Preparation method of platinum anticancer drug key intermediate 3-aminocyclobutane-1, 1-dicarboxylic acid diethyl ester

Abstract

The invention relates to a preparation method of a platinum anticancer drug key intermediate 3-aminocyclobutane-1, 1-dicarboxylic acid diethyl ester. The preparation method comprises the following steps: by taking 3-hydroximido cyclobutane-1, 1-dicarboxylic acid diethyl ester as an initial raw material, oxidizing to obtain 3-nitro cyclobutane-1, 1-dicarboxylic acid diethyl ester; and reducing the 3-nitro cyclobutane-1, 1-dicarboxylic acid diethyl ester to obtain the 3-amino cyclobutane-1, 1-dicarboxylic acid diethyl ester. According to the process route, raw materials are easy to obtain, steps are simple and efficient, the obtained product is stable and considerable in yield and good in purity, and the feasibility of kilogram-level and even larger-scale amplification is achieved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology. Specifically, it relates to a method for preparing diethyl 3-aminocyclobutane-1,1-dicarboxylic acid, a key intermediate in platinum-based anticancer drugs. Background Technology

[0002] Jing Jiang, Fuguo Han, Kaixuan Cai, et al. Synthesis and biological evaluation of cholic acid-conjugated oxaliplatin as a new prodrug for liver cancer[J]. Journal of Inorganic Biochemistry. 2023, 24(3): 112-120. This compound was designed as a novel prodrug targeting liver cancer. The prodrug uses 3-aminocyclobutane-1,1-dicarboxylic acid ester as a linker, stably connecting the oxaliplatin analog to the cholic acid moiety via an amide bond. Pharmacokinetic studies showed that after intravenous injection in Sprague-Dawley rats, LLC-202 was mainly distributed in the liver and exhibited significant hepatic accumulation, demonstrating its good liver targeting properties. Compared with normal human hepatocytes, LLC-202 was more readily taken up by human liver cancer cells. In in vitro experiments, this prodrug exhibited stronger antitumor activity. In a C57BL / 6 mouse model of primary hepatocellular carcinoma, its therapeutic effect was comparable to or even better than oxaliplatin, significantly prolonging the survival time of tumor-bearing mice by inducing tumor cell apoptosis and inhibiting proliferation. Furthermore, compared to oxaliplatin, LLC-202 showed lower toxicity to normal human hepatocytes, and its acute toxicity level after intravenous administration in healthy Kunming mice was comparable to that of oxaliplatin. Histopathological analysis further indicated that the main toxic effect of LLC-202 in mice was the inhibition of bone marrow hematopoietic cells. In summary, LLC-202, as a prodrug specific for liver cancer, shows promising development potential. Currently, no reagent companies sell 3-aminocyclobutane-1,1-dicarboxylic acid ester on the market; only custom synthesis is available, but this involves small synthesis quantities and high prices, making it difficult to meet the preparation needs of related active pharmaceutical ingredients in LLC-202 pharmaceutical research. The accessibility and cost of this raw material have become key bottlenecks restricting the progress of this project. The structures of 3-aminocyclobutane-1,1-dicarboxylic acid diethyl ester and LLC-202 are shown below:

[0003]

[0004] The following is an overview and analysis of the main synthetic routes of 3-aminocyclobutane-1,1-dicarboxylic acid diethyl ester.

[0005] Jiang et al. reported a multi-step synthetic route for diethyl 3-aminocyclobutane-1,1-dicarboxylate: starting with 3-hydroxycyclobutane-1,1-dicarboxylic acid, it reacts with ethanol under acidic catalysis to generate diethyl 3-hydroxycyclobutane-1,1-dicarboxylate; subsequently, it reacts with p-toluenesulfonyl chloride to give diethyl 3-p-toluenesulfonyloxycyclobutane-1,1-dicarboxylate; this intermediate then undergoes nucleophilic substitution with sodium azide to generate diethyl 3-azidocyclobutane-1,1-dicarboxylate; finally, a reduction step yields the target product, diethyl 3-aminocyclobutane-1,1-dicarboxylate. A key step in this route involves the use of sodium azide, a compound with high toxicity and a high explosion risk, subject to strict regulations. Its procurement, storage, and transportation all require specific qualifications and permits, resulting in complex supply chain management and high costs. The process route is shown below:

[0006]

[0007] Margarete Avram et al. (Margarete Avram, Nenitzescu Maria. Untersuchungenin der cyclobutanreihe 1,3-disubstituierte cyclobutanderivate[J]. Chemische Berichte. 1957, 90(8): 1424-1427) reported a synthetic process for diethyl 3-aminocyclobutane-1,1-dicarboxylic acid: 3-hydroxyoxime-cyclobutane-1,1-dicarboxylic acid diethyl ester was directly reduced in one step under hydrogen conditions using palladium as a catalyst to obtain the target product, diethyl 3-aminocyclobutane-1,1-dicarboxylic acid. The hydroxyoxime group exhibits complex reactivity during the reduction process: the hydroxyoxime group contains two easily reduced sites, a carbon-nitrogen double bond (C=N) and a nitrogen-oxygen bond (N–O), and may introduce another active center via a ketone carbonyl (C=O) intermediate during the reaction. These active groups are unstable under acidic, alkaline, or thermal conditions and are prone to decomposition. Therefore, this reduction reaction faces multiple competing reaction pathways, resulting in poor selectivity, catalyst poisoning, and high condition sensitivity, ultimately leading to low yields of the target product and a large amount of byproducts. In multiple batches of experiments repeating the original process route, the yield only remained between 10% and 30%. To improve the economy and feasibility of this process, we conducted catalyst and solvent substitution studies, attempting to use a nickel catalyst and an ethanol solution of ammonia as alternative systems. After multiple rounds of small-scale experiments, the average yield could be increased to approximately 35%, preliminarily confirming the feasibility of this synthetic route. However, the challenges of process reproducibility and yield during scale-up have not yet been fully overcome, and the stability of the product and corresponding control strategies need further improvement. The process route is shown below:

[0008]

[0009] The synthesis process of 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester in the above-mentioned route is mature and has been extensively reported in the literature. The main synthetic route uses 3-hydroxycyclobutane-1,1-dicarboxylic acid as a raw material, which is esterified to obtain 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester; 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester is oxidized to obtain 3-carbonylcyclobutane-1,1-dicarboxylic acid diethyl ester; 3-carbonylcyclobutane-1,1-dicarboxylic acid diethyl ester is then oximated with hydroxylamine to obtain 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester. The process route is shown below:

[0010]

[0011] In summary, the synthesis of diethyl 3-aminocyclobutane-1,1-dicarboxylic acid mainly involves two technical routes: azide reduction and hydroxyoxime reduction. However, the former uses highly toxic and explosive sodium azide as a raw material, posing serious safety hazards; the latter suffers from low yield and numerous byproducts, resulting in poor economic viability. Therefore, developing a safe, efficient, and kilogram-scale synthetic route is particularly urgent. Summary of the Invention

[0012] This invention discloses a method for preparing diethyl 3-aminocyclobutane-1,1-dicarboxylate, a key intermediate in platinum-based anticancer drugs. The method uses diethyl 3-hydroxyoxime-cyclobutane-1,1-dicarboxylate as a starting material, which is oxidized to obtain diethyl 3-nitrocyclobutane-1,1-dicarboxylate; the diethyl 3-nitrocyclobutane-1,1-dicarboxylate is then reduced to obtain diethyl 3-aminocyclobutane-1,1-dicarboxylate. This process route uses readily available raw materials, is simple and efficient, yields stable and considerable product yields with good purity, and is feasible for kilogram-scale scaling-up.

[0013] To achieve the objectives of this invention, the technical solution is as follows:

[0014] This invention discloses a method for preparing diethyl 3-aminocyclobutane-1,1-dicarboxylate, a key intermediate in platinum-based anticancer drugs. The method uses diethyl 3-hydroxyoxime-cyclobutane-1,1-dicarboxylate as a starting material, which is oxidized to obtain diethyl 3-nitrocyclobutane-1,1-dicarboxylate; the diethyl 3-nitrocyclobutane-1,1-dicarboxylate is then reduced to obtain diethyl 3-aminocyclobutane-1,1-dicarboxylate. This process route uses readily available raw materials, is simple and efficient, and yields a stable and considerable product with good purity.

[0015] This invention relates to a method for preparing diethyl 3-aminocyclobutane-1,1-dicarboxylic acid, a key intermediate in platinum-based anticancer drugs, characterized by comprising the following steps:

[0016] (1) In a solvent, using 3-hydroxyoxime-cyclobutane-1,1-dicarboxylic acid diethyl ester as the starting material, 3-nitrocyclobutane-1,1-dicarboxylic acid diethyl ester was obtained under the combined action of an oxidant, a catalyst and a stabilizer.

[0017] (2) In a solvent, 3-nitrocyclobutane-1,1-dicarboxylic acid diethyl ester is reduced by a reducing agent to obtain 3-aminocyclobutane-1,1-dicarboxylic acid diethyl ester.

[0018] The solvent in step (1) is one of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, xylene, acetonitrile, dichloromethane, chloroform, DMSO and DMF.

[0019] In step (1), the oxidant is one of the following: urea hydrogen peroxide complex (UHP), hydrogen peroxide aqueous solution, sodium percarbonate, persulfate, and potassium persulfate monosulfate complex salt.

[0020] The catalyst in step (1) is one of acetic anhydride, trifluoroacetic anhydride, phthalic anhydride, acetyl chloride, and trifluoroacetyl chloride.

[0021] The stabilizer in step (1) is one or two of the following: disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium bicarbonate, sodium acetate, potassium acetate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate.

[0022] In step (1), the molar equivalent ratio of 3-hydroxyoxime-cyclobutane-1,1-dicarboxylic acid diethyl ester, oxidant, catalyst and stabilizer is 1.0:2.0-5.0:2.0-5.0:4.0-10.0, and the preferred molar equivalent ratio is 1.0:3.0:3.0:7.0.

[0023] In step (2), the solvent is one or two of methanol, ethanol, water, tetrahydrofuran, and 1,4-dioxane; the reducing agent can be a chemical reducing agent or a catalytic hydrogenation system. The chemical reducing agent is one of iron powder, zinc powder, magnesium powder, sodium hydrosulfite, tin chloride, and hydrazine hydrate; the catalytic hydrogenation system is hydrogen and one of palladium, platinum, or Raney nickel. Preferably, a catalytic hydrogenation system of Raney nickel and hydrogen is used.

[0024] The present invention discloses a method for preparing 3-aminocyclobutane-1,1-dicarboxylic acid diethyl ester, a key intermediate for platinum-based anticancer drugs. The method includes a method for synthesizing 3-aminocyclobutane-1,1-dicarboxylic acid diethyl ester, and also includes a method for purifying 3-aminocyclobutane-1,1-dicarboxylic acid diethyl ester.

[0025] The preparation process route involved in this invention is as follows:

[0026]

[0027] The key point of this invention lies in the chemical synthesis preparation method. The principle is as follows: This invention relates to a method for preparing 3-aminocyclobutane-1,1-dicarboxylic acid diethyl ester, a key intermediate in platinum-based anticancer drugs. The core of this method is to oxidize 3-hydroxyoxime-cyclobutane-1,1-dicarboxylic acid diethyl ester to 3-nitrocyclobutane-1,1-dicarboxylic acid diethyl ester, and further reduce it to 3-aminocyclobutane-1,1-dicarboxylic acid diethyl ester.

[0028] The oxidation reaction uses a stable hydrogen peroxide source as the main oxidant, including but not limited to urea hydrogen peroxide complex (UHP), hydrogen peroxide aqueous solution, sodium percarbonate, persulfate or potassium persulfate monosulfate complex salt, etc., which provides active oxygen in a safe and controllable manner.

[0029] To further improve oxidation efficiency, activators such as trifluoroacetic anhydride are introduced into the reaction system. These activators can form highly reactive peroxyacid species (such as trifluoroperacetic acid) with hydrogen peroxide in situ, thereby significantly enhancing the oxidation ability of hydroxyoxime groups.

[0030] To suppress side reactions such as the Lossen rearrangement of hydroxyoxime under acidic conditions, buffers such as disodium hydrogen phosphate are added during the reaction. By adjusting and maintaining the pH of the system, the reaction is ensured to proceed efficiently along the predetermined path.

[0031] The obtained intermediate 3-nitrocyclobutane-1,1-dicarboxylic acid diethyl ester can be further converted into the target product 3-aminocyclobutane-1,1-dicarboxylic acid diethyl ester under the action of a suitable reducing agent.

[0032] The preparation method of 3-aminocyclobutane-1,1-dicarboxylic acid diethyl ester, a key intermediate in platinum-based anticancer drugs according to the present invention, compared with existing technologies:

[0033] (1) It has the significant advantages of readily available raw materials and simple and efficient steps.

[0034] (2) Kilogram-scale preparation has been completed, and it has excellent scalability.

[0035] (3) The post-processing is simple and does not require complex purification processes.

[0036] (4) The final product yield is stable and considerable, and the purity is good.

[0037] (5) This process avoids the use of highly toxic and explosive azides, and has significant advantages in terms of safety and environmental protection.

[0038] (6) Compared with the hydroxyoxime reduction process, which has many side reactions and low yield, the nitro reduction pathway (nitro → nitroso → hydroxylamine → amino) used in this process has advantages such as clear mechanism and predictable process, which can efficiently generate the target product, thus resulting in higher yield and more stable and controllable process. Attached Figure Description

[0039] Figure 1 It is diethyl 3-nitrocyclobutane-1,1-dicarboxylic acid ester. 1 H NMR.

[0040] Figure 2 It is diethyl 3-nitrocyclobutane-1,1-dicarboxylic acid ester. 13 C NMR.

[0041] Figure 3 It is diethyl 3-aminocyclobutane-1,1-dicarboxylic acid. 1 H NMR.

[0042] Figure 4It is diethyl 3-aminocyclobutane-1,1-dicarboxylic acid. 13 C NMR.

[0043] Figure 5 LC-MS of 3-nitrocyclobutane-1,1-dicarboxylic acid diethyl ester.

[0044] Figure 6 The LC-MS of 3-aminocyclobutane-1,1-dicarboxylic acid diethyl ester was obtained. Detailed Implementation

[0045] The present invention will be described in detail below with reference to specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but do not limit the present invention in any way. It should be noted that those skilled in the art can make several modifications or improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention.

[0046] Example 1

[0047] Step (1) Preparation of diethyl 3-nitrocyclobutane-1,1-dicarboxylic acid

[0048] In a 100 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, and constant-pressure dropping funnel, add urea-hydrogen peroxide complex (2.8 g, 30 mmol, 3.0 eq) and acetonitrile (20 ml), and cool to -5 to 0 °C. Slowly add acetonitrile solution (30 ml) containing trifluoroacetic anhydride (6.3 g, 30 mmol, 3.0 eq). After the addition is complete, continue stirring for 0.5 h. The resulting solution is labeled as reaction solution A and used for later use.

[0049] In a separate 100 ml three-necked round-bottom flask equipped with a condenser, magnetic stirrer, and constant-pressure dropping funnel, add diethyl 3-hydroxyoxime-cyclobutane-1,1-dicarboxylic acid (2.3 g, 10 mmol, 1.0 eq), dipotassium hydrogen phosphate (12.3 g, 70 mmol, 7.0 eq), and acetonitrile (40 ml), and stir until homogeneous. Slowly add the above reaction solution A dropwise, and after the addition is complete, reflux and stir for 1–2 h. Monitor the reaction by TLC, and the reaction endpoint is defined as the disappearance of the starting material in the reaction solution. Filter, concentrate the filtrate to recover the solvent, add water (100 ml) and ethyl acetate (100 ml) to the residue, separate the layers, extract the aqueous phase with ethyl acetate (100 ml × 2), combine the organic phases, wash with saturated brine (100 ml), and dry to anhydrous magnesium sulfate. The filtrate was filtered and concentrated under reduced pressure at 50°C to obtain 2.1 g of a yellow oily substance of diethyl 3-nitrocyclobutane-1,1-dicarboxylic acid, with a yield of approximately 84.5%.

[0050] ESI-MS m / z 246.08 [M+H] + .

[0051] 1 H NMR (600 MHz, CDCl3) δ 4.95-4.88(m, 1H), 4.20-4.13(m, 4H), 3.09-3.05(m, 2H), 3.00-2.95(m, 2H), 1.22-1.17(t, 6H).

[0052] 13 C NMR (150 MHz, CDCl3) δ 170.33, 170.15, 71.59, 62.21, 61.96, 55.39, 46.39, 34.80, 13.86, 13.83.

[0053] Step (2) Preparation of diethyl 3-aminocyclobutane-1,1-dicarboxylic acid

[0054] In a 100 ml three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, and constant-pressure dropping funnel, add reduced iron powder (1.8 g, 32.8 mmol, 4.0 eq), diethyl 3-nitrocyclobutane-1,1-dicarboxylic acid (2 g, 8.2 mmol, 1.0 eq), and pure water (100 ml), and cool to 0–5 °C. Slowly add 5% ammonium chloride solution (50 ml), generating a large number of bubbles, and continue stirring for 3–5 h. Monitor the reaction by TLC, and the reaction endpoint is defined as the disappearance of the reactants in the reaction solution. Add ethyl acetate (200 ml), adjust the pH to 8–9 with saturated sodium bicarbonate solution, and stir for 0.5 h. Filter, separate the layers, collect the organic phase, and extract the aqueous phase with ethyl acetate (100 ml × 2), combining the organic phases. Wash with saturated brine (100 ml) and dry over anhydrous magnesium sulfate. The filtrate was filtered and concentrated under reduced pressure at 50°C to obtain 1.3 g of a pale yellow oily substance of diethyl 3-aminocyclobutane-1,1-dicarboxylic acid, with a yield of approximately 76.3%.

[0055] ESI-MS m / z 216.09 [M+H] + .

[0056] 1 H NMR(600 MHz, CDCl3) δ 4.17-4.12(dq, J=12.5, 7.1 Hz, 4H), 3.48-3.45(p, J=8.0 Hz, 1H), 2.79-2.71(m, 2H), 2.22–2.14(m, 2H), 1.49(s, 2H), 1.23-1.17(t, J=7.1 Hz, 6H).

[0057] 13 C NMR (150 MHz, CDCl3) δ 171.83, 171.61, 61.51, 61.47, 46.62, 43.25, 40.72, 14.05.

[0058] Example 2

[0059] Step (1) Preparation of diethyl 3-nitrocyclobutane-1,1-dicarboxylic acid

[0060] In a 2 L three-necked round-bottom flask equipped with a thermometer, magnetic stirrer, and constant-pressure dropping funnel, add urea-hydrogen peroxide complex (40.4 g, 0.44 mol, 2.0 eq), diethyl 3-hydroxyoxime-cyclobutane-1,1-dicarboxylate (50 g, 0.22 mol, 1.0 eq), disodium hydrogen phosphate (125 g, 0.88 mol, 4.0 eq), and acetonitrile (800 ml). Slowly add 400 ml of acetonitrile solution containing trifluoroacetic anhydride (94 g, 0.44 mol, 2.0 eq), and continue stirring for 0.5 h after the addition is complete. Slowly raise the temperature to reflux and continue stirring for 1–2 h. Monitor the reaction by TLC, and the reaction endpoint is defined as the disappearance of the reactants in the reaction solution. The mixture was filtered, and the filtrate was concentrated to remove the solvent. The residue was then treated with water (400 ml) and ethyl acetate (400 ml), separated, and the aqueous phase was extracted with ethyl acetate (200 ml × 2). The combined organic phases were washed with saturated brine (300 ml) and dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure at 50 °C to give 41 g of a yellow oily substance of diethyl 3-nitrocyclobutane-1,1-dicarboxylic acid, with a yield of approximately 76.8%.

[0061] The obtained product was analyzed by MS, 1 H NMR and 13 C NMR confirmed that its spectral data was consistent with the data of the product obtained in step (1) of Example 1, confirming that it has the same structure.

[0062] Step (2) Preparation of diethyl 3-aminocyclobutane-1,1-dicarboxylic acid

[0063] In a 1 L hydrogenation reactor, 40 g (0.16 mol, 1.0 eq) of diethyl 3-nitrocyclobutane-1,1-dicarboxylic acid, 10% Pd / C (approximately 1 g), and 500 ml of anhydrous ethanol were added. The reactor was purged with nitrogen five times, then purged with hydrogen to 0.1 MPa. Stirring was initiated and the mixture was kept at room temperature for 3–5 h. The reaction was terminated when no more hydrogen was absorbed and the pressure remained constant. The residual hydrogen in the reactor was slowly vented to atmospheric pressure, and diatomaceous earth was added to aid filtration. The filtrate was collected. The filtrate was concentrated under reduced pressure at 50 °C to obtain 28.4 g of a pale yellow oily substance of diethyl 3-aminocyclobutane-1,1-dicarboxylic acid, with a yield of approximately 82.5%.

[0064] The obtained product was analyzed by MS, 1 H NMR and 13 C NMR confirmed that its spectral data was consistent with the data of the product obtained in step (2) of Example 1, confirming that it has the same structure.

[0065] Example 3

[0066] Step (1) Preparation of diethyl 3-nitrocyclobutane-1,1-dicarboxylic acid

[0067] In a 5 L three-necked round-bottom flask equipped with a thermometer, mechanical stirrer, and constant-pressure dropping funnel, urea-hydrogen peroxide complex (611 g, 6.5 mol, 5.0 eq), diethyl 3-hydroxyoxime-cyclobutane-1,1-dicarboxylate (300 g, 1.3 mol, 1.0 eq), disodium hydrogen phosphate (1.8 kg, 13 mol, 10.0 eq), and acetonitrile (2 L) were added. A solution of acetonitrile containing acetic anhydride (663 g, 6.5 mol, 5.0 eq) (1.2 L) was slowly added dropwise, and the mixture was stirred for 0.5 h after the addition was complete. The mixture was then slowly heated to reflux and stirred for 1–2 h. The reaction was monitored by TLC, and the endpoint was reached when the reactants disappeared from the reaction solution. The mixture was filtered, and the filtrate was concentrated to recover the solvent. The residue was then treated with water (800 ml) and ethyl acetate (800 ml), separated, and the aqueous phase was extracted with ethyl acetate (400 ml × 2). The combined organic phases were washed with saturated brine (500 ml) and dried over anhydrous magnesium sulfate. The filtrate was filtered, and the extract was subjected to reduced pressure at 50 °C to give 265.8 g of a yellow oily substance of diethyl 3-nitrocyclobutane-1,1-dicarboxylic acid, with a yield of approximately 82.8%.

[0068] The obtained product was analyzed by MS, 1 H NMR and 13 C NMR confirmed that its spectral data was consistent with the data of the product obtained in step (1) of Example 1, confirming that it has the same structure.

[0069] Step (2) Preparation of diethyl 3-aminocyclobutane-1,1-dicarboxylic acid

[0070] Add 250 g (1.02 mol, 1.0 eq) of 3-nitrocyclobutane-1,1-dicarboxylic acid diethyl ester, approximately 10 g of Raney nickel, and 500 ml of anhydrous methanol to a 2 L hydrogenation reactor. Purge the reactor with nitrogen five times, then purge with hydrogen to 0.1 MPa. Start stirring and maintain the mixture at room temperature for 5–8 h. Terminate the reaction when no more hydrogen is absorbed and the pressure remains constant. Slowly vent the residual hydrogen in the reactor to atmospheric pressure, add diatomaceous earth to aid filtration, and collect the filtrate. Concentrate the filtrate under reduced pressure at 50 °C to recover the solvent. Add 800 ml of 5% citric acid solution and 800 ml of ethyl acetate to the residue. Separate the solutions, collect the aqueous phase, adjust the pH of the aqueous phase to 9–10 with saturated sodium bicarbonate solution, extract with ethyl acetate (500 ml × 3), combine the organic phases, wash with 500 ml of saturated brine, and dry to anhydrous magnesium sulfate. The filtrate was filtered and subjected to reduced pressure at 50°C to obtain 187.8 g of a colorless oily substance of diethyl 3-aminocyclobutane-1,1-dicarboxylic acid, with a yield of approximately 85.6%.

[0071] The obtained product was analyzed by MS, 1 H NMR and 13 C NMR confirmed that its spectral data was consistent with the data of the product obtained in step (2) of Example 1, confirming that it has the same structure.

Claims

1. A method for preparing diethyl 3-aminocyclobutane-1,1-dicarboxylic acid, a key intermediate in platinum-based anticancer drugs, characterized in that, Includes the following steps: (1) In a solvent, using 3-hydroxyoxime-cyclobutane-1,1-dicarboxylic acid diethyl ester as the starting material, 3-nitrocyclobutane-1,1-dicarboxylic acid diethyl ester was obtained under the combined action of an oxidant, a catalyst and a stabilizer. (2) In a solvent, 3-nitrocyclobutane-1,1-dicarboxylic acid diethyl ester is reduced by a reducing agent to obtain 3-aminocyclobutane-1,1-dicarboxylic acid diethyl ester.

2. The method for preparing diethyl 3-aminocyclobutane-1,1-dicarboxylic acid, a key intermediate in platinum-based anticancer drugs according to claim 1, is characterized in that: The solvent in step (1) is one of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, xylene, acetonitrile, dichloromethane, chloroform, DMSO and DMF.

3. The method for preparing diethyl 3-aminocyclobutane-1,1-dicarboxylic acid, a key intermediate in platinum-based anticancer drugs according to claim 1, is characterized in that: In step (1), the oxidant is one of the following: urea hydrogen peroxide complex (UHP), hydrogen peroxide aqueous solution, sodium percarbonate, persulfate, and potassium persulfate monosulfate complex salt.

4. The method for preparing diethyl 3-aminocyclobutane-1,1-dicarboxylic acid, a key intermediate in platinum-based anticancer drugs according to claim 1, is characterized in that: The catalyst in step (1) is one of acetic anhydride, trifluoroacetic anhydride, phthalic anhydride, acetyl chloride, and trifluoroacetyl chloride.

5. The method for preparing diethyl 3-aminocyclobutane-1,1-dicarboxylic acid, a key intermediate in platinum-based anticancer drugs according to claim 1, characterized in that: The stabilizer in step (1) is one or two of the following: disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium bicarbonate, sodium acetate, potassium acetate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate.

6. The method for preparing diethyl 3-aminocyclobutane-1,1-dicarboxylic acid, a key intermediate in platinum-based anticancer drugs according to claim 1, is characterized in that: In step (1), the molar equivalent ratio of 3-hydroxyoxime-cyclobutane-1,1-dicarboxylic acid diethyl ester, oxidant, catalyst and stabilizer is 1.0:2.0-5.0:2.0-5.0:4.0-10.0, and the preferred molar equivalent ratio is 1.0:3.0:3.0:7.

0.

7. The method for preparing diethyl 3-aminocyclobutane-1,1-dicarboxylic acid, a key intermediate in platinum-based anticancer drugs according to claim 1, characterized in that: The solvent in step (2) is one or two of methanol, ethanol, water, tetrahydrofuran and 1,4-dioxane.

8. The method for preparing diethyl 3-aminocyclobutane-1,1-dicarboxylic acid, a key intermediate in platinum-based anticancer drugs according to claim 1, characterized in that: In step (2), the reducing agent is a chemical reducing agent or a catalytic hydrogenation system; wherein, the chemical reducing agent is one of iron powder, zinc powder, magnesium powder, sodium hydrosulfite, tin chloride and hydrazine hydrate; the catalytic hydrogenation system is one of hydrogen and metallic palladium, platinum or Raney nickel; preferably, it is a catalytic hydrogenation system of Raney nickel and hydrogen.

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