Preparation process of 1-carbobenzoxy-4-ethyl pyrrole-3-carboxylic acid

Abstract

According to the process reaction, N-Cbz-4-oxo-3-pyrrolidine ethyl formate and a Wittig reagent of ethyl triphenyl phosphorus iodide are used as synthesis starting points, firstly, N-Cbz-4-oxo-3-pyrrolidine ethyl formate and the Wittig reagent of ethyl triphenyl phosphorus iodide are subjected to nucleophilic addition to generate olefin reaction, then the olefin reaction is subjected to hydrolysis reaction under the alkaline condition to generate acid, and the acid is subjected to acid hydrolysis reaction under the alkaline condition to generate the N-Cbz-4-oxo-3-pyrrolidine ethyl formate and the Wittig reagent of ethyl triphenyl phosphorus iodide. The method is reasonable in process, high in yield, simple to operate, low in production cost and beneficial to large-scale industrial production, and fills up the process blank in related fields.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical intermediate synthesis, and in particular to a preparation process of 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid. Background Art

[0002] The key intermediate of a JAK1 inhibitor, Upadacitinib, has a chiral pyrrole ring: 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid. Upadacitinib is a highly effective and selective JAK1 inhibitor. JAK kinase is a family of non-receptor tyrosine kinases, and four members have been discovered, namely JAK1, JAK2, JAK3 and TYK1. The substrate of JAK is STAT, i.e. signal transducer and activator of transcription. STAT dimerizes after being phosphorylated by JAK, and then crosses the nuclear membrane into the nucleus to regulate the expression of related genes. This signaling pathway is called the JAK-STAT pathway. Therefore, JAK plays an important role in the pathophysiological process of immune-mediated diseases, and has shown good efficacy in clinical trials for the treatment of various autoimmune diseases and inflammatory diseases, such as atopic dermatitis, rheumatoid arthritis, psoriasis, ulcerative colitis, etc. Upadacitinib is a small molecule oral targeted drug developed by AbbVie, a leading international biopharmaceutical company. In August 2019, it was approved by the FDA for the treatment of rheumatoid arthritis. On August 24, 2021, it was announced that the European Commission approved it for the treatment of moderate to severe atopic dermatitis in adolescents, and it has become the selective JAK1 inhibitor with the most indications in my country. However, its current production capacity is low, and the process parameters of the preparation process are high, which cannot achieve high-purity large-scale production. Therefore, how to provide a preparation process of 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid with high production value. Summary of the invention

[0003] In order to provide 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid with higher yield, simple operation and low production cost, the present application provides a preparation process of 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid.

[0004] The present application provides a process for preparing 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid, comprising the following steps: S1: adding a compound N-Cbz-4-oxo-3-pyrrolidinecarboxylic acid ethyl ester and triethylamine to dichloromethane, and adding ethyl triphenylphosphonium iodide dropwise after cooling. After the addition is complete, the reaction mixture is warmed to room temperature, and the reaction is continued at this temperature. The solvent is removed by treatment, and the residue is dissolved by adding a solvent to precipitate triphenylphosphine oxide, which is filtered, and the solvent is removed from the filtrate under reduced pressure to obtain a crude product, and the crude product is subjected to mixed solvent column chromatography to obtain an intermediate product; S2: dissolving the intermediate product in a solvent, adding lithium hydroxide, stirring the reaction mixture at room temperature, removing the organic solvent, extracting the remaining liquid with dichloromethane, combining the organic phases, washing, drying and further removing the solvent under reduced pressure, then recrystallizing with ethyl acetate or petroleum ether, and drying to obtain a semi-finished product; S3: dissolving the semi-finished product in a solvent, adding target carbon, stirring and standing, monitoring the completion of the reaction by thin layer chromatography and liquid chromatography, filtering out the catalyst after the reaction is completed, washing the filter cake, combining the filtrate and the washing liquid, and evaporating the solvent under reduced pressure to obtain 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid.

[0005]

[0006] By adopting the technical scheme, N-Cbz-4-oxo-3-pyrrolidinecarboxylic acid ethyl ester and Wittig reagent ethyl triphenyl phosphonium iodide are used as synthesis starting points, N-Cbz-4-oxo-3-pyrrolidinecarboxylic acid ethyl ester and Wittig reagent ethyl triphenyl phosphonium iodide are first subjected to nucleophilic addition reaction to generate olefin, then subjected to hydrolysis reaction under alkaline conditions to generate acid, and then subjected to double bond reduction reaction under catalytic hydrogen conditions. The process is reasonable, the yield is high, the operation is simple, the production cost is low, and large-scale industrial production is conducive.

[0007] In a specific embodiment, the molar ratio of ethyl N-Cbz-4-oxo-3-pyrrolidinecarboxylate, triethylamine and ethyltriphenylphosphonium iodide in S1 is 1:2-2.1:1.1, and the cooling temperature is 0-2°C.

[0008] By adopting the above technical scheme, ethyl N-Cbz-4-oxo-3-pyrrolidinecarboxylate and Wittig reagent ethyl triphenylphosphonium iodide can be fully substituted, less side reactions occur, which is beneficial to subsequent separation, simple operation, high yield, and by limiting the cooling temperature, the occurrence of side reactions is further reduced.

[0009] In a specific embodiment, the mixed solvent in S1 is ethyl acetate and petroleum ether in a volume ratio of 10:1-3.

[0010] By adopting the above technical scheme, the setting of the mixed solvent is suitable for the reaction raw materials of the present application, and no other side reactions occur with the reaction raw materials, thereby improving 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 the raw materials is improved.

[0011] In a specific embodiment, the washing in S1 is washing with saturated sodium chloride and drying with sodium sulfate.

[0012] By adopting the above technical solution, the reactants in the washed filter cake are fully washed, which further improves the utilization rate of the raw materials. By using sodium sulfate for drying, the drying is sufficient, which is beneficial to the subsequent reaction and further improves the stability of the reaction.

[0013] In a specific embodiment, the drying in S2 is performed by heating and drying under a vacuum environment, and the heating temperature is 43-47°C.

[0014] By adopting the above technical solution, the reactants are dried more fully and are not prone to deterioration, and the reaction stability is higher.

[0015] In a specific embodiment, after adding the target carbon into S3, hydrogen is also introduced.

[0016] By adopting the above technical solution, the catalytic effect of the target carbon is good, hydrogen is activated into free hydrogen and participates in the reduction, and the reaction can be carried out under relatively mild conditions while maintaining stable performance of the reactants.

[0017] In a specific embodiment, washing the filter cake in S3 is washing with methanol.

[0018] By adopting the above technical solution, the washing effect is better, it is suitable for the reactant setting of this application, and no other side reactions occur.

[0019] The process for preparing 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid according to claim 1, characterized in that the mass of the target carbon in S3 is 1-7wt% of the semi-finished product.

[0020] 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 produced.

[0021] In a specific embodiment, the solvent in S2 is methanol, and the solvent in S3 is ethanol.

[0022] By adopting the above technical solution and setting different solvents for the two reaction steps, it is more suitable for the reactant setting of the present application. 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.

[0023] In summary, this application has the following beneficial technical effects: The process reaction of the present application uses N-Cbz-4-oxo-3-pyrrolidinecarboxylic acid ethyl ester and Wittig reagent ethyl triphenylphosphonium iodide as synthesis starting points, and the raw materials are easily 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 higher, the product post-treatment is simple, and the three wastes are less. DETAILED DESCRIPTION

[0024] To further help understand 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 the embodiments described are only partial embodiments of the present invention, not all of them; the embodiments can be combined with each other, and the same or similar concepts or processes may not be described in detail in some embodiments. The following embodiments are further explanations of the present invention, and the present invention is not limited thereto.

[0025] The components of the preparation examples used in the examples of this application all refer to components obtained by the preparation examples. The experimental reagents in the preparation examples, embodiments, and comparative examples, unless otherwise specified, are conventional commercial brands or obtained by conventional preparation processes. Example Example 1

[0026] 29.1 g (0.1 mol) of the compound N-Cbz-4-oxo-3-pyrrolidinecarboxylic acid ethyl ester and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After the mixed solution was cooled to 0°C, 4.6 g (0.011) mol of ethyl triphenylphosphonium iodide was added. After the addition was complete, the reaction mixture was warmed to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment. The residue was dissolved in 1000 mL of n-hexane and ether in a volume ratio of 3:1. Triphenylphosphine oxide was precipitated and filtered. The solvent was removed from the filtrate under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography using 1000 mL of a mixed solvent of ethyl acetate: petroleum ether in a volume ratio of 10:1 to obtain an intermediate product. The intermediate product was a light yellow oily substance with an intermediate product yield of 90.0%.

[0027] 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 at room temperature overnight (8 hours). 500 ml of organic solvent was removed by treatment. 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 with sodium sulfate, and the solvent was removed under reduced pressure. The solid was then recrystallized with ethyl acetate to obtain a solid. The solid was dried in vacuo at 45°C to obtain a semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, which was a light yellow solid. The semi-finished product yield was 99.99%.

[0028] 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 at room temperature under H2 atmosphere overnight (8 hours), and the completion of the reaction was monitored by thin layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered out using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and the washing liquid were combined, and the solvent was evaporated under reduced pressure to obtain 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid as a light yellow solid with a yield of 99.99%. Example 2

[0029] 29.1 g (0.1 mol) of the compound N-Cbz-4-oxo-3-pyrrolidinecarboxylic acid ethyl ester and 67.0 g (0.18 mol) of triethylamine were added to 100 mL of dichloromethane. After the mixed solution was cooled to 0°C, 4.6 g (0.011) mol of ethyl triphenylphosphonium iodide was added. After the addition was complete, the reaction mixture was warmed to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment. The residue was dissolved in 1000 mL of n-hexane and ether in a volume ratio of 3:1. Triphenylphosphine oxide was precipitated and filtered. The solvent was removed from the filtrate under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography using 1000 mL of a mixed solvent of ethyl acetate: petroleum ether in a volume ratio of 10:1 to obtain an intermediate product. The intermediate product was a light yellow oily substance with an intermediate product yield of 86.1%.

[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 at room temperature overnight (8 hours). 500 ml of organic solvent was removed by treatment. 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 with sodium sulfate, and the solvent was removed under reduced pressure. The solid was then recrystallized with ethyl acetate to obtain a solid. The solid was dried in vacuo at 45°C to obtain a semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, which was a light yellow solid. The semi-finished product yield was 99.72%.

[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 at room temperature under H2 atmosphere overnight (8 hours), and the completion of the reaction was monitored by thin layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered out using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and the washing liquid were combined, and the solvent was evaporated under reduced pressure to obtain 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid as a light yellow solid with a yield of 99.85%. Example 3

[0032] 29.1 g (0.1 mol) of the compound N-Cbz-4-oxo-3-pyrrolidinecarboxylic acid ethyl ester and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After the mixed solution was cooled to 0°C, 3.8 g (0.009) mol of ethyl triphenylphosphonium iodide was added. After the addition was complete, the reaction mixture was warmed to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment. The residue was dissolved in 1000 mL of n-hexane and ether in a volume ratio of 3:1. Triphenylphosphine oxide was precipitated and filtered. The solvent was removed from the filtrate under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography using 1000 mL of a mixed solvent of ethyl acetate: petroleum ether in a volume ratio of 10:1 to obtain an intermediate product. The intermediate product was a light yellow oily substance with an intermediate product yield of 76.2%.

[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 at room temperature overnight (8 hours). 500 ml of organic solvent was removed by treatment. 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 with sodium sulfate, and the solvent was removed under reduced pressure. The solid was then recrystallized with ethyl acetate to obtain a solid. The solid was dried in vacuo at 45°C to obtain a semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, which was a light yellow solid. The semi-finished product yield was 97.79%.

[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) under H2 atmosphere at room temperature, and the completion of the reaction was monitored by thin layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered out using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and the washing liquid were combined, and the solvent was evaporated under reduced pressure to obtain 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid as a light yellow solid with a yield of 98.97%. Example 4

[0035] 29.1 g (0.1 mol) of the compound N-Cbz-4-oxo-3-pyrrolidinecarboxylic acid ethyl ester and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After the mixed solution was cooled to 0°C, 4.6 g (0.011) mol of ethyl triphenylphosphonium iodide was added. After the addition was complete, the reaction mixture was warmed to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment. The residue was dissolved in 1000 mL of n-hexane and ether in a volume ratio of 3:1. Triphenylphosphine oxide was precipitated and filtered. The solvent was removed from the filtrate under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography with 1000 mL of ethyl acetate solvent to obtain an intermediate product. The intermediate product was a light yellow oily substance with an intermediate product yield of 87.9%.

[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 at room temperature overnight (8 hours). 500 ml of organic solvent was removed by treatment. 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 with sodium sulfate, and the solvent was removed under reduced pressure. The solid was then recrystallized with ethyl acetate to obtain a solid. The solid was dried in vacuo at 45°C to obtain a semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, which was a light yellow solid. The semi-finished product yield was 93.44%.

[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) under H2 atmosphere at room temperature, and the completion of the reaction was monitored by thin layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered out using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and the washing liquid were combined, and the solvent was evaporated under reduced pressure to obtain 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid as a light yellow solid with a yield of 96.65%. Example 5

[0038] 29.1 g (0.1 mol) of the compound N-Cbz-4-oxo-3-pyrrolidinecarboxylic acid ethyl ester and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After the mixed solution was cooled to 0°C, 4.6 g (0.011) mol of ethyl triphenylphosphonium iodide was added. After the addition was complete, the reaction mixture was warmed to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment. The residue was dissolved in 1000 mL of n-hexane and ether in a volume ratio of 3:1. Triphenylphosphine oxide was precipitated and filtered. The solvent was removed from the filtrate under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography using 1000 mL of a mixed solvent of ethyl acetate: petroleum ether in a volume ratio of 12:1 to obtain an intermediate product. The intermediate product was a light yellow oily substance with an intermediate product yield of 89.1%.

[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 at room temperature overnight (8 hours). 500 ml of organic solvent was removed by treatment. 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 with sodium sulfate, and the solvent was removed under reduced pressure. The solid was then recrystallized with ethyl acetate to obtain a solid. The solid was dried in vacuo at 45°C to obtain a semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, which was a light yellow solid. The semi-finished product yield was 99.78%.

[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 at room temperature under H2 atmosphere overnight (8 hours), and the completion of the reaction was monitored by thin layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered out using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and the washing liquid were combined, and the solvent was evaporated under reduced pressure to obtain 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid as a light yellow solid with a yield of 99.98%. Example 6

[0041] 29.1 g (0.1 mol) of the compound N-Cbz-4-oxo-3-pyrrolidinecarboxylic acid ethyl ester and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After the mixed solution was cooled to 0°C, 4.6 g (0.011) mol of ethyl triphenylphosphonium iodide was added. After the addition was complete, the reaction mixture was warmed to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment. The residue was dissolved in 1000 mL of n-hexane and ether in a volume ratio of 3:1. Triphenylphosphine oxide was precipitated and filtered. The solvent was removed from the filtrate under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography using 1000 mL of a mixed solvent of ethyl acetate: petroleum ether in a volume ratio of 10:1 to obtain an intermediate product. The intermediate product was a light yellow oily substance with an intermediate product yield of 90.0%.

[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 at room temperature overnight (8 hours). 500 ml of organic solvent was removed by treatment. 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 with sodium sulfate, and the solvent was removed under reduced pressure. The solid was then recrystallized with ethyl acetate to obtain a solid. The solid was allowed to stand and dry at room temperature to obtain a semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, which was a light yellow solid. The semi-finished product yield was 99.94%.

[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 at room temperature under H2 atmosphere overnight (8 hours), and the completion of the reaction was monitored by thin layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered out using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and the washing liquid were combined, and the solvent was evaporated under reduced pressure to obtain 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid as a light yellow solid with a yield of 99.97%. Example 7

[0044] 29.1 g (0.1 mol) of the compound N-Cbz-4-oxo-3-pyrrolidinecarboxylic acid ethyl ester and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After the mixed solution was cooled to 0°C, 4.6 g (0.011) mol of ethyl triphenylphosphonium iodide was added. After the addition was complete, the reaction mixture was warmed to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment. The residue was dissolved in 1000 mL of n-hexane and ether in a volume ratio of 3:1. Triphenylphosphine oxide was precipitated and filtered. The solvent was removed from the filtrate under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography using 1000 mL of a mixed solvent of ethyl acetate: petroleum ether in a volume ratio of 10:1 to obtain an intermediate product. The intermediate product was a light yellow oily substance with an intermediate product 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 at room temperature overnight (8 hours). 500 ml of organic solvent was removed by treatment. 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 with sodium sulfate, and the solvent was removed under reduced pressure. The solid was then recrystallized with ethyl acetate to obtain a solid. The solid was dried in vacuo at 45°C to obtain a semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, which was a light yellow solid. The semi-finished product yield was 99.99%.

[0046] 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 at room temperature under H2 atmosphere overnight (8 hours), and the completion of the reaction was monitored by thin layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered out using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and the washing liquid were combined, and the solvent was evaporated under reduced pressure to obtain 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid as a light yellow solid with a yield of 99.99%. Example 8

[0047] 29.1 g (0.1 mol) of the compound N-Cbz-4-oxo-3-pyrrolidinecarboxylic acid ethyl ester and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After the mixed solution was cooled to 0°C, 4.6 g (0.011) mol of ethyl triphenylphosphonium iodide was added. After the addition was complete, the reaction mixture was warmed to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment. The residue was dissolved in 1000 mL of n-hexane and ether in a volume ratio of 3:1. Triphenylphosphine oxide was precipitated and filtered. The solvent was removed from the filtrate under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography using 1000 mL of a mixed solvent of ethyl acetate: petroleum ether in a volume ratio of 10:1 to obtain an intermediate product. The intermediate product was a light yellow oily substance with an intermediate product 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 at room temperature overnight (8 hours). 500 ml of organic solvent was removed by treatment. 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 with sodium sulfate, and the solvent was removed under reduced pressure. The solid was then recrystallized with ethyl acetate to obtain a solid. The solid was dried in vacuo at 45°C to obtain a semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, which was a light yellow solid. The semi-finished product yield was 99.99%.

[0049] 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) under H2 atmosphere at room temperature, and the completion of the reaction was monitored by thin layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered out using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and the washing liquid were combined, and the solvent was evaporated under reduced pressure to obtain 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid as a light yellow solid with a yield of 99.87%. Example 9

[0050] 29.1 g (0.1 mol) of the compound N-Cbz-4-oxo-3-pyrrolidinecarboxylic acid ethyl ester and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After the mixed solution was cooled to 0°C, 4.6 g (0.011) mol of ethyl triphenylphosphonium iodide was added. After the addition was complete, the reaction mixture was warmed to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment. The residue was dissolved in 1000 mL of n-hexane to precipitate triphenylphosphine oxide. The residue was filtered and the solvent was removed from the filtrate under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography using 1000 mL of a mixed solvent of ethyl acetate: petroleum ether in a volume ratio of 10:1 to obtain an intermediate product. The intermediate product was a light yellow oily substance with an intermediate product yield of 89.2%.

[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 at room temperature overnight (8 hours). 500 ml of organic solvent was removed by treatment. 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 with sodium sulfate, and the solvent was removed under reduced pressure. The solid was then recrystallized with ethyl acetate to obtain a solid. The solid was dried in vacuo at 45°C to obtain a semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, which was a light yellow solid. The semi-finished product yield was 99.98%.

[0052] 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 at room temperature under H2 atmosphere overnight (8 hours), and the completion of the reaction was monitored by thin layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered out using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and the washing liquid were combined, and the solvent was evaporated under reduced pressure to obtain 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid as a light yellow solid with a yield of 99.99%. Example 10

[0053] 29.1 g (0.1 mol) of the compound N-Cbz-4-oxo-3-pyrrolidinecarboxylic acid ethyl ester and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After the mixed solution was cooled to 0°C, 4.6 g (0.011) mol of ethyl triphenylphosphonium iodide was added. After the addition was complete, the reaction mixture was warmed to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment. The residue was dissolved in 1000 mL of n-hexane and ether in a volume ratio of 3:1. Triphenylphosphine oxide was precipitated and filtered. The solvent was removed from the filtrate under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography using 1000 mL of a mixed solvent of ethyl acetate: petroleum ether in a volume ratio of 10:1 to obtain an intermediate product. The intermediate product was a light yellow oily substance with an intermediate product yield of 90.0%.

[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 at room temperature overnight (8 hours). 500 ml of organic solvent was removed by treatment. 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 with sodium sulfate, and the solvent was removed under reduced pressure. The solid was then recrystallized with ethyl acetate to obtain a solid. The solid was dried in vacuo at 45°C to obtain a semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, which was a light yellow solid. The semi-finished product yield was 99.99%.

[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 at room temperature under H2 atmosphere overnight (8 hours), and the completion of the reaction was monitored by thin layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered out using a Buchner funnel, and the filter cake was washed with 500 mL of ethanol. The filtrate and the washing liquid were combined, and the solvent was evaporated under reduced pressure to obtain 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid as a light yellow solid with a yield of 99.95%. Embodiment 11

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

[0057] 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 at room temperature overnight (8 hours). 500 ml of organic solvent was removed by treatment. 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 with sodium sulfate, and the solvent was removed under reduced pressure. The solid was then recrystallized with ethyl acetate to obtain a solid. The solid was dried in vacuo at 45°C to obtain a semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, which was a light yellow solid. The semi-finished product yield was 98.89%.

[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 at room temperature under H2 atmosphere overnight (8 hours), and the completion of the reaction was monitored by thin layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered out using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and the washing liquid were combined, and the solvent was evaporated under reduced pressure to obtain 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid as a light yellow solid with a yield of 99.99%. Example 12

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

[0060] 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 at room temperature overnight (8 hours). 500 ml of organic solvent was removed by treatment. 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 with sodium sulfate, and the solvent was removed under reduced pressure. The solid was then recrystallized with ethyl acetate to obtain a solid. The solid was dried in vacuo at 45°C to obtain a semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, which was a light yellow solid. The semi-finished product yield was 99.99%.

[0061] 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 at room temperature under H2 atmosphere overnight (8 hours), and the completion of the reaction was monitored by thin layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered out using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and the washing liquid were combined, and the solvent was evaporated under reduced pressure to obtain 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid as a light yellow solid with a yield of 99.73%. Example 13

[0062] 29.1 g (0.1 mol) of the compound N-Cbz-4-oxo-3-pyrrolidinecarboxylic acid ethyl ester and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After the mixed solution was cooled to 0°C, 4.6 g (0.011) mol of ethyl triphenylphosphonium iodide was added. After the addition was complete, the reaction mixture was warmed to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment. The residue was dissolved in 1000 mL of n-hexane and ether in a volume ratio of 3:1. Triphenylphosphine oxide was precipitated and filtered. The solvent was removed from the filtrate under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography using 1000 mL of a mixed solvent of ethyl acetate: petroleum ether in a volume ratio of 10:1 to obtain an intermediate product. The intermediate product was a light yellow oily substance with an intermediate product 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 at room temperature overnight (8 hours). 500 ml of organic solvent was removed by treatment. 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 with sodium sulfate, and the solvent was removed under reduced pressure. The solid was then recrystallized with ethyl acetate to obtain a solid. The solid was dried in vacuo at 45°C to obtain a semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, which was a light yellow solid. The semi-finished product yield was 99.99%.

[0064] 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 at room temperature under H2 atmosphere overnight (8 hours), and the completion of the reaction was monitored by thin layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered out using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and the washing liquid were combined, and the solvent was evaporated under reduced pressure to obtain 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid as a light yellow solid with a yield of 84.56%.

[0065] Comparative Example 1 29.1 g (0.1 mol) of the compound N-Cbz-4-oxo-3-pyrrolidinecarboxylic acid ethyl ester and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane, and then 4.6 g (0.011) mol of ethyl triphenylphosphonium iodide was directly added. After the addition was completed, the reaction mixture was warmed 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 by adding 1000 mL of n-hexane and ether in a volume ratio of 3:1 to precipitate triphenylphosphine oxide. The residue was filtered and the solvent was removed from the filtrate under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography using 1000 mL of a mixed solvent of ethyl acetate: petroleum ether in a volume ratio of 10:1 to obtain an intermediate product. The intermediate product was a light yellow oily substance, and the yield of the intermediate product was 64.23.0%.

[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 at room temperature overnight (8 hours). 500 ml of organic solvent was removed by treatment. 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 with sodium sulfate, and the solvent was removed under reduced pressure. The solid was then recrystallized with ethyl acetate to obtain a solid. The solid was dried in vacuo at 45°C to obtain a semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, which was a light yellow solid. The semi-finished product yield was 94.55%.

[0067] 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 at room temperature under H2 atmosphere overnight (8 hours), and the completion of the reaction was monitored by thin layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered out using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and the washing liquid were combined, and the solvent was evaporated under reduced pressure to obtain 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid as a light yellow solid with a yield of 94.65%.

[0068] Comparative Example 2 29.1 g (0.1 mol) of the compound N-Cbz-4-oxo-3-pyrrolidinecarboxylic acid ethyl ester and 83.7 g (0.2 mol) of triethylamine were added to 200 mL of dichloromethane. After the mixed solution was cooled to 0°C, 4.6 g (0.011) mol of ethyl triphenylphosphonium iodide was added. After the addition was complete, the reaction mixture was warmed to room temperature and the reaction was continued at this temperature for 3 hours. The solvent was removed by treatment. The residue was dissolved in 1000 mL of n-hexane and ether in a volume ratio of 3:1. Triphenylphosphine oxide was precipitated and filtered. The solvent was removed from the filtrate under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography using 1000 mL of a mixed solvent of ethyl acetate: petroleum ether in a volume ratio of 10:1 to obtain an intermediate product. The intermediate product was a light yellow oily substance with an intermediate product yield of 90.0%.

[0069] The intermediate product was dissolved in 150 ml of ethanol, 0.29 g (0.012 mol) of lithium hydroxide was added, and the mixture was stirred at room temperature overnight (8 hours). All solvents were removed at once under reduced pressure, and then recrystallized from ethyl acetate to obtain a solid. The solid was dried in vacuo at 45°C to obtain a semi-finished product 1-benzyloxycarbonyl-4-ethyldihydropyrrole-3-carboxylic acid, a light yellow solid, with a semi-finished product yield of 91.09%.

[0070] 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 at room temperature under H2 atmosphere overnight (8 hours), and the completion of the reaction was monitored by thin layer chromatography and liquid chromatography. After the reaction was completed, the catalyst was filtered out using a Buchner funnel, and the filter cake was washed with 500 mL of methanol. The filtrate and the washing liquid were combined, and the solvent was evaporated under reduced pressure to obtain 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid as a light yellow solid with a yield of 96.77%.

[0071] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make non-creative modifications to the present embodiment as needed, but as long as they are within the scope of the claims of the present application, they are protected by the patent law.

Claims

1. The preparation process of 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid is characterized by: The steps include: S1: Add the compound N-Cbz-4-oxo-3-pyrrolidinecarboxylic acid ethyl ester and triethylamine to dichloromethane, cool and add ethyl triphenylphosphonium iodide dropwise, after the addition is complete, the reaction mixture is warmed to room temperature, the reaction is continued at this temperature, the solvent is removed, the residue is dissolved with a solvent, triphenylphosphine oxide is precipitated, filtered, the filtrate is removed under reduced pressure to obtain a crude product, the crude product is subjected to mixed solvent column chromatography to obtain an intermediate product; S2: dissolving the intermediate product in a solvent, adding lithium hydroxide, stirring the reaction mixture at room temperature, removing the organic solvent, extracting the remaining liquid with dichloromethane, combining the organic phases, washing, drying and further removing the solvent under reduced pressure, then recrystallizing with ethyl acetate or petroleum ether, and drying to obtain a semi-finished product; S3: dissolving the semi-finished product in a solvent, adding target carbon, stirring and standing, monitoring the completion of the reaction by thin layer chromatography and liquid chromatography, filtering out the catalyst after the reaction is completed, washing the filter cake, combining the filtrate and the washing liquid, and evaporating the solvent under reduced pressure to obtain 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid. .

2. The process for preparing 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid according to claim 1, characterized in that: The molar ratio of N-Cbz-4-oxo-3-pyrrolidinecarboxylic acid ethyl ester, triethylamine and ethyltriphenylphosphonium iodide in S1 is 1:2-2.1:1.1, and the cooling temperature is 0-2°C.

3. The process for preparing 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid according to claim 1, characterized in that: The mixed solvent in S1 is ethyl acetate and petroleum ether in a volume ratio of 10:1-3.

4. The process for preparing 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid according to claim 1, characterized in that: The washing in S1 is washing with saturated sodium chloride and drying with sodium sulfate.

5. The process for preparing 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid according to claim 1, characterized in that: The drying in S2 is performed by heating and drying under a vacuum environment, and the heating temperature is 43-47°C.

6. The process for preparing 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid according to claim 1, characterized in that: After adding the target carbon into S3, hydrogen is also introduced.

7. The process for preparing 1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid according to claim 1, characterized in that: The filter cake is washed with methanol in S3.

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

9. The process for preparing 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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