogen chloride; and the inorganic mineral acid (19) solution is a solution prepared by dissolving the inorganic mineral acid (19) in water.

[0123] As a preferred technical solution, in step S9, the molar ratio of valerate (18) to inorganic mineral acid (19) is controlled to be 1: (0.75-30).

[0124] As a preferred technical solution, in step S9, the temperature in the ninth micro-mixer is controlled at -10 to 25°C.

[0125] As a preferred technical solution, in step S9, the temperature in the ninth microchannel reactor is controlled at 25-200° C.;

[0126] As a preferred technical solution, in step S9, the residence time of the mixed reaction materials in the ninth microchannel reactor is controlled to be 0.1 to 30 minutes.

[0127] As a preferred technical solution, in step S9, the ninth micromixer is any one of a static mixer, a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer or a flow-focusing micromixer.

[0128] As a preferred technical solution, in step S9, the ninth microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 100 microns to 50 mm, more preferably 120 microns to 30 mm; the hydraulic diameter of the reaction fluid channel of the plate microchannel reactor is 100 microns to 50 mm, more preferably 120 microns to 30 mm.

[0129] As a preferred technical solution, in step S9, the microchannel reactor is a microwave flow chemical reactor, and the hydraulic diameter of the reaction fluid channel thereof is 100 microns to 50 mm, more preferably 120 microns to 30 mm.

[0130] As a preferred technical solution, in step S9, the outlet of the ninth microchannel reactor is connected to a fluid inlet of the tenth microchannel reactor, and the reaction liquid flowing out of the outlet of the ninth microchannel reactor directly enters the tenth microchannel reactor.

[0131] As a preferred technical solution, in step S9, the tenth microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 1 mm to 10 mm; the hydraulic diameter of the reaction fluid channel of the plate microchannel reactor is 1 mm to 10 mm.

[0132] As a preferred technical solution, the temperature in the tenth microchannel reactor is controlled within the range of -35 to 10°C, the target product can be crystallized and precipitated, and the reaction mixture flowing out of the tenth microchannel reactor is collected and filtered to obtain the target product (+)-biotin.

[0133] Beneficial effects of the present invention: The method for continuously preparing (+)-biotin of the present invention has the following advantages over the existing multi-step intermittent reactor synthesis method:

[0134] 1. Achieve a continuous nine-step synthesis from raw materials to the target product (+)-biotin. The process is continuous and uninterrupted, with a high degree of automation, no external intervention required in the middle, high time and space efficiency, greatly reducing the number of operators and labor intensity, and significantly reducing production costs.

[0135] 2. Dangerous reaction processes such as high temperature, high pressure and hydrogenation reactions are all completed in the reaction fluid channel of the microchannel reactor. The total volume of the reaction fluid channel is small, which makes the online liquid holdup small and the entire process is inherently safe.

[0136] 3. The nine-step continuous reaction greatly shortens the total preparation time, from about two weeks of nine-step intermittent batch synthesis (including the reaction and the corresponding post-processing time for each step) to less than 1 hour.

[0137] 4. The material mixing, mass transfer and reaction process of the reaction process are completed in the reaction fluid channel of the micromixer and microchannel reactor, without the need for a stirring device, which greatly reduces the total energy consumption of the process.

[0138] 5. By strengthening the reaction process through a microchannel reactor and improving the yield of each step of the reaction, and by connecting multiple steps in series, reducing the intermediate post-processing process and reducing material loss, the total yield of the nine-step reaction was increased from about 30-35% in the intermittent batch method to more than 48.7%. DETAILED DESCRIPTION

[0139] In order to explain the technical content, structural features, achieved objectives and effects of the technical solution in detail, the following is a further description in conjunction with specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the scope of protection of the present invention is not limited to the following embodiments.

[0140] Example 1

[0141] A tetrahydrofuran solution (0.1 M) of the cyclic anhydride (2) was delivered to one fluid inlet of a first micromixer (T-type micromixer with an inner diameter of 0.8 mm) using a feed pump, and a tetrahydrofuran solution of a biphenyl-type chiral propylene glycol (3, wherein R1 is hydrogen and R2 is hydrogen) and tri-n-butylamine was delivered to another fluid inlet of the first micromixer. The flow ratio of the two reaction liquids was precisely controlled so that the molar ratio of the cyclic anhydride (2), the biphenyl-type chiral propylene glycol (3, wherein R1 is hydrogen and R2 is hydrogen) and the tri-n-butylamine was 1:1.05:1. The temperature in the first micromixer was controlled to 0°C. The reaction mixture flowing out of the outlet of the first micromixer then directly enters the first microchannel reactor (polytetrafluoroethylene tube, inner diameter 0.8 mm, volume 1.5 ml). The temperature in the first microchannel reactor is controlled at 25°C. After 7.5 minutes of reaction (i.e., the residence time of the mixed reaction materials in the first microchannel reactor is 7.5 minutes), the mixed reaction materials flow out from the outlet of the first microchannel reactor.

[0142] The mixed reaction material flowing out of the outlet of the first microchannel reactor enters a fluid inlet of a second micromixer (T-type micromixer with an inner diameter of 0.8 mm), and a tetrahydrofuran solution of lithium borohydride (0.8 M) is delivered to another fluid inlet of the second micromixer by a feed pump. The flow rate of the tetrahydrofuran solution of lithium borohydride is adjusted so that the molar ratio of lithium borohydride to cyclic anhydride (2) is 1.5:1. The temperature in the second micromixer is controlled at 25°C. The mixed reaction material flowing out of the outlet of the second micromixer then directly enters a second microchannel reactor (polytetrafluoroethylene tube with an inner diameter of 0.8 mm and a volume of 3.0 ml). The temperature in the second microchannel reactor is controlled at 45°C. After reacting for 2.5 minutes (i.e., the residence time of the mixed reaction material in the second microchannel reactor is 2.5 minutes), the mixed reaction material flows out of the outlet of the second microchannel reactor. The reaction mixture flowing out of the outlet of the second microchannel reactor is mixed with water in the second A micromixer, and then enters the first continuous liquid-liquid extractor for continuous extraction with ethyl acetate. The organic phase flows out from the organic phase outlet of the first continuous liquid-liquid extractor, and the aqueous phase flows out from the aqueous phase outlet of the first continuous liquid-liquid extractor.

[0143] The reaction liquid flowing out of the aqueous phase outlet of the first continuous liquid-liquid extractor directly enters a fluid inlet of a third micromixer (T-type micromixer with an inner diameter of 0.8 mm), and a hydrochloric acid aqueous solution (1.0 M) is delivered to another fluid inlet of the third micromixer by a feed pump. The flow rate of the hydrochloric acid aqueous solution is adjusted so that the molar ratio of hydrogen chloride to cyclic anhydride (2) is 5:1. The temperature in the third micromixer is controlled at 60°C. The aqueous phase separated from the first continuous liquid-liquid extractor and the hydrochloric acid aqueous solution are mixed in the third micromixer; the mixed reaction material flowing out of the outlet of the third micromixer then directly enters a third microchannel reactor (polytetrafluoroethylene tube with an inner diameter of 0.6 mm and a volume of 3.0 ml). The temperature in the third microchannel reactor is controlled at 60°C. After reacting for 1 minute (i.e., the residence time of the mixed reaction material in the microchannel reactor is 1 minute), the mixed reaction material flows out from the outlet of the third microchannel reactor. The reaction mixture flowing out of the outlet of the third microchannel reactor then enters the second continuous liquid-liquid extractor for extraction with toluene. The organic phase flows out of the organic phase outlet of the second continuous liquid-liquid extractor, and the aqueous phase flows out of the aqueous phase outlet of the second continuous liquid-liquid extractor. The reaction liquid flowing out of the organic phase outlet of the second continuous liquid-liquid extractor then enters the first continuous concentrator for concentration.

[0144] The reaction liquid flowing out of the outlet of the first continuous concentrator enters a fluid inlet of the fourth micromixer (T-type micromixer with an inner diameter of 0.8 mm), and the potassium thioacetate solution (thio reagent solution, 0.3 M) is delivered to the other fluid inlet of the fourth micromixer by a feed pump. The flow rate of the potassium thioacetate solution is adjusted so that the molar ratio of methyl thioacetate to cyclic anhydride (2) is 1.2:1. The temperature in the fourth micromixer is controlled at 145°C. The mixed reaction material flowing out of the outlet of the third microchannel reactor is continuously concentrated and mixed with the second solution of potassium thioacetate. The methylformamide solution was mixed in the fourth micromixer; the mixed reaction mass flowing out of the outlet of the fourth micromixer then directly entered the fourth microchannel reactor (polytetrafluoroethylene tube, inner diameter of 0.8 mm, volume of 4.0 ml), the temperature in the fourth microchannel reactor was controlled to 145° C., and after 10 minutes of reaction (i.e., the residence time of the mixed reaction mass in the microchannel reactor was 10 minutes), the mixed reaction mass flowed out of the outlet of the fourth microchannel reactor, entered the inlet of the first back pressure valve, and then flowed out of the outlet of the first back pressure valve.

[0145] The mixed reaction materials flowing out of the outlet of the first back pressure valve directly enter a fluid inlet of the fifth micro mixer (T-type micro mixer with an inner diameter of 0.8 mm), and a (5-ethoxy-5-oxopentyl)zinc bromide tetrahydrofuran solution (zinc reagent solution, 0.25 M) containing 5 mol% palladium acetate is delivered to another fluid inlet of the fifth micro mixer by a feed pump. The molar ratio of cyclic anhydride (2) to (5-ethoxy-5-oxopentyl)zinc bromide is controlled to be 1:1.05, and the temperature in the fifth micro mixer is controlled to be 105°C. The mixed reaction materials flowing out of the outlet of the micromixer then directly enter the fifth microchannel reactor (polytetrafluoroethylene tube, inner diameter of 0.6 mm, volume of 4.0 ml), where the reaction materials undergo Fukuyama coupling reaction. The temperature in the fifth microchannel reactor is controlled at 105° C. After 10 minutes of reaction (i.e., the residence time of the mixed reaction materials in the microchannel reactor is 10 minutes), the mixed reaction materials flow out of the outlet of the fifth microchannel reactor and enter the inlet of the second back pressure valve, and then flow out of the outlet of the second back pressure valve.

[0146] The mixed reaction material flowing out of the outlet of the second back pressure valve directly enters a fluid inlet of the sixth micro mixer (T-type micro mixer with an inner diameter of 0.8 mm), and a hydrochloric acid aqueous solution (1.0 M) is delivered to the other fluid inlet of the sixth micro mixer by a feed pump. The flow rate of the hydrochloric acid aqueous solution is adjusted so that the molar ratio of the cyclic anhydride (2) to the hydrogen chloride is 1:8. The temperature in the sixth micro mixer is controlled to 45°C. The mixed reaction material flowing out of the outlet of the second back pressure valve and the hydrochloric acid aqueous solution are mixed in the sixth micro mixer; the mixed reaction material flowing out of the outlet of the sixth micro mixer then directly enters a sixth micro channel reactor (polytetrafluoroethylene tube with an inner diameter of 0.8 mm and a volume of 3.0 ml), where the reaction material undergoes an elimination reaction. The temperature in the sixth micro channel reactor is controlled to 45°C. After 10 minutes of reaction (i.e., the residence time of the mixed reaction material in the micro channel reactor is 10 minutes), the mixed reaction material flows out of the outlet of the sixth micro channel reactor. The reaction mixture flowing out of the outlet of the sixth microchannel reactor enters the first continuous liquid-liquid separator, the organic phase flows out from the organic phase outlet of the first continuous liquid-liquid separator, and the aqueous phase flows out from the aqueous phase outlet of the first continuous liquid-liquid separator.

[0147] The reaction liquid flowing out of the organic phase outlet of the first continuous liquid-liquid separator directly enters a fluid inlet of the seventh micromixer (T-type micromixer with an inner diameter of 0.8 mm), hydrogen is transported to another fluid inlet of the seventh micromixer, and the flow rate of hydrogen is adjusted so that the molar ratio of cyclic anhydride (2) to hydrogen is 1:3. The temperature in the seventh micromixer is controlled at 25°C, and the mixed reaction material flowing out of the outlet of the seventh micromixer directly enters the seventh microchannel reactor (a micro fixed bed reactor with a length of 20 cm and an inner diameter of 1 cm, filled with 5.8 g of palladium / carbon catalyst with a loading of 10%). A uniform mixture of a catalyst and 14.2 grams of quartz sand, a reaction volume of about 4.0 ml in a micro fixed-bed reactor after filling with palladium / carbon catalyst, the temperature in the controlled micro fixed-bed reactor was controlled to 25° C., and after 2 minutes of reaction (i.e., the residence time of the mixed reaction materials in the micro channel reactor was 2 minutes), the mixed reaction materials flowed out from the outlet of the seventh micro channel reactor; the reaction mixture flowing out from the outlet of the seventh micro channel reactor entered the buffer tank, the back pressure value of the third back pressure valve connected to the top of the buffer tank was set to 1.0 MPa, and the pressure of the nitrogen connected to the top of the buffer tank was adjusted to 1.5 MPa.

[0148] The reaction liquid in the buffer tank was delivered to a fluid inlet of an eighth micromixer (T-type micromixer with an inner diameter of 0.8 mm) by a feed pump, and a sodium hydroxide aqueous solution (1.0 M) was delivered to another fluid inlet of the eighth micromixer by a feed pump. The flow rate of the sodium hydroxide aqueous solution was adjusted so that the molar ratio of the cyclic anhydride (2) to the sodium hydroxide aqueous solution was 1:1.5. The temperature in the eighth micromixer was controlled to 45°C. The mixed reaction material flowing out of the outlet of the eighth micromixer then directly entered the eighth microchannel reactor. The temperature in the eighth microchannel reactor was controlled to 25°C. After reacting for 5.0 minutes (i.e., the residence time of the mixed reaction material in the microchannel reactor was 5.0 minutes), the mixed reaction material flowed out of the outlet of the eighth microchannel reactor. The reaction mixture flowing out of the outlet of the eighth microchannel reactor entered the second continuous liquid-liquid separator, the organic phase flowed out from the organic phase outlet of the second continuous liquid-liquid separator, and the aqueous phase flowed out from the aqueous phase outlet of the second continuous liquid-liquid separator.

[0149] The reaction material flowing out of the aqueous phase outlet of the second continuous liquid-liquid separator directly enters a fluid inlet of the ninth micromixer (T-type micromixer with an inner diameter of 0.8 mm), and a 47% HBr aqueous solution is transported to another fluid inlet of the ninth micromixer by a feed pump. The molar ratio of cyclic anhydride (2) to HBr is controlled to be 1:5, and the temperature in the ninth micromixer is controlled to be 5°C. The mixed reaction material flowing out of the outlet of the ninth micromixer then directly enters the ninth microchannel reactor (the ninth microchannel reactor is a microwave continuous flow reactor, the hydraulic diameter of the reaction fluid channel is 0.8 mm, and the reaction volume is 8.6 ml). The temperature in the ninth microchannel reactor is controlled to be 145°C. After 10 minutes of reaction (i.e., the residence time of the mixed reaction material in the microchannel reactor is 10 minutes), the mixed reaction material flows out from the outlet of the ninth microchannel reactor.

[0150] The mixed reaction materials flowing out of the outlet of the ninth microchannel reactor were directly fed into the tenth microchannel reactor (PTFE tubing with an inner diameter of 3.2 mm and a reaction volume of 20 ml). The temperature within the microchannel reactor was controlled at -10°C. The reaction mixture flowing out of the tenth microchannel reactor was collected and filtered to obtain the target product (+)-biotin. Analysis showed a total yield of 48% and an enantioselectivity of 100% for the target product (+)-biotin.

[0151] Example 2

[0152] This example is the same as Example 1, except that the temperature in the fourth microchannel reactor is controlled at 160° C. The total yield of the target product (+)-biotin in this example is 49.6%, and the enantioselectivity is 100%.

[0153] Example 3

[0154] This example is the same as Example 1, except that the temperature in the fifth microchannel reactor is controlled at 120° C. The total yield of the target product (+)-biotin in this example is 50.2%, and the enantioselectivity is 100%.

[0155] Example 4

[0156] This example is the same as Example 1, except that the temperature in the ninth microchannel reactor is controlled at 155° C. The total yield of the target product (+)-biotin in this example is 49.8%, and the enantioselectivity is 100%.

[0157] Example 5

[0158] This example is identical to Example 1, except that the ninth microchannel reactor in this example is a conventional polytetrafluoroethylene (PTFE) tube (0.8 mm inner diameter, 8.6 ml reaction volume) and is heated using an oil bath rather than a microwave continuous flow reactor. The total yield of the target product (+)-biotin in this example is 0%.

[0159] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A fully continuous flow method for preparing (+)-biotin (1), characterized in that: The reaction is carried out in a multi-stage micro-reaction system in series, each micro-reaction system includes a connected micro-reaction mixer and a micro-channel reactor; the structure of (+)-biotin is shown in formula (1) The chemical name is (3aS,4S,6aR)-hexahydro-2-oxo-1H-thieno[3,4-d]imidazole-4-n-pentanoic acid, and the specific preparation steps are as follows: S1: Cyclic anhydride (2) and biphenyl chiral propylene glycol (3) are subjected to an asymmetric ring-opening reaction in the presence of an organic base (4) to obtain a first product, a dicarboxylic acid monoester compound (5), which contains two diastereomers (5a) and (5b), and their structural formulas are: Wherein, the structural formula of the cyclic anhydride (2) is: The biphenyl chiral propylene glycol (3) is (S)-1,1-diphenyl-1,2-propylene glycol, and its structural formula is: wherein R1 is hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy; R2 is hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy; The organic base (4) is an organic tertiary amine, denoted as NR3R4R5, selected from the group consisting of triethylamine, tripropylamine, triisobutylamine, tri-n-butylamine, tripentylamine, trihexylamine, triheptylamine, trioctylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 4-dimethylaminopyridine, and 1,8-diazabicycloundec-7-ene (DBU), or a mixture of multiple thereof; S2: subjecting the first product, the dicarboxylic acid monoester compound (5) produced in step S1, to a selective reduction reaction with a borohydride (6) to produce a second product, a 5-hydroxymethyl-4-carboxylic acid compound (7); S3: The second product 5-hydroxymethyl-4-carboxylic acid compound (7) generated in step S2 is subjected to a cyclization reaction with an inorganic mineral acid (8) to obtain a third product (3aS, 6aR) lactone (9), the structural formula of which is: S4: The third product (3aS, 6aR) lactone (9) generated in step S3 is subjected to a thiolation reaction with a thiolation reagent (10) to obtain a fourth product (3aS, 6aR) thiolactone (11), the structural formula of which is: The structural formula of the thiolation reagent (10) is: Wherein, R6 is C1-C6 alkyl, C3-C6 cycloalkyl, X is oxygen or sulfur, and Q is potassium or sodium; S5: The fourth product (3aS, 6aR) thiolactone (11) generated in step S4 is subjected to a Fukuyama coupling reaction with a zinc reagent (12) under the catalysis of a palladium catalyst to obtain a fifth product, a hydroxyvalerate compound (13), having the structural formula: The structural formula of the zinc reagent (12) is: Wherein, Y is any one of fluorine, chlorine, bromine and iodine; R7 is C1-C6 alkyl, C3-C6 cycloalkyl, monosubstituted or polysubstituted aryl or aralkyl; S6: The fifth product, the hydroxyvalerate compound (13), produced in step S5, is subjected to an elimination reaction under the catalysis of an inorganic mineral acid (14) to produce a sixth product, the alkenylvalerate compound (15), whose structural formula is: S7: The sixth product alkenyl valerate compound (15) generated in step S6 is subjected to a selective reduction reaction in the presence of a palladium / carbon catalyst to obtain a seventh product valerate (16), the structural formula of which is: S8: The seventh product valerate (16) generated in step S7 is hydrolyzed under the action of an inorganic base (17) to obtain an eighth product valerate (18), whose structural formula is: Wherein, Z is a sodium or potassium ion; S9: The eighth product valerate (18) generated in step S8 is subjected to a debenzylation reaction under the action of an inorganic mineral acid (19) to obtain the target product (+)-biotin (1); Among them, steps S1, S2, S3, S4, S5, S6, S7, S8 and step S9 are performed continuously in sequence without interruption; step S2 is performed after S1, step S3 is performed after S2, step S4 is performed after S3, step S5 is performed after S4, step S6 is performed after S5, step S7 is performed after S6, step S8 is performed after S7, and step S9 is performed after S8; In step S1, an asymmetric ring-opening reaction of a cyclic anhydride (2) and a biphenyl chiral propylene glycol (3) in the presence of an organic base (4) is carried out in a first microchannel reactor; the solution of the cyclic anhydride (2) enters a fluid inlet of the first micromixer, and the solution of the biphenyl chiral propylene glycol (3) and the organic base (4) enters another fluid inlet of the first micromixer, and the outlet of the first micromixer is directly connected to a fluid inlet of the first microchannel reactor; the solution of the cyclic anhydride (2) and the solution of the biphenyl chiral propylene glycol (3) and the organic base (4) are mixed in the first micromixer and then directly enter the first microchannel reactor for continuous asymmetric ring-opening reaction; and: the temperature in the first micromixer is controlled to be -20 to 80°C; Controlling the temperature in the first microchannel reactor to be between -20°C and 80°C; The first microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 100 μm to 10 mm; the plate microchannel reactor comprises a first heat exchange layer, a reaction layer, and a second heat exchange layer arranged in sequence from top to bottom; the reaction layer is provided with a reaction fluid channel; the hydraulic diameter of the reaction fluid channel is 100 μm to 10 mm; The first microchannel reactor is an oscillating microchannel reactor; controlling the total flow rate of the two reaction liquids entering the first micromixer so that the residence time of the mixed reaction material flowing out of the first micromixer in the first microchannel reactor is within the range of 1 to 40 minutes; In step S2, the selective reduction reaction of the first product dicarboxylic acid monoester compound (5) and the borohydride (6) is carried out in a second microchannel reactor; the outlet of the first microchannel reactor is connected to a fluid inlet of a second micromixer, the reaction liquid flowing out of the first microchannel reactor directly enters the fluid inlet of the second micromixer, the borohydride (6) solution enters another fluid inlet of the second micromixer, and the outlet of the second micromixer is directly connected to a fluid inlet of the second microchannel reactor; the reaction liquid flowing out of the first microchannel reactor and the borohydride (6) solution are mixed in the second micromixer and then directly enter the second microchannel reactor for continuous selective reduction reaction; Control the temperature in the second micro mixer to be 0-100°C; controlling the temperature in the second microchannel reactor to be 0-100° C.; The second microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 100 μm to 10 mm; the plate microchannel reactor comprises a first heat exchange layer, a reaction layer, and a second heat exchange layer arranged in sequence from top to bottom; the reaction layer is provided with a reaction fluid channel; the hydraulic diameter of the reaction fluid channel is 100 μm to 10 mm; The outlet of the second microchannel reactor is connected to a fluid inlet of the second A micromixer, and water is introduced into the other fluid inlet of the second A micromixer. The reaction mixture flowing out of the second microchannel reactor is mixed with water in the second A micromixer, and then enters the first continuous liquid-liquid extractor. After extraction with ethyl acetate or toluene, the organic phase flows out from the organic phase outlet of the first continuous liquid-liquid extractor, and the aqueous phase flows out from the aqueous phase outlet of the first continuous liquid-liquid extractor. The organic phase is collected, and the biphenyl chiral propylene glycol (3) is recovered for reuse; In step S3, a continuous cyclization reaction of the second product 5-hydroxymethyl-4-carboxylic acid compound (7) and an inorganic mineral acid (8) solution is carried out in a third microchannel reactor; the aqueous phase outlet of the first continuous liquid-liquid extractor is connected to a fluid inlet of a third micromixer, the reaction liquid flowing out of the aqueous phase outlet of the first continuous liquid-liquid extractor directly enters the fluid inlet of the third micromixer, the inorganic mineral acid (8) solution enters another fluid inlet of the third micromixer, and the outlet of the third micromixer is directly connected to a fluid inlet of the third microchannel reactor; the reaction liquid flowing out of the second microchannel reactor and the inorganic mineral acid (8) solution are mixed in the third micromixer and then directly enter the third microchannel reactor for a continuous cyclization reaction; The third microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 100 μm to 10 mm; the plate microchannel reactor comprises a first heat exchange layer, a reaction layer, and a second heat exchange layer arranged in sequence from top to bottom; the reaction layer is provided with a reaction fluid channel; the hydraulic diameter of the reaction fluid channel is 100 μm to 10 mm; The outlet of the third microchannel reactor is connected to a fluid inlet of the second continuous liquid-liquid extractor. The reaction mixture flowing out of the third microchannel reactor then enters the second continuous liquid-liquid extractor. After extraction with ethyl acetate or toluene, the organic phase flows out from the organic phase outlet of the second continuous liquid-liquid extractor, and the aqueous phase flows out from the aqueous phase outlet of the second continuous liquid-liquid extractor. The organic phase outlet of the second continuous liquid-liquid extractor is connected to the inlet of the first continuous concentrator. The reaction liquid flowing out of the organic phase outlet of the second continuous liquid-liquid extractor enters the first continuous concentrator for continuous concentration. In step S4, the thiolation reaction of (3aS, 6aR) lactone (9) and the thiolation reagent (10) is carried out in a fourth microchannel reactor; the outlet of the first continuous concentrator is connected to a fluid inlet of the fourth micromixer, the reaction liquid flowing out of the outlet of the first continuous concentrator directly enters the fluid inlet of the fourth micromixer, the solution of the thiolation reagent (10) enters another fluid inlet of the fourth micromixer, the outlet of the fourth micromixer is directly connected to a fluid inlet of the fourth microchannel reactor, and the outlet of the fourth microchannel reactor is connected to the inlet of the first back-pressure valve; the reaction liquid flowing out of the outlet of the first continuous concentrator and the solution of the thiolation reagent (10) are mixed in the fourth micromixer and then directly enter the fourth microchannel reactor for continuous thiolation reaction; the reaction liquid flowing out of the fourth microchannel reactor then enters the first back-pressure valve; Control the temperature in the fourth micro mixer to be 60-250°C; controlling the temperature in the fourth microchannel reactor to be 60-250° C.; The fourth microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 100 μm to 10 mm; the plate microchannel reactor comprises a first heat exchange layer, a reaction layer, and a second heat exchange layer arranged in sequence from top to bottom; the reaction layer is provided with a reaction fluid channel; the hydraulic diameter of the reaction fluid channel is 100 μm to 10 mm; Controlling the residence time of the mixed reaction materials in the fourth microchannel reactor to be 1 to 30 minutes; The back pressure value of the first back pressure valve is set to 0.1-2 MPa; In step S5, the Fukuyama coupling reaction of (3aS, 6aR) thiolactone (11) and the zinc reagent (12) is carried out in the fifth microchannel reactor; the outlet of the first back-pressure valve is connected to a fluid inlet of the fifth micromixer, the reaction liquid flowing out of the outlet of the first back-pressure valve enters the fluid inlet of the fifth micromixer, and the zinc reagent solution containing the palladium catalyst enters another fluid inlet of the fifth micromixer; the outlet of the fifth micromixer is connected to a fluid inlet of the fifth microchannel reactor, the reaction liquid flowing out of the fifth micromixer directly enters the fluid inlet of the fifth microchannel reactor, and the outlet of the fifth microchannel reactor is connected to the inlet of the second back-pressure valve; the reaction mixture formed after the reaction liquid flowing out of the first back-pressure valve and the zinc reagent solution containing the palladium catalyst are mixed in the fifth micromixer is directly fed into the fifth microchannel reactor for continuous Fukuyama coupling reaction; the reaction mixture flowing out of the fifth microchannel reactor is directly fed into the second back-pressure valve; The fifth microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 100 μm to 10 mm; the plate microchannel reactor includes a first heat exchange layer, a reaction layer, and a second heat exchange layer arranged in sequence from top to bottom; the reaction layer is provided with a reaction fluid channel; the hydraulic diameter of the reaction fluid channel is 100 μm to 10 mm; Controlling the residence time of the mixed reaction materials in the fifth microchannel reactor to be 0.5 to 30 minutes; In step S6, the elimination reaction of the fifth product hydroxyvalerate compound (13) under the action of the inorganic mineral acid (14) solution is carried out in the sixth microchannel reactor; the outlet of the second back-pressure valve is connected to a fluid inlet of the sixth micromixer, and the reaction liquid flowing out of the outlet of the second back-pressure valve directly enters the fluid inlet of the sixth micromixer, and the inorganic mineral acid (14) solution enters another fluid inlet of the sixth micromixer; the outlet of the sixth micromixer is directly connected to a fluid inlet of the sixth microchannel reactor, and the reaction mixture flowing out of the sixth micromixer directly enters the fluid inlet of the sixth microchannel reactor; the reaction mixture flowing out of the outlet of the second back-pressure valve and the inorganic mineral acid (14) solution are mixed in the sixth micromixer and then directly enter the sixth microchannel reactor for continuous elimination reaction; The outlet of the sixth microchannel reactor is connected to a fluid inlet of the first continuous liquid-liquid separator, and the reaction mixture flowing out of the sixth microchannel reactor directly enters the first continuous liquid-liquid separator, the aqueous phase flows out from the aqueous phase outlet of the first continuous liquid-liquid separator, and the organic phase flows out from the organic phase outlet of the first continuous liquid-liquid separator; The sixth microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 100 μm to 10 mm; the plate microchannel reactor comprises a first heat exchange layer, a reaction layer, and a second heat exchange layer arranged in sequence from top to bottom; the reaction layer is provided with a reaction fluid channel; the hydraulic diameter of the reaction fluid channel is 100 μm to 10 mm; controlling the temperature in the sixth microchannel reactor to be 5-100° C.; Controlling the residence time of the mixed reaction materials in the sixth microchannel reactor to be 0.5 to 30 minutes; In step S7, the hydrogenation reduction reaction of the sixth product, alkenyl valerate compound (15), is carried out in the seventh microchannel reactor under the action of a palladium / carbon catalyst; the organic phase outlet of the first continuous liquid-liquid separator is connected to a fluid inlet of the seventh micromixer, and the reaction liquid flowing out of the organic phase outlet of the first continuous liquid-liquid separator directly enters the fluid inlet of the seventh micromixer, and the hydrogen enters another fluid inlet of the seventh micromixer; the outlet of the seventh micromixer is directly connected to a fluid inlet of the seventh microchannel reactor, and the reaction mixture flowing out of the seventh micromixer directly enters the seventh microchannel reactor; the reaction liquid flowing out of the organic phase outlet of the first continuous liquid-liquid separator and the hydrogen are mixed in the seventh micromixer and then directly enter the seventh microchannel reactor. A continuous hydrogenation reduction reaction is carried out in the seventh microchannel reactor; the outlet of the seventh microchannel reactor is connected to a buffer tank, the bottom of the buffer tank is provided with a liquid outlet with a valve, the top of the buffer tank has a first interface connected to a nitrogen pipeline, a second interface connected to the outlet of the seventh microchannel reactor, and a third interface connected to a back pressure valve; the first interface is connected to nitrogen for providing pressure to the buffer tank, and the pressure of the connected nitrogen is adjustable in a range of 0.1 to 2.0 MPa, the third interface is connected to a third back pressure valve; the back pressure range of the third back pressure valve is 0.1 to 1.5 MPa; the pressure value of the connected nitrogen is 0.2 to 1.0 MPa greater than the back pressure value set by the third back pressure valve; the second interface is connected to the outlet of the seventh microchannel reactor; controlling the temperature in the seventh micromixer to be 10-120° C.; controlling the temperature in the seventh microchannel reactor to be 15-120° C.; Controlling the residence time of the mixed reaction materials in the seventh microchannel reactor to be 0.1 to 30 minutes; The seventh microchannel reactor is a micro fixed bed reactor filled with a palladium / carbon catalyst; the inner diameter of the micro fixed bed reactor is 1 mm to 100 mm; In step S8, the hydrolysis reaction of the seventh product valerate (16) under the action of the inorganic base (17) solution is carried out in the eighth microchannel reactor; the reaction liquid in the buffer tank is transported to a fluid inlet of the eighth micromixer, and the inorganic base (17) solution enters another fluid inlet of the eighth micromixer; the outlet of the eighth micromixer is directly connected to a fluid inlet of the eighth microchannel reactor, and the reaction mixture flowing out of the eighth micromixer directly enters the eighth microchannel reactor for continuous hydrolysis reaction; The outlet of the eighth microchannel reactor is connected to a fluid inlet of the second continuous liquid-liquid separator, and the reaction mixture flowing out of the eighth microchannel reactor directly enters the second continuous liquid-liquid separator, the aqueous phase flows out from an aqueous phase outlet of the second continuous liquid-liquid separator, and the organic phase flows out from an organic phase outlet of the second continuous liquid-liquid separator; controlling the temperature in the eighth micromixer to be 2 to 120° C.; controlling the temperature in the eighth microchannel reactor to be 15 to 150° C.; The eighth microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 100 μm to 50 mm; the hydraulic diameter of the reaction fluid channel of the plate microchannel reactor is 100 μm to 50 mm; Controlling the residence time of the mixed reaction materials in the eighth microchannel reactor to be within the range of 0.1 to 30 minutes; In step S9, a debenzylation reaction of the eighth product, valerate (18), under the action of an inorganic mineral acid (19) solution is carried out in a ninth microchannel reactor; the reaction liquid flowing out of the aqueous phase outlet of the second continuous liquid-liquid separator enters a fluid inlet of a ninth micromixer, and the inorganic mineral acid (19) solution enters another fluid inlet of the ninth micromixer; the outlet of the ninth micromixer is connected to a fluid inlet of the ninth microchannel reactor, and the reaction mixture flowing out of the ninth micromixer directly enters the ninth microchannel reactor for a continuous debenzylation reaction; Controlling the temperature in the ninth micromixer to be between -10°C and 25°C; controlling the temperature in the ninth microchannel reactor to be 25-200° C.; Controlling the residence time of the mixed reaction materials in the ninth microchannel reactor to be 0.1 to 30 minutes; The ninth micromixer is any one of a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer or a flow focusing micromixer; The ninth microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 100 μm to 50 mm; the hydraulic diameter of the reaction fluid channel of the plate microchannel reactor is 100 μm to 50 mm; The ninth microchannel reactor is a microwave flow chemical reactor; The outlet of the ninth microchannel reactor is connected to a fluid inlet of the tenth microchannel reactor, and the reaction liquid flowing out of the outlet of the ninth microchannel reactor directly enters the tenth microchannel reactor; The tenth microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 1 mm to 10 mm; the hydraulic diameter of the reaction fluid channel of the plate microchannel reactor is 1 mm to 10 mm; The temperature in the tenth microchannel reactor is controlled within the range of -35 to 10° C., and the target product can be crystallized and precipitated. The reaction mixture flowing out of the tenth microchannel reactor is collected and filtered to obtain the target product (+)-biotin.

2. The method according to claim 1, characterized in that In step S1: The molar ratio of the cyclic anhydride (2), the biphenyl chiral propylene glycol (3) and the organic base (4) is controlled within the range of 1:(0.8-3.0):(0.8-3.0); The solvent used to prepare the solution of the cyclic anhydride (2) and the solution of the biphenyl chiral propylene glycol (3) and the organic base (4) is selected from one of benzene, toluene, xylene, anisole, fluorobenzene, chlorobenzene, bromobenzene, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, ethyl ether, n-hexane, cyclohexane, acetonitrile, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, N-alkylpyridinium salt, 1,3-dialkylimidazolium salt, or a mixed solvent of multiple thereof.

3. The method according to claim 1, characterized in that In step S2: The borohydride (6) is selected from any one of lithium borohydride, sodium borohydride, potassium borohydride, and calcium borohydride; The solvent used to prepare the borohydride (6) solution is selected from one of benzene, toluene, xylene, anisole, fluorobenzene, chlorobenzene, bromobenzene, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, ethyl ether, n-hexane, cyclohexane, acetonitrile, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, N-alkylpyridinium salt, 1,3-dialkylimidazolium salt, or a mixed solvent of multiple thereof; The second micromixer is any one of a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer and a flow focusing micromixer; The molar ratio of the borohydride (6) to the first product dicarboxylic acid monoester compound (5) is controlled to be (1-8):

1.

4. The method according to claim 1, wherein In step S3: The inorganic mineral acid (8) is selected from any one of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; the inorganic mineral acid (8) solution is a solution prepared by dissolving the inorganic mineral acid (8) in water; The third micromixer is any one of a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer and a flow focusing micromixer; The molar ratio of the inorganic mineral acid (8) to the second product 5-hydroxymethyl-4-carboxylic acid compound (7) is controlled to be (1-50):

1.

5. The method according to claim 1, characterized in that In step S4: The solvent used to prepare the solution of the thio reagent (10) is any one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and sulfolane.

6. The method according to claim 1, characterized in that In step S5: The palladium catalyst is any one of palladium acetate, bis(triphenylphosphine)palladium dichloride, palladium / carbon, nano palladium and palladium hydroxide / carbon; The solvent used to prepare the zinc reagent solution containing the palladium catalyst is any one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and sulfolane; controlling the molar ratio of (3aS, 6aR) thiolactone (11) to the palladium catalyst to be 1:(0.001-0.500); The molar ratio of (3aS,6aR)thiolactone (11) to zinc reagent (12) is controlled to be 1:(1.0-8.0).

7. The method according to claim 1, characterized in that In step S6: The inorganic mineral acid (14) is any one of sulfuric acid, hydrochloric acid, boric acid, phosphoric acid, carbonic acid and nitric acid; The inorganic mineral acid (14) solution is a solution prepared by dissolving the inorganic mineral acid (14) in water; The molar ratio of the fifth product hydroxyvalerate compound (13) to the inorganic mineral acid (14) is controlled to be 1:(1-50).

8. The method according to claim 1, characterized in that In step S7: The palladium / carbon catalyst is a palladium-carbon Pd / C catalyst with a loading amount of 0.5 to 30%, or the palladium / carbon catalyst is a mixture formed by mixing a palladium-carbon Pd / C catalyst with a loading amount of 0.5 to 30% with inert solid medium particles; The molar ratio of the sixth product, the alkenyl valerate compound (15), to hydrogen is controlled to be 1:(0.8-50.0).

9. The method according to claim 1, characterized in that In step S8: The inorganic base (17) is any one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and lithium carbonate; the inorganic base (17) solution is a solution prepared by dissolving the inorganic base (17) in water; The molar ratio of valerate (16) to inorganic base (17) is controlled to be 1: (0.75-30).

10. The method according to claim 1, characterized in that In step S9, the eighth product valerate (18) is subjected to a debenzylation reaction in the presence of an inorganic mineral acid (19) solution to convert it into the target product (+)-biotin (1); The inorganic mineral acid (19) is hydrogen bromide or hydrogen chloride; the inorganic mineral acid (19) solution is a solution prepared by dissolving the inorganic mineral acid (19) in water; The molar ratio of valerate (18) to inorganic mineral acid (19) is controlled to be 1: (0.75-30).

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