Method for continuous photocatalytic synthesis of 2-(4-cyanophenyl)-N-Boc-ethylamine

Abstract

The invention discloses a method for continuously synthesizing 2-(4-cyanophenyl)-N-Boc-ethylamine by virtue of photocatalysis. The preparation method comprises the following steps: in the presence of a photocatalyst, enabling 4-chlorobenzonitrile, tert-butyl vinyl carbamate and (tri (trimethylsilyl) silane to react in a solvent through a photoreactor; and after the reaction is finished, extracting, drying and purifying by silica gel column chromatography to obtain a target product. By using the micro-channel photoreactor, efficient mixing, mass transfer enhancement, reaction time shortening and yield and purity improvement can be realized. The whole reaction process is continuous and closed, the liquid holdup is small, and the exposure risk of toxic chemicals is remarkably reduced. The solvent can be recycled, and the COD of the waste liquid is reduced by 70% or above. Equipment is easy to amplify, small in occupied area, energy-saving and economical, the obtained product meets the quality standard of GMP bulk drug intermediates, and the method is suitable for industrial production of vilazodone and other drugs.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for the continuous photocatalytic synthesis of 2-(4-cyanophenyl)-N-Boc-ethylamine. This product is a key intermediate in the antidepressant vilazorone. Background Technology

[0002] 2-(4-Cyanophenyl)-N-Boc-ethylamine is a high-value organic synthetic intermediate. Its molecule contains both an aromatic cyano group and a protected amino group, exhibiting excellent reactivity and functional group compatibility, making it widely applicable in the synthesis of pharmaceuticals, pesticides, and fine chemicals. Particularly in the pharmaceutical field, this compound is a key chiral precursor for the synthesis of the antidepressant vilazodone. Vilazodone, a partial agonist of the 5-HT1A receptor and a serotonin reuptake inhibitor (SSRI), has been approved in many countries worldwide for the treatment of major depressive disorder, placing stringent requirements on the purity, impurity profile, and batch consistency of the raw material intermediate.

[0003] Existing technologies primarily employ a batch-type photocatalytic process to synthesize this intermediate: 4-chlorobenzonitrile, tert-butylvinylcarbamate, a photocatalyst, and auxiliaries are placed in a glass or stainless steel reactor and reacted for several hours under LED or mercury lamp irradiation with stirring. However, this traditional process suffers from a fundamental bottleneck:

[0004] (1) Uneven illumination: The light path inside the vessel is long and the light intensity decreases sharply with depth, resulting in uneven distribution of reaction rate and local over-reaction to generate dimer byproducts;

[0005] (2) Mass transfer is limited: free radical intermediates have short lifespans, low mixing efficiency in the reactor, difficulty in achieving instantaneous uniform contact, and increased side reactions;

[0006] (3) Difficulty in thermal management: Photocatalysis is often accompanied by exothermic reactions. The slow heat dissipation of the batch system can easily cause a temperature surge, affecting selectivity and even causing safety accidents.

[0007] (4) Large liquid holding capacity: The volume of a single batch of reaction is usually tens to hundreds of liters, and a large amount of highly toxic raw materials (such as 4-chlorobenzonitrile) accumulate, resulting in high operational risks;

[0008] (5) Serious waste: It relies on high-boiling-point solvents, which are difficult to recover, and generate a large amount of nitrogen- and sulfur-containing organic waste liquid, resulting in high treatment costs;

[0009] (6) Scale-up difficulties: The conditions need to be re-optimized from the laboratory to the production, the "scale-up effect" is significant, and it is difficult to ensure consistent quality.

[0010] In contrast, continuous flow microreaction technology offers a systematic solution to the above problems:

[0011] (1) Enhanced light transmission: The microchannel size (usually <2 mm) is much smaller than the light penetration depth, ensuring uniform illumination across the entire reaction cross section and increasing photon utilization efficiency by 3-5 times;

[0012] (2) Enhanced mass transfer: The diffusion distance is extremely short at the microscale, the Reynolds number is controllable, and millisecond-level mixing is achieved, effectively suppressing side reactions;

[0013] (3) Precise temperature control: The high specific surface area allows heat to be removed instantly, and the reaction temperature fluctuation is <±1℃, ensuring high selectivity;

[0014] (4) Intrinsically safe: The liquid holding volume can be controlled to <50 mL. Even if an abnormality occurs, the energy of the hazard is extremely small, which meets the principle of "minimizing the amount of dangerous stock";

[0015] (5) Green and efficient: Solvent consumption is reduced by more than 70%, the acetonitrile / water system can be recycled, and the COD of waste liquid is significantly reduced;

[0016] (6) Seamless scaling up: Through the “numerical scaling up” strategy, linear scaling up from gram level to ton level can be achieved directly without redeveloping the process.

[0017] Therefore, developing a 2-(4-cyanophenyl)-N-Boc-ethylamine synthesis process based on a continuous flow photocatalytic microreactor can not only break through the performance ceiling of traditional batch technology, but also meet the modern pharmaceutical industry's manufacturing requirements for high quality, high efficiency, high safety, and high environmental protection, and has significant technological advancement and industrialization value. Summary of the Invention

[0018] The purpose of this invention is to provide a method for the continuous photocatalytic synthesis of 2-(4-cyanophenyl)-N-Boc-ethylamine.

[0019] To achieve the above objectives, this invention employs a continuous flow microchannel photoreactor. Under visible light irradiation, 10-phenylphenthiazide is used as a photocatalyst, tris(trimethylsilyl)silane is used as a hydrogen atom transfer (HAT) cocatalyst, and sodium formate is used as a sacrificial electron donor. The radical addition coupling of 4-chlorobenzonitrile and tert-butyl vinyl carbamate is achieved in an acetonitrile / water mixed solvent.

[0020] The photocatalytic reaction described in this invention follows a radical addition-hydrogen atom transfer (HAT) pathway. Under visible light irradiation at 330-450 nm, the photocatalyst 10-phenylphenthiazine (PTH) is excited to a singlet state, which then undergoes intersystem crossing to generate a triplet excited state (PTH). This excited state reduces 4-chlorobenzonitrile via single-electron transfer (SET), breaking the C-Cl bond to generate a 4-cyanophenyl radical (Ar·), while simultaneously converting PTH into a cationic radical (PTH·). +Ar· rapidly undergoes regioselective addition with tert-butylvinylcarbamate to form a carbon-centered radical intermediate. Subsequently, mediated by the co-catalyst tris(trimethylsilyl)silane, this intermediate seizes a hydrogen atom from the silane to generate the target product 2-(4-cyanophenyl)-N-Boc-ethylamine. Sodium formate is mainly responsible for regenerating the photocatalyst and maintaining the catalytic cycle; while tris(trimethylsilyl)silane specifically provides hydrogen atoms to the added alkyl radical, completing the hydrogen atom transfer (HAT) step and inhibiting dimerization or oxidation side reactions.

[0021] The present invention provides a method for the continuous photocatalytic synthesis of 2-(4-cyanophenyl)-N-Boc-ethylamine, and the reaction route is shown below:

[0022] .

[0023] Specifically, the following steps are included:

[0024] Step 1: Prepare solution A (main reaction solution): In a dry three-necked flask, add tert-butyl vinyl carbamate, 4-chlorobenzonitrile and sodium formate, add mixed solvent, stir to dissolve, so that the concentration of 4-chlorobenzonitrile in the system is 0.1-0.15M (preferably 0.14M), and obtain homogeneous solution A for later use.

[0025] Step 2: Prepare solution B (photocatalytic initiation solution): Add the photocatalyst and HAT reagent to another dry vial, dissolve them with an appropriate amount of anhydrous acetonitrile, and dilute to 20%–50% of the volume of solution A, preferably 40%, to obtain solution B. Prepare and use immediately to avoid prolonged storage.

[0026] Step 3: Continuous photoreaction: Solution A from Step 1 and Solution B from Step 2 are transported to a static mixer for premixing under an inert atmosphere via pumps 1 and 2, respectively. Then, they enter a continuous photoreactor made of transparent material and undergo photochemical reaction under visible light irradiation. The reaction solution flows into storage tank 1 for later use.

[0027] Step 4: Quenching: Add quenching solution (such as saturated sodium bicarbonate solution) to the reaction solution obtained in step 3, extract with organic solvent (such as ethyl acetate), and dry with drying agent (such as anhydrous magnesium sulfate);

[0028] Step 5: Purification: The organic phase obtained in Step 4 was concentrated and purified by silica gel column chromatography using a mixed solvent of ethyl acetate and n-hexane (volume ratio 5:95 to 40:60) as the eluent. The fraction containing the target product was collected by TLC monitoring (developing solvent: ethyl acetate / n-hexane = 1:3, Rf≈0.4). After concentration, a white solid 2-(4-cyanophenyl)-N-Boc-ethylamine was obtained.

[0029] As a further preferred option:

[0030] In step 1, the mixed solvent is composed of acetonitrile and water in a volume ratio of 10:1 to 20:1, preferably 14:1.

[0031] In step 1, the molar ratio of tert-butyl vinyl carbamate, 4-chlorobenzonitrile and sodium formate is controlled at 0.5-3: 1: 1-3, preferably 2.5: 1: 3.

[0032] In step 2, the photocatalyst is N-phenylphenoxazine, 10-phenylphenthiazine, 1,2,3,5-tetra(carbazole-9-yl)-4,6-dicyanophenyl (4CzIPN), or 9-mesine-10-methylacridinium salt (Mes-Acr). + The HAT reagent is one or more of the following: tris(trimethsilyl)silane, triethylsilane, cyclohexylthiol, and tert-butylthiol.

[0033] In step 2, the molar amount of the photocatalyst is 0.05-0.6 times the molar amount of 4-chlorobenzonitrile, more preferably 0.1 times; the molar amount of the HAT reagent is 0.01-0.5 times the molar amount of 4-chlorobenzonitrile, more preferably 0.2 times.

[0034] Furthermore, the molar ratio of the photocatalyst to the HAT reagent is 1:1.

[0035] In step 3, the photoreactor uses one of incandescent lamp, high-pressure mercury lamp, or LED lamp; the light-transmitting material of the photoreactor is selected from one of PFA, quartz, sapphire, or FEP; the feed pump is one or a combination of plunger pump, peristaltic pump, or diaphragm pump; the photochemical reaction pressure range is 0-3 MPa, the photoreaction residence time is 0.1-30 min, and the photochemical reaction temperature is 0-25℃; the inert gas is nitrogen, argon, or neon.

[0036] Furthermore, in step 3, the feed pump is preferably a plunger pump or a diaphragm pump; the photoreactor lamp is preferably a high-pressure mercury lamp or an LED lamp; the photoreactor is preferably made of quartz or sapphire; the pressure of the photochemical reaction is preferably 0.5-2 MPa; the residence time of the photochemical reaction is preferably 0.2-10 min; the wavelength of the photoreactor is preferably 330-450 nm; and the light intensity of the photoreactor is preferably 0-600 mw / cm². 2 .

[0037] In step 4, the quenching solution is one of water, saturated ammonium chloride solution, dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium bisulfite solution, and sodium thiosulfate solution. The desiccant is one or a combination of anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride, and silica gel.

[0038] Furthermore, the desiccant is preferably anhydrous magnesium sulfate; the quenching solution is preferably a saturated sodium bicarbonate solution, and the amount of saturated sodium bicarbonate solution used is preferably 2-3 times the volume of the reaction liquid.

[0039] The core of this invention lies in utilizing the structural characteristics of microchannel reactors to achieve synergistic enhancement of the light, mass, and heat fields, thereby completing highly selective conversion within a short residence time (10-30 min), avoiding the accumulation of highly active intermediates, and fundamentally improving reaction efficiency and safety.

[0040] Compared with the prior art, the present invention has the following outstanding advantages:

[0041] 1. Significantly improved reaction efficiency: The residence time is only 0.2-30 minutes, which is more than 98% shorter than the traditional batch reactor (8-12 hours), and the space-time yield is increased by dozens of times.

[0042] 2. Excellent product quality: GC purity ≥ 93.5%, total amount of key impurities (such as 4-cyanostyl styrene, dimer byproducts) < 1.5%, meeting GMP standards for active pharmaceutical ingredients intermediates.

[0043] 3. Intrinsically safe design: The reaction liquid holding volume is <50 mL, and the instantaneous amount of highly toxic materials is extremely low, eliminating the risk of thermal runaway and explosion.

[0044] 4. Green and sustainable: It adopts an acetonitrile / water green solvent system with a solvent recovery rate of ≥95% and a waste liquid COD value of ≤850mg / L, which is more than 70% lower than the traditional process.

[0045] 5. Easy to scale up industrially: Through parallel multi-channel "digital amplification", there is no need to re-optimize process parameters, achieving a seamless transition from laboratory to ton-level production.

[0046] 6. High degree of automation: The entire process is closed and continuous, reducing human intervention, lowering the risk of operator exposure, and meeting the requirements of modern intelligent manufacturing.

[0047] 7. Compared with traditional batch reactions, this invention employs continuous flow microreactor technology, which significantly improves reaction efficiency and product quality. For example, Example 1 (continuous flow) achieved a yield of 88.7% and a purity of 94% within 30 minutes, while the comparative example (Example 7, batch reaction) only achieved a yield of 75.9% after 10 hours of reaction, with a significant increase in byproducts. This fully demonstrates that this invention effectively solves the technical problems of uneven illumination, limited mass transfer, long reaction time, and poor selectivity in the prior art.

[0048] 8. After the reaction is complete, the acetonitrile solvent in the system can be recovered by conventional distillation or rectification, with a recovery rate of not less than 95%, which reflects the green sustainability of this process.

[0049] In summary, this invention not only solves the technical bottlenecks in traditional photocatalytic synthesis, but also constructs a standardized continuous flow process platform suitable for highly reactive free radical reactions, providing a replicable technical paradigm for the green, safe, and efficient manufacturing of pharmaceutical intermediates. Attached Figure Description

[0050] The invention will now be further described with reference to the accompanying drawings.

[0051] Figure 1 A process flow diagram for the photoreaction preparation of 2-(4-cyanophenyl)-N-Boc-ethylamine.

[0052] Figure 2 The image shows the 1H NMR spectrum of 2-(4-cyanophenyl)-N-Boc-ethylamine in Example 1.

[0053] Figure 3 The image shows the mass spectrum (MS) of 2-(4-cyanophenyl)-N-Boc-ethylamine. Detailed Implementation

[0054] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as described in detail in the claims. Unless otherwise specified, the experimental methods described in the following embodiments are conventional methods; the reagents and materials described, unless otherwise specified, are commercially available.

[0055] The reaction equations and microchannel reactor process flow diagrams in the following examples are described below:

[0056]

[0057] Example 1: Standard Conditions

[0058] (1) Preparation of solution A (main reaction solution): Add 5.00 g (34.92 mmol) tert-butylvinylcarbamate, 2.85 g (41.91 mmol) sodium formate and 1.92 g (13.96 mmol) 4-chlorobenzonitrile to a dry three-necked flask, add mixed solvent (acetonitrile:water = 14:1), and prepare a solution with a main substrate concentration of about 0.14 M and a total volume of about 100 mL. Stir until dissolved evenly, and use it as solution A for later use.

[0059] (2) Preparation of solution B (photocatalytic initiator): Add 192 mg (0.697 mmol, 5 mol%) of 10-phenylphenthiazide and 210 uL (0.697 mmol, 5 mol%) of tris(trimethylsilyl)silane to another dry vial, dissolve and dilute with anhydrous acetonitrile to 40 mL to obtain solution B. Prepare and use immediately to avoid prolonged storage.

[0060] (3) Start the continuous flow photocatalytic reaction system: Turn on the continuous flow photocatalytic reactor, turn on the temperature control to stabilize the reactor temperature at 10℃, and set the light source intensity to 400 mW / cm². 2 Solution A and solution B are pumped in separately using two independent feed pumps and then combined immediately before entering the photoreactor via a PTFE T-type mixer.

[0061] (4) Set the flow rate and reaction conditions: Adjust the flow rates of the two feed streams as follows: Solution A: (Pump 1, 0.7 mL / min), Solution B: (Pump 2, 0.3 mL / min) (total flow rate 1.0 mL / min). The reactor residence volume is 30 mL, corresponding to a residence time of 30 min. Maintain the reaction temperature at 5℃ and the system pressure at 1.0 MPa.

[0062] (5) Conduct the reaction and collect the product: Simultaneously pump all of solution A (100 mL) and solution B (40 mL) into the reaction system (total running time is about 140 min). Discard the first 30 mL of dead volume liquid that flows out initially, and collect the subsequent 140 mL of reaction liquid containing the product into storage tank 1 for later use.

[0063] (6) Quenching and extraction: Add 420 mL of saturated sodium bicarbonate aqueous solution to storage tank 1 to quench the reaction, then extract with ethyl acetate (3 × 250 mL), combine the organic phases, and dry with anhydrous magnesium sulfate.

[0064] (7) Concentration: The desiccant is removed by filtration, and the solvent is removed by rotary evaporation of the filtrate.

[0065] (8) Purification: The crude product was purified by silica gel column chromatography (silica gel 200-300 mesh, about 50g, dry loading). A gradient elution program was used: first, eluted for 3 column volumes with n-hexane / ethyl acetate = 95:5 (v / v) to remove nonpolar impurities; then, the gradient was increased to 90:10 and eluted for 3 column volumes to remove unreacted 4-chlorobenzonitrile; then, eluted for 2 column volumes each with 85:15 and 80:20 eluents, and the target compound 2-(4-cyanophenyl)-N-Boc-ethylamine was concentrated in this stage (monitored by TLC, the developing solvent was n-hexane / ethyl acetate = 80:20, Rf≈0.5); finally, residual polar byproducts (such as trace amounts of 4-cyanobenzylamine) were eluted with a gradient from 70:30 to 60:40. The fractions containing the target product were combined (shown as a single spot by TLC) and concentrated under reduced pressure to yield 3.05 g of the target compound 2-(4-cyanophenyl)-N-Boc-ethylamine, with a yield of 88.7%. HPLC analysis revealed that the key impurity, 4-cyanostylenite, was present at 0.32%. Acetonitrile was recovered from the reaction solution by vacuum distillation (40 °C, 0.09 MPa) with a recovery rate of 96.2%. The recovered solvent could be directly used in the next batch of reaction, and there was no significant difference in product quality.

[0066] 2-(4-cyanophenyl)-N-Boc-ethylamine NMR 1H NMR Figure 2 As shown, the 1H NMR (400 MHz, DMSO-D6) values ​​are δ 7.79 – 7.69 (m, 2H), 7.44 – 7.34 (m, 2H), 6.88 (s, 1H), 3.22 – 3.12 (m, 2H), 2.77 (q, J = 8.9 Hz, 2H), and 1.35 (s, 9H). The mass spectra are as follows. Figure 3 As shown: ESI-MS m / z: 217.1[M+H]⁺.

[0067] Example 2: Dwell time 5 min

[0068] (1) Preparation of solution A (main reaction solution): Add 5g (34.92 mmol) tert-butylvinylcarbamate, 2.85g (41.91 mmol) sodium formate and 1.92g (13.96 mmol) 4-chlorobenzonitrile to a dry three-necked flask, add mixed solvent (acetonitrile:water = 14:1) to prepare a solution with a main substrate concentration of about 0.14 M and a total volume of about 100 mL. Stir until dissolved evenly and use as solution A.

[0069] (2) Preparation of solution B (photocatalytic initiator): Add 192 mg (0.697 mmol, 5 mol%) of 10-phenylphenthiazide and 210 μL (0.697 mmol, 5 mol%) of tris(trimethylsilyl)silane to another dry vial, dissolve and dilute with anhydrous acetonitrile to 40 mL to obtain solution B. Prepare and use immediately to avoid prolonged storage.

[0070] (3) Start the continuous flow photocatalytic reaction system: turn on Figure 2 The continuous flow photocatalytic reactor shown was equipped with temperature control to stabilize the reactor temperature at 10°C, and the light source intensity was set to 400 mW / cm². 2 Solution A and solution B are pumped in separately using two independent feed pumps and then combined immediately before entering the photoreactor via a PTFE T-type mixer.

[0071] (4) Set the flow rate and reaction conditions: Adjust the flow rates of the two feed streams as follows: Solution A: (Pump 1, 8 mL / min), Solution B: (Pump 2, 2 mL / min) (total flow rate 10 mL / min). The reactor residence volume is 50 mL, corresponding to a residence time of 5 min. Maintain the reaction temperature at 5℃ and the system pressure at 1.0 MPa.

[0072] (5) Conduct the reaction and collect the product: Simultaneously pump all of solution A (100 mL) and solution B (40 mL) into the reaction system (total running time is about 14 min). Discard the first 50 mL of dead volume liquid that flows out initially, and collect the subsequent 140 mL of reaction liquid containing the product into storage tank 1 for later use.

[0073] (6) Quenching and extraction: Add 420 mL of saturated sodium bicarbonate aqueous solution to storage tank 1 to quench the reaction, and then extract with ethyl acetate (3 × 250 mL). Combine the organic phases and dry with anhydrous magnesium sulfate.

[0074] (7) Concentration: The desiccant is removed by filtration, and the solvent is removed by rotary evaporation of the filtrate.

[0075] (8) Purification: The crude product was purified by silica gel column chromatography (eluent gradient: ethyl acetate: n-hexane = 5:95 → 40:60) (silica gel 200-300 mesh, about 50 g, dry loading). The gradient elution program was as follows: first, elute 3 column volumes with n-hexane / ethyl acetate = 95:5 (v / v) to remove non-polar impurities; then, the gradient was increased to 90:10 to elute 3 column volumes to remove unreacted 4-chlorobenzonitrile; then, elute 2 column volumes each with 85:15 and 80:20 eluents, and the target compound 2-(4-cyanophenyl)-N-Boc-ethylamine was concentrated in this stage (by TLC monitoring, the developing solvent was n-hexane / ethyl acetate = 80:20, Rf ≈ 0.5); finally, residual polar byproducts (such as trace amounts of 4-cyanobenzylamine) were eluted with a gradient of 70:30 to 60:40. The fractions containing the target product were combined and concentrated under reduced pressure to give 2.35 g of the target compound 2-(4-cyanophenyl)-N-Boc-ethylamine, with a yield of 68.4%.

[0076] Example 3: Temperature 25℃

[0077] (1) Preparation of solution A (main reaction solution): Add 5.00 g (34.92 mmol) tert-butylvinylcarbamate, 2.85 g (41.91 mmol) sodium formate and 1.92 g (13.96 mmol) 4-chlorobenzonitrile to a dry three-necked flask, add mixed solvent (acetonitrile:water = 14:1) to prepare a solution with a main substrate concentration of about 0.14 M and a total volume of about 100 mL. Stir until dissolved evenly and use as solution A for later use.

[0078] (2) Preparation of solution B (photocatalytic initiator): Add 192 mg (0.697 mmol, 5 mol%) of 10-phenylphenthiazide and 210 μL (0.697 mmol, 5 mol%) of tris(trimethylsilyl)silane to another dry vial, dissolve and dilute with anhydrous acetonitrile to 40 mL to obtain solution B. Prepare and use immediately to avoid prolonged storage.

[0079] (3) Start the continuous flow photocatalytic reaction system: turn on Figure 2 The continuous flow photocatalytic reactor shown was equipped with temperature control to stabilize the reactor temperature at 25°C, and the light source intensity was set to 400 mW / cm². 2 Solution A and solution B are pumped in separately using two independent feed pumps and then combined immediately before entering the photoreactor via a PTFE T-type mixer.

[0080] (4) Setting the flow rate and reaction conditions: Adjust the flow rates of the two feed streams to 0.7 mL / min for solution A and 0.3 mL / min for solution B (total flow rate 1.0 mL / min). The reactor residence volume is 30 mL, corresponding to a residence time of 30 min. Maintain the reaction temperature at 25℃ and the system pressure at 1.0 MPa.

[0081] (5) Conduct the reaction and collect the product: Simultaneously pump all of solution A (100 mL) and solution B (40 mL) into the reaction system (total running time is about 140 min). Discard the first 30 mL of dead volume liquid that flows out initially, and collect the subsequent 110 mL of reaction liquid containing the product into storage tank 1 for later use.

[0082] (6) Quenching and extraction: Add 420 mL of saturated sodium bicarbonate aqueous solution to storage tank 1 to quench the reaction, and then extract with ethyl acetate (3 × 250 mL). Combine the organic phases and dry with anhydrous magnesium sulfate.

[0083] (7) Concentration: The desiccant is removed by filtration, and the solvent is removed by rotary evaporation of the filtrate.

[0084] (8) Purification: The crude product was purified by silica gel column chromatography (silica gel 200-300 mesh, about 50g, dry loading). A gradient elution program was used: first, eluted for 3 column volumes with n-hexane / ethyl acetate = 95:5 (v / v) to remove nonpolar impurities; then, the gradient was increased to 90:10 and eluted for 3 column volumes to remove unreacted 4-chlorobenzonitrile; then, eluted for 2 column volumes each with 85:15 and 80:20 eluents, and the target compound 2-(4-cyanophenyl)-N-Boc-ethylamine was concentrated in this stage (monitored by TLC, the developing solvent was n-hexane / ethyl acetate = 80:20, Rf≈0.5); finally, residual polar byproducts (such as trace amounts of 4-cyanobenzylamine) were eluted with a gradient from 70:30 to 60:40. The fractions containing the target product were combined (shown as a single spot by TLC) and concentrated under reduced pressure to give 2.54 g of the target compound 2-(4-cyanophenyl)-N-Boc-ethylamine, with a yield of 73.8%.

[0085] Example 4: No light conditions

[0086] (1) Preparation of solution A (main reaction solution): Add 5.00 g (34.92 mmol) tert-butylvinylcarbamate, 2.85 g (41.91 mmol) sodium formate and 1.92 g (13.96 mmol) 4-chlorobenzonitrile to a dry three-necked flask, add mixed solvent (acetonitrile:water = 14:1) to prepare a solution with a main substrate concentration of about 0.14 M and a total volume of about 100 mL. Stir until dissolved evenly and use as solution A.

[0087] (2) Preparation of solution B (photocatalytic initiator): Add 192 mg (0.697 mmol, 5 mol%) of 10-phenylphenthiazide and 210 μL (0.697 mmol, 5 mol%) of tris(trimethylsilyl)silane to another dry vial, dissolve and dilute with anhydrous acetonitrile to 40 mL to obtain solution B, which should be prepared and used immediately.

[0088] (3) Start the continuous flow reaction system (turn off the light source): Turn on Figure 2 The continuous flow reactor shown is controlled by temperature control to stabilize the reactor temperature at 10°C, and the light source is turned off (intensity 0 mW / cm²). 2 Solution A and solution B are pumped in separately using two independent feed pumps and then combined immediately before entering the reactor via a PTFE T-type mixer.

[0089] (4) Set the flow rate and reaction conditions: Adjust the flow rates of the two feed streams to 0.7 mL / min for solution A and 0.3 mL / min for solution B (total flow rate 1.0 mL / min). The reactor residence volume is 30 mL, corresponding to a residence time of 30 min. Maintain the reaction temperature at 10℃ and the system pressure at 1.0 MPa.

[0090] (5) Conduct the reaction and collect the products: Simultaneously pump all of solution A (100 mL) and solution B (40 mL) into the reaction system (total running time is about 140 min). Discard the first 30 mL of dead volume liquid that flows out initially, and collect the remaining 110 mL of reaction solution into storage tank 1.

[0091] (6) Quenching and extraction: Quench with 420 mL of saturated sodium bicarbonate aqueous solution in storage tank 1, and then extract with ethyl acetate (3 × 250 mL). Combine the organic phases and dry with anhydrous magnesium sulfate.

[0092] (7) Concentration: The desiccant is removed by filtration, and the solvent is removed by rotary evaporation of the filtrate.

[0093] (8) Purification: The crude product was purified by silica gel column chromatography (silica gel 200-300 mesh, about 50g, dry loading). A gradient elution program was used: first, eluted for 3 column volumes with n-hexane / ethyl acetate = 95:5 (v / v) to remove nonpolar impurities; then, the gradient was increased to 90:10 and eluted for 3 column volumes to remove unreacted 4-chlorobenzonitrile; then, eluted for 2 column volumes each with 85:15 and 80:20 eluents, and the target compound 2-(4-cyanophenyl)-N-Boc-ethylamine was concentrated in this stage (monitored by TLC, the developing solvent was n-hexane / ethyl acetate = 80:20, Rf ≈ 0.5); finally, residual polar byproducts (such as trace amounts of 4-cyanobenzylamine) were eluted with a gradient from 70:30 to 60:40. The fractions containing the target product were combined (TLC showed a single spot), concentrated under reduced pressure, and only trace amounts of the target product (<5%) were obtained, indicating that light irradiation is a necessary condition for this conversion.

[0094] Example 5: Catalyst amount 1 mol%

[0095] (1) Preparation of solution A (main reaction solution): Add 5.00 g (34.92 mmol) tert-butylvinylcarbamate, 2.85 g (41.91 mmol) sodium formate and 1.92 g (13.96 mmol) 4-chlorobenzonitrile to a dry three-necked flask, add mixed solvent (acetonitrile:water = 14:1) to prepare a solution with a main substrate concentration of about 0.14 M and a total volume of about 100 mL. Stir until dissolved evenly and use as solution A.

[0096] (2) Preparation of solution B (photocatalytic initiator): Add 34.8 mg (0.139 mmol, 1 mol%) of 10-phenylphenthiazide and 210 μL (0.697 mmol, 5 mol%) of tris(trimethylsilyl)silane to another dry vial, dissolve and dilute with anhydrous acetonitrile to 40 mL to obtain solution B. Prepare and use immediately to avoid prolonged storage.

[0097] (3) Start the continuous flow photocatalytic reaction system: turn on Figure 2 The continuous flow photocatalytic reactor shown was equipped with temperature control to stabilize the reactor temperature at 10°C, and the light source intensity was set to 400 mW / cm². 2 Solution A and solution B are pumped in separately using two independent feed pumps, and then combined immediately before entering the photoreactor via a PTFE T-type mixer.

[0098] (4) Set the flow rate and reaction conditions: Adjust the flow rates of the two feed streams to 0.7 mL / min for solution A and 0.3 mL / min for solution B (total flow rate 1.0 mL / min). The reactor residence volume is 30 mL, corresponding to a residence time of 30 min. Maintain the reaction temperature at 10℃ and the system pressure at 1.0 MPa.

[0099] (5) Conduct the reaction and collect the product: Simultaneously pump all of solution A (100 mL) and solution B (40 mL) into the reaction system (total running time is about 140 min). Discard the first 30 mL of dead volume liquid that flows out initially, and collect the subsequent 110 mL of reaction liquid containing the product into storage tank 1 for later use.

[0100] (6) Quenching and extraction: Add 420 mL of saturated sodium bicarbonate aqueous solution to storage tank 1 to quench the reaction, and then extract with ethyl acetate (3 × 250 mL). Combine the organic phases and dry with anhydrous magnesium sulfate.

[0101] (7) Concentration: The desiccant is removed by filtration, and the solvent is removed by rotary evaporation of the filtrate.

[0102] (8) Purification: The crude product was purified by silica gel column chromatography (silica gel 200-300 mesh, about 50g, dry loading). A gradient elution program was used: first, eluted for 3 column volumes with n-hexane / ethyl acetate = 95:5 (v / v) to remove nonpolar impurities; then, the gradient was increased to 90:10 to elute for 3 column volumes to remove unreacted 4-chlorobenzonitrile; then, eluted for 2 column volumes each with 85:15 and 80:20 eluents, and the target compound 2-(4-cyanophenyl)-N-Boc-ethylamine was concentrated in this stage (monitored by TLC, the developing solvent was n-hexane / ethyl acetate = 80:20, Rf ≈ 0.5); finally, residual polar byproducts (such as trace amounts of 4-cyanobenzylamine) were eluted with a gradient of 70:30 to 60:40. The fractions containing the target product were combined (shown as a single spot by TLC), concentrated under reduced pressure, and 1.98 g of the target compound 2-(4-cyanophenyl)-N-Boc-ethylamine was obtained, with a yield of 57.6%.

[0103] Example 6: HAT-free reagent

[0104] (1) Preparation of solution A (main reaction solution): Add 5.00 g (34.92 mmol) tert-butylvinylcarbamate, 2.85 g (41.91 mmol) sodium formate and 1.92 g (13.96 mmol) 4-chlorobenzonitrile to a dry three-necked flask, add mixed solvent (acetonitrile:water = 14:1) to prepare a solution with a main substrate concentration of about 0.14 M and a total volume of about 100 mL. Stir until dissolved evenly and use as solution A.

[0105] (2) Preparation of solution B (photocatalytic initiator, without HAT reagent): Add 192 mg (0.697 mol, 5 mol%) of 10-phenylphenthiazide to another dry vial, without adding tris(trimethylsilyl)silane, dissolve and dilute with anhydrous acetonitrile to 40 mL to obtain solution B, which should be prepared and used immediately.

[0106] (3) Start the continuous flow photocatalytic reaction system: turn on Figure 2 The continuous flow photocatalytic reactor shown was equipped with temperature control to stabilize the reactor temperature at 10°C, and the light source intensity was set to 400 mW / cm². 2 Solution A and solution B are pumped in separately using two independent feed pumps and then combined immediately before entering the photoreactor via a PTFE T-type mixer.

[0107] (4) Set the flow rate and reaction conditions: Adjust the flow rates of the two feed streams as follows: Solution A: (Pump 1, 0.7 mL / min), Solution B: (Pump 2, 0.3 mL / min) (total flow rate 1.0 mL / min). The reactor residence volume is 30 mL, corresponding to a residence time of 30 min. Maintain the reaction temperature at 5℃ and the system pressure at 1.0 MPa.

[0108] (5) Conduct the reaction and collect the product: Simultaneously pump all of solution A (100 mL) and solution B (40 mL) into the reaction system (total running time is about 140 min). Discard the first 30 mL of dead volume liquid that flows out initially, and collect the subsequent 140 mL of reaction liquid containing the product into storage tank 1 for later use.

[0109] (6) Quenching and extraction: Add 420 mL of saturated sodium bicarbonate aqueous solution to storage tank 1 to quench the reaction, and then extract with ethyl acetate (3 × 250 mL). Combine the organic phases and dry with anhydrous magnesium sulfate.

[0110] (7) Concentration: The desiccant is removed by filtration, and the solvent is removed by rotary evaporation of the filtrate.

[0111] (8) Purification: The crude product was purified by silica gel column chromatography (silica gel 200-300 mesh, about 50g, dry loading). A gradient elution program was used: first, eluted for 3 column volumes with n-hexane / ethyl acetate = 95:5 (v / v) to remove nonpolar impurities; then, the gradient was increased to 90:10 and eluted for 3 column volumes to remove unreacted 4-chlorobenzonitrile; then, eluted for 2 column volumes each with 85:15 and 80:20 eluents, and the target compound 2-(4-cyanophenyl)-N-Boc-ethylamine was concentrated in this stage (monitored by TLC, the developing solvent was n-hexane / ethyl acetate = 80:20, Rf≈0.5); finally, residual polar byproducts (such as trace amounts of 4-cyanobenzylamine) were eluted with a gradient from 70:30 to 60:40. The fractions containing the target product were combined (shown as a single spot by TLC) and concentrated under reduced pressure to yield 1.42 g of the target compound 2-(4-cyanophenyl)-N-Boc-ethylamine, with a yield of only 41.2%. HPLC analysis showed a significant increase in byproducts, mainly including incompletely converted intermediates and a small amount of dimerizing byproducts.

[0112] Conclusion: The HAT reagent (tris(trimethylsilyl)silane) plays a key role in the hydrogen atom transfer process. Its absence leads to the obstruction of free radical chain propagation, resulting in a significant decrease in reaction efficiency and selectivity.

[0113] Example 7: Sodium formate-free

[0114] (1) Prepare solution A (main reaction solution, without sodium formate): Add 5.00 g (34.92 mmol) tert-butylvinyl carbamate and 1.92 g (13.96 mmol) 4-chlorobenzonitrile to a dry three-necked flask without adding sodium formate. Add 100 mL of acetonitrile and stir until dissolved evenly. This solution is prepared for use as solution A.

[0115] (2) Preparation of solution B (photocatalytic initiator): Add 192 mg (0.697 mmol, 5 mol%) of 10-phenylphenthiazide and 210 μL (0.697 mmol, 5 mol%) of tris(trimethylsilyl)silane to another dry vial, dissolve and dilute with anhydrous acetonitrile to 40 mL to obtain solution B, which should be prepared and used immediately.

[0116] (3) Start the continuous flow photocatalytic reaction system: turn on Figure 2 The continuous flow photocatalytic reactor shown was equipped with temperature control to stabilize the reactor temperature at 10°C, and the light source intensity was set to 400 mW / cm². 2 Solution A and solution B are pumped in separately using two independent feed pumps and then combined immediately before entering the photoreactor via a PTFE T-type mixer.

[0117] (4) Set the flow rate and reaction conditions: Adjust the flow rates of the two feed streams as follows: Solution A: (Pump 1, 0.7 mL / min), Solution B: (Pump 2, 0.3 mL / min) (total flow rate 1.0 mL / min). The reactor residence volume is 30 mL, corresponding to a residence time of 30 min. Maintain the reaction temperature at 5℃ and the system pressure at 1.0 MPa.

[0118] (5) Conduct the reaction and collect the product: Simultaneously pump all of solution A (100 mL) and solution B (40 mL) into the reaction system (total running time is about 140 min). Discard the first 30 mL of dead volume liquid that flows out initially, and collect the subsequent 140 mL of reaction liquid containing the product into storage tank 1 for later use.

[0119] (6) Quenching and extraction: Add 420 mL of saturated sodium bicarbonate aqueous solution to storage tank 1 to quench the reaction, and then extract with ethyl acetate (3 × 250 mL). Combine the organic phases and dry with anhydrous magnesium sulfate.

[0120] (7) Concentration: The desiccant is removed by filtration, and the solvent is removed by rotary evaporation of the filtrate.

[0121] (8) Purification: The crude product was purified by silica gel column chromatography (silica gel 200-300 mesh, about 50g, dry loading). A gradient elution program was used: first, eluted for 3 column volumes with n-hexane / ethyl acetate = 95:5 (v / v) to remove nonpolar impurities; then, the gradient was increased to 90:10 and eluted for 3 column volumes to remove unreacted 4-chlorobenzonitrile; then, eluted for 2 column volumes each with 85:15 and 80:20 eluents, and the target compound 2-(4-cyanophenyl)-N-Boc-ethylamine was concentrated in this stage (monitored by TLC, the developing solvent was n-hexane / ethyl acetate = 80:20, Rf≈0.5); finally, residual polar byproducts (such as trace amounts of 4-cyanobenzylamine) were eluted with a gradient of 70:30 to 60:40. The fractions containing the target product were combined (shown as a single spot by TLC) and concentrated under reduced pressure to give 1.34 g of the target compound 2-(4-cyanophenyl)-N-Boc-ethylamine, with a yield of only 38.7%. A high proportion of unreacted 4-chlorobenzonitrile was detected in the reaction solution.

[0122] Conclusion: The electron donor (sodium formate) acts as a sacrificial reducing agent, regenerating the photocatalyst and promoting the generation of free radicals in the photocatalytic cycle. Its absence leads to low efficiency of the catalytic cycle and makes it difficult for the reaction to proceed fully.

[0123] Example 8: Traditional batch photocatalytic reaction

[0124] To verify the superiority of the continuous flow process described in this invention in terms of reaction efficiency, product purity, and by-product control, the following control experiment was conducted:

[0125] Take a solution A with the same composition as in Example 1, containing 1.92 g (13.96 mmol) of 4-chlorobenzonitrile, 5 g (34.92 mol) of tert-butylvinylcarbamate, 192 mg (0.697 mmol, 5 mol%) of 10-phenylphenthiazide, 210 μL (0.697 mmol, 5 mol%) of tris(trimethylsilyl)silane, and 41.91 mmol of sodium formate, and dissolve it in a mixed solvent of 133 mL of acetonitrile and 7 mL of deionized water. Transfer the entire solution to a 250 mL three-necked round-bottom flask. Place the flask in an ice-water bath and maintain the temperature at 10°C. Use the same LED light source as in Example 1 (main wavelength 400 nm, light intensity 400 mW / cm²). 2 The reaction liquid was illuminated vertically from above while being magnetically stirred at 600 rpm to ensure uniform mixing. The reaction was allowed to proceed for 10 hours. After the reaction was complete, the illumination was stopped, the ice bath was removed, and 420 mL of saturated sodium bicarbonate aqueous solution was added to the reaction liquid to quench the reaction. The product was then extracted with ethyl acetate (3 × 250 mL), and the organic phases were combined. The mixture was washed successively with saturated brine (200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200–300 mesh silica gel, approximately 50 g, dry loading) using a gradient elution program: first, eluted for 3 column volumes with n-hexane / ethyl acetate = 95:5 (v / v) to remove nonpolar impurities; then, eluted for 3 column volumes with a gradient increasing to 90:10 to remove unreacted 4-chlorobenzonitrile; next, eluted for 2 column volumes each with 85:15 and 80:20 eluents, during which the target compound 2-(4-cyanophenyl)-N-Boc-ethylamine was concentrated (monitored by TLC, developing solvent was n-hexane / ethyl acetate = 80:20, Rf ≈ 0.5); finally, eluted with 70:30 to 60:40... Gradient elution was performed to remove residual polar byproducts (such as trace amounts of 4-cyanobenzylamine). The fractions containing the target product were combined (shown as a single spot by TLC) and concentrated under reduced pressure to give 2.62 g of a white solid. Major impurities included trace amounts of unreacted 4-chlorobenzonitrile and trace amounts of the reduction byproduct 4-cyanobenzylamine, with a yield of 75.9%.

[0126] Conclusion: The photocatalyst, HAT reagent, and electron donor work synergistically and are indispensable, forming the technical basis for the efficient and highly selective conversion of this invention. Reaction temperature, light intensity, material residence time, and catalyst dosage are key parameters affecting product yield and purity. The optimal conditions are: temperature 10℃ and light intensity 400 mW / cm². 2The residence time is 30 min and the photocatalyst dosage is 5 mol. Compared with the batch process, the continuous flow process increases the yield by 13%, the purity by 7%, reduces by-products by more than 50%, shortens the time by 30 times, and significantly improves safety.

[0127] The above detailed embodiments describe the analytical methods involved in this invention. It should be noted that the above description is only to help those skilled in the art better understand the methods and ideas of this invention, and is not intended to limit the scope of the invention. This invention provides a simple and environmentally friendly photocatalytic synthesis method for 2-(4-cyanophenyl)-N-Boc-ethylamine, suitable for large-scale production. By optimizing the reaction conditions, the reaction efficiency and product yield are significantly improved.

[0128] The continuous photocatalytic synthesis method provided by this invention overcomes many technical bottlenecks of traditional batch-process synthesis. The product quality meets GMP standards and can be directly applied to the industrial production of antidepressants such as vilazorone. This process can also be extended to the photocatalytic addition reactions of other cyano-containing aromatic compounds, providing a standardized technical platform for the green manufacturing of pharmaceutical and pesticide intermediates.

Claims

1. A method for the continuous photocatalytic synthesis of 2-(4-cyanophenyl)-N-Boc-ethylamine, characterized in that: A continuous flow microchannel photoreactor was used to achieve radical addition coupling of 4-chlorobenzonitrile and tert-butyl vinyl carbamate in an acetonitrile / water mixed solvent under visible light irradiation, in the presence of a photocatalyst and HAT reagent, with sodium formate as a sacrificial electron donor. The reaction route is shown below: 。 2. The method according to claim 1, characterized in that... Includes the following steps: Step 1: Prepare solution A In a dry reactor, tert-butyl vinyl carbamate, 4-chlorobenzonitrile and sodium formate are added, along with a mixed solvent. The mixture is stirred to dissolve the 4-chlorobenzonitrile in the system to a concentration of 0.1-0.15 M, yielding a homogeneous solution A for later use. Step 2: Prepare solution B In another dry reactor, add the photocatalyst and HAT reagent, dissolve them in anhydrous acetonitrile, and dilute to 20%-50% of the volume of solution A to obtain solution B, which should be prepared and used immediately. Step 3: Continuous light reaction Solution A obtained in step 1 and solution B obtained in step 2 are transported to a static mixer for premixing under an inert atmosphere via pump 1 and pump 2, respectively. Then they enter a continuous flow photoreactor made of transparent material and undergo photochemical reaction under visible light irradiation. The reaction solution flows into storage tank 1 for later use. Step 4: Quenching Add quenching solution to the reaction solution obtained in step 3, extract with organic solvent, and dry with desiccant; Step 5: Refining The organic phase obtained in step 4 was concentrated and purified by silica gel column chromatography using a mixed solvent of ethyl acetate and n-hexane as the eluent. The fraction containing the target product was collected by TLC monitoring and concentrated to obtain a white solid 2-(4-cyanophenyl)-N-Boc-ethylamine.

3. The method according to claim 2, characterized in that: In step 1, the mixed solvent is composed of acetonitrile and water in a volume ratio of 10:1 to 20:

1.

4. The method according to claim 2, characterized in that: In step 1, the molar ratio of tert-butyl vinyl carbamate, 4-chlorobenzonitrile, and sodium formate is controlled at 0.5-3 : 1 : 1-3.

5. The method according to claim 2, characterized in that: In step 2, the photocatalyst is one or more of N-phenylphenoxazine, 10-phenylphenthiazine, 1,2,3,5-tetra(carbazole-9-yl)-4,6-dicyanobenzene, and 9-trimethylmethyl-10-methylacridinium salt; the HAT reagent is one or more of tris(trimethyl)silane, triethylsilane, cyclohexylthiol, and tert-butylthiol.

6. The method according to claim 5, characterized in that: The molar amount of the photocatalyst is 0.05-0.6 times the molar amount of 4-chlorobenzonitrile; the molar amount of the HAT reagent is 0.01-0.5 times the molar amount of 4-chlorobenzonitrile.

7. The method according to claim 6, characterized in that: The molar ratio of the photocatalyst to the HAT reagent is 1:

1.

8. The method according to claim 2, characterized in that: In step 3, the photochemical reaction pressure range is 0-3 MPa, the photochemical reaction residence time is 0.1-30 min, and the photochemical reaction temperature is 0-25℃.

9. The method according to claim 2, characterized in that: In step 4, the quenching solution is one of water, saturated ammonium chloride solution, dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium bisulfite solution, and sodium thiosulfate solution.

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