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CN-122010784-A - Method for continuously synthesizing 2- (4-cyanophenyl) -N-Boc-ethylamine by photocatalysis

CN122010784ACN 122010784 ACN122010784 ACN 122010784ACN-122010784-A

Abstract

The invention discloses a method for continuously synthesizing 2- (4-cyanophenyl) -N-Boc-ethylamine by photocatalysis. The invention uses a micro-channel photo-reactor to realize efficient mixing, strengthen mass transfer, shorten reaction time, improve yield and purity, and the whole reaction process is continuously sealed, has small liquid holdup, obviously reduces exposure risk of toxic chemicals, can recycle the solvent, reduces COD of waste liquid by more than 70 percent, is easy to enlarge equipment, occupies small area, saves energy and is economical, and the obtained product accords with the quality standard of GMP bulk drug intermediates, and is suitable for industrial production of medicines such as vilazodone.

Inventors

  • MENG XIANGMING
  • ZHANG YONGFU
  • TONG JIANCHENG

Assignees

  • 安徽大学

Dates

Publication Date
20260512
Application Date
20260202

Claims (9)

  1. 1. A method for continuously synthesizing 2- (4-cyanophenyl) -N-Boc-ethylamine by photocatalysis is characterized in that: adopting a continuous flow micro-channel photoreactor, and under the existence of visible light irradiation, a photocatalyst and a HAT reagent, taking sodium formate as a sacrificial electron donor, and realizing the free radical addition coupling of 4-chlorobenzonitrile and tert-butyl vinyl carbamate in an acetonitrile/water mixed solvent; The reaction scheme is as follows: 。
  2. 2. the method according to claim 1, characterized by the steps of: Step 1, preparing a solution A Adding tert-butyl vinyl carbamate, 4-chlorobenzonitrile and sodium formate into a dry reactor, adding a mixed solvent, stirring and dissolving to ensure that the concentration of the 4-chlorobenzonitrile in the system is 0.1-0.15M, and obtaining a homogeneous phase solution A for later use; Step 2, preparing solution B Adding a photocatalyst and a HAT reagent into another dry reactor, dissolving by using anhydrous acetonitrile, and diluting to 20-50% of the volume of the solution A to obtain a solution B, wherein the solution B is prepared for use at present; Step 3 continuous photoreaction The solution A obtained in the step 1 and the solution B obtained in the step 2 are respectively conveyed to a static mixer for premixing under inert atmosphere through a pump 1 and a pump 2, then enter a continuous flow photoreactor made of transparent materials, carry out photochemical reaction under visible light irradiation, and the reaction liquid flows into a storage tank 1 for standby; Step 4, quenching Adding quenching liquid into the reaction liquid obtained in the step 3, extracting with an organic solvent, and drying with a drying agent; Step 5, refining The organic phase obtained in the step 4 is concentrated and purified by silica gel column chromatography, a mixed solvent of ethyl acetate and normal hexane is used as an eluent, the fraction containing the target product is monitored and collected by TLC, and the white solid 2- (4-cyanophenyl) -N-Boc-ethylamine is obtained after concentration.
  3. 3. The method according to claim 2, characterized in that: In the step 1, the mixed solvent is formed by mixing acetonitrile and water, and the volume ratio is 10:1 to 20:1.
  4. 4. The method according to claim 2, characterized in that: In the step 1, the mol ratio of the tert-butyl vinyl carbamate, the 4-chlorobenzonitrile and the sodium formate is controlled to be 0.5-3:1:1-3.
  5. 5. The method according to claim 2, characterized in that: In the step 2, the photocatalyst is one or more of N-phenylphenoxazine, 10-phenylphenothiazine, 1,2,3, 5-tetra (carbazole-9-yl) -4, 6-dicyanobenzene and 9-mesityl-10-methylacridine salt, and the HAT reagent is one or more of tri (trimethylsilyl) silane, triethylsilane, cyclohexanediol and tert-butylmercaptan.
  6. 6. The method according to claim 5, wherein: the molar quantity of the photocatalyst is 0.05-0.6 times of that of the 4-chlorobenzonitrile, and the molar quantity of the HAT reagent is 0.01-0.5 times of that of the 4-chlorobenzonitrile.
  7. 7. The method according to claim 6, wherein: the molar ratio of the photocatalyst to the HAT reagent is 1:1.
  8. 8. The method according to claim 2, characterized in that: In the step 3, the photochemical reaction pressure is in the range of 0-3MPa, the photoreaction residence time is in the range of 0.1-30 min, and the photochemical reaction temperature is in the range of 0-25 ℃.
  9. 9. The method according to claim 2, characterized in that: In the step 4, the quenching liquid is one of water, saturated ammonium chloride solution, dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium bisulphite solution and sodium thiosulfate solution.

Description

Method for continuously synthesizing 2- (4-cyanophenyl) -N-Boc-ethylamine by photocatalysis Technical Field The invention belongs to the field of organic synthesis, and particularly relates to a method for continuously synthesizing 2- (4-cyanophenyl) -N-Boc-ethylamine by photocatalysis. The product is a key intermediate of antidepressant vilazodone. Background The 2- (4-cyanophenyl) -N-Boc-ethylamine is an organic synthesis intermediate with high added value, contains an aromatic cyano group and a protective amino structure in the molecule, has excellent reactivity and functional group compatibility, and has wide application value in the synthesis of medicines, pesticides and fine chemicals. In particular in the medical field, the compound is a key chiral precursor for synthesizing an antidepressant drug vilazodone (Vilazodone). Vilazodone, a 5-HT 1 a receptor partial agonist and 5-hydroxytryptamine reuptake inhibitor (SSRI), has been approved in various countries worldwide for the treatment of major depressive disorder, placing stringent demands on the purity of the starting intermediates, impurity profile and batch consistency. In the prior art, the intermediate is synthesized mainly by adopting an intermittent kettle type photocatalysis method, namely, 4-chlorobenzonitrile, tert-butyl vinyl carbamate, a photocatalyst and an auxiliary agent are placed in a glass or stainless steel reaction kettle, and stirred and reacted for several hours under the irradiation of an LED or mercury lamp. However, this conventional process has a fundamental bottleneck: (1) Uneven illumination, namely, the optical path length in the kettle, the light intensity is attenuated sharply along with the depth, the uneven distribution of reaction rate is caused, and the dimerization byproducts are generated by local overreaction; (2) Mass transfer limitation, short life of free radical intermediate, low mixing efficiency in the kettle, difficulty in realizing instant uniform contact and increased side reaction; (3) The heat management is difficult, photocatalysis is often accompanied with heat release, kettle type systems are slow in heat release, temperature rise is easy to occur, selectivity is influenced, and even safety accidents are caused; (4) The liquid holdup is large, the reaction volume of a single batch is usually tens to hundreds of liters, high-toxicity raw materials (such as 4-chlorobenzonitrile) are accumulated in a large amount, and the operation risk is high; (5) The three wastes are seriously recovered by relying on high boiling point solvents, a large amount of nitrogen-containing and sulfur-containing organic waste liquid is generated, and the treatment cost is high; (6) The amplification difficulty is that the conditions need to be re-optimized from laboratory to production, the amplification effect is remarkable, and the quality consistency is difficult to ensure. In contrast, continuous flow microreaction technology provides a systematic solution to the above-mentioned challenges: (1) The light transmission is enhanced, the size of a micro-channel (generally <2 mm) is far smaller than the light penetration depth, the illumination uniformity of the whole reaction section is ensured, and the photon utilization efficiency is improved by 3-5 times; (2) The reinforced mass transfer is that the diffusion distance is extremely short under the micro-scale, the Reynolds number is controllable, the millisecond mixing is realized, and the side reaction is effectively inhibited; (3) The temperature is precisely controlled, namely, heat is removed in real time due to the high specific surface area, the fluctuation of the reaction temperature is less than +/-1 ℃, and the high selectivity is ensured; (4) The intrinsic safety is that the liquid holding volume can be controlled to be less than 50mL, even if abnormality occurs, the hazard energy is extremely small, and the principle of minimizing the hazard stock is met; (5) The method is green and efficient, the solvent consumption is reduced by more than 70%, the acetonitrile/water system can be recycled, and the COD of the waste liquid is obviously reduced; (6) Seamless amplification, namely directly realizing linear amplification from gram level to ton level through a digital amplification strategy without re-development process. Therefore, the 2- (4-cyanophenyl) -N-Boc-ethylamine synthesis process based on the continuous flow photocatalysis microreactor is developed, not only can break through the performance ceiling of the traditional kettle type technology, but also can meet the manufacturing requirements of the modern pharmaceutical industry on high quality, high efficiency, high safety and high environmental protection, and has remarkable technical advancement and industrialization value. Disclosure of Invention The invention aims to provide a method for synthesizing 2- (4-cyanophenyl) -N-Boc-ethylamine by continuous photocatalysis. In order to achieve the aim, the inv