Preparation process of 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid

Abstract

The process described in this application uses ethyl N-Cbz-4-oxo-3-pyrrolidinecarboxylate and Wittig reagent ethyltriphenylphosphine iodide as the starting points for synthesis. First, ethyl N-Cbz-4-oxo-3-pyrrolidinecarboxylate undergoes a nucleophilic addition reaction with Wittig reagent ethyltriphenylphosphine iodide to generate an olefin. Then, it undergoes a hydrolysis reaction under alkaline conditions to generate an acid, followed by a double bond reduction reaction under catalytic hydrogen conditions. The process is reasonable, has high yield, is simple to operate, and has low production cost, which is conducive to large-scale industrial production and fills a technological gap in related fields.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical intermediate synthesis technology, and in particular to the preparation process of 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid. Background Technology

[0002] A key intermediate of the JAK1 inhibitor utadacitinib is a chiral pyrrole ring: 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid. Upatinib is a highly potent and selective JAK1 inhibitor. JAK kinases belong to a family of non-receptor tyrosine kinases, of which four members have been identified: JAK1, JAK2, JAK3, and TYK1. JAK substrates are STATs, signal transducers and transcription activators. STATs dimerize upon phosphorylation by JAKs, then cross the nuclear membrane into the nucleus to regulate the expression of related genes. This signaling pathway is called the JAK-STAT pathway. Therefore, JAKs play an important role in immune-mediated disease pathophysiology and have shown good efficacy in clinical trials treating various autoimmune and inflammatory diseases, such as atopic dermatitis, rheumatoid arthritis, psoriasis, and ulcerative colitis. Upatinib is a small-molecule oral targeted drug developed by AbbVie, a leading international biopharmaceutical company. In August 2019, the FDA approved it for the treatment of rheumatoid arthritis. On August 24, 2021, the European Commission announced its approval for the treatment of moderate to severe atopic dermatitis in adolescents, making it the selective JAK1 inhibitor with the most comprehensive indication coverage in my country. However, its current production capacity is low, and the process parameters for its preparation are demanding, preventing large-scale production with high purity. Therefore, developing a preparation process for 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid has significant production value. Summary of the Invention

[0003] To provide a high-yield, simple-to-operate, and low-cost preparation process for 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid, this application provides a preparation process for 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid.

[0004] This application provides a process for preparing 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid, comprising the following steps: S1: Ethyl N-Cbz-4-oxo-3-pyrrolidinecarboxylate and triethylamine are added to dichloromethane, cooled, and then ethyltriphenylphosphine iodide is added dropwise. After the addition is complete, the reaction mixture is raised to room temperature, and the reaction continues at this temperature. The solvent is removed by treatment, and the residue is dissolved in a solvent to precipitate triphenylphosphine oxide. The mixture is filtered, and the solvent is removed from the filtrate under reduced pressure to obtain a crude product. The crude product is then subjected to column chromatography with a mixed solvent to obtain an intermediate product.

[0005] S2: Dissolve the intermediate product in a solvent, add lithium hydroxide, stir the reaction mixture at room temperature and let it stand to remove the organic solvent, extract the remaining liquid with dichloromethane, combine the organic phases, wash, dry and continue to remove the solvent under reduced pressure, then recrystallize with ethyl acetate or petroleum ether, dry, and obtain the semi-finished product.

[0006] S3: Dissolve the semi-finished product in a solvent, add target carbon, stir and let stand, monitor the reaction progress using thin-layer chromatography and liquid chromatography, when the reaction is complete, filter off the catalyst, wash the filter cake, combine the filtrate and washing liquid, and evaporate the solvent under reduced pressure to obtain 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid.

[0007]

[0008] By adopting the above technical solution, using ethyl N-Cbz-4-oxo-3-pyrrolidinecarboxylate and Wittig reagent ethyltriphenylphosphine iodide as the starting point for synthesis, ethyl N-Cbz-4-oxo-3-pyrrolidinecarboxylate undergoes nucleophilic addition with Wittig reagent ethyltriphenylphosphine iodide to generate an olefin. Then, it undergoes hydrolysis under alkaline conditions to generate an acid, followed by double bond reduction under catalytic hydrogen conditions. The process is reasonable, has high yield, is simple to operate, and has low production cost, which is conducive to large-scale industrial production.

[0009] In one specific feasible implementation, the molar ratio of N-Cbz-4-oxo-3-pyrrolidinecarboxylate, triethylamine, and ethyltriphenylphosphine iodide in S1 is 1:2-2.1:1.1, and the cooling temperature is 0-2℃.

[0010] By adopting the above technical solution, ethyl N-Cbz-4-oxo-3-pyrrolidinecarboxylate and Wittig reagent ethyltriphenylphosphine iodide can be fully substituted with fewer side reactions, which is beneficial for subsequent separation. The operation is simple and the yield is high. By limiting the cooling temperature, the occurrence of side reactions is further reduced.

[0011] In one specific feasible embodiment, the mixed solvent in S1 is ethyl acetate and petroleum ether in a volume ratio of 10:1-3.

[0012] By adopting the above technical solution, the mixed solvent is suitable for the reaction raw materials of this application, does not undergo other side reactions with the reaction raw materials, improves the stability of the reaction, the reactants can be fully dissolved and dispersed in the solvent, the reaction system is a homogeneous system, the reaction is more thorough, and the utilization rate of raw materials is improved.

[0013] In one specific feasible implementation, the washing in S1 is washing with saturated sodium chloride and drying with sodium sulfate.

[0014] By adopting the above technical solution, the reactants in the washed filter cake are thoroughly washed, which further improves the utilization rate of raw materials. The drying by using sodium sulfate is thorough and conducive to the subsequent reaction, which further improves the stability of the reaction.

[0015] In one specific feasible implementation, drying in S2 is performed by heating under vacuum, with the heating temperature being 43-47°C.

[0016] By adopting the above technical solution, the reactants are dried more thoroughly and are less prone to deterioration, resulting in higher reaction stability.

[0017] In one specific implementation, the addition of target carbon to S3 also includes the introduction of hydrogen gas.

[0018] By adopting the above technical solution, the target carbon has a good catalytic effect, hydrogen is activated into free hydrogen and participates in reduction, the reaction can be carried out under relatively mild conditions, and the properties of the reactants are kept stable.

[0019] In one specific implementation, the filter cake in S3 is washed with methanol.

[0020] By adopting the above technical solution, the washing effect is good, it is suitable for the reactant settings of this application, and no other side reactions occur.

[0021] The preparation process of 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid according to claim 1 is characterized in that: the mass of the target carbon in S3 is 1-7 wt% of the semi-finished product.

[0022] By adopting the above technical solution, the catalysis of the target carbon is complete, the reaction rate is appropriate, and no large number of by-products are generated.

[0023] In one specific implementation scheme, the solvent in S2 is methanol, and the solvent in S3 is ethanol.

[0024] By adopting the above technical solution and setting different solvents for the two reaction steps, the reactant settings of this application are more suitable. The reactants can be fully dissolved and dispersed in the solvent, the reaction system is a homogeneous system, the reaction is more thorough, and the utilization rate of raw materials is improved.

[0025] In summary, this application has the following beneficial technical effects:

[0026] The process of this application uses ethyl N-Cbz-4-oxo-3-pyrrolidinecarboxylate and Wittig reagent ethyltriphenylphosphine iodide as the starting point for synthesis. The raw materials are readily available, the steps are short, the process is reasonable, the yield is high, the operation is simple, the production cost is low, and it is conducive to large-scale industrial production. By setting the reactant ratio, process parameters and solvent selection in the reaction process, the yield is even higher, the product post-processing is simple, and there is less waste. Detailed Implementation

[0027] To further aid in understanding the technical solution of the present invention, several specific embodiments are provided to describe the technical solution of the present invention in more detail. All described embodiments are only some embodiments of the present invention, not all of them; embodiments can be combined with each other, and the same or similar concepts or processes may not be repeated in some embodiments. The following embodiments are further illustrations of the present invention, but the present invention is not limited thereto.

[0028] The components used in the preparation examples in this application refer to components obtained through the preparation methods described in the preparation examples. Unless otherwise specified, the experimental reagents used in the preparation examples, embodiments, and comparative examples are all from commercially available brands or obtained through conventional preparation processes. Example Example 1

[0029] 29.1 g (0.1 mol) of compound N-Cbz-4-oxo-3-pyrrolidinecarboxylate and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After cooling the mixture to 0 °C, 4.6 g (0.011) mol of ethyltriphenylphosphine iodide was added dropwise. After the addition was complete, the reaction mixture was brought to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment, and the residue was dissolved in 1000 mL of n-hexane and diethyl ether in a volume ratio of 3:1. Triphenylphosphine oxide precipitated, and the mixture was filtered. The solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography in 1000 mL of ethyl acetate and petroleum ether mixed solvent in a volume ratio of 10:1 to obtain the intermediate product. The intermediate product was a pale yellow oil with a yield of 90.0%.

[0030] The intermediate product was dissolved in 150 mL of ethanol, and 0.29 g (0.012 mol) of lithium hydroxide was added. The mixture was stirred overnight (8 hours) at room temperature. 500 mL of organic solvent was removed, and the remaining liquid was extracted with 300 mL of dichloromethane. The extraction was repeated 3 times. The organic phases were combined, washed with saturated sodium chloride, dried over sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then recrystallized from ethyl acetate to give a solid. The solid was dried under vacuum at 45 °C to give the semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, a pale yellow solid. The yield of the semi-finished product was 99.99%.

[0031] The semi-finished product was dissolved in 150 mL of methanol, and 0.91 g of Pd / C was added. The reaction mixture was stirred overnight (8 hours) at room temperature under H2 atmosphere. The reaction progress was monitored by thin-layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered off using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and washings were combined, and the solvent was evaporated under reduced pressure to give 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid, a pale yellow solid, with a yield of 99.99%. Example 2

[0032] 29.1 g (0.1 mol) of compound N-Cbz-4-oxo-3-pyrrolidinecarboxylate and 67.0 g (0.18 mol) of triethylamine were added to 100 mL of dichloromethane. After cooling the mixture to 0 °C, 4.6 g (0.011) mol of ethyltriphenylphosphine iodide was added dropwise. After the addition was complete, the reaction mixture was brought to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment, and the residue was dissolved in 1000 mL of n-hexane and diethyl ether in a volume ratio of 3:1. Triphenylphosphine oxide precipitated, and the mixture was filtered. The solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography in 1000 mL of ethyl acetate and petroleum ether mixed solvent in a volume ratio of 10:1 to obtain the intermediate product. The intermediate product was a pale yellow oil with a yield of 86.1%.

[0033] The intermediate product was dissolved in 150 mL of ethanol, and 0.29 g (0.012 mol) of lithium hydroxide was added. The mixture was stirred overnight (8 hours) at room temperature. 500 mL of organic solvent was removed, and the remaining liquid was extracted with 300 mL of dichloromethane. The extraction was repeated 3 times. The organic phases were combined, washed with saturated sodium chloride, dried over sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then recrystallized from ethyl acetate to give a solid. The solid was dried under vacuum at 45 °C to give the semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, a pale yellow solid. The yield of the semi-finished product was 99.72%.

[0034] The semi-finished product was dissolved in 150 mL of methanol, and 0.91 g of Pd / C was added. The reaction mixture was stirred overnight (8 hours) at room temperature under H2 atmosphere. The reaction progress was monitored by thin-layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered off using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and washings were combined, and the solvent was evaporated under reduced pressure to give 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid, a pale yellow solid, with a yield of 99.85%. Example 3

[0035] 29.1 g (0.1 mol) of compound N-Cbz-4-oxo-3-pyrrolidinecarboxylate and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After cooling the mixture to 0 °C, 3.8 g (0.009) mol of ethyltriphenylphosphine iodide was added dropwise. After the addition was complete, the reaction mixture was brought to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment, and the residue was dissolved in 1000 mL of n-hexane and diethyl ether in a volume ratio of 3:1. Triphenylphosphine oxide precipitated, and the mixture was filtered. The solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography in 1000 mL of ethyl acetate and petroleum ether mixed solvent in a volume ratio of 10:1 to obtain the intermediate product. The intermediate product was a pale yellow oil with a yield of 76.2%.

[0036] The intermediate product was dissolved in 150 mL of ethanol, and 0.29 g (0.012 mol) of lithium hydroxide was added. The mixture was stirred overnight (8 hours) at room temperature. 500 mL of organic solvent was removed, and the remaining liquid was extracted with 300 mL of dichloromethane. The extraction was repeated 3 times. The organic phases were combined, washed with saturated sodium chloride, dried over sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then recrystallized from ethyl acetate to give a solid. The solid was dried under vacuum at 45 °C to give the semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, a pale yellow solid. The yield of the semi-finished product was 97.79%.

[0037] The semi-finished product was dissolved in 150 mL of methanol, and 0.91 g of Pd / C was added. The reaction mixture was stirred overnight (8 hours) at room temperature under H2 atmosphere. The reaction progress was monitored by thin-layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered off using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and washings were combined, and the solvent was evaporated under reduced pressure to give 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid, a pale yellow solid, with a yield of 98.97%. Example 4

[0038] 29.1 g (0.1 mol) of compound N-Cbz-4-oxo-3-pyrrolidinecarboxylate and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After cooling the mixture to 0 °C, 4.6 g (0.011) mol of ethyltriphenylphosphine iodide was added dropwise. After the addition was complete, the reaction mixture was brought to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment, and the residue was dissolved in 1000 mL of n-hexane and diethyl ether in a volume ratio of 3:1. Triphenylphosphine oxide precipitated. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography with 1000 mL of ethyl acetate to obtain the intermediate product, which was a pale yellow oil with a yield of 87.9%.

[0039] The intermediate product was dissolved in 150 mL of ethanol, and 0.29 g (0.012 mol) of lithium hydroxide was added. The mixture was stirred overnight (8 hours) at room temperature. 500 mL of organic solvent was removed, and the remaining liquid was extracted with 300 mL of dichloromethane. The extraction was repeated 3 times. The organic phases were combined, washed with saturated sodium chloride, dried over sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then recrystallized from ethyl acetate to give a solid. The solid was dried under vacuum at 45 °C to give the semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, a pale yellow solid. The yield of the semi-finished product was 93.44%.

[0040] The semi-finished product was dissolved in 150 mL of methanol, and 0.91 g of Pd / C was added. The reaction mixture was stirred overnight (8 hours) at room temperature under H2 atmosphere. The reaction progress was monitored by thin-layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered off using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and washings were combined, and the solvent was evaporated under reduced pressure to give 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid, a pale yellow solid, with a yield of 96.65%. Example 5

[0041] 29.1 g (0.1 mol) of compound N-Cbz-4-oxo-3-pyrrolidinecarboxylate and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After cooling the mixture to 0 °C, 4.6 g (0.011) mol of ethyltriphenylphosphine iodide was added dropwise. After the addition was complete, the reaction mixture was brought to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment, and the residue was dissolved in 1000 mL of n-hexane and diethyl ether in a volume ratio of 3:1. Triphenylphosphine oxide precipitated, and the mixture was filtered. The solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography in 1000 mL of ethyl acetate and petroleum ether mixed solvent in a volume ratio of 12:1 to obtain the intermediate product. The intermediate product was a pale yellow oil with a yield of 89.1%.

[0042] The intermediate product was dissolved in 150 mL of ethanol, and 0.29 g (0.012 mol) of lithium hydroxide was added. The mixture was stirred overnight (8 hours) at room temperature. 500 mL of organic solvent was removed, and the remaining liquid was extracted with 300 mL of dichloromethane. The extraction was repeated 3 times. The organic phases were combined, washed with saturated sodium chloride, dried over sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then recrystallized from ethyl acetate to give a solid. The solid was dried under vacuum at 45 °C to give the semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, a pale yellow solid. The yield of the semi-finished product was 99.78%.

[0043] The semi-finished product was dissolved in 150 mL of methanol, and 0.91 g of Pd / C was added. The reaction mixture was stirred overnight (8 hours) at room temperature under H2 atmosphere. The reaction progress was monitored by thin-layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered off using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and washings were combined, and the solvent was evaporated under reduced pressure to give 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid, a pale yellow solid, with a yield of 99.98%. Example 6

[0044] 29.1 g (0.1 mol) of compound N-Cbz-4-oxo-3-pyrrolidinecarboxylate and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After cooling the mixture to 0 °C, 4.6 g (0.011) mol of ethyltriphenylphosphine iodide was added dropwise. After the addition was complete, the reaction mixture was brought to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment, and the residue was dissolved in 1000 mL of n-hexane and diethyl ether in a volume ratio of 3:1. Triphenylphosphine oxide precipitated, and the mixture was filtered. The solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography in 1000 mL of ethyl acetate and petroleum ether mixed solvent in a volume ratio of 10:1 to obtain the intermediate product. The intermediate product was a pale yellow oil with a yield of 90.0%.

[0045] The intermediate product was dissolved in 150 mL of ethanol, and 0.29 g (0.012 mol) of lithium hydroxide was added. The mixture was stirred overnight (8 hours) at room temperature. 500 mL of organic solvent was removed, and the remaining liquid was extracted with 300 mL of dichloromethane. The extraction was repeated 3 times. The organic phases were combined, washed with saturated sodium chloride, dried over sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then recrystallized from ethyl acetate to give a solid. The solid was dried at room temperature to give the semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, a pale yellow solid. The yield of the semi-finished product was 99.94%.

[0046] The semi-finished product was dissolved in 150 mL of methanol, and 0.91 g of Pd / C was added. The reaction mixture was stirred overnight (8 hours) at room temperature under H2 atmosphere. The reaction progress was monitored by thin-layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered off using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and washings were combined, and the solvent was evaporated under reduced pressure to give 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid, a pale yellow solid, with a yield of 99.97%. Example 7

[0047] 29.1 g (0.1 mol) of compound N-Cbz-4-oxo-3-pyrrolidinecarboxylate and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After cooling the mixture to 0 °C, 4.6 g (0.011) mol of ethyltriphenylphosphine iodide was added dropwise. After the addition was complete, the reaction mixture was brought to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment, and the residue was dissolved in 1000 mL of n-hexane and diethyl ether in a volume ratio of 3:1. Triphenylphosphine oxide precipitated, and the mixture was filtered. The solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography in 1000 mL of ethyl acetate and petroleum ether mixed solvent in a volume ratio of 10:1 to obtain the intermediate product. The intermediate product was a pale yellow oil with a yield of 90.0%.

[0048] The intermediate product was dissolved in 150 mL of ethanol, and 0.29 g (0.012 mol) of lithium hydroxide was added. The mixture was stirred overnight (8 hours) at room temperature. 500 mL of organic solvent was removed, and the remaining liquid was extracted with 300 mL of dichloromethane. The extraction was repeated 3 times. The organic phases were combined, washed with saturated sodium chloride, dried over sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then recrystallized from ethyl acetate to give a solid. The solid was dried under vacuum at 45 °C to give the semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, a pale yellow solid. The yield of the semi-finished product was 99.99%.

[0049] The semi-finished product was dissolved in 150 mL of methanol, and 0.30 g of Pd / C was added. The reaction mixture was stirred overnight (8 hours) at room temperature under H2 atmosphere. The reaction progress was monitored by thin-layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered off using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and washings were combined, and the solvent was evaporated under reduced pressure to give 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid, a pale yellow solid, with a yield of 99.99%. Example 8

[0050] 29.1 g (0.1 mol) of compound N-Cbz-4-oxo-3-pyrrolidinecarboxylate and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After cooling the mixture to 0 °C, 4.6 g (0.011) mol of ethyltriphenylphosphine iodide was added dropwise. After the addition was complete, the reaction mixture was brought to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment, and the residue was dissolved in 1000 mL of n-hexane and diethyl ether in a volume ratio of 3:1. Triphenylphosphine oxide precipitated, and the mixture was filtered. The solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography in 1000 mL of ethyl acetate and petroleum ether mixed solvent in a volume ratio of 10:1 to obtain the intermediate product. The intermediate product was a pale yellow oil with a yield of 90.0%.

[0051] The intermediate product was dissolved in 150 mL of ethanol, and 0.29 g (0.012 mol) of lithium hydroxide was added. The mixture was stirred overnight (8 hours) at room temperature. 500 mL of organic solvent was removed, and the remaining liquid was extracted with 300 mL of dichloromethane. The extraction was repeated 3 times. The organic phases were combined, washed with saturated sodium chloride, dried over sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then recrystallized from ethyl acetate to give a solid. The solid was dried under vacuum at 45 °C to give the semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, a pale yellow solid. The yield of the semi-finished product was 99.99%.

[0052] The semi-finished product was dissolved in 150 mL of methanol, and 0.15 g of Pd / C was added. The reaction mixture was stirred overnight (8 hours) at room temperature under H2 atmosphere. The reaction progress was monitored by thin-layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered off using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and washings were combined, and the solvent was evaporated under reduced pressure to give 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid, a pale yellow solid, with a yield of 99.87%. Example 9

[0053] 29.1 g (0.1 mol) of compound N-Cbz-4-oxo-3-pyrrolidinecarboxylate and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After cooling the mixture to 0 °C, 4.6 g (0.011) mol of ethyltriphenylphosphine iodide was added dropwise. After the addition was complete, the reaction mixture was brought to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment, and the residue was dissolved in 1000 mL of n-hexane, precipitating triphenylphosphine oxide. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography in 1000 mL of a 10:1 mixture of ethyl acetate and petroleum ether to obtain the intermediate product, which was a pale yellow oil with a yield of 89.2%.

[0054] The intermediate product was dissolved in 150 mL of ethanol, and 0.29 g (0.012 mol) of lithium hydroxide was added. The mixture was stirred overnight (8 hours) at room temperature. 500 mL of organic solvent was removed, and the remaining liquid was extracted with 300 mL of dichloromethane. The extraction was repeated 3 times. The organic phases were combined, washed with saturated sodium chloride, dried over sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then recrystallized from ethyl acetate to give a solid. The solid was dried under vacuum at 45 °C to give the semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, a pale yellow solid. The yield of the semi-finished product was 99.98%.

[0055] The semi-finished product was dissolved in 150 mL of methanol, and 0.91 g of Pd / C was added. The reaction mixture was stirred overnight (8 hours) at room temperature under H2 atmosphere. The reaction progress was monitored by thin-layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered off using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and washings were combined, and the solvent was evaporated under reduced pressure to give 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid, a pale yellow solid, with a yield of 99.99%. Example 10

[0056] 29.1 g (0.1 mol) of compound N-Cbz-4-oxo-3-pyrrolidinecarboxylate and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After cooling the mixture to 0 °C, 4.6 g (0.011) mol of ethyltriphenylphosphine iodide was added dropwise. After the addition was complete, the reaction mixture was brought to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment, and the residue was dissolved in 1000 mL of n-hexane and diethyl ether in a volume ratio of 3:1. Triphenylphosphine oxide precipitated, and the mixture was filtered. The solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography in 1000 mL of ethyl acetate and petroleum ether mixed solvent in a volume ratio of 10:1 to obtain the intermediate product. The intermediate product was a pale yellow oil with a yield of 90.0%.

[0057] The intermediate product was dissolved in 150 mL of ethanol, and 0.29 g (0.012 mol) of lithium hydroxide was added. The mixture was stirred overnight (8 hours) at room temperature. 500 mL of organic solvent was removed, and the remaining liquid was extracted with 300 mL of dichloromethane. The extraction was repeated 3 times. The organic phases were combined, washed with saturated sodium chloride, dried over sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then recrystallized from ethyl acetate to give a solid. The solid was dried under vacuum at 45 °C to give the semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, a pale yellow solid. The yield of the semi-finished product was 99.99%.

[0058] The semi-finished product was dissolved in 150 mL of methanol, and 0.91 g of Pd / C was added. The reaction mixture was stirred overnight (8 hours) at room temperature under H2 atmosphere. The reaction progress was monitored by thin-layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered off using a Buchner funnel, and the filter cake was washed with 500 mL of ethanol. The filtrate and washings were combined, and the solvent was evaporated under reduced pressure to give 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid, a pale yellow solid, with a yield of 99.95%. Example 11

[0059] 29.1 g (0.1 mol) of compound N-Cbz-4-oxo-3-pyrrolidinecarboxylate and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After cooling the mixture to 0 °C, 4.6 g (0.011) mol of ethyltriphenylphosphine iodide was added dropwise. After the addition was complete, the reaction mixture was brought to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment, and the residue was dissolved in 1000 mL of n-hexane and diethyl ether in a volume ratio of 3:1. Triphenylphosphine oxide precipitated, and the mixture was filtered. The solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography in 1000 mL of ethyl acetate and petroleum ether mixed solvent in a volume ratio of 10:1 to obtain the intermediate product. The intermediate product was a pale yellow oil with a yield of 90.0%.

[0060] The intermediate product was dissolved in 150 mL of methanol, and 0.29 g (0.012 mol) of lithium hydroxide was added. The mixture was stirred overnight (8 hours) at room temperature. 500 mL of organic solvent was removed, and the remaining liquid was extracted with 300 mL of dichloromethane. The extraction was repeated 3 times. The organic phases were combined, washed with saturated sodium chloride, dried over sodium sulfate, and the solvent was removed under reduced pressure. The product was then recrystallized from ethyl acetate to obtain a solid. The solid was dried under vacuum at 45 °C to obtain the semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, a pale yellow solid. The yield of the semi-finished product was 98.89%.

[0061] The semi-finished product was dissolved in 150 mL of methanol, and 0.91 g of Pd / C was added. The reaction mixture was stirred overnight (8 hours) at room temperature under H2 atmosphere. The reaction progress was monitored by thin-layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered off using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and washings were combined, and the solvent was evaporated under reduced pressure to give 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid, a pale yellow solid, with a yield of 99.99%. Example 12

[0062] 29.1 g (0.1 mol) of compound N-Cbz-4-oxo-3-pyrrolidinecarboxylate and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After cooling the mixture to 0 °C, 4.6 g (0.011) mol of ethyltriphenylphosphine iodide was added dropwise. After the addition was complete, the reaction mixture was brought to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment, and the residue was dissolved in 1000 mL of n-hexane and diethyl ether in a volume ratio of 3:1. Triphenylphosphine oxide precipitated, and the mixture was filtered. The solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography in 1000 mL of ethyl acetate and petroleum ether mixed solvent in a volume ratio of 10:1 to obtain the intermediate product. The intermediate product was a pale yellow oil with a yield of 90.0%.

[0063] The intermediate product was dissolved in 150 mL of ethanol, and 0.29 g (0.012 mol) of lithium hydroxide was added. The mixture was stirred overnight (8 hours) at room temperature. 500 mL of organic solvent was removed, and the remaining liquid was extracted with 300 mL of dichloromethane. The extraction was repeated 3 times. The organic phases were combined, washed with saturated sodium chloride, dried over sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then recrystallized from ethyl acetate to give a solid. The solid was dried under vacuum at 45 °C to give the semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, a pale yellow solid. The yield of the semi-finished product was 99.99%.

[0064] The semi-finished product was dissolved in 150 mL of ethanol, and 0.91 g of Pd / C was added. The reaction mixture was stirred overnight (8 hours) at room temperature under H2 atmosphere. The reaction progress was monitored by thin-layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered off using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and washings were combined, and the solvent was evaporated under reduced pressure to give 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid, a pale yellow solid, with a yield of 99.73%. Example 13

[0065] 29.1 g (0.1 mol) of compound N-Cbz-4-oxo-3-pyrrolidinecarboxylate and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After cooling the mixture to 0 °C, 4.6 g (0.011) mol of ethyltriphenylphosphine iodide was added dropwise. After the addition was complete, the reaction mixture was brought to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment, and the residue was dissolved in 1000 mL of n-hexane and diethyl ether in a volume ratio of 3:1. Triphenylphosphine oxide precipitated, and the mixture was filtered. The solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography in 1000 mL of ethyl acetate and petroleum ether mixed solvent in a volume ratio of 10:1 to obtain the intermediate product. The intermediate product was a pale yellow oil with a yield of 90.0%.

[0066] The intermediate product was dissolved in 150 mL of ethanol, and 0.29 g (0.012 mol) of lithium hydroxide was added. The mixture was stirred overnight (8 hours) at room temperature. 500 mL of organic solvent was removed, and the remaining liquid was extracted with 300 mL of dichloromethane. The extraction was repeated 3 times. The organic phases were combined, washed with saturated sodium chloride, dried over sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then recrystallized from ethyl acetate to give a solid. The solid was dried under vacuum at 45 °C to give the semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, a pale yellow solid. The yield of the semi-finished product was 99.99%.

[0067] The semi-finished product was dissolved in 150 mL of methanol, and 2.43 g of Pd / C was added. The reaction mixture was stirred overnight (8 hours) at room temperature under H2 atmosphere. The reaction progress was monitored by thin-layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered off using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and washings were combined, and the solvent was evaporated under reduced pressure to give 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid, a pale yellow solid, with a yield of 84.56%.

[0068] Comparative Example 1

[0069] 29.1 g (0.1 mol) of compound N-Cbz-4-oxo-3-pyrrolidinecarboxylate and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane, followed by the direct addition of 4.6 g (0.011) mol of ethyltriphenylphosphine iodide. After the addition was complete, the reaction mixture was brought to room temperature and reacted for another 3 hours. The solvent was removed, and the residue was dissolved in 1000 mL of a mixture of n-hexane and diethyl ether in a volume ratio of 3:1. Triphenylphosphine oxide precipitated, and the mixture was filtered. The solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was then subjected to column chromatography in 1000 mL of a mixture of ethyl acetate and petroleum ether in a volume ratio of 10:1 to obtain the intermediate product, which was a pale yellow oil with a yield of 64.2-3.0%.

[0070] The intermediate product was dissolved in 150 mL of ethanol, and 0.29 g (0.012 mol) of lithium hydroxide was added. The mixture was stirred overnight (8 hours) at room temperature. 500 mL of organic solvent was removed, and the remaining liquid was extracted with 300 mL of dichloromethane. The extraction was repeated 3 times. The organic phases were combined, washed with saturated sodium chloride, dried over sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then recrystallized from ethyl acetate to give a solid. The solid was dried under vacuum at 45 °C to give the semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, a pale yellow solid. The yield of the semi-finished product was 94.55%.

[0071] The semi-finished product was dissolved in 150 mL of methanol, and 0.91 g of Pd / C was added. The reaction mixture was stirred overnight (8 hours) at room temperature under H2 atmosphere. The reaction progress was monitored by thin-layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered off using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and washings were combined, and the solvent was evaporated under reduced pressure to give 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid, a pale yellow solid, with a yield of 94.65%.

[0072] Comparative Example 2

[0073] 29.1 g (0.1 mol) of compound N-Cbz-4-oxo-3-pyrrolidinecarboxylate and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After cooling the mixture to 0 °C, 4.6 g (0.011) mol of ethyltriphenylphosphine iodide was added dropwise. After the addition was complete, the reaction mixture was brought to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment, and the residue was dissolved in 1000 mL of n-hexane and diethyl ether in a volume ratio of 3:1. Triphenylphosphine oxide precipitated, and the mixture was filtered. The solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography in 1000 mL of ethyl acetate and petroleum ether mixed solvent in a volume ratio of 10:1 to obtain the intermediate product. The intermediate product was a pale yellow oil with a yield of 90.0%.

[0074] The intermediate product was dissolved in 150 ml of ethanol, and 0.29 g (0.012 mol) of lithium hydroxide was added. The mixture was stirred overnight (8 hours) at room temperature. All solvent was removed under reduced pressure, and the product was recrystallized from ethyl acetate to obtain a solid. The solid was dried under vacuum at 45 °C to obtain the semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, a pale yellow solid. The yield of the semi-finished product was 91.09%.

[0075] The semi-finished product was dissolved in 150 mL of methanol, and 0.91 g of Pd / C was added. The reaction mixture was stirred overnight (8 hours) at room temperature under H2 atmosphere. The reaction progress was monitored by thin-layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered off using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and washings were combined, and the solvent was evaporated under reduced pressure to give 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid, a pale yellow solid, with a yield of 96.77%.

[0076] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

The preparation process of 1,1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid, characterized in that: The steps include: S1: Ethyl N-Cbz-4-oxopyrrolidine-3-carboxylic acid ester. Triethylamine was added to dichloromethane, and after cooling, ethyltriphenylphosphine iodide was added dropwise. After the addition was complete, the reaction mixture was brought to room temperature, and the reaction continued at this temperature. The solvent was removed by treatment, and the residue was dissolved in a solvent to precipitate triphenylphosphine oxide. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was then subjected to column chromatography with a mixed solvent to obtain the intermediate product. S2: intermediate products Dissolved in a solvent, lithium hydroxide was added, and the reaction mixture was stirred and allowed to stand at room temperature. The organic solvent was removed by treatment, and the remaining liquid was extracted with dichloromethane. The organic phases were combined, washed, dried, and the solvent was further removed under reduced pressure. The mixture was then recrystallized from ethyl acetate or petroleum ether and dried to obtain the semi-finished product. S3: The semi-finished product Dissolve the catalyst in a solvent, add palladium on carbon, purge with hydrogen gas, stir and let stand. Monitor the reaction progress using thin-layer chromatography and liquid chromatography. Once the reaction is complete, filter off the palladium on carbon catalyst, wash the filter cake, combine the filtrate and washings, and evaporate the solvent under reduced pressure to obtain the final product. ; The molar ratio of N-Cbz-4-oxo-3-pyrrolidinecarboxylate, triethylamine, and ethyltriphenylphosphine iodide in S1 is 1:2-2.1:1.1, and the cooling temperature is 0-2℃. The mixed solvent in S1 is ethyl acetate and petroleum ether in a volume ratio of 10:1-3. In S1, the washing process involves washing with saturated sodium chloride and drying with sodium sulfate.

2. The preparation process of 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid according to claim 1, characterized in that: In step S3, the filter cake is washed with methanol.

3. The preparation process of 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid according to claim 1, characterized in that: The mass of palladium on carbon in S3 is 1-7 wt% of the semi-finished product.

4. The preparation process of 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid according to claim 1, characterized in that: The solvent in S2 is methanol, and the solvent in S3 is ethanol.

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