WO2021103257A1 - 一种2-氨基吡咯-3-羧酸乙酯的连续化制备方法 - Google Patents

一种2-氨基吡咯-3-羧酸乙酯的连续化制备方法 Download PDF

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WO2021103257A1
WO2021103257A1 PCT/CN2019/129408 CN2019129408W WO2021103257A1 WO 2021103257 A1 WO2021103257 A1 WO 2021103257A1 CN 2019129408 W CN2019129408 W CN 2019129408W WO 2021103257 A1 WO2021103257 A1 WO 2021103257A1
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solution
continuous
ethyl
chloroacetaldehyde
amino
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PCT/CN2019/129408
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English (en)
French (fr)
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洪浩
张恩选
卢江平
申慰
张涛
符旭
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凯莱英生命科学技术(天津)有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
    • C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
    • C07C45/60—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the invention relates to the technical field of synthesis of ethyl 2-aminopyrrole-3-carboxylate, in particular to a continuous preparation method of ethyl 2-aminopyrrole-3-carboxylate.
  • 2-aminopyrrole-3-carboxylic acid ethyl ester has the following synthetic routes:
  • the PCT international application with the International Publication No. WO2016/073891A1 discloses that chloroacetaldehyde and ethyl 3-amino-3-iminopropionate are refluxed in triethylamine and ethyl acetate for 20 minutes to prepare the target compound. The rate is 39%.
  • the PCT international application with the International Publication No. WO2017/004408A1 discloses that chloroacetaldehyde and ethyl 3-amino-3-iminopropionate are refluxed in ethyl acetate for 20 minutes to prepare the target compound with a yield of 47%.
  • the chloroacetaldehyde must be converted from the aqueous solution to the organic solvent before the subsequent reaction can be carried out. Moreover, the yield of 2-aminopyrrole-3-carboxylic acid ethyl ester when the current process is industrially applied Lower.
  • the main purpose of the present invention is to provide a continuous preparation method of ethyl 2-aminopyrrole-3-carboxylate, so as to solve the problem of low yield in the industrial synthesis of ethyl 2-aminopyrrole-3-carboxylate in the prior art .
  • a continuous preparation method of ethyl 2-aminopyrrole-3-carboxylate includes: continuously feeding the chloral solution to the first continuous reaction
  • the chloral aldehyde is continuously acid-catalyzed and depolymerized in the vessel to obtain a chloroacetaldehyde solution;
  • the 3-amino-3-imino ethyl propionate solution, the alkali solution and the chloroacetaldehyde solution are continuously sent to the first Condensation reaction is carried out in two continuous reactors to obtain ethyl 2-aminopyrrole-3-carboxylate, acetaldehyde solution, ethyl 3-amino-3-iminopropionate solution and alkali solution are organic Solution.
  • the solvent of the chloroacetaldehyde solution, the solvent of the ethyl 3-amino-3-iminopropionate solution, and the solvent of the alkali solution are each independently selected from the group consisting of chloroform, ethyl acetate, tetrahydrofuran, 2-methyl Any one or more of the group consisting of tetrahydrofuran, toluene, dichloromethane, isopropyl acetate, acetonitrile, and N,N-dimethylformamide.
  • the aforementioned chloral solution also includes an acid catalyst, the acid catalyst is selected from any one or more of organic acids and inorganic acids, the inorganic acid is hydrochloric acid or sulfuric acid, and the organic acid is selected from methanesulfonic acid and p-toluene. Any one or more of the group consisting of sulfonic acid, acetic acid, formic acid, and trifluoromethanesulfonic acid.
  • the temperature of the continuous acid-catalyzed depolymerization is 110-180°C.
  • the temperature of the continuous acid-catalyzed depolymerization is 150-170°C.
  • the temperature of the continuous acid-catalyzed depolymerization is 155-165°C.
  • the pressure of the continuous acid-catalyzed depolymerization is 0.4-1.0 MPa.
  • the pressure of the continuous acid-catalyzed depolymerization is 0.5-0.8 MPa.
  • the molar ratio of the acid catalyst and the chloral in the above-mentioned chloral solution is 0.1:100 to 1:100.
  • the retention time of the first continuous reactor is 5-60 min.
  • the retention time of the first continuous reactor is 10-20 min.
  • the base in the above alkaline solution is selected from triethylamine, diisopropylethylamine, 1,8-diazabicycloundec-7-ene, 4-dimethylaminopyridine, tri-n-propylamine , Tri-n-butylamine, pyridine, piperidine, tetramethylguanidine, N-methylmorpholine, N-methylimidazole.
  • the temperature of the condensation reaction is 40-100°C.
  • the temperature of the condensation reaction is 50 to 70°C.
  • the molar ratio of ethyl 3-amino-3-iminopropionate in the ethyl 3-amino-3-iminopropionate solution to the chloroacetaldehyde in the chloroacetaldehyde solution is 1:1 to 1 :3.
  • the molar ratio of ethyl 3-amino-3-iminopropionate in the ethyl 3-amino-3-iminopropionate solution to the chloroacetaldehyde in the chloroacetaldehyde solution is 1:1.1 ⁇ 1 :1.5.
  • the retention time of the second continuous reactor is 10 to 120 minutes.
  • the retention time of the second continuous reactor is 30-60 min.
  • first continuous reactor and the second continuous reactor are each independently a continuous coil reactor or a continuous reactor.
  • the continuous process breaks through the limitation of anhydrous chloroacetaldehyde, and the continuous reaction is used to prepare anhydrous chloroacetaldehyde, the reaction speed is faster than the batch, the yield is higher, and the prepared chloroacetaldehyde solution
  • the material ratio is more controllable, and the temperature of the two steps before and after the pressure drop is very compatible, thereby increasing the overall 2-aminopyrrole-3-carboxylic acid ethyl ester The yield.
  • the continuous process avoids the amplification effect of the batch, and the unique attributes of the continuous equipment (the reaction system is small, the heat exchange speed is much higher than that of the batch equipment) makes the reaction conditions more severe, but the safety is higher than that of the batch Reaction; At the same time, compared with the existing batch process, it is safer and controllable; it is more suitable for scale-up production and has a lower cost.
  • the various synthetic routes in the prior art are limited by the substrate chloroacetaldehyde, and it is necessary to convert the chloroacetaldehyde from an aqueous solution to an organic solvent before the next reaction can be carried out.
  • This operation leads to a limitation in the direction of process improvement.
  • the inventor of the present application envisaged using a continuous process to continuously send the depolymerized chloral into the next reaction system. Based on the stability of the chloral, The above assumption can avoid the limitation of chloroacetaldehyde on the process.
  • the compatibility of the two steps has become a huge problem.
  • the inventor of the present application has further studied the two-step continuous process and found that if the condensation reaction adopts a traditional batch reaction, the material ratio is unbalanced, the reaction efficiency is low, and side reactions are more likely to occur. . If the condensation reaction also adopts a continuous reaction, the material composition is relatively easy to control, and the condensation reaction pressure drops sharply relative to the depolymerization pressure. According to the ideal gas state equation, it can be inferred that the material temperature will also drop sharply, so the depolymerization and condensation reactions are continuous It should be possible to do so.
  • this application provides a continuous preparation method of 2-aminopyrrole-3-carboxylic acid ethyl ester, which includes: The solution is continuously fed into the first continuous reactor for continuous acid-catalyzed depolymerization of chloral to obtain a chloroacetaldehyde solution; the ethyl 3-amino-3-iminopropionate solution and the alkali solution And chloroacetaldehyde solution are continuously fed into the second continuous reactor for condensation reaction to obtain 2-aminopyrrole-3-carboxylic acid ethyl ester, chloroacetaldehyde solution, 3-amino-3-iminopropyl Ethyl acid solution and alkali solution are organic solutions.
  • the continuous preparation method of the present application uses structurally stable chloroacetaldehyde as a raw material to continuously prepare anhydrous chloroacetaldehyde that is not commercially available and easily deteriorated, and the obtained chloroacetaldehyde is dispersed in the solvent of the raw material to form ethyl chloride Aldehyde solution saves the treatment process of chloroacetaldehyde; then the chloroacetaldehyde solution is directly sent to the second continuous reactor with the 3-amino-3-iminoethyl propionate solution through continuous condensation reaction to obtain 2- Ethyl aminopyrrole-3-carboxylate (a homogeneous reaction).
  • the synthetic route is as follows:
  • This continuous process breaks through the limitation of anhydrous chloroacetaldehyde, and uses continuous reaction to prepare anhydrous chloroacetaldehyde.
  • the reaction speed is faster than batches and the yield is higher.
  • the prepared chloroacetaldehyde solution is used in the next condensation reaction.
  • the material ratio is more controllable, and the temperature of the two steps before and after the pressure drop can be well compatible, thereby increasing the yield of 2-aminopyrrole-3-carboxylic acid ethyl ester as a whole.
  • the continuous process avoids the amplification effect of the batch, and the unique attributes of the continuous equipment (the reaction system is small, the heat exchange speed is much higher than that of the batch equipment) makes the reaction conditions more severe, but the safety is higher than that of the batch Reaction; At the same time, compared with the existing batch process, it is safer and controllable; it is more suitable for scale-up production and has a lower cost.
  • the solvent for forming the solution of each of the above raw materials may be an organic solvent that has solubility for the corresponding substance, and preferably the solvent of the above-mentioned chloral solution, the solvent of the ethyl 3-amino-3-iminopropionate solution,
  • the solvent of the alkaline solution is each independently selected from the group consisting of chloroform, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane, isopropyl acetate, acetonitrile, N,N-dimethylformamide Any one or more.
  • the solvents can be the same or different, and a mixed solvent can also be used for each solvent to improve the solubility of the solute.
  • the depolymerization of chloral in the above-mentioned continuous preparation method can adopt the depolymerization methods commonly used in the prior art, preferably acid-catalyzed depolymerization, that is, the above-mentioned chloral solution also includes an acid catalyst, and the acid catalyst is selected.
  • the inorganic acid is hydrochloric acid or sulfuric acid
  • the organic acid is selected from the group consisting of methanesulfonic acid, p-toluenesulfonic acid, acetic acid, formic acid, and trifluoromethanesulfonic acid
  • the temperature of continuous acid-catalyzed depolymerization is preferably controlled to 110-185°C, preferably 150-170°C, more preferably 155-165°C, preferably continuous
  • the pressure of acid-catalyzed depolymerization is 0.4-1.0 MPa, preferably 0.5-0.8 MPa. In order to improve the efficiency of depolymerization and improve the safety of the reaction.
  • the molar ratio of the acid catalyst to the chloral in the chloral solution is 0.1:100 to 1:100. In order to improve the utilization efficiency of the acid catalyst, and to increase the depolymerization rate as much as possible.
  • the retention time of the first continuous reactor is 5-60 min, preferably 10 min-20 min.
  • the specific reaction conditions and material ratio of the above-mentioned condensation reaction can be referred to the conditions and material ratio of the condensation reaction carried out in a batch manner in the prior art.
  • the base in the above-mentioned alkaline solution is selected from Triethylamine, diisopropylethylamine, 1,8-diazabicycloundec-7-ene (DBU), 4-dimethylaminopyridine (DMAP), tri-n-propylamine, tri-n-butylamine , Pyridine, piperidine, tetramethylguanidine, N-methylmorpholine, N-methylimidazole.
  • the efficiency of the continuous condensation reaction is relatively high under the same controlled conditions.
  • the temperature of the condensation reaction is 40-100°C, preferably 50- 70°C.
  • the molar ratio of ethyl 3-amino-3-iminopropionate in the ethyl 3-amino-3-iminopropionate solution to the chloroacetaldehyde in the chloroacetaldehyde solution is preferred It is 1:1 to 1:3, preferably 1:1.1 to 1:1.5.
  • the retention time of the second continuous reactor is 10 ⁇ 120min, preferably 30min ⁇ 60min. Separate the target product in time.
  • the first continuous reactor and the second continuous reactor used in the present application can adopt continuous coil reactors, continuous reactors, continuous column reactors, etc. commonly used in the prior art, and it is preferable that the two are independently independent. It is a continuous coil reactor or a continuous reactor.
  • the above-mentioned first continuous reactor and the second continuous reactor are each equipped with temperature adjustment equipment to provide a corresponding suitable reaction temperature for each reaction.
  • Step1 Add 50g (0.21mol, 1eq) of chloral acetaldehyde into the feed bottle, add 500ml of chloroform, 0.32g (2.13mmol, 1%eq) of trifluoromethanesulfonic acid in sequence, stir to dissolve, obtain three Polychloroacetaldehyde solution.
  • Step2 Add 15g (0.12mol, 1eq) ethyl 3-amino-3-iminopropionate and 225mL tetrahydrofuran into the feed bottle, stir to dissolve to obtain ethyl 3-amino-3-iminopropionate The solution is placed in the beater system A.
  • beater system A The respective speeds of beater system A, beater system B, and beater system C are 2.30g/min, 1.93g/min, 2.14g/min, and the three strands of material converge at the tee, and then enter the coil for processing Reaction, retention time is 30min.
  • the receiving system concentrates the received product system containing ethyl 2-aminopyrrole-3-carboxylate at 40°C to no fractions to obtain a viscous oil, namely ethyl 2-aminopyrrole-3-carboxylate, with a yield of 60 %.
  • the two-step yield was 48%.
  • Step1 Add 50g (0.21mol, 1eq) of chloroacetaldehyde into the feed bottle, add 500ml of ethyl acetate and 0.32g (2.13mmol, 1%eq) of trifluoromethanesulfonic acid in sequence, and stir to dissolve. Obtain a chloral solution.
  • Step2 Add 15g (0.12mol, 1eq) ethyl 3-amino-3-iminopropionate and 225mL tetrahydrofuran into the feed bottle, stir to dissolve to obtain ethyl 3-amino-3-iminopropionate The solution is placed in the beater system A.
  • beater system A The respective speeds of beater system A, beater system B, and beater system C are 2.21g/min, 1.86g/min, and 1.44g/min respectively.
  • the three strands of material converge at the tee, and then enter the coil for processing. Reaction, retention time is 30min.
  • the receiving system concentrated the product system containing ethyl 2-aminopyrrole-3-carboxylate at 40° C. to no fractions to obtain a viscous oil with a yield of 57%.
  • the two-step yield was 42%.
  • Step1 Add 50g (0.21mol, 1eq) chloral acetaldehyde to the feed bottle, add 500ml N,N-dimethylformamide, 0.32g (2.13mmol, 1%eq) trifluoromethanesulfonate in turn Acid, stir to dissolve, obtain chloral solution.
  • Step2 Add 15g (0.12mol, 1eq) ethyl 3-amino-3-iminopropionate and 225mL tetrahydrofuran into the feed bottle, stir to dissolve to obtain ethyl 3-amino-3-iminopropionate The solution is placed in the beater system A.
  • beater system A The respective speeds of beater system A, beater system B, and beater system C are 1.49g/min, 1.25g/min, 2.89g/min, and the three strands of material converge at the tee, and then enter the coil for processing. Reaction, retention time is 30min.
  • the receiving system concentrated the product system containing ethyl 2-aminopyrrole-3-carboxylate at 40° C. to no fractions to obtain a viscous oil with a yield of 55%.
  • the two-step yield was 39%.
  • Step1 Add 50g (0.21mol, 1eq) of chloral to the feed bottle, add 500ml of chloroform and 0.21g (2.14mmol, 1%eq) of sulfuric acid in sequence, stir to dissolve, and obtain the chloral solution .
  • Step2 Add 15g (0.12mol, 1eq) ethyl 3-amino-3-iminopropionate and 225mL tetrahydrofuran into the feed bottle, stir to dissolve to obtain ethyl 3-amino-3-iminopropionate The solution is placed in the beater system A.
  • the respective speeds of the beater system A, the beater system B, and the beater system C are 2.08g/min, 1.74g/min, 2.81g/min, respectively.
  • the three strands of material converge at the tee, and then enter the coil. Reaction, retention time is 30min.
  • the receiving system concentrated the product system containing ethyl 2-aminopyrrole-3-carboxylate at 40° C. to no fractions to obtain a viscous oil with a yield of 43%.
  • the two-step yield was 24%.
  • Step1 Add 50g (0.21mol, 1eq) of chloral to the feeding bottle, add 500ml of chloroform and 0.13g (2.16mmol, 1%eq) of acetic acid in sequence, and stir to dissolve to obtain the chloral solution .
  • Step2 Add 15g (0.12mol, 1eq) ethyl 3-amino-3-iminopropionate and 225mL tetrahydrofuran into the feed bottle, stir to dissolve to obtain ethyl 3-amino-3-iminopropionate The solution is placed in the beater system A.
  • the chloroform solution of 248 g of chloroacetaldehyde (0.13 mol, 1.1 eq) obtained in the previous step was added to the beater bottle and placed in the beater system C.
  • beater system A The respective speeds of beater system A, beater system B, and beater system C are 2.18g/min, 1.83g/min, and 2.51g/min respectively.
  • the three strands of material converge at the tee, and then enter the coil for processing. Reaction, retention time is 30min.
  • the receiving system concentrated the product system containing ethyl 2-aminopyrrole-3-carboxylate at 40°C to no fractions to obtain a viscous oil with a yield of 49%.
  • the two-step yield was 32%.
  • Step1 Add 50g (0.21mol, 1eq) of chloral to the feed bottle, add 500ml of chloroform and 0.37g of p-toluenesulfonic acid (2.14mmol, 1%eq) in sequence, stir to dissolve, and obtain melamine Acetaldehyde solution.
  • Step2 Add 15g (0.12mol, 1eq) ethyl 3-amino-3-iminopropionate and 225mL tetrahydrofuran into the feed bottle, stir to dissolve to obtain ethyl 3-amino-3-iminopropionate The solution is placed in the beater system A.
  • the chloroform solution of 207g (0.13mol, 1.1eq) of chloroacetaldehyde obtained in the previous step was added to the beater bottle and placed in the beater system C.
  • beater system A The respective speeds of beater system A, beater system B, and beater system C are 2.28g/min, 1.92g/min, 2.19g/min respectively.
  • the three strands of material converge at the tee, and then enter the coil for reaction.
  • the retention time is 30min.
  • the receiving system concentrated the product system containing ethyl 2-aminopyrrole-3-carboxylate at 40°C to no fractions to obtain a viscous oil with a yield of 50%.
  • the two-step yield was 39%.
  • Step1 Add 50g (0.21mol, 1eq) of chloral acetaldehyde into the feed bottle, add 500ml of chloroform, 0.32g (2.13mmol, 1%eq) of trifluoromethanesulfonic acid in sequence, stir to dissolve, obtain three Polychloroacetaldehyde solution.
  • Step2 Add 15g (0.12mol, 1eq) ethyl 3-amino-3-iminopropionate and 225mL tetrahydrofuran into the feed bottle, stir to dissolve to obtain ethyl 3-amino-3-iminopropionate The solution is placed in the beater system A.
  • feeding speeds of feeding system A, feeding system B, and feeding system C are respectively 2.27g/min, 1.90g/min, and 2.23g/min.
  • the three strands of material converge at the tee, and then enter the coil. Reaction, retention time is 30min.
  • the receiving system concentrated the product system containing ethyl 2-aminopyrrole-3-carboxylate at 40°C to no fractions to obtain a viscous oil with a yield of 59%.
  • the two-step yield was 45%.
  • Step1 Add 50g (0.21mol, 1eq) of chloral acetaldehyde into the feed bottle, add 500ml of chloroform, 0.32g (2.13mmol, 1%eq) of trifluoromethanesulfonic acid in sequence, stir to dissolve, obtain three Polychloroacetaldehyde solution.
  • Step2 Add 15g (0.12mol, 1eq) ethyl 3-amino-3-iminopropionate and 225mL tetrahydrofuran into the feed bottle, stir and dissolve to obtain ethyl 3-amino-3-iminopropionate The solution is placed in the beater system A.
  • beater system A The respective speeds of beater system A, beater system B, and beater system C are 1.92g/min, 1.61g/min, 1.96g/min, respectively.
  • the three strands of material converge at the tee, and then enter the coil. Reaction, retention time is 30min.
  • the receiving system concentrated the product system containing ethyl 2-aminopyrrole-3-carboxylate at 40°C to no fractions to obtain a viscous oil with a yield of 50%.
  • the two-step yield was 37%.
  • Step1 The depolymerization of chloral is the same as in Example 1.
  • Step2 Add 15g (0.12mol, 1eq) ethyl 3-amino-3-iminopropionate and 225mL tetrahydrofuran into the feed bottle, stir to dissolve to obtain ethyl 3-amino-3-iminopropionate The solution is placed in the beater system A.
  • feeding speeds of feeding system A, feeding system B, and feeding system C are respectively 2.77g/min, 2.04g/min, 2.60g/min.
  • the three strands of material converge at the tee, and then enter the coil. Reaction, retention time is 30min.
  • the receiving system concentrated the product system containing ethyl 2-aminopyrrole-3-carboxylate at 40° C. to no fractions to obtain a viscous oil with a yield of 55%.
  • the two-step yield was 44%.
  • Step1 The depolymerization of chloral is the same as in Example 1.
  • Step2 Add 15g (0.12mol, 1eq) ethyl 3-amino-3-iminopropionate and 225mL tetrahydrofuran into the feed bottle, stir to dissolve to obtain ethyl 3-amino-3-iminopropionate The solution is placed in the beater system A.
  • beater system A The respective speeds of beater system A, beater system B, and beater system C are 2.61g/min, 1.72g/min, and 1.39g/min respectively.
  • the three strands of material converge at the tee, and then enter the coil for processing. Reaction, retention time is 30min.
  • the receiving system concentrated the product system containing ethyl 2-aminopyrrole-3-carboxylate at 40°C to no fractions to obtain a viscous oil with a yield of 42%.
  • the two-step yield was 34%.
  • Step1 The depolymerization of chloral is the same as in Example 1.
  • Step2 Add 15g (0.12mol, 1eq) ethyl 3-amino-3-iminopropionate and 225mL tetrahydrofuran into the feed bottle, stir to dissolve to obtain ethyl 3-amino-3-iminopropionate The solution is placed in the beater system A.
  • beater system A The respective speeds of beater system A, beater system B, and beater system C are 2.85g/min, 1.67g/min, and 1.52g/min, respectively.
  • the three strands of material converge at the tee, and then enter the coil. Reaction, retention time is 30min.
  • the receiving system concentrated the product system containing ethyl 2-aminopyrrole-3-carboxylate at 40°C to no fractions to obtain a viscous oil with a yield of 23%.
  • the two-step yield was 18%.
  • Step1 The depolymerization of chloral is the same as in Example 1.
  • Step2 Add 15g (0.12mol, 1eq) ethyl 3-amino-3-iminopropionate and 225mL tetrahydrofuran into the feed bottle, stir to dissolve to obtain ethyl 3-amino-3-iminopropionate The solution is placed in the beater system A.
  • feeding speeds of feeding system A, feeding system B, and feeding system C are 2.80g/min, 1.70g/min, and 1.49g/min respectively.
  • the three strands of material converge at the tee, and then enter the coil. Reaction, retention time is 30min.
  • the receiving system concentrated the product system containing ethyl 2-aminopyrrole-3-carboxylate at 40°C to no fractions to obtain a viscous oil with a yield of 30%.
  • the two-step yield was 24%.
  • Step1 The depolymerization of chloral is the same as in Example 1.
  • Step2 Add 15g of ethyl 3-amino-3-iminopropionate and 225mL of tetrahydrofuran to the feeding bottle, stir to dissolve, and obtain a solution of ethyl 3-amino-3-iminopropionate, and place it in the feeding bottle.
  • System A
  • beater system A The respective speeds of beater system A, beater system B, and beater system C are 2.65g/min, 1.88g/min, 1.42g/min, respectively.
  • the three strands of material converge at the tee and then enter the coil. Reaction, retention time is 30min.
  • the receiving system concentrated the product system containing ethyl 2-aminopyrrole-3-carboxylate at 40°C to no fractions to obtain a viscous oil with a yield of 47%.
  • the two-step yield was 38%.
  • Example 2 The difference from Example 1 is that in the Step2 reaction, the coil is placed in a 40°C hot bath, and the temperature is controlled at 30-40°C.
  • the receiving system concentrated the product system containing ethyl 2-aminopyrrole-3-carboxylate at 40° C. to no fractions to obtain a viscous oil with a yield of 29%.
  • the two-step yield was 23%.
  • Example 2 The difference from Example 1 is that in the Step2 reaction, the coil is placed in a 70°C hot bath, and the temperature is controlled at 60-70°C.
  • the receiving system concentrated the product system containing ethyl 2-aminopyrrole-3-carboxylate at 40°C to no fractions to obtain a viscous oil with a yield of 54%.
  • the two-step yield was 43%.
  • Example 2 The difference from Example 1 is that in the second step of the reaction, the coil is placed in a 100°C hot bath, and the temperature is controlled at 90-100°C.
  • the receiving system concentrated the product system containing ethyl 2-aminopyrrole-3-carboxylate to no fraction at 40°C to obtain a viscous oil with a yield of 28%.
  • the two-step yield was 22%.
  • Step1 During the reaction, the feeding speed is 2.17 g/min, and the retention time is 20 min. The chloroform solution of chloroacetaldehyde was obtained, and the yield of chloroacetaldehyde calculated by nuclear magnetic internal standard method was 78% and the content was 4.8%.
  • Step2 Add 15g (0.12mol, 1eq) ethyl 3-amino-3-iminopropionate and 225mL tetrahydrofuran into the feed bottle, stir to dissolve to obtain ethyl 3-amino-3-iminopropionate The solution is placed in the beater system A.
  • the chloroform solution of 207g (0.13mol, 1.1eq) of chloroacetaldehyde obtained in the previous step was added to the beater bottle and placed in the beater system C.
  • feeding speeds of feeding system A, feeding system B, and feeding system C are respectively 2.75g/min, 2.31g/min, and 2.64g/min.
  • the three strands of material converge at the tee, and then enter the coil. Reaction, retention time is 30min.
  • the receiving system concentrates the product system containing ethyl 2-aminopyrrole-3-carboxylate at 40°C to no fractions, and obtains a viscous oily substance, ethyl 2-aminopyrrole-3-carboxylate, with a yield of 58 %.
  • the two-step yield was 45%.
  • Step1 During the reaction, the feeding speed is 0.72 g/min, and the retention time is 60 min. The chloroform solution of chloroacetaldehyde was obtained, and the yield of chloroacetaldehyde calculated by nuclear magnetic internal standard method was 44% and the content was 2.7%.
  • Step2 Add 15g (0.12mol, 1eq) ethyl 3-amino-3-iminopropionate and 225mL tetrahydrofuran into the feed bottle, stir to dissolve to obtain ethyl 3-amino-3-iminopropionate The solution is placed in the beater system A.
  • feeding speeds of feeding system A, feeding system B, and feeding system C are respectively 2.24g/min, 1.88g/min, 3.81g/min.
  • the three strands of material converge at the tee, and then enter the coil for processing. Reaction, retention time is 30min.
  • the receiving system concentrates the product system containing ethyl 2-aminopyrrole-3-carboxylate at 40°C to no fractions, and obtains a viscous oil, namely ethyl 2-aminopyrrole-3-carboxylate, with a yield of 52 %.
  • the two-step yield was 23%, and the decrease in yield compared with Example 1 was due to the longer retention time in Step1, which resulted in the destruction of the product.
  • Step 1 In the reaction, the amount of trifluoromethanesulfonic acid is 0.032 g (0.21 mol, 0.1% eq). The chloroform solution of chloroacetaldehyde was obtained, and the yield of chloroacetaldehyde calculated by nuclear magnetic internal standard method was 43% and the content was 2.7%.
  • Step2 Add 15g (0.12mol, 1eq) ethyl 3-amino-3-iminopropionate and 225mL tetrahydrofuran into the feed bottle, stir to dissolve to obtain ethyl 3-amino-3-iminopropionate The solution is placed in the beater system A.
  • beater system A The respective speeds of beater system A, beater system B, and beater system C are 2.56g/min, 2.15g/min, and 1.37g/min respectively.
  • the three strands of material converge at the tee, and then enter the coil for processing. Reaction, retention time is 30min.
  • the receiving system concentrates the received product system containing ethyl 2-aminopyrrole-3-carboxylate at 40°C to no fractions to obtain a viscous oil, namely ethyl 2-aminopyrrole-3-carboxylate, with a yield of 60 %.
  • the two-step yield was 26%.
  • Step1 The depolymerization of chloral is the same as in Example 1.
  • Step2 Add 15g (0.12mol, 1eq) ethyl 3-amino-3-iminopropionate and 225mL tetrahydrofuran into the feed bottle, stir to dissolve to obtain ethyl 3-amino-3-iminopropionate The solution is placed in the beater system A.
  • beater system A The respective speeds of beater system A, beater system B, and beater system C are 8.33g/min, 6.99g/min, and 7.74g/min, respectively.
  • the three strands of material converge at the tee, and then enter the coil.
  • the reaction, the retention time is 10min.
  • the receiving system concentrates the product system containing ethyl 2-aminopyrrole-3-carboxylate at 40°C to no fractions, and obtains a viscous oil, namely ethyl 2-aminopyrrole-3-carboxylate, with a yield of 26 %.
  • the two-step yield was 21%.
  • Step1 The depolymerization of chloral is the same as in Example 1.
  • Step2 Add 15g (0.12mol, 1eq) ethyl 3-amino-3-iminopropionate and 225mL tetrahydrofuran into the feed bottle, stir to dissolve to obtain ethyl 3-amino-3-iminopropionate The solution is placed in the beater system A.
  • beater system A The respective speeds of beater system A, beater system B, and beater system C are 1.39g/min, 1.17g/min, 1.29g/min, respectively.
  • the three strands of material converge at the tee and then enter the coil.
  • the reaction, the retention time is 60min.
  • the receiving system concentrates the accepted product system containing ethyl 2-aminopyrrole-3-carboxylate at 40°C to no fractions to obtain a viscous oil, namely ethyl 2-aminopyrrole-3-carboxylate, with a yield of 49 %.
  • the two-step yield was 39%.
  • Step1 The depolymerization of chloral is the same as in Example 1.
  • Step2 Add 15g (0.12mol, 1eq) ethyl 3-amino-3-iminopropionate and 225mL tetrahydrofuran into the feed bottle, stir to dissolve to obtain ethyl 3-amino-3-iminopropionate The solution is placed in the beater system A.
  • beater system A The respective speeds of beater system A, beater system B, and beater system C are 0.69g/min, 0.58g/min, and 0.64g/min, respectively.
  • the three strands of material converge at the tee, and then enter the coil for processing.
  • the reaction, the retention time is 120min.
  • the receiving system concentrates the product system containing 2-aminopyrrole-3-carboxylic acid ethyl ester at 40°C to no distillate to obtain a viscous oily substance, namely 2-aminopyrrole-3-carboxylic acid ethyl ester, with a yield of 21 %.
  • the two-step yield was 17%.
  • Step1 Add 50g (0.21mol, 1eq) of chloral acetaldehyde into the feed bottle, add 500ml of chloroform, 0.32g (2.13mmol, 1%eq) of trifluoromethanesulfonic acid in sequence, stir to dissolve, obtain three Polychloroacetaldehyde solution.
  • Step2 Add 15g (0.12mol, 1eq) ethyl 3-amino-3-iminopropionate and 225mL tetrahydrofuran into the feed bottle, stir to dissolve to obtain ethyl 3-amino-3-iminopropionate The solution is placed in the beater system A.
  • beater system A The respective speeds of beater system A, beater system B, and beater system C are 2.30g/min, 1.93g/min, 2.14g/min, and the three strands of material converge at the tee, and then enter the coil for processing Reaction, retention time is 30min.
  • the receiving system concentrates the product system containing ethyl 2-aminopyrrole-3-carboxylate at 40°C to no fractions, and obtains a viscous oil, namely ethyl 2-aminopyrrole-3-carboxylate, with a yield of 54 %.
  • the two-step yield was 26.5%.
  • the continuous preparation method of the present application uses structurally stable chloroacetaldehyde as a raw material to continuously prepare anhydrous chloroacetaldehyde that is not commercially available and easily deteriorated, and the obtained chloroacetaldehyde is dispersed in the solvent of the raw material to form ethyl chloride Aldehyde solution; then the chloroacetaldehyde solution and the ethyl 3-amino-3-iminopropionate solution are continuously reacted to obtain ethyl 2-aminopyrrole-3-carboxylate.
  • This continuous process breaks through the limitation of anhydrous chloroacetaldehyde, and uses continuous reaction to prepare anhydrous chloroacetaldehyde.
  • the reaction speed is faster than batches and the yield is higher.
  • the prepared chloroacetaldehyde solution is used in the next condensation reaction.
  • the material ratio is more controllable, and the temperature of the two steps before and after the pressure drop can be well compatible, thereby increasing the yield of 2-aminopyrrole-3-carboxylic acid ethyl ester as a whole.
  • the continuous process avoids the amplification effect of the batch, and the unique attributes of the continuous equipment (the reaction system is small, the heat exchange speed is much higher than that of the batch equipment) makes the reaction conditions more severe, but the safety is higher than that of the batch Reaction; At the same time, compared with the existing batch process, it is safer and controllable; it is more suitable for scale-up production and has a lower cost.

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Abstract

本发明提供了一种2-氨基吡咯-3-羧酸乙酯的连续化制备方法。该制备方法包括：将三聚氯乙醛溶液连续送入第一连续化反应器中以对三聚氯乙醛进行连续化酸催化解聚，得到氯乙醛溶液；将3-氨基-3-亚胺基丙酸乙酯溶液、碱溶液和氯乙醛溶液连续送入第二连续化反应器中以进行缩合反应，得到2-氨基吡咯-3-羧酸乙酯。该连续工艺突破了无水氯乙醛的限制，且使用连续反应制备无水氯乙醛，反应速度比批次快，收率较高，所制备的氯乙醛溶液直接用于下一步的缩合反应时，物料配比更加可控，前后两步可以兼容，从而在整体上提高了2-氨基吡咯-3-羧酸乙酯的收率。另外，连续化工艺避免了批次的放大效应，也保证了工业应用时的高收率。

Description

一种2-氨基吡咯-3-羧酸乙酯的连续化制备方法 技术领域
本发明涉及2-氨基吡咯-3-羧酸乙酯的合成技术领域，具体而言，涉及一种2-氨基吡咯-3-羧酸乙酯的连续化制备方法。
背景技术
2-氨基吡咯-3-羧酸乙酯作为一种重要的医药合成原料，其合成路线主要有如下几条：
国际公开号为WO2016/073891A1的PCT国际申请公开了，使用氯乙醛和3-氨基-3-亚胺基丙酸乙酯在三乙胺和乙酸乙酯中回流反应20min来制备目标化合物，收率39％。国际公开号为WO2017/004408A1的PCT国际申请公开了，使用氯乙醛和3-氨基-3-亚胺基丙酸乙酯在乙酸乙酯中回流反应20min来制备目标化合物，收率47％。2018年/Tetrahedron Letters 59(2018)中报道，使用氯乙醛和3-氨基-3-亚胺基丙酸乙酯盐酸盐在三乙胺和乙酸乙酯中反应20min，再加入氯仿水的混合物回流20min来制备目标化合物，收率14％。
上述各合成路线均采用氯乙醛为原料，但是氯乙醛不稳定，一般都是以40％～50％的水溶液方式储存，且无水氯乙醛无市售。但是上述合成路线中都不希望水的存在，因此在合成2-氨基吡咯-3-羧酸乙酯之前需要去除氯乙醛水溶液中的水，而氯乙醛在水中是以水合氯乙醛的形式存在的，没有反应活性的，必须将氯乙醛从水溶液中转化到有机溶剂中才能进行后续的反应，而且目前的工艺在工业应用时2-氨基吡咯-3-羧酸乙酯的收率较低。
发明内容
本发明的主要目的在于提供一种2-氨基吡咯-3-羧酸乙酯的连续化制备方法，以解决现有技术中工业合成2-氨基吡咯-3-羧酸乙酯收率低的问题。
为了实现上述目的，根据本发明的一个方面，提供了一种2-氨基吡咯-3-羧酸乙酯的连续化制备方法，包括：将三聚氯乙醛溶液连续送入第一连续化反应器中以对三聚氯乙醛进行连续化酸催化解聚，得到氯乙醛溶液；将3-氨基-3-亚胺基丙酸乙酯溶液、碱溶液和氯乙醛溶液连续送入第二连续化反应器中以进行缩合反应，得到2-氨基吡咯-3-羧酸乙酯，三聚氯乙醛溶液、3-氨基-3-亚胺基丙酸乙酯溶液和碱溶液为有机溶液。
进一步地，上述三聚氯乙醛溶液的溶剂、3-氨基-3-亚胺基丙酸乙酯溶液的溶剂、碱溶液的溶剂各自独立地选自氯仿、乙酸乙酯、四氢呋喃、2-甲基四氢呋喃、甲苯、二氯甲烷、醋酸异丙酯、乙腈、N,N-二甲基甲酰胺组成的组中的任意一种或多种。
进一步地，上述三聚氯乙醛溶液中还包括酸催化剂，酸催化剂选自有机酸和无机酸中任意一种或多种，无机酸为盐酸或硫酸，有机酸选自甲磺酸、对甲苯磺酸、醋酸、甲酸、三氟甲基磺酸组成的组中的任意一种或多种。
进一步地，上述连续化酸催化解聚的温度为110～180℃。
进一步地，上述连续化酸催化解聚的温度为150～170℃。
进一步地，上述连续化酸催化解聚的温度为155～165℃。
进一步地，上述连续化酸催化解聚的压力为0.4～1.0MPa。
进一步地，上述连续化酸催化解聚的压力为0.5～0.8MPa。
进一步地，上述三聚氯乙醛溶液中酸催化剂和三聚氯乙醛的摩尔比为：0.1:100～1:100。
进一步地，上述第一连续化反应器的保留时间为5～60min。
进一步地，上述第一连续化反应器的保留时间为10～20min。
进一步地，上述碱溶液中的碱选自三乙胺、二异丙基乙基胺、1,8-二氮杂二环十一碳-7-烯、4-二甲氨基吡啶、三正丙胺、三正丁胺、吡啶、哌啶、四甲基胍、N-甲基吗啉、N-甲基咪唑中的任意一种。
进一步地，上述缩合反应的温度为40～100℃。
进一步地，上述缩合反应的温度为50～70℃。
进一步地，上述3-氨基-3-亚胺基丙酸乙酯溶液中3-氨基-3-亚胺基丙酸乙酯和氯乙醛溶液中氯乙醛的摩尔比为1:1～1:3。
进一步地，上述3-氨基-3-亚胺基丙酸乙酯溶液中3-氨基-3-亚胺基丙酸乙酯和氯乙醛溶液中氯乙醛的摩尔比为1:1.1～1:1.5。
进一步地，上述第二连续化反应器的保留时间为10～120min。
进一步地，上述第二连续化反应器的保留时间为30～60min。
进一步地，上述第一连续化反应器和第二连续化反应器各自独立地为连续盘管反应器或连续化反应釜。
应用本发明的技术方案，该连续工艺突破了无水氯乙醛的限制，且使用连续反应制备无水氯乙醛，反应速度比批次快，收率较高，所制备的氯乙醛溶液用于下一步的缩合反应时，物料配比更加可控，且由于压力陡降使得前后两步的温度得以很好的兼容，从而在整体上提高了2-氨基吡咯-3-羧酸乙酯的收率。另外，连续化工艺避免了批次的放大效应，且连续化设备特有的属性(反应体系小，热交换速度远高于批次设备)使反应条件即便更加剧烈，但安 全性也是高于批次反应；同时与现有的批次工艺相比，更加安全可控；更适合放大生产，成本更加低廉。
具体实施方式
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将结合实施例来详细说明本发明。
如本申请背景技术所分析的，工业合成2-氨基吡咯-3-羧酸乙酯收率较低，为了解决该问题本申请对2-氨基吡咯-3-羧酸乙酯的合成工艺进行了综合深入研究，发现优化反应温度、物料比例等反应条件对于增加2-氨基吡咯-3-羧酸乙酯收率的效果有限，即使在实验室阶段能够取得一定效果，但是在中试阶段所取得的效果并不能发挥出来，导致无法推广至工业应用。而且现有技术中各合成路线受限于底物氯乙醛的限制，需要将氯乙醛从水溶液中转化到有机溶剂中才能进行下一步反应，这一操作导致了工艺改进方向受到限制。在多个试验方向均不能取得突破后，本申请发明人设想采用连续化工艺将三聚氯乙醛解聚后得到的连续送入下一步反应体系中，基于三聚氯乙醛的稳定性，上述设想可以避免氯乙醛对工艺的限制。但是，由于解聚温度和下一步骤的缩合反应温度相差太大，导致两个步骤的兼容性成为极大的问题。为了进一步解决该问题，本申请发明人进一步对两步连续后的工艺进行了进一步研究，发现如果缩合反应采用传统批次反应时，导致物料配比不平衡，反应效率低且副反应较易发生。如果缩合反应也采用连续化反应，物料配比较易控制，且缩合反应压力相对于解聚压力陡降，根据理想气体状态方程可以推知物料温度也会出现陡降，那么解聚和缩合反应的连续化进行应该就可以实现。
在进行了上述理论推导和试验研究基础上，
为了解决2-氨基吡咯-3-羧酸乙酯收率低的问题，本申请提供了一种2-氨基吡咯-3-羧酸乙酯的连续化制备方法，包括：将三聚氯乙醛溶液连续送入第一连续化反应器中以对三聚氯乙醛进行连续化酸催化解聚，得到氯乙醛溶液；将3-氨基-3-亚胺基丙酸乙酯溶液、碱溶液和氯乙醛溶液连续送入第二连续化反应器中以进行缩合反应，得到2-氨基吡咯-3-羧酸乙酯，三聚氯乙醛溶液、3-氨基-3-亚胺基丙酸乙酯溶液和碱溶液为有机溶液。
本申请的连续化制备方法以结构稳定的三聚氯乙醛为原料，连续制备出无市售且易变质的无水氯乙醛，所得到的氯乙醛分散在原料的溶剂中形成氯乙醛溶液，节约了氯乙醛的处理流程；然后将氯乙醛溶液直接送入第二连续化反应器中与3-氨基-3-亚胺基丙酸乙酯溶液通过连续缩合反应得到2-氨基吡咯-3-羧酸乙酯(为均相反应)。合成路线如下：
Figure PCTCN2019129408-appb-000001
该连续工艺突破了无水氯乙醛的限制，且使用连续反应制备无水氯乙醛，反应速度比批次快，收率较高，所制备的氯乙醛溶液用于下一步的缩合反应时，物料配比更加可控，且由于压力陡降使得前后两步的温度得以很好的兼容，从而在整体上提高了2-氨基吡咯-3-羧酸乙酯的收率。另外，连续化工艺避免了批次的放大效应，且连续化设备特有的属性(反应体系小，热交换速度远高于批次设备)使反应条件即便更加剧烈，但安全性也是高于批次反应；同时与现有的批次工艺相比，更加安全可控；更适合放大生产，成本更加低廉。
形成上述各原料的溶液的溶剂可以采用对相应物质具有溶解性的有机溶剂即可，优选上述三聚氯乙醛溶液的溶剂、3-氨基-3-亚胺基丙酸乙酯溶液的溶剂、碱溶液的溶剂各自独立地选自氯仿、乙酸乙酯、四氢呋喃、2-甲基四氢呋喃、甲苯、二氯甲烷、醋酸异丙酯、乙腈、N,N-二甲基甲酰胺组成的组中的任意一种或多种。在实际生产中，各溶剂可以相同也可以不同，且各溶剂也可以采用混合溶剂以提高对溶质的溶解性。
上述连续化制备方法中三聚氯乙醛的解聚可以采用现有技术中常用的解聚方式，优选采用酸催化解聚，即上述三聚氯乙醛溶液中还包括酸催化剂，酸催化剂选自有机酸和无机酸中的任意一种或多种，无机酸为盐酸或硫酸，有机酸选自甲磺酸、对甲苯磺酸、醋酸、甲酸、三氟甲基磺酸组成的组中的任意一种或多种，在上述酸催化剂存在的条件下，优选控制连续化酸催化解聚的温度为110～185℃，优选为150～170℃，更优选为155～165℃，优选连续化酸催化解聚的压力为0.4～1.0MPa，优选为0.5～0.8MPa。以提高解聚效率并提高反应的安全性。
在一种实施例中，上述三聚氯乙醛溶液中酸催化剂和三聚氯乙醛的摩尔比为0.1:100～1:100。以提高酸催化剂的利用效率，并尽可能提高解聚速率。
由于解聚反应在高温下效率较高，但是高温下解聚对反应设备的要求也高，为了降低设备成本，并尽可能保证较高的解聚效率、避免解聚时间过长产物被破坏，优选上述第一连续化反应器的保留时间为5～60min，优选为10min～20min。
上述缩合反应的具体反应条件、物料配比等可以以现有技术中批次方式进行的缩合反应的条件和物料配比为参考，为了提高反应的稳定性，优选上述碱溶液中的碱选自三乙胺、二异丙基乙基胺、1,8-二氮杂二环十一碳-7-烯(DBU)、4-二甲氨基吡啶(DMAP)、三正丙胺、三正丁胺、吡啶、哌啶、四甲基胍、N-甲基吗啉、N-甲基咪唑中的任意一种。
由于连续化反应的换热效率要高于批次反应，因此在同样的控制条件下连续化的缩合反应效率相对较高，优选地，上述缩合反应的温度为40～100℃，优选为50～70℃。
为了提高底物的转化率，优选上述3-氨基-3-亚胺基丙酸乙酯溶液中3-氨基-3-亚胺基丙酸乙酯和氯乙醛溶液中氯乙醛的摩尔比为1:1～1:3，优选为1:1.1～1:1.5。
由于本申请的目标产物2-氨基吡咯-3-羧酸乙酯不稳定，为了避免副产物的过度生成，优选上述第二连续化反应器的保留时间为10～120min优选为30min～60min，以及时将目标产物进行分离。
用于本申请的第一连续化反应器和第二连续化反应器可以采用现有技术中常用的连续盘管反应器、连续化反应釜、连续柱式反应器等，优选二者各自独立地为连续盘管反应器或连续化反应釜。上述第一连续化反应器和第二连续化反应器各自配置温度调节设备，以为各反应提供相应合适的反应温度。
以下将结合实施例和对比例，进一步说明本申请的有益效果。
实施例1
Step1：将50g(0.21mol,1eq)三聚氯乙醛加入到打料瓶中，依次加入500ml氯仿、0.32g(2.13mmol,1％eq)三氟甲基磺酸，搅拌至溶解，得到三聚氯乙醛溶液。
将30ml白钢盘管打满氯仿，并调节温度至155～165℃(目标温度为160℃)，压力控制在0.4～0.8MPa(目标压力为0.5～1.0MPa)，温度稳定10min后，可进行打料。
将三聚氯乙醛溶液的流速设定为4.34g/min，三聚氯乙醛溶液进入30ml盘管进行反应，保留时间为10min，得到氯乙醛的氯仿溶液，核磁内标法计算氯乙醛收率为80％，含量4.9％。
Step2：将15g(0.12mol，1eq)3-氨基-3-亚胺基丙酸乙酯和225mL四氢呋喃加入到打料瓶中，搅拌溶解，得到3-氨基-3-亚胺基丙酸乙酯溶液，置于打料体系A中。
将114g(0.75mol,6.5eq)1,8-二氮杂二环十一碳-7-烯(DBU)和75mL THF加入打料瓶，搅拌均匀，得到碱溶液，置于打料体系B中。
将前述步骤得到的200g(0.13mol，1.1eq)氯乙醛的氯仿溶液加入打料瓶，置于打料体系C中。
将180mL白钢盘管中打满THF，将盘管置于60℃热浴中，控温50～60℃。
打料体系A、打料体系B、打料体系C的各自打料速度分别为2.30g/min，1.93g/min，2.14g/min，三股股物料在三通处汇合，然后进入盘管进行反应，保留时间为30min。
接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物即2-氨基吡咯-3-羧酸乙酯，收率60％。两步收率为48％。
终产物核磁共振检测结果如下：
1H NMR(500MHz,CDCl3):δ6.26(d,J＝3.5Hz,1H),6.11(d,J＝3.5Hz,1H),5.24–4.92(br.s.,2H),4.23(q,J＝7.0Hz,2H),1.32ppm(t,J＝7.0Hz,3H).
实施例2
Step1：将50g(0.21mol,1eq)三聚氯乙醛加入到打料瓶中，依次加入500ml乙酸乙酯、0.32g(2.13mmol,1％eq)三氟甲基磺酸，搅拌至溶解，得到三聚氯乙醛溶液。
将30ml白钢盘管打满乙酸乙酯，并调节温度至155～165℃(目标温度为160℃)，压力控制在0.4～0.8MPa(目标压力为0.5～1.0MPa)，温度稳定10min后，可进行打料。
将三聚氯乙醛溶液的流速设定为2.72g/min，三聚氯乙醛溶液进入30ml盘管进行反应，保留时间为10min，得到氯乙醛的乙酸乙酯溶液，氯乙醛收率为73％，含量7.2％。
Step2：将15g(0.12mol，1eq)3-氨基-3-亚胺基丙酸乙酯和225mL四氢呋喃加入到打料瓶中，搅拌溶解，得到3-氨基-3-亚胺基丙酸乙酯溶液，置于打料体系A中。
将114g(0.75mol,6.5eq)1,8-二氮杂二环十一碳-7-烯(DBU)和75mL THF加入打料瓶，搅拌均匀，得到碱溶液，置于打料体系B中。
将前述步骤得到的140g(0.13mol，1.1eq)氯乙醛的乙酸乙酯溶液加入打料瓶，置于打料体系C中。
将180mL白钢盘管中打满THF，将盘管置于60℃热浴中，控温50～60℃。
打料体系A、打料体系B、打料体系C的各自打料速度分别为2.21g/min，1.86g/min，1.44g/min，三股股物料在三通处汇合，然后进入盘管进行反应，保留时间为30min。
接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物，收率57％。两步收率为42％。
实施例3
Step1：将50g(0.21mol,1eq)三聚氯乙醛加入到打料瓶中，依次加入500ml N,N-二甲基甲酰胺、0.32g(2.13mmol,1％eq)三氟甲基磺酸，搅拌至溶解，得到三聚氯乙醛溶液。
将30ml白钢盘管打满N,N-二甲基甲酰胺，并调节温度至155～165℃(目标温度为160℃)，压力控制在0.4～0.8MPa(目标压力为0.5～1.0MPa)，温度稳定10min后，可进行打料。
将三聚氯乙醛溶液的流速设定为2.87g/min，三聚氯乙醛溶液进入30ml盘管进行反应，保留时间为10min，得到氯乙醛的N,N-二甲基甲酰胺溶液，氯乙醛收率为70％，含量6.6％。
Step2：将15g(0.12mol，1eq)3-氨基-3-亚胺基丙酸乙酯和225mL四氢呋喃加入到打料瓶中，搅拌溶解，得到3-氨基-3-亚胺基丙酸乙酯溶液，置于打料体系A中。
将114g(0.75mol,6.5eq)1,8-二氮杂二环十一碳-7-烯(DBU)和75mL THF加入打料瓶，搅拌均匀，得到碱溶液，置于打料体系B中。
将前述步骤得到的418g(0.35mol，3.0eq)氯乙醛的N,N-二甲基甲酰胺溶液加入打料瓶，置于打料体系C中。
将180mL白钢盘管中打满THF，将盘管置于60℃热浴中，控温50～60℃。
打料体系A、打料体系B、打料体系C的各自打料速度分别为1.49g/min，1.25g/min，2.89g/min，三股股物料在三通处汇合，然后进入盘管进行反应，保留时间为30min。
接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物，收率55％。两步收率为39％。
实施例4
Step1：将50g(0.21mol,1eq)三聚氯乙醛加入到打料瓶中，依次加入500ml氯仿、0.21g(2.14mmol,1％eq)硫酸，搅拌至溶解，得到三聚氯乙醛溶液。
将30ml白钢盘管打满氯仿，并调节温度至155～165℃(目标温度为160℃)，压力控制在0.4～0.8MPa(目标压力为0.5～1.0MPa)，温度稳定10min后，可进行打料。
将三聚氯乙醛溶液的流速设定为4.34g/min，三聚氯乙醛溶液进入30ml盘管进行反应，保留时间为10min，得到氯乙醛的氯仿溶液，氯乙醛收率为55％，含量3.4％。
Step2：将15g(0.12mol，1eq)3-氨基-3-亚胺基丙酸乙酯和225mL四氢呋喃加入到打料瓶中，搅拌溶解，得到3-氨基-3-亚胺基丙酸乙酯溶液，置于打料体系A中。
将114g(0.75mol,6.5eq)1,8-二氮杂二环十一碳-7-烯(DBU)和75mL THF加入打料瓶，搅拌均匀，得到碱溶液，置于打料体系B中。
将前述步骤得到的291g(0.13mol,1.1eq)氯乙醛的氯仿溶液加入打料瓶，置于打料体系C中。
将180mL白钢盘管中打满THF，将盘管置于60℃热浴中，控温50～60℃。
打料体系A、打料体系B、打料体系C的各自打料速度分别为2.08g/min，1.74g/min，2.81g/min，三股股物料在三通处汇合，然后进入盘管进行反应，保留时间为30min。
接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物，收率43％。两步收率为24％。
实施例5
Step1：将50g(0.21mol,1eq)三聚氯乙醛加入到打料瓶中，依次加入500ml氯仿、0.13g(2.16mmol,1％eq)醋酸，搅拌至溶解，得到三聚氯乙醛溶液。
将30ml白钢盘管打满氯仿，并调节温度至155～165℃(目标温度为160℃)，压力控制在0.4～0.8MPa(目标压力为0.5～1.0MPa)，温度稳定10min后，可进行打料。
将三聚氯乙醛溶液的流速设定为4.34g/min，三聚氯乙醛溶液进入30ml盘管进行反应，保留时间为10min，得到氯乙醛的氯仿溶液，氯乙醛收率为65％，含量4.0％。
Step2：将15g(0.12mol，1eq)3-氨基-3-亚胺基丙酸乙酯和225mL四氢呋喃加入到打料瓶中，搅拌溶解，得到3-氨基-3-亚胺基丙酸乙酯溶液，置于打料体系A中。
将114g(0.75mol,6.5eq)1,8-二氮杂二环十一碳-7-烯(DBU)和75mL THF加入打料瓶，搅拌均匀，得到碱溶液，置于打料体系B中。
将前述步骤得到的248g氯乙醛(0.13mol,1.1eq)的氯仿溶液加入打料瓶，置于打料体系C中。
将180mL白钢盘管中打满THF，将盘管置于60℃热浴中，控温50～60℃。
打料体系A、打料体系B、打料体系C的各自打料速度分别为2.18g/min，1.83g/min，2.51g/min，三股股物料在三通处汇合，然后进入盘管进行反应，保留时间为30min。
接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物，收率49％。两步收率为32％。
实施例6
Step1：将50g(0.21mol,1eq)三聚氯乙醛加入到打料瓶中，依次加入500ml氯仿、0.37g对甲苯磺酸(2.14mmol,1％eq)，搅拌至溶解，得到三聚氯乙醛溶液。
将30ml白钢盘管打满氯仿，并调节温度至155～165℃(目标温度为160℃)，压力控制在0.4～0.8MPa(目标压力为0.5～1.0MPa)，温度稳定10min后，可进行打料。
将三聚氯乙醛溶液的流速设定为4.34g/min，三聚氯乙醛溶液进入30ml盘管进行反应，保留时间为10min，得到氯乙醛的氯仿溶液，氯乙醛收率为78％，含量4.8％。
Step2：将15g(0.12mol，1eq)3-氨基-3-亚胺基丙酸乙酯和225mL四氢呋喃加入到打料瓶中，搅拌溶解，得到3-氨基-3-亚胺基丙酸乙酯溶液，置于打料体系A中。
将114g(0.75mol,6.5eq)1,8-二氮杂二环十一碳-7-烯(DBU)和75mL THF加入打料瓶，搅拌均匀，得到碱溶液，置于打料体系B中。
将前述步骤得到的207g(0.13mol,1.1eq)氯乙醛的氯仿溶液加入打料瓶，置于打料体系C中。
将180mL白钢盘管中打满THF，将盘管置于60℃热浴中，控温50～60℃。
打料体系A、打料体系B、打料体系C的各自打料速度分别为2.28g/min，1.92/min，2.19g/min，三股股物料在三通处汇合，然后进入盘管进行反应，保留时间为30min。
接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物，收率50％。两步收率为39％。
实施例7
Step1：将50g(0.21mol,1eq)三聚氯乙醛加入到打料瓶中，依次加入500ml氯仿、0.32g(2.13mmol,1％eq)三氟甲基磺酸，搅拌至溶解，得到三聚氯乙醛溶液。
将30ml白钢盘管打满氯仿，并调节温度至175～185℃(目标温度为180℃)，压力控制在0.4～0.8MPa(目标压力为0.5～1.0MPa)，温度稳定10min后，可进行打料。
将三聚氯乙醛溶液的流速设定为8.7g/min，三聚氯乙醛溶液进入30ml盘管进行反应，保留时间为5min，得到氯乙醛的氯仿溶液，氯乙醛收率为76％，含量4.7％。
Step2：将15g(0.12mol，1eq)3-氨基-3-亚胺基丙酸乙酯和225mL四氢呋喃加入到打料瓶中，搅拌溶解，得到3-氨基-3-亚胺基丙酸乙酯溶液，置于打料体系A中。
将114g(0.75mol,6.5eq)1,8-二氮杂二环十一碳-7-烯(DBU)和75mL THF加入打料瓶，搅拌均匀，得到碱溶液，置于打料体系B中。
将前述步骤得到的212g(0.07mol,0.60eq)氯乙醛的氯仿溶液加入打料瓶，置于打料体系C中。
将180mL白钢盘管中打满THF，将盘管置于60℃热浴中，控温50～60℃。
打料体系A、打料体系B、打料体系C的各自打料速度分别为2.27g/min，1.90g/min，2.23g/min，三股股物料在三通处汇合，然后进入盘管进行反应，保留时间为30min。
接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物，收率59％。两步收率为45％。
实施例8
Step1：将50g(0.21mol,1eq)三聚氯乙醛加入到打料瓶中，依次加入500ml氯仿、0.32g(2.13mmol,1％eq)三氟甲基磺酸，搅拌至溶解，得到三聚氯乙醛溶液。
将30ml白钢盘管打满氯仿，并调节温度至145～155℃(目标温度为150℃)，压力控制在0.4～0.8MPa(目标压力为0.5～1.0MPa)，温度稳定10min后，可进行打料。
将三聚氯乙醛溶液的流速设定为8.7g/min，三聚氯乙醛溶液进入30ml盘管进行反应，保留时间为5min，得到氯乙醛的氯仿溶液，氯乙醛收率为73％，含量4.5％。
Step2：将15g(0.12mol，1eq)3-氨基-3-亚胺基丙酸乙酯和225mL四氢呋喃加入到打料瓶中，搅拌溶解，得到3-氨基-3-亚胺基丙酸乙酯溶液，置于打料体系A中。
将114g(0.75mol,6.5eq)1,8-二氮杂二环十一碳-7-烯(DBU)和75mL THF加入打料瓶，搅拌均匀，得到碱溶液，置于打料体系B中。
将前述步骤得到的220g(0.13mol,1.1eq)氯乙醛的氯仿溶液加入打料瓶，置于打料体系C中。
将180mL白钢盘管中打满THF，将盘管置于60℃热浴中，控温50～60℃。
打料体系A、打料体系B、打料体系C的各自打料速度分别为1.92g/min，1.61g/min，1.96g/min，三股股物料在三通处汇合，然后进入盘管进行反应，保留时间为30min。
接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物，收率50％。两步收率为37％。
实施例9
Step1：三聚氯乙醛的解聚同实施例1。
Step2：将15g(0.12mol，1eq)3-氨基-3-亚胺基丙酸乙酯和225mL四氢呋喃加入到打料瓶中，搅拌溶解，得到3-氨基-3-亚胺基丙酸乙酯溶液，置于打料体系A中。
将91.5g(0.75mol,6.5eq)4-二甲基氨基吡啶(DMAP)和75mL THF加入打料瓶，搅拌均匀，得到碱溶液，置于打料体系B中。
将前述步骤得到的202g(0.13mol,1.1eq)氯乙醛的氯仿溶液加入打料瓶，置于打料体系C中。
将180mL白钢盘管中打满THF，将盘管置于60℃热浴中，控温50～60℃。
打料体系A、打料体系B、打料体系C的各自打料速度分别为2.77g/min，2.04g/min，2.60g/min，三股股物料在三通处汇合，然后进入盘管进行反应，保留时间为30min。
接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物，收率55％。两步收率为44％。
实施例10
Step1：三聚氯乙醛的解聚同实施例1。
Step2：将15g(0.12mol，1eq)3-氨基-3-亚胺基丙酸乙酯和225mL四氢呋喃加入到打料瓶中，搅拌溶解，得到3-氨基-3-亚胺基丙酸乙酯溶液，置于打料体系A中。
将75.5g(0.75mol，6.5eq)三乙胺和75mL THF加入打料瓶，搅拌均匀，得到碱溶液，置于打料体系B中。
将前述步骤得到的200g(0.13mol,1.1eq)氯乙醛的氯仿溶液加入打料瓶，置于打料体系C中。
将180mL白钢盘管中打满THF，将盘管置于60℃热浴中，控温50～60℃。
打料体系A、打料体系B、打料体系C的各自打料速度分别为2.61g/min，1.72g/min，1.39g/min，三股股物料在三通处汇合，然后进入盘管进行反应，保留时间为30min。
接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物，收率42％。两步收率为34％。
实施例11
Step1：三聚氯乙醛的解聚同实施例1。
Step2:将15g(0.12mol，1eq)3-氨基-3-亚胺基丙酸乙酯和225mL四氢呋喃加入到打料瓶中，搅拌溶解，得到3-氨基-3-亚胺基丙酸乙酯溶液，置于打料体系A中。
将59.3g(0.75mol，6.5eq)吡啶和75mL THF加入打料瓶，搅拌均匀，得到碱溶液，置于打料体系B中。
将前述步骤得到的202g(0.13mol,1.1eq)氯乙醛的氯仿溶液加入打料瓶，置于打料体系C中。
将180mL白钢盘管中打满THF，将盘管置于60℃热浴中，控温50～60℃。
打料体系A、打料体系B、打料体系C的各自打料速度分别为2.85g/min，1.67g/min，1.52g/min，三股股物料在三通处汇合，然后进入盘管进行反应，保留时间为30min。
接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物，收率23％。两步收率为18％。
实施例12
Step1：三聚氯乙醛的解聚同实施例1。
Step2：将15g(0.12mol，1eq)3-氨基-3-亚胺基丙酸乙酯和225mL四氢呋喃加入到打料瓶中，搅拌溶解，得到3-氨基-3-亚胺基丙酸乙酯溶液，置于打料体系A中。
将63.8g(0.75mol，6.5eq)哌啶和75mL THF加入打料瓶，搅拌均匀，得到碱溶液，置于打料体系B中。
将前述步骤得到的202g(0.13mol,1.1eq)氯乙醛的氯仿溶液加入打料瓶，置于打料体系C中。
将180mL白钢盘管中打满THF，将盘管置于60℃热浴中，控温50～60℃。
打料体系A、打料体系B、打料体系C的各自打料速度分别为2.80g/min，1.70g/min，1.49g/min，三股股物料在三通处汇合，然后进入盘管进行反应，保留时间为30min。
接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物，收率30％。两步收率为24％。
实施例13
Step1：三聚氯乙醛的解聚同实施例1。
Step2：将15g 3-氨基-3-亚胺基丙酸乙酯和225mL四氢呋喃加入到打料瓶中，搅拌溶解，得到3-氨基-3-亚胺基丙酸乙酯溶液，置于打料体系A中。
将86.3g四甲基胍和75mL THF加入打料瓶，搅拌均匀，得到碱溶液，置于打料体系B中。
将前述步骤得到的202g(0.13mol,1.1eq)氯乙醛的氯仿溶液加入打料瓶，置于打料体系C中。
将180mL白钢盘管中打满THF，将盘管置于60℃热浴中，控温50～60℃。
打料体系A、打料体系B、打料体系C的各自打料速度分别为2.65g/min，1.88g/min，1.42g/min，三股股物料在三通处汇合，然后进入盘管进行反应，保留时间为30min。
接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物，收率47％。两步收率为38％。
实施例14
与实施例1不同之处在于，Step2反应中，将盘管置于40℃热浴中，控温30～40℃。接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物，收率29％。两步收率为23％。
实施例15
与实施例1不同之处在于，Step2反应中，将盘管置于70℃热浴中，控温60～70℃。接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物，收率54％。两步收率为43％。
实施例16
与实施例1不同之处在于，第二步反应中，将盘管置于100℃热浴中，控温90～100℃。接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物，收率28％。两步收率为22％。
实施例17
与实施例1不同之处在于，Step1：反应中，打料速度为2.17g/min，保留时间为20min。得到氯乙醛的氯仿溶液，核磁内标法计算氯乙醛收率为78％，含量4.8％。
Step2：将15g(0.12mol，1eq)3-氨基-3-亚胺基丙酸乙酯和225mL四氢呋喃加入到打料瓶中，搅拌溶解，得到3-氨基-3-亚胺基丙酸乙酯溶液，置于打料体系A中。
将114g(0.75mol,6.5eq)1,8-二氮杂二环十一碳-7-烯(DBU)和75mL THF加入打料瓶，搅拌均匀，得到碱溶液，置于打料体系B中。
将前述步骤得到的207g(0.13mol，1.1eq)氯乙醛的氯仿溶液加入打料瓶，置于打料体系C中。
将180mL白钢盘管中打满THF，将盘管置于60℃热浴中，控温50～60℃。
打料体系A、打料体系B、打料体系C的各自打料速度分别为2.75g/min，2.31g/min，2.64g/min，三股股物料在三通处汇合，然后进入盘管进行反应，保留时间为30min。
接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物即2-氨基吡咯-3-羧酸乙酯，收率58％。两步收率为45％。
实施例18
与实施例1不同之处在于，Step1：反应中，打料速度为0.72g/min，保留时间为60min。得到氯乙醛的氯仿溶液，核磁内标法计算氯乙醛收率为44％，含量2.7％。
Step2：将15g(0.12mol，1eq)3-氨基-3-亚胺基丙酸乙酯和225mL四氢呋喃加入到打料瓶中，搅拌溶解，得到3-氨基-3-亚胺基丙酸乙酯溶液，置于打料体系A中。
将114g(0.75mol,6.5eq)1,8-二氮杂二环十一碳-7-烯(DBU)和75mL THF加入打料瓶，搅拌均匀，得到碱溶液，置于打料体系B中。
将前述步骤得到的366g(0.13mol，1.1eq)氯乙醛的氯仿溶液加入打料瓶，置于打料体系C中。
将180mL白钢盘管中打满THF，将盘管置于60℃热浴中，控温50～60℃。
打料体系A、打料体系B、打料体系C的各自打料速度分别为2.24g/min，1.88g/min，3.81g/min，三股股物料在三通处汇合，然后进入盘管进行反应，保留时间为30min。
接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物即2-氨基吡咯-3-羧酸乙酯，收率52％。两步收率为23％，与实施例1相比收率降低是由于S tep1中的保留时间较长，导致产物被破坏。
实施例19
与实施例1不同之处在于，Step1：反应中，三氟甲基磺酸用量为0.032g(0.21mol，0.1％eq)。得到氯乙醛的氯仿溶液，核磁内标法计算氯乙醛收率为43％，含量2.7％。
Step2：将15g(0.12mol，1eq)3-氨基-3-亚胺基丙酸乙酯和225mL四氢呋喃加入到打料瓶中，搅拌溶解，得到3-氨基-3-亚胺基丙酸乙酯溶液，置于打料体系A中。
将114g(0.75mol,6.5eq)1,8-二氮杂二环十一碳-7-烯(DBU)和75mL THF加入打料瓶，搅拌均匀，得到碱溶液，置于打料体系B中。
将前述步骤得到的376g(0.13mol，1.1eq)氯乙醛的氯仿溶液加入打料瓶，置于打料体系C中。
将180mL白钢盘管中打满THF，将盘管置于60℃热浴中，控温50～60℃。
打料体系A、打料体系B、打料体系C的各自打料速度分别为2.56g/min，2.15g/min，1.37g/min，三股股物料在三通处汇合，然后进入盘管进行反应，保留时间为30min。
接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物即2-氨基吡咯-3-羧酸乙酯，收率60％。两步收率为26％。
实施例20
Step1：三聚氯乙醛的解聚同实施例1。
Step2：将15g(0.12mol，1eq)3-氨基-3-亚胺基丙酸乙酯和225mL四氢呋喃加入到打料瓶中，搅拌溶解，得到3-氨基-3-亚胺基丙酸乙酯溶液，置于打料体系A中。
将114g(0.75mol,6.5eq)1,8-二氮杂二环十一碳-7-烯(DBU)和75mL THF加入打料瓶，搅拌均匀，得到碱溶液，置于打料体系B中。
将前述步骤得到的200g(0.13mol，1.1eq)氯乙醛的氯仿溶液加入打料瓶，置于打料体系C中。
将180mL白钢盘管中打满THF，将盘管置于60℃热浴中，控温50～60℃。
打料体系A、打料体系B、打料体系C的各自打料速度分别为8.33g/min，6.99g/min，7.74g/min，三股股物料在三通处汇合，然后进入盘管进行反应，保留时间为10min。
接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物即2-氨基吡咯-3-羧酸乙酯，收率26％。两步收率为21％。
实施例21
Step1：三聚氯乙醛的解聚同实施例1。
Step2：将15g(0.12mol，1eq)3-氨基-3-亚胺基丙酸乙酯和225mL四氢呋喃加入到打料瓶中，搅拌溶解，得到3-氨基-3-亚胺基丙酸乙酯溶液，置于打料体系A中。
将114g(0.75mol,6.5eq)1,8-二氮杂二环十一碳-7-烯(DBU)和75mL THF加入打料瓶，搅拌均匀，得到碱溶液，置于打料体系B中。
将前述步骤得到的200g(0.13mol，1.1eq)氯乙醛的氯仿溶液加入打料瓶，置于打料体系C中。
将180mL白钢盘管中打满THF，将盘管置于60℃热浴中，控温50～60℃。
打料体系A、打料体系B、打料体系C的各自打料速度分别为1.39g/min，1.17g/min，1.29g/min，三股股物料在三通处汇合，然后进入盘管进行反应，保留时间为60min。
接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物即2-氨基吡咯-3-羧酸乙酯，收率49％。两步收率为39％。
实施例22
Step1：三聚氯乙醛的解聚同实施例1。
Step2：将15g(0.12mol，1eq)3-氨基-3-亚胺基丙酸乙酯和225mL四氢呋喃加入到打料瓶中，搅拌溶解，得到3-氨基-3-亚胺基丙酸乙酯溶液，置于打料体系A中。
将114g(0.75mol,6.5eq)1,8-二氮杂二环十一碳-7-烯(DBU)和75mL THF加入打料瓶，搅拌均匀，得到碱溶液，置于打料体系B中。
将前述步骤得到的200g(0.13mol，1.1eq)氯乙醛的氯仿溶液加入打料瓶，置于打料体系C中。
将180mL白钢盘管中打满THF，将盘管置于60℃热浴中，控温50～60℃。
打料体系A、打料体系B、打料体系C的各自打料速度分别为0.69g/min，0.58g/min，0.64g/min，三股股物料在三通处汇合，然后进入盘管进行反应，保留时间为120min。
接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物即2-氨基吡咯-3-羧酸乙酯，收率21％。两步收率为17％。
实施例23
Step1：将50g(0.21mol,1eq)三聚氯乙醛加入到打料瓶中，依次加入500ml氯仿、0.32g(2.13mmol,1％eq)三氟甲基磺酸，搅拌至溶解，得到三聚氯乙醛溶液。
将30ml白钢盘管打满氯仿，并调节温度至105～115℃(目标温度为110℃)，压力控制在0.4～0.8MPa(目标压力为0.5～1.0MPa)，温度稳定10min后，可进行打料。
将三聚氯乙醛溶液的流速设定为2.17g/min，三聚氯乙醛溶液进入30ml盘管进行反应，保留时间为20min，得到氯乙醛的氯仿溶液，核磁内标法计算氯乙醛收率为49％，含量2.8％。
Step2：将15g(0.12mol，1eq)3-氨基-3-亚胺基丙酸乙酯和225mL四氢呋喃加入到打料瓶中，搅拌溶解，得到3-氨基-3-亚胺基丙酸乙酯溶液，置于打料体系A中。
将114g(0.75mol,6.5eq)1,8-二氮杂二环十一碳-7-烯(DBU)和75mL THF加入打料瓶，搅拌均匀，得到碱溶液，置于打料体系B中。
将前述步骤得到的330g(0.13mol，1.1eq)氯乙醛的氯仿溶液加入打料瓶，置于打料体系C中。
将180mL白钢盘管中打满THF，将盘管置于60℃热浴中，控温50～60℃。
打料体系A、打料体系B、打料体系C的各自打料速度分别为2.30g/min，1.93g/min，2.14g/min，三股股物料在三通处汇合，然后进入盘管进行反应，保留时间为30min。
接收体系在40℃将所接受的含有2-氨基吡咯-3-羧酸乙酯的产物体系浓缩至无馏分，得到粘稠油状物即2-氨基吡咯-3-羧酸乙酯，收率54％。两步收率为26.5％。
从以上的描述中，可以看出，本发明上述的实施例实现了如下技术效果：
本申请的连续化制备方法以结构稳定的三聚氯乙醛为原料，连续制备出无市售且易变质的无水氯乙醛，所得到的氯乙醛分散在原料的溶剂中形成氯乙醛溶液；然后将氯乙醛溶液与3-氨基-3-亚胺基丙酸乙酯溶液通过连续反应得到2-氨基吡咯-3-羧酸乙酯。该连续工艺突破了无水氯乙醛的限制，且使用连续反应制备无水氯乙醛，反应速度比批次快，收率较高，所制备的氯乙醛溶液用于下一步的缩合反应时，物料配比更加可控，且由于压力陡降使得前后两步的温度得以很好的兼容，从而在整体上提高了2-氨基吡咯-3-羧酸乙酯的收率。另外，连续化工艺避免了批次的放大效应，且连续化设备特有的属性(反应体系小，热交换速度远高于批次设备)使反应条件即便更加剧烈，但安全性也是高于批次反应；同时与现有的批次工艺相比，更加安全可控；更适合放大生产，成本更加低廉。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (19)

  1. 一种2-氨基吡咯-3-羧酸乙酯的连续化制备方法，其特征在于，包括：
    将三聚氯乙醛溶液连续送入第一连续化反应器中以对三聚氯乙醛进行连续化酸催化解聚，得到氯乙醛溶液；
    将3-氨基-3-亚胺基丙酸乙酯溶液、碱溶液和所述氯乙醛溶液连续送入第二连续化反应器中以进行缩合反应，得到所述2-氨基吡咯-3-羧酸乙酯，所述三聚氯乙醛溶液、所述3-氨基-3-亚胺基丙酸乙酯溶液和所述碱溶液为有机溶液。
  2. 根据权利要求1所述的连续化制备方法，其特征在于，所述三聚氯乙醛溶液的溶剂、所述3-氨基-3-亚胺基丙酸乙酯溶液的溶剂、所述碱溶液的溶剂各自独立地选自氯仿、乙酸乙酯、四氢呋喃、2-甲基四氢呋喃、甲苯、二氯甲烷、醋酸异丙酯、乙腈、N,N-二甲基甲酰胺组成的组中的任意一种或多种。
  3. 根据权利要求1所述的连续化制备方法，其特征在于，所述三聚氯乙醛溶液中还包括酸催化剂，所述酸催化剂选自有机酸或无机酸中的任意一种或多种，所述无机酸为盐酸或硫酸，所述有机酸选自甲磺酸、对甲苯磺酸、醋酸、甲酸、三氟甲基磺酸组成的组中的任意一种或多种。
  4. 根据权利要求1所述的连续化制备方法，其特征在于，所述连续化酸催化解聚的温度为110～180℃。
  5. 根据权利要求4所述的连续化制备方法，其特征在于，所述连续化酸催化解聚的温度为150～170℃。
  6. 根据权利要求5所述的连续化制备方法，其特征在于，所述连续化酸催化解聚的温度为155～165℃。
  7. 根据权利要求1所述的连续化制备方法，其特征在于，所述连续化酸催化解聚的压力为0.4～1.0MPa。
  8. 根据权利要求7所述的连续化制备方法，其特征在于，所述连续化酸催化解聚的压力为0.5～0.8MPa。
  9. 根据权利要求3所述的连续化制备方法，其特征在于，所述三聚氯乙醛溶液中所述酸催化剂和所述三聚氯乙醛的摩尔比为：0.1:100～1:100。
  10. 根据权利要求1所述的连续化制备方法，其特征在于，所述第一连续化反应器的保留时间为5～60min。
  11. 根据权利要求10所述的连续化制备方法，其特征在于，所述第一连续化反应器的保留时间为10～20min。
  12. 根据权利要求1所述的连续化制备方法，其特征在于，所述碱溶液中的碱选自三乙胺、二异丙基乙基胺、1,8-二氮杂二环十一碳-7-烯、4-二甲氨基吡啶、三正丙胺、三正丁胺、吡啶、哌啶、四甲基胍、N-甲基吗啉、N-甲基咪唑中的任意一种。
  13. 根据权利要求1所述的连续化制备方法，其特征在于，所述缩合反应的温度为40～100℃。
  14. 根据权利要求13所述的连续化制备方法，其特征在于，所述缩合反应的温度为50～70℃。
  15. 根据权利要求1所述的连续化制备方法，其特征在于，所述3-氨基-3-亚胺基丙酸乙酯溶液中所述3-氨基-3-亚胺基丙酸乙酯和所述氯乙醛溶液中所述氯乙醛的摩尔比为1:1～1:3。
  16. 根据权利要求15所述的连续化制备方法，其特征在于，所述3-氨基-3-亚胺基丙酸乙酯溶液中所述3-氨基-3-亚胺基丙酸乙酯和所述氯乙醛溶液中所述氯乙醛的摩尔比为1:1.1～1:1.5。
  17. 根据权利要求1所述的连续化制备方法，其特征在于，所述第二连续化反应器的保留时间为10～120min。
  18. 根据权利要求17所述的连续化制备方法，其特征在于，所述第二连续化反应器的保留时间为30～60min。
  19. 根据权利要求1所述的连续化制备方法，其特征在于，所述第一连续化反应器和所述第二连续化反应器各自独立地为连续盘管反应器或连续化反应釜。
PCT/CN2019/129408 2019-11-25 2019-12-27 一种2-氨基吡咯-3-羧酸乙酯的连续化制备方法 WO2021103257A1 (zh)

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JPH06247889A (ja) * 1993-02-25 1994-09-06 Kureha Chem Ind Co Ltd クロロアルデヒド三量体の解重合方法
WO2016073891A1 (en) * 2014-11-06 2016-05-12 Lysosomal Therapeutics Inc. Substituted pyrrolo[1,2-a]pyrimidines and their use in the treatment of medical disorders
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