Preparation method of trans-cyclobutane-1, 2-dicarboxamide

Abstract

The invention provides a preparation method of trans-cyclobutane-1, 2-dicarboxamide, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: S1, carrying out substitution reaction on raw materials including 1, 1, 2-ethane tricarboxylic acid triethyl ester, 1-bromo-2-chloroethane and a first alkali reagent in a first polar aprotic solvent to obtain 4-chlorobutane-1, 2, 2-tricarboxylic acid triethyl ester; step S2, carrying out cyclization reaction on raw materials comprising 4-chlorobutane-1, 2, 2-tricarboxylic acid triethyl ester and a second alkali reagent, so as to obtain cyclobutane-1, 1, 2-tricarboxylic acid triethyl ester; step S3, carrying out hydrolysis reaction on raw materials comprising the cyclobutane-1, 1, 2-tricarboxylic acid triethyl ester and a third alkali reagent to obtain cyclobutane-1, 1, 2-tricarboxylic acid; according to the method, the trans-cyclobutane-1, 2-dicarboxamide is finally prepared from cyclobutane-1, 1, 2-tricarboxylic acid, and the trans-cyclobutane-1, 2-dicarboxamide is obtained.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and more specifically, to a method for preparing trans-cyclobutane-1,2-dicarboxamide. Background Technology

[0002] Trans-cyclobutane-1,2-dicarboxamide is a key starting material for the synthesis of the antitumor drug lobaplatin, and its purity and optical purity directly affect the quality and safety of the final drug. Existing synthetic routes suffer from problems such as low yield, use of hazardous reagents (such as bromine and red phosphorus), complex processes, and poor environmental performance, making it difficult to meet the needs of industrial production.

[0003] This invention provides a method for preparing trans-cyclobutane-1,2-dicarboxamide that is simple in procedure, has a high yield, is safe to operate, environmentally friendly, and has controllable product quality. Summary of the Invention

[0004] The main objective of this invention is to provide a method for preparing trans-cyclobutane-1,2-dicarboxamide, in order to solve the problems of low yield, low purity, complex process, and poor environmental performance in the existing methods for preparing trans-cyclobutane-1,2-dicarboxamide.

[0005] To achieve the above objectives, according to one aspect of the present invention, a method for preparing trans-cyclobutane-1,2-dicarboxamide is provided, the method comprising: step S1, subjecting a raw material comprising 1,1,2-ethanetricarboxylic acid triethyl ester, 1-bromo-2-chloroethane, and a first base reagent to a substitution reaction in a first polar aprotic solvent to obtain 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester; step S2, subjecting a raw material comprising 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester and a second base reagent to a cyclization reaction in a second polar aprotic solvent to obtain cyclobutane-1,1,2-tricarboxylic acid triethyl ester; step S3, ... The raw materials, including triethyl cyclobutane-1,1,2-tricarboxylic acid and a third base reagent, are hydrolyzed in a protic solvent to obtain cyclobutane-1,1,2-tricarboxylic acid; in step S4, the cyclobutane-1,1,2-tricarboxylic acid is subjected to heating deacidification and chiral resolution sequentially to obtain trans-cyclobutane-1,2-dicarboxylic acid; in step S5, the trans-cyclobutane-1,2-dicarboxylic acid is subjected to acylation and ammonolysis sequentially to generate crude trans-cyclobutane-1,2-dicarboxamide; in step S6, the crude trans-cyclobutane-1,2-dicarboxamide is recrystallized to obtain trans-cyclobutane-1,2-dicarboxamide.

[0006] Further, in step S1, the molar ratio of triethyl 1,1,2-ethanetricarboxylate to 1-bromo-2-chloroethane is 1:2 to 1:4; and / or, the mass ratio of triethyl 1,1,2-ethanetricarboxylate, the first base reagent, and the first polar aprotic solvent is 1 to 1.5:1.5 to 2:4 to 6.

[0007] Further, in step S1, the first base reagent is cesium carbonate; and / or, the first polar aprotic solvent is selected from any one or more of N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone; and / or, the temperature of the substitution reaction is 50~70℃, preferably 55~65℃; and / or, the endpoint of the substitution reaction is controlled so that the residual rate of 1,1,2-ethanetricarboxylic acid triethyl ester is ≤5.0%.

[0008] Further, in step S2, the mass ratio of 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester, the second base reagent, and the second polar aprotic solvent is 1~1.5:0.2~0.6:7~9.

[0009] Further, in step S2, the second base reagent is selected from any one or more of potassium tert-butoxide and sodium tert-butoxide; and / or, the second polar aprotic solvent is selected from any one or more of N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone; and / or, the cyclization reaction temperature is 0~15℃; and / or, the endpoint of the cyclization reaction is controlled so that the residual rate of 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester is ≤5.0%.

[0010] Further, in step S3, the third base reagent is selected from any one or more of sodium hydroxide and potassium hydroxide; and / or, the protic solvent is selected from any one or more of water, ethanol, and isopropanol; and / or, the temperature of the hydrolysis reaction is 30~40℃; and / or, the endpoint of the hydrolysis reaction is controlled so that the residual rate of triethyl cyclobutane-1,1,2-tricarboxylic acid is ≤3.0%.

[0011] Further, in step S4, the temperature of the heating deacidification reaction is 90~100℃; and / or, the endpoint of the heating deacidification reaction is controlled so that the residual rate of cyclobutane-1,1,2-tricarboxylic acid is ≤1.0%; a chiral resolving agent is added during the chiral resolution process; and / or, the chiral resolving agent is (R)-(+)-phenylethylamine.

[0012] Further, in step S5, the acyl chloride reagent used in the acyl chloride reaction is thionyl chloride; and / or, the reaction solvent used in the acyl chloride reaction is selected from any one or more of toluene, benzene and xylene; and / or, the temperature of the acyl chloride reaction is 75~85℃; and / or, the temperature of the ammonolysis reaction is 0~10℃.

[0013] Further, in step S6, the solvent used in the recrystallization process is a mixed solvent of ethanol and water, wherein the mass ratio of ethanol to water is 3~4:1, preferably 3.6~4:1; the recrystallization process includes: heating the crude trans-cyclobutane-1,2-dicarboxamide to 75~85℃ to dissolve it, stirring at this temperature for 2~3 hours, then slowly cooling it to 15~25℃ under nitrogen protection, and continuing to stir at 15~25℃ for 12~14 hours, then filtering and drying to obtain trans-cyclobutane-1,2-dicarboxamide with a purity ≥98.0%.

[0014] Furthermore, the mass content of cis-cyclobutane-1,2-dicarboxamide impurities in trans-cyclobutane-1,2-dicarboxamide is ≤0.5%, the moisture content of trans-cyclobutane-1,2-dicarboxamide determined by Karl Fischer method is ≤0.5%, and the mass ratio of (1R,2R)-cyclobutane-1,2-diamide enantiomer to (1S,2S)-cyclobutane-1,2-diamide enantiomer in trans-cyclobutane-1,2-dicarboxamide is 45:55 to 55:45.

[0015] Applying the technical solution of this invention, this application constructs a highly efficient synthetic route for trans-cyclobutane-1,2-dicarboxamide by using triethyl 1,1,2-ethanetricarboxylate as the starting material. The route involves a highly efficient substitution reaction with 1-bromo-2-chloroethane in a first polar aprotic solvent and under the action of a first base reagent; subsequent intramolecular cyclization to construct a cyclobutane skeleton under the guidance of a second polar aprotic solvent and a second base reagent; selective hydrolysis catalyzed by a third base reagent in a protic solvent; and precise separation of the trans configuration through a combination of heating deacidification and chiral resolution. Finally, a two-step continuous transformation of acylation and ammonolysis, supplemented by recrystallization purification, is completed. This route completely eliminates the dependence on high-risk reagents such as bromine and red phosphorus in traditional processes, significantly reducing operational risks and environmental pollution. Simultaneously, through precise matching of solvent systems between steps and the introduction of a chiral resolution strategy, the generation of byproducts is effectively suppressed, achieving highly selective removal of the cis isomer and significantly improving product purity and yield. The recrystallization step further ensures the uniformity of the final product's crystal form and its quality stability. The overall process is simple, the conditions are mild, and the repeatability is strong. It has both industrial scale-up potential and green chemical properties, and it significantly solves the core technical problems of low yield, low purity, poor safety, complex process and insufficient environmental protection in the existing technology. Attached Figure Description

[0016] The accompanying drawings, which form part of this application, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings:

[0017] Figure 1The 1H NMR spectrum of trans-cyclobutane-1,2-dicarboxamide provided in Example 1 of the present invention is shown. Detailed Implementation

[0018] It should be noted that, unless otherwise specified, the embodiments and features described in this application can be combined with each other. The present invention will now be described in detail with reference to the accompanying drawings and embodiments.

[0019] As analyzed in the background section of this application, existing methods for preparing trans-cyclobutane-1,2-dicarboxamide suffer from problems such as low yield, low purity, complex processes, and poor environmental friendliness. To address these issues, this application provides a method for preparing trans-cyclobutane-1,2-dicarboxamide.

[0020] According to a typical embodiment of this application, a method for preparing trans-cyclobutane-1,2-dicarboxamide is provided. The method includes: step S1, subjecting a raw material comprising triethyl 1,1,2-ethanetricarboxylate, 1-bromo-2-chloroethane, and a first base reagent to a substitution reaction in a first polar aprotic solvent to obtain triethyl 4-chlorobutane-1,2,2-tricarboxylate; step S2, subjecting a raw material comprising triethyl 4-chlorobutane-1,2,2-tricarboxylate and a second base reagent to a cyclization reaction in a second polar aprotic solvent to obtain triethyl cyclobutane-1,1,2-tricarboxylate; step S3, subjecting a raw material comprising... The raw materials, including triethyl cyclobutane-1,1,2-tricarboxylic acid and a third base reagent, are hydrolyzed in a protic solvent to obtain cyclobutane-1,1,2-tricarboxylic acid; in step S4, cyclobutane-1,1,2-tricarboxylic acid is subjected to heating deacidification and chiral resolution sequentially to obtain trans-cyclobutane-1,2-dicarboxylic acid; in step S5, trans-cyclobutane-1,2-dicarboxylic acid is subjected to acylation and ammonolysis sequentially to generate crude trans-cyclobutane-1,2-dicarboxamide; in step S6, the crude trans-cyclobutane-1,2-dicarboxamide is recrystallized to obtain trans-cyclobutane-1,2-dicarboxamide.

[0021] This application presents a highly efficient synthetic route for trans-cyclobutane-1,2-dicarboxylate, starting with triethyl 1,1,2-ethanetricarboxylate. The route involves a highly efficient substitution reaction with 1-bromo-2-chloroethane in a first polar aprotic solvent and under the action of a first base reagent; subsequent intramolecular cyclization in a second polar aprotic solvent and under the guidance of a second base reagent to construct a cyclobutane skeleton; selective hydrolysis catalyzed by a third base reagent in a protic solvent; and precise separation of the trans configuration through a combination of heating deacidification and chiral resolution. Finally, a two-step continuous transformation via acylation and ammonolysis, supplemented by recrystallization purification, completes the synthesis of this route. This method completely eliminates the dependence on high-risk reagents such as bromine and red phosphorus in traditional processes, significantly reducing operational risks and environmental pollution. It significantly solves the core technical problems of low yield, low purity, poor safety, complex processes, and insufficient environmental friendliness in existing technologies.

[0022] In some preferred embodiments of this application, in step S1 above, the molar ratio of triethyl 1,1,2-ethanetricarboxylate to 1-bromo-2-chloroethane is 1:2 to 1:4; and / or, the mass ratio of triethyl 1,1,2-ethanetricarboxylate, the first base reagent, and the first polar aprotic solvent is 1 to 1.5:1.5 to 2:4 to 6.

[0023] By controlling the molar ratio of triethyl 1,1,2-ethanetricarboxylate to 1-bromo-2-chloroethane within the above range, and the mass ratio of triethyl 1,1,2-ethanetricarboxylate, the first base reagent, and the first polar aprotic solvent within the above range, the efficient nucleophilic substitution reaction was promoted, and the multiple substitution side reactions caused by excess haloalkanes were avoided. At the same time, the synergistic effect of the base and solvent was maintained to promote the complete reaction, and the yield of the intermediate 4-chlorobutane-1,2,2-tricarboxylate triethyl ester was kept stable above 92%. HPLC detection showed that the residual starting material was ≤5.0%, providing high-purity raw materials for subsequent cyclization steps, reducing the risk of impurity accumulation, and improving the reproducibility and scalability of the overall process.

[0024] In some embodiments of this application, in step S1 above, the first base reagent is cesium carbonate; and / or, the first polar aprotic solvent is selected from any one or more of N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone; and / or, the temperature of the substitution reaction is 50~70°C, preferably 55~65°C; and / or, the endpoint of the substitution reaction is controlled so that the residual rate of triethyl 1,1,2-ethanetricarboxylic acid is ≤5.0%.

[0025] The preferred first base reagent effectively promotes the substitution reaction between triethyl 1,1,2-ethanetricarboxylate and 1-bromo-2-chloroethane, reducing the safety risks associated with using highly corrosive or toxic alkali metal reagents and improving reaction selectivity. The first polar aprotic solvent, such as N,N-dimethylformamide, effectively dissolves the reactants and stabilizes the transition state, increasing the reaction rate and conversion efficiency. Controlling the substitution reaction temperature within the aforementioned range ensures the reaction proceeds fully while suppressing side reactions and reducing impurity formation. By controlling the reaction endpoint to ensure a 1,1,2-ethanetricarboxylate residual rate of ≤5.0%, complete conversion of the raw materials is guaranteed, providing a high-purity intermediate for subsequent cyclization steps. This improves overall process stability and product yield, laying the foundation for obtaining high-purity trans-cyclobutane-1,2-dicarboxamide.

[0026] In some embodiments of this application, in step S2 above, the mass ratio of 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester, the second base reagent, and the second polar aprotic solvent is 1~1.5:0.2~0.6:7~9.

[0027] By controlling the mass ratio of 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester, the second base reagent, and the second polar aprotic solvent within the above range, the cyclization reaction was promoted to proceed efficiently under low-temperature conditions, side reactions were reduced, and the yield and selectivity of cyclobutane-1,1,2-tricarboxylic acid triethyl ester were significantly improved. At the same time, the risk of excessive deprotonation of the ester group or solvent decomposition due to excess base was reduced, thereby ensuring the purity of the intermediate and providing a stable and homogeneous raw material basis for subsequent hydrolysis and decarboxylation steps. Ultimately, the reproducibility of the overall process and the optical purity of the final product were improved.

[0028] In some embodiments of this application, the mass ratio of 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester, the second base reagent, and the second polar aprotic solvent can be 1:0.5:8, 1:0.2:7, 1.5:0.6:9, or 1.5:0.4:9, or any of the above two ratios.

[0029] In some embodiments of this application, in step S2 above, the second base reagent is selected from any one or more of potassium tert-butoxide and sodium tert-butoxide; and / or, the second polar aprotic solvent is selected from any one or more of N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone; and / or, the cyclization reaction temperature is 0~15℃; and / or, the endpoint of the cyclization reaction is controlled so that the residual rate of 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester is ≤5.0%.

[0030] Potassium tert-butoxide and other base reagents were used, and the reaction was carried out in polar aprotic solvents such as N,N-dimethylformamide at 0–15 °C. These conditions effectively promoted the intramolecular nucleophilic substitution of 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester to form a cyclobutane ring, inhibited side reactions, and improved cyclization selectivity and intermediate purity. Simultaneously, by controlling the reaction endpoint to a residual rate of 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester ≤ 5.0%, the cyclization reaction was ensured to proceed completely, reducing the interference of unreacted raw materials on subsequent hydrolysis and decarboxylation steps, improving overall process stability and product yield, and providing a reliable intermediate guarantee for obtaining high-purity trans-cyclobutane-1,2-dicarboxylic acid and the final product.

[0031] In some embodiments of this application, in step S3 above, the third alkali reagent is selected from any one or more of sodium hydroxide and potassium hydroxide; and / or, the protic solvent is selected from any one or more of water, ethanol, and isopropanol; and / or, the temperature of the hydrolysis reaction is 30~40℃; and / or, the endpoint of the hydrolysis reaction is controlled so that the residual rate of triethyl cyclobutane-1,1,2-tricarboxylic acid is ≤3.0%.

[0032] The hydrolysis reaction uses sodium hydroxide or potassium hydroxide as the third base reagent and is carried out in protic solvents such as water or ethanol at 30~40℃. This temperature range can effectively control the hydrolysis rate, reduce the probability of excessive hydrolysis or side reactions, and ensure that the residual rate of triethyl cyclobutane-1,1,2-tricarboxylic acid is controlled at ≤3.0%, which significantly improves the completeness of hydrolysis conversion and the purity of intermediates. The selected base reagent and solvent combination takes into account both reaction efficiency and post-processing feasibility, which helps to reduce the risk of impurity introduction.

[0033] In some embodiments of this application, in step S4 above, the temperature of the heating deacidification reaction is 90~100℃; and / or, the endpoint of the heating deacidification reaction is controlled to have a residual rate of cyclobutane-1,1,2-tricarboxylic acid ≤1.0%; a chiral resolving agent is added during the chiral resolution process; and / or, the chiral resolving agent is (R)-(+)-phenylethylamine.

[0034] The deacidification reaction is carried out in the range of 90~100℃, and the residual rate of cyclobutane-1,1,2-tricarboxylic acid is controlled to ≤1.0%, which can effectively promote the selective removal of the 1-carboxyl group in the tricarboxylic acid system, significantly improve the formation efficiency and reaction completeness of trans-cyclobutane-1,2-dicarboxylic acid, and reduce the interference of unreacted raw material residues on subsequent steps. At the same time, R-(+)-phenylethylamine is introduced as a chiral resolving agent after deacidification, which can selectively form diastereomer salts with significantly different solubilities with the cis isomer, thereby achieving effective separation of cis-cyclobutane-1,2-dicarboxylic acid, improving the optical purity of the trans isomer, providing highly selective raw materials for subsequent acylation and ammonolysis reactions, and ultimately significantly reducing the content of cis isomer impurities in the final product, ensuring its structural consistency and quality stability as the starting material for the antitumor drug lobaplatin.

[0035] In some embodiments of this application, in step S5 above, the acyl chloride reagent used in the acyl chloride reaction is thionyl chloride; and / or, the reaction solvent used in the acyl chloride reaction is selected from any one or more of toluene, benzene and xylene; and / or, the temperature of the acyl chloride reaction is 75~85℃; and / or, the temperature of the ammonolysis reaction is 0~10℃.

[0036] The acyl chloride reaction uses thionyl chloride as the acyl chloride reagent and is carried out in toluene solvent at 75-85°C. This effectively promotes the conversion of trans-cyclobutane-1,2-dicarboxylic acid into a highly reactive acyl chloride intermediate, reducing the probability of side reactions. At the same time, toluene, as a non-polar solvent, helps dissolve organic acids and facilitates subsequent impurity removal. The ammonolysis reaction is carried out at a low temperature of 0-10°C, which can significantly inhibit the hydrolysis of acyl chloride and the formation of by-products, improve the selectivity of ammonolysis, and ensure the structural integrity and yield stability of the target product. The process conditions match the characteristics of the intermediate formed in the preceding steps, enabling the acyl chloride and ammonolysis reactions to be efficiently linked in a mild and controllable environment, reducing the accumulation of impurities and providing a high-purity crude product for subsequent recrystallization and purification.

[0037] In some embodiments of this application, in step S6 above, the solvent used in the recrystallization process is a mixed solvent of ethanol and water, wherein the mass ratio of ethanol to water is 3~4:1, preferably 3.6~4:1; the recrystallization process includes: heating the crude trans-cyclobutane-1,2-dicarboxamide to 75~85°C to dissolve it, stirring at this temperature for 2~3 hours, slowly cooling it to 15~25°C under nitrogen protection, and continuing to stir at 15~25°C for 12~14 hours, then filtering and drying to obtain trans-cyclobutane-1,2-dicarboxamide with a purity ≥98.0%.

[0038] Controlling the mass ratio of ethanol to water within the aforementioned range effectively regulates the solubility of the target product at high temperatures and the precipitation rate at low temperatures. Combined with process conditions of dissolving at 75–85℃, slowly cooling to 15–25℃ under nitrogen protection, and continuous stirring for 12–14 hours, the separation efficiency of cis isomers and other structurally similar impurities is significantly improved, resulting in a final product purity consistently above 98.0%, cis impurity content below 0.5%, and moisture content controlled below 0.1%. Simultaneously, it effectively reduces residual solvent levels such as toluene and ethyl acetate, ensuring the product meets the high purity and high stability requirements of the starting material for the antitumor drug lobaplatin. Furthermore, this process exhibits good batch reproducibility and industrial adaptability.

[0039] In some preferred embodiments of this application, the mass content of cis-cyclobutane-1,2-dicarboxamide impurities in the trans-cyclobutane-1,2-dicarboxamide is ≤0.5%, the water content of trans-cyclobutane-1,2-dicarboxamide determined by Karl Fischer method is ≤0.5%, and the mass ratio of (1R,2R)-cyclobutane-1,2-dicarboxamide enantiomer to (1S,2S)-cyclobutane-1,2-dicarboxamide enantiomer in trans-cyclobutane-1,2-dicarboxamide is 45:55 to 55:45.

[0040] The content of cis isomer impurities in the trans-cyclobutane-1,2-dicarboxamide of this application is controlled to be below 0.5%, the water content is below 0.5%, and the enantiomeric ratio is maintained in the range of 45:55 to 55:45. This level of quality control stems from the precise control of reaction conditions in each step of the entire synthetic route. In particular, after decarboxylation in step S4, a chiral resolving agent is used to selectively separate diastereomers, effectively removing cis configuration impurities. At the same time, the recrystallization process in step S6 achieves efficient control of crystal growth through an ethanol-water mixed solvent (ratio 3.6:1) and a slow cooling strategy, significantly reducing the content of residual solvent and trace impurities. This ensures that the final product meets the stringent requirements of the starting material for the antitumor drug lobaplatin in terms of purity, configuration uniformity, and stability, providing a stable and reliable quality foundation for subsequent processes.

[0041] The beneficial effects that this application can achieve will be further illustrated below with reference to embodiments and comparative examples.

[0042] The chemical reagents involved in the following examples are as follows:

[0043] Ethyl acetate, analytical grade, 99.5%;

[0044] Methanol, chromatographic grade, 99.9%;

[0045] Sodium chloride, analytical grade, 99.8%;

[0046] N,N-Dimethylformamide: AR;

[0047] Cs2CO3: AR;

[0048] Purified water;

[0049] Ethanol: AR;

[0050] Sodium hydroxide: purity > 95%;

[0051] Potassium tert-butoxide: Purity > 95%;

[0052] Dichlorosulfoxide: AR;

[0053] Pyridine: AR;

[0054] 1-Bromo-2-chloroethane: Purity > 95%;

[0055] (R)-(+)-Phenylacetamine: AR;

[0056] Toluene: purity > 99%, KF < 0.5%;

[0057] Ammonia solution: mass concentration of 25-28%.

[0058] Example 1

[0059] Preparation of triethyl 4-chlorobutane-1,2,2-tricarboxylic acid (Step 1)

[0060] 474.0 kg of DMF was pumped into a dry 2000L enamel-lined reactor. Under nitrogen protection at 20-30℃, 198.5 kg of Cs₂CO₃ was added and stirred for 30 minutes. Then, 100.0 kg of triethyl 1,1,2-ethanetricarboxylate (purity >95%) and 174.7 kg of 1-bromo-2-chloroethane were slowly added sequentially. The reaction system was heated to 65℃ and stirred for 3 hours. Samples were taken for HPLC analysis. The reaction was stopped once the residual amounts of both triethyl 1,1,2-ethanetricarboxylate and 1-bromo-2-chloroethane were ≤5.0%.

[0061] The reaction solution was cooled to 0-10℃, and quenched slowly with 500.0 kg of water (temperature controlled ≤25℃). After standing, the mixture was separated, and the aqueous phase was extracted twice with 130.0 kg of petroleum ether (60-90℃ fraction). The combined organic phases were washed twice with 5% sodium chloride aqueous solution. The organic phase was concentrated to dryness at 50℃ under high vacuum (≤ -0.08 MPa) to obtain crude 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester (pale yellow oil). HPLC analysis showed that the average purity of the product was ≥75%, and the average yield was approximately 98% (based on 1,1,2-ethanetricarboxylic acid triethyl ester).

[0062] Preparation of triethyl cyclobutane-1,1,2-tricarboxylic acid (step 2)

[0063] In the presence of potassium tert-butoxide, in the polar aprotic solvent N,N-dimethylformamide, 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester, potassium tert-butoxide, and N,N-dimethylformamide were reacted at a mass ratio of 1:0.5:8 and a reaction temperature of 10°C to induce a cyclization reaction of 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester. The reaction endpoint was controlled at ≤5.0% residual 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester, yielding cyclobutane-1,1,2-tricarboxylic acid triethyl ester. HPLC analysis showed an average yield of approximately 97% (based on 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester).

[0064] Preparation of cyclobutane-1,1,2-tricarboxylic acid (step 3)

[0065] In a mixed solvent of water and ethanol (mass ratio of ethanol to water of 3.6:1), under sodium hydroxide conditions, at a reaction temperature of 35℃, the reaction endpoint was controlled to be ≤3.0% residual cyclobutane-1,1,2-tricarboxylic acid triethyl ester, which caused the cyclobutane-1,1,2-tricarboxylic acid triethyl ester to undergo a hydrolysis reaction to obtain cyclobutane-1,1,2-tricarboxylic acid.

[0066] Preparation of trans-cyclobutane-1,2-dicarboxylic acid (step 4)

[0067] In the presence of pyridine and water, the reaction temperature was 100℃. Heating caused decarboxylation of cyclobutane-1,1,2-tricarboxylic acid. The reaction endpoint was controlled at ≤1.0% residual cyclobutane-1,1,2-tricarboxylic acid to obtain trans-cyclobutane-1,2-dicarboxylic acid. After this step, a chiral resolving agent (such as (R)-(+)-phenylethylamine) was added and stirred at 20℃ for 4 hours to resolve the reaction product to remove cis isomer impurities, thus obtaining trans-cyclobutane-1,2-dicarboxylic acid with higher optical purity.

[0068] Preparation of crude trans-cyclobutane-1,2-dicarboxamide (step 5)

[0069] To a 200L enamel-lined reactor, add 39.0 kg of toluene, 9.0 kg of trans-cyclobutane-1,2-dicarboxylic acid, and 22.3 kg of thionyl chloride. Heat to 75°C and maintain the temperature with stirring for 5 hours. After the reaction is complete, concentrate the solution at 65°C under high vacuum, and remove residual thionyl chloride by distillation with toluene (11.0 kg × 2 times) to obtain an acyl chloride intermediate solution.

[0070] In another 500L reactor, 64.9 kg of 25wt% ammonia solution was added and cooled to 5°C. The above acyl chloride intermediate solution was slowly added dropwise to the ammonia solution, controlling the adding temperature at 5°C. After the addition was complete, stirring was continued at 5°C for 1 hour. The mixture was filtered, and the filter cake was washed twice with 11.0 kg of water and dried in a 60°C oven until the moisture content was ≤1.0%, yielding a white solid crude trans-cyclobutane-1,2-dicarboxamide. The average yield of four pilot-scale production batches was approximately 75%, with an average purity (GC) ≥98.2%.

[0071] Purification of trans-cyclobutane-1,2-dicarboxamide (Step 6)

[0072] Add 23.3 kg of anhydrous ethanol and 6.5 kg of purified water to a 50 L glass reactor and stir until well mixed. Add 11.2 kg of crude trans-cyclobutane-1,2-dicarboxamide obtained in step 5. Heat the system to 85 °C and stir for 2-3 hours to completely dissolve the solid, obtaining a clear solution.

[0073] Under nitrogen protection, stop heating and allow the reaction system to cool down slowly to 25°C, and continue stirring within this temperature range for 14 hours.

[0074] The slurry was transferred to a centrifuge for filtration, and the mother liquor was temporarily stored. The filter cake was washed with a small amount of cold ethanol / water mixture (ethanol:water = 3.6:1). The wet filter cake was transferred to a vacuum drying oven and dried at 55°C and ≤ -0.08 MPa for 14 hours.

[0075] 10.1 kg of high-purity trans-cyclobutane-1,2-dicarboxamide was obtained, with a yield of approximately 90%. Its 1H NMR data were as follows: Figure 1 The product is an off-white solid with a GC purity ≥99.8%, cis isomer ≤0.5%, moisture ≤0.1%, an enantiomeric ratio of approximately 50:50, and all residual solvents are below the standard limits.

[0076] Example 2

[0077] The difference from Example 1 is that in step 1, the molar ratio of 1,1,2-ethanetricarboxylic acid triethyl ester to 1-bromo-2-chloroethane is controlled at 1:2 to obtain crude 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester (pale yellow oil). HPLC analysis showed that the average purity of the product was ≥78%, and the average yield was approximately 97% (based on 1,1,2-ethanetricarboxylic acid triethyl ester).

[0078] The final product obtained was a high-purity trans-cyclobutane-1,2-dicarboxamide with a yield of approximately 86%. The product was an off-white solid with a GC purity of ≥99.5%, cis isomer ≤0.5%, moisture ≤0.1%, an enantiomeric ratio of approximately 50:50, and all residual solvents were below the standard limits.

[0079] Example 3

[0080] The difference from Example 1 is that in step 1, the molar ratio of triethyl 1,1,2-ethanetricarboxylate to 1-bromo-2-chloroethane is controlled at 1:1.5 to obtain crude 4-chlorobutane-1,2,2-tricarboxylate (pale yellow oil). HPLC analysis showed that the average purity of the product was ≥70%, and the average yield was approximately 91% (based on triethyl 1,1,2-ethanetricarboxylate).

[0081] The final product obtained was a high-purity trans-cyclobutane-1,2-dicarboxamide with a yield of approximately 66%. The product was an off-white solid with a GC purity of ≥98.3%, cis isomer ≤0.5%, moisture ≤0.1%, an enantiomeric ratio of approximately 50:50, and all residual solvents were below the standard limits.

[0082] Example 4

[0083] The difference from Example 1 is that in step 1, the mass ratio of triethyl 1,1,2-ethanetricarboxylate, cesium carbonate, and N,N-dimethylformamide is controlled at 1.5:2:6 to obtain crude triethyl 4-chlorobutane-1,2,2-tricarboxylate (a pale yellow oil). HPLC analysis showed that the average purity of the product was ≥78%, and the average yield was approximately 97% (based on triethyl 1,1,2-ethanetricarboxylate).

[0084] The final product obtained was a high-purity trans-cyclobutane-1,2-dicarboxamide with a yield of approximately 85%. The product was an off-white solid with a GC purity of ≥99.0%, cis isomer ≤0.5%, moisture ≤0.3%, an enantiomeric ratio of approximately 50:50, and all residual solvents were below the standard limits.

[0085] Example 5

[0086] The difference from Example 1 is that in step 1, the mass ratio of triethyl 1,1,2-ethanetricarboxylate, cesium carbonate, and N,N-dimethylformamide is controlled at 1.5:1.3:6 to obtain crude triethyl 4-chlorobutane-1,2,2-tricarboxylate (a pale yellow oil). HPLC analysis showed that the average purity of the product was ≥75%, and the average yield was approximately 93% (based on triethyl 1,1,2-ethanetricarboxylate).

[0087] The final product obtained was a high-purity trans-cyclobutane-1,2-dicarboxamide with a yield of approximately 78%. The product was an off-white solid with a GC purity of ≥96.7%, cis isomer ≤0.5%, moisture ≤0.3%, an enantiomeric ratio of approximately 50:50, and all residual solvents were below the standard limits.

[0088] Example 6

[0089] The difference from Example 1 is that in step 1, the temperature of the substitution reaction was controlled at 50°C, yielding crude 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester (a pale yellow oil). HPLC analysis showed that the average purity of the product was ≥70%, and the average yield was approximately 94% (based on 1,1,2-ethanetricarboxylic acid triethyl ester).

[0090] The final product obtained was a high-purity trans-cyclobutane-1,2-dicarboxamide with a yield of approximately 72%. The product was an off-white solid with a GC purity of ≥97.6%, cis isomer ≤0.5%, moisture ≤0.1%, an enantiomeric ratio of approximately 50:50, and all residual solvents were below the standard limits.

[0091] Example 7

[0092] The difference from Example 1 is that in step 2, the mass ratio of 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester, potassium tert-butoxide, and N,N-dimethylformamide is controlled at 1.5:0.4:9 to obtain cyclobutane-1,1,2-tricarboxylic acid triethyl ester. HPLC analysis showed an average yield of approximately 98% (based on 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester).

[0093] The final product obtained was a high-purity trans-cyclobutane-1,2-dicarboxamide with a yield of approximately 88%. The product was an off-white solid with a GC purity of ≥98.1%, cis isomer ≤1.0%, moisture ≤0.5%, and an enantiomeric ratio of approximately 47:53. All residual solvents were below the standard limits.

[0094] Example 8

[0095] The difference from Example 1 is that in step 2, the mass ratio of 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester, potassium tert-butoxide, and N,N-dimethylformamide is controlled at 1:0.1:9 to obtain cyclobutane-1,1,2-tricarboxylic acid triethyl ester. HPLC analysis showed an average yield of approximately 94% (based on 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester).

[0096] The final product obtained was a high-purity trans-cyclobutane-1,2-dicarboxamide with a yield of approximately 74%. The product was an off-white solid with a GC purity of ≥96.2%, cis isomer ≤1.0%, moisture ≤0.5%, and an enantiomeric ratio of approximately 43:67. All residual solvents were below the standard limits.

[0097] Example 9

[0098] The difference from Example 1 is that in step 6, the mass ratio of ethanol to water is controlled at 3.0:1, ultimately yielding a high-purity trans-cyclobutane-1,2-dicarboxamide product with a yield of approximately 87%. The product is an off-white solid with a GC purity ≥99.8%, cis isomer ≤0.5%, water content ≤0.1%, an enantiomeric ratio of approximately 50:50, and all residual solvents are below the standard limits.

[0099] Performance testing:

[0100] 1. The water content in the above trans-cyclobutane-1,2-dicarboxamide was tested using the Karl Fischer method, as detailed below:

[0101] Instruments and equipment:

[0102] Moisture analyzer: Metrohm moisture analyzer (model: 885 (titer unit) + 852 (control terminal));

[0103] Weighing equipment: 1 / 100,000 electronic balance (or equivalent precision instrument);

[0104] Blank test:

[0105] Take two clean 10 mL water bottles, tighten the caps, and place them on the sample rack.

[0106] Measurement conditions:

[0107] Furnace temperature: 110℃;

[0108] Carrier gas flow rate: 50 mL / min;

[0109] Objective: To determine the background moisture content of empty bottles for subsequent sample result correction;

[0110] Sample measurement:

[0111] Sample quantity: approximately 50 mg, accurately weigh two portions.

[0112] Container: Place in a 10 mL water bottle, tighten the cap, and use as the test sample.

[0113] Measurement conditions:

[0114] Furnace temperature: 110℃;

[0115] Carrier gas flow rate: 50 mL / min;

[0116] Parallelism requirement: Each batch of samples must be measured in duplicate.

[0117] Results evaluation criteria:

[0118] Moisture content determination results must meet any of the following conditions:

[0119] Absolute deviation ≤ 0.10%;

[0120] Relative average deviation ≤ 15%;

[0121] Calculation formula:

[0122] Average deviation = Σ|measured value - average value| / number of measurements;

[0123] Absolute deviation = |single measurement value - average value|;

[0124] Relative average deviation % = (average deviation / average value) × 100%.

[0125] 2. The method for determining trans-cyclobutane-1,2-dicarboxamide using 1H NMR spectroscopy is as follows:

[0126] Instruments and equipment:

[0127] Nuclear magnetic resonance spectrometer: Bruker AVIII 400;

[0128] Weighing equipment: 1 / 100,000 electronic balance (or equivalent precision instrument);

[0129] Pipetting equipment: pipette (accuracy ±1 µL);

[0130] Sample tube: NMR tube (5 mm outer diameter);

[0131] Solvent: DMSO-d6;

[0132] Solution preparation:

[0133] Accurately weigh 10-20 mg of trans-cyclobutane-1,2-dicarboxamide sample into a clean centrifuge tube.

[0134] Add approximately 1 mL of DMSO-d6 (deuterated ≥99.0% atom%D) using a pipette.

[0135] Shake or vortex until the sample is completely dissolved, ensuring a homogeneous solution.

[0136] Transfer all the solution to the NMR tube and wait for testing.

[0137] The ¹H NMR data (DMSO-d6, 400 MHz) for trans-cyclobutane-1,2-dicarboxamide are shown in Table 1:

[0138] Table 1. ¹H NMR data of trans-cyclobutane-1,2-dicarboxamide (DMSO-d6, 400 MHz)

[0139]

[0140] 3. HPLC detection conditions for trans-cyclobutane-1,2-dicarboxamide

[0141] Column: Agilent ZORBAX SB-Aq, 2.1 × 50 mm, 5.0 μm;

[0142] Mobile phase A: 0.0375% trifluoroacetic acid aqueous solution (v / v);

[0143] Mobile phase B: 0.01875% trifluoroacetic acid acetonitrile solution (v / v);

[0144] The gradient elution procedure is shown in Table 2:

[0145] Table 2. Gradient elution procedure for HPLC detection of trans-cyclobutane-1,2-dicarboxamide

[0146]

[0147] Column temperature: 50℃;

[0148] Detectors: DAS (210nm, 215nm, 220nm, 254nm);

[0149] Capillary voltage: 2500V;

[0150] Injection volume: 1 μL;

[0151] Detector: Single-stage quadrupole mass spectrometer (ESI source);

[0152] Ion source mode: Positive ion mode;

[0153] Drying airflow rate: 10 L / min;

[0154] Drying gas temperature: 350℃;

[0155] Atomizer pressure: 40 psi;

[0156] Scan range: m / z 100-1000;

[0157] Detection mode: Full scan;

[0158] Carrier gas: Nitrogen;

[0159] Collection time: up to 4.5 minutes.

[0160] The retention time of trans-cyclobutane-1,2-dicarboxamide was 0.51 min.

[0161] 4. GC detection conditions

[0162] Gas chromatograph: Shimadzu GC-2010;

[0163] Column: DB-624;

[0164] Column specifications: 0.53 mm ID × 30 m, 3 μm;

[0165] Carrier gas: Nitrogen;

[0166] Carrier gas linear velocity: linear flow velocity, 30 cm / sec;

[0167] Inlet temperature: 200°C;

[0168] Injection volume: 1 μL;

[0169] Flow split ratio: 20:1;

[0170] Detector: Flame ionization detector (FID);

[0171] Detector temperature: 260°C;

[0172] Outlet gas flow rate: Outlet gas flow rate;

[0173] Hydrogen flow rate: 40 mL / min;

[0174] Airflow rate: 400 mL / min;

[0175] The column temperature program is shown in Table 3:

[0176] Table 3. Column temperature program for GC detection of trans-cyclobutane-1,2-dicarboxamide

[0177]

[0178] The retention time of trans-cyclobutane-1,2-dicarboxamide was 15.65 min.

[0179] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing trans-cyclobutane-1,2-dicarboxamide, characterized in that, The preparation method includes: Step S1: The raw materials including 1,1,2-ethanetricarboxylic acid triethyl ester, 1-bromo-2-chloroethane, and the first base reagent are subjected to a substitution reaction in the first polar aprotic solvent to obtain 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester. Step S2 involves cyclizing the raw material, including the 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester and the second base reagent, in a second polar aprotic solvent to obtain cyclobutane-1,1,2-tricarboxylic acid triethyl ester. Step S3: The raw material including the triethyl cyclobutane-1,1,2-tricarboxylic acid and the third base reagent is hydrolyzed in a protic solvent to obtain cyclobutane-1,1,2-tricarboxylic acid; Step S4: The cyclobutane-1,1,2-tricarboxylic acid is subjected to heating deacidification reaction and chiral resolution sequentially to obtain trans-cyclobutane-1,2-dicarboxylic acid; Step S5: The trans-cyclobutane-1,2-dicarboxylic acid is subjected to acylation and ammonolysis reactions in sequence to generate crude trans-cyclobutane-1,2-dicarboxamide. Step S6: Recrystallize the crude trans-cyclobutane-1,2-dicarboxamide to obtain trans-cyclobutane-1,2-dicarboxamide.

2. The method for preparing trans-cyclobutane-1,2-dicarboxamide according to claim 1, characterized in that, In step S1, the molar ratio of 1,1,2-ethanetricarboxylic acid triethyl ester to 1-bromo-2-chloroethane is 1:2 to 1:

4. And / or, the mass ratio of the 1,1,2-ethanetricarboxylic acid triethyl ester, the first base reagent, and the first polar aprotic solvent is 1~1.5:1.5~2:4~6.

3. The method for preparing trans-cyclobutane-1,2-dicarboxamide according to claim 1, characterized in that, In step S1, the first alkaline reagent is cesium carbonate; And / or, the first polar aprotic solvent is selected from any one or more of N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone; And / or, the temperature of the substitution reaction is 50~70°C; And / or, the endpoint of the substitution reaction controls the residual percentage of the 1,1,2-ethanetricarboxylic acid triethyl ester to be ≤5.0%.

4. The method for preparing trans-cyclobutane-1,2-dicarboxamide according to any one of claims 1 to 3, characterized in that, In step S2, the mass ratio of the 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester, the second base reagent, and the second polar aprotic solvent is 1~1.5:0.2~0.6:7~9.

5. The method for preparing trans-cyclobutane-1,2-dicarboxamide according to any one of claims 1 to 3, characterized in that, In step S2, the second alkaline reagent is selected from any one or more of potassium tert-butoxide and sodium tert-butoxide. And / or, the second polar aprotic solvent is selected from any one or more of N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone; And / or, the cyclization reaction is carried out at a temperature of 0~15°C; And / or, the endpoint of the cyclization reaction controls the residual rate of the 4-chlorobutane-1,2,2-tricarboxylic acid triethyl ester to be ≤5.0%.

6. The method for preparing trans-cyclobutane-1,2-dicarboxamide according to any one of claims 1 to 3, characterized in that, In step S3, the third alkali reagent is selected from any one or more of sodium hydroxide and potassium hydroxide; And / or, the proton solvent is selected from any one or more of water, ethanol, and isopropanol; And / or, the hydrolysis reaction is carried out at a temperature of 30~40℃; And / or, the endpoint of the hydrolysis reaction is controlled to ensure that the residual rate of the cyclobutane-1,1,2-tricarboxylic acid triethyl ester is ≤3.0%.

7. The method for preparing trans-cyclobutane-1,2-dicarboxamide according to any one of claims 1 to 3, characterized in that, In step S4, the temperature of the heating deacidification reaction is 90~100℃; And / or, the endpoint of the heating deacidification reaction is controlled to ensure that the residual rate of the cyclobutane-1,1,2-tricarboxylic acid is ≤1.0%; A chiral resolving agent is added during the chiral resolution process; And / or, the chiral resolving agent is (R)-(+)-phenylethylamine.

8. The method for preparing trans-cyclobutane-1,2-dicarboxamide according to any one of claims 1 to 3, characterized in that, In step S5, the acyl chloride reagent used in the acyl chloride reaction is thionyl chloride. And / or, the reaction solvent used in the acyl chloride reaction is selected from any one or more of toluene, benzene, and xylene; And / or, the temperature of the acyl chloride reaction is 75~85°C; And / or, the temperature of the ammonolysis reaction is 0~10℃.

9. The method for preparing trans-cyclobutane-1,2-dicarboxamide according to any one of claims 1 to 3, characterized in that, In step S6, the solvent used in the recrystallization process is a mixture of ethanol and water, wherein the mass ratio of ethanol to water is 3~4:

1. The recrystallization process includes: The crude trans-cyclobutane-1,2-dicarboxamide was heated to 75-85°C to dissolve it. After stirring at this temperature for 2-3 hours, the temperature was slowly lowered to 15-25°C under nitrogen protection. Stirring was continued at 15-25°C for 12-14 hours, and then the mixture was filtered and dried to obtain trans-cyclobutane-1,2-dicarboxamide with a purity ≥98.0%.

10. The method for preparing trans-cyclobutane-1,2-dicarboxamide according to any one of claims 1 to 3, characterized in that, The trans-cyclobutane-1,2-dicarboxamide contains cis-cyclobutane-1,2-dicarboxamide impurities with a mass content ≤0.5%, the trans-cyclobutane-1,2-dicarboxamide has a moisture content ≤0.5% as determined by Karl Fischer method, and the mass ratio of (1R,2R)-cyclobutane-1,2-dicarboxamide enantiomer to (1S,2S)-cyclobutane-1,2-dicarboxamide enantiomer is 45:55 to 55:45.

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