A method for preparing a pharmaceutical intermediate, 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester

Abstract

The present application relates to a kind of medical intermediates 3-hydroxyl cyclobutane-1,1-dicarboxylic acid diethyl ester preparation method.The present application is with diethyl malonate as starting material, by reaction with allyl bromide 2-propenyl malonic acid diethyl ester is obtained;2-propenyl malonic acid diethyl ester is oxidized to obtain 2-epoxy propyl malonic acid diethyl ester, then ring-opening halogenation 2-(3-X-2-hydroxypropyl) malonic acid diethyl ester (X is halogen);The hydroxyl of 2-(3-X-2-hydroxypropyl) malonic acid diethyl ester is protected further ring closure to obtain 3-hydroxyl protected 3-hydroxyl cyclobutane-1,1-dicarboxy acid diethyl ester;Finally, the protecting group of 3-hydroxyl is removed, and 3-hydroxyl cyclobutane-1,1-dicarboxy diethyl ester is obtained.The preparation process of the present application has the advantages of cheap and easy-to-obtain raw materials, simple and efficient synthesis route, stable reaction yield of each step, high product purity, especially good scalability and industrial application potential.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, and relates to a method for preparing diethyl 3-hydroxycyclobutane-1,1-dicarboxylate. Specifically, the method uses diethyl malonate and allyl bromide as raw materials, and proceeds through six steps: substitution, epoxidation, ring-opening bromination, hydroxyl protection, ring closure, and deprotection, to prepare diethyl 3-hydroxycyclobutane-1,1-dicarboxylate. This preparation method has advantages such as a novel synthetic route, process safety, mild conditions, simple operation, and controllable cost, and possesses good scalability, making it of urgent practical significance for promoting the research and development and industrialization of related drugs. Background Technology

[0002] Diethyl 3-hydroxycyclobutane-1,1-dicarboxylic acid is an intermediate with significant applications in drug synthesis. Since RD Allan et al. first used it in 1990 to synthesize a highly effective NMDA receptor agonist (RDAllan, JR Hanrahan, TW Hambley, et al. Synthesis and activity of apotent N-methyl-D-aspartic acid agonist, trans-1-aminocyclobutane-1,3-dicarboxylic acid, and related phosphonic and carboxylic acids[J]. J. Med. Chem., 1990, 33(10): 2905-2915), this compound has played a central role in multiple drug development directions. Its application is particularly prominent in the field of platinum-based antitumor drugs: G. Bernhardt reported its application in the synthesis of carboplatin derivatives in 2004 (G. Bernhardt, H. Brunner, N., Gruber, et al. Carboplatinderivatives with superior antitumor activity compared to the parent compound[J]. Inorg. Chim. Acta., 2004, 357(15): 4452-4466); In 2013, Professor Liu Weiping of the Kunming Institute of Precious Metals developed a novel water-soluble platinum-based antitumor drug based on it (WP Liu, XZ Chen, QS Ye, et al. A novel water-soluble heptaplatin analogue with improved antitumor activity and reduced toxicity[J]. Inorg. Chem., 2011, 50(12): 5324-5326); In 2012, Professor Shaohua Gou of Southeast University used it to construct a class of NO-based platinum-based anticancer drug precursors (J. Zhao, SH Gou, YY Sun, et al. Nitric oxide donor-based platinum complexes as potential anticancer agents[J]. Chem. Eur. J.)., 2012, 45(18):14276-14281); In 2020, LM Rečnik synthesized a carboplatin analogue (LM Rečnik, C. Cantelli, C. Fersing, et al. Synthesis and in vitro antitumour activity of carboplatin analogues containing functional handles compatible for conjugation to drug delivery systems[J]. Bioorg. Med. Chem. Lett., 2020, 30(20): 127527); In 2022, Professor Sun Xuanrong of Zhejiang University of Technology reported a fluorinated platinum complex based on this intermediate and demonstrated its potential antitumor activity (FF Liu, C. Yang, SG Li, et al. Design and biological features of platinum(II) complexes with 3-hydroxy-3-(trifluoromethyl)cyclobutane-1,1-dicarboxylate as a leaving ligand[J]. Eur.J. Med. Chem., 2012, 45(18):14276-14281); In 2020, LM Rečnik synthesized a carboplatin analogue (LM Rečnik, C. Cantelli, C. Fersing, et al. Synthesis and in vitro antitumour activity of carboplatin analogues containing functional handles compatible for conjugation to drug delivery systems[J]. Bioorg. Med. Chem., 2020, 30(20): 127527); In 2022, Professor Sun Xuanrong of Zhejiang University of Technology reported a fluorinated platinum complex based on this intermediate and demonstrated its potential antitumor activity (FF Liu, C. Yang, SG Li, et al. Design and biological features of platinum(II) complexes with 3-hydroxy-3-(trifluoromethyl)cyclobutane-1,1-dicarboxylate as a leaving ligand[J]. Eur.J. Med. Chem., 2012, 45(18):14276-1 2022, 15(242): 114673); In 2023, Researcher Jiang Jing of the Kunming Institute of Precious Metals further applied it to the research and development of a novel targeted prodrug for liver cancer (J. Jiang, FG Han, KX Cai, et al. Synthesis and biological evaluation of cholic acid-conjugated oxaliplatin as a new prodrug for liver cancer[J]. J. Inorg. Biochem., 2023, 243: 112200).

[0003] In other areas of drug research, this intermediate also has important applications: In 2010, S. Venkatraman reported that it was a key intermediate in the synthesis of HCV NS3 protease ketoamide inhibitors (S. Venkatraman, F. Velazquez, WL Wu, et al. Potent ketoamide inhibitors of HCV NS3 protease derived from quaternized groups[J]. Bioorg. Med. Chem. Lett., 2010, 20(7):2151-2155); in the same year, the UK company MEDIVIR's patent WO2011070539A1 disclosed that it was a key intermediate in the synthesis of cysteine ​​protease inhibitors; in 2013, Novartis' patent US2013059846A1 also disclosed its key role in the synthesis of c-Kit kinase inhibitors. In summary, 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester plays an indispensable role in the development of many important drugs, including NMDA receptor modulators, platinum-based antitumor drugs, antiviral drugs, and kinase inhibitors. It is a key pharmaceutical intermediate with high development potential and broad application prospects.

[0004] Currently, there are limited reports on the preparation methods of 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester, and they mainly focus on the preparation of diethyl malonate with (2-bromo-1-bromomethylethoxymethyl)benzene (J. Slade, J. Bajwa, H. Liu, et al. A concise synthesis of a novel insulin-like growth factor I receptor (IGF-IR) inhibitor[J]. Org. Process Res. Dev., 2007, 11(5): 825–835) or 1-bromo-2-benzyloxy-3-chloropropane (compound 1, LM Rečnik, C. Cantelli, C. Fersing, et al. Synthesis and in vitro antitumour activity of carboplatin analogues containing functional handles compatible for conjugation to drug delivery systems[J]. Bioorg. Med. Chem. Lett., 2022, 30(22): The method uses 127527 as a raw material, undergoes ring closure, and then removes the benzyl group via hydrogenation. In the ring closure step, this method typically requires high-temperature conditions of 120–140°C with NaH as a base, and a reaction time of 24–48 hours. These conditions are harsh and lack selectivity, easily generating disubstituted and polysubstituted byproducts, resulting in low and unstable yields of the target product (approximately 30%–67%), difficult product purification, and limited scale-up. Furthermore, after obtaining the key intermediate 3-(benzyloxy)cyclobutane-1,1-dicarboxylic acid diethyl ester, further hydrogenation to remove the benzyl group is required under the catalysis of noble metal catalysts (Pd / C, Pd(OH)₂ / C, Pt₂O, etc.). This step not only has a long reaction time (72–120 hours), high catalyst cost, and high operational risks, but the noble metal catalysts are also susceptible to poisoning and deactivation by heavy metals (such as residual HgCl₂), further increasing the uncertainty and scale-up risk of the process, limiting its applicability in industrial production.

[0005]

[0006] Regarding the aforementioned route, the inventors discovered that in the scale-up preparation of diethyl 3-hydroxycyclobutane-1,1-dicarboxylic acid, the HgCl2 used in the first step of the reaction is difficult to completely remove and tends to remain in subsequent systems. This HgCl2 poisons and deactivates the Pd / C or Pd(OH)2 / C catalyst in the third step of the debenzylation reaction, leading not only to material waste and increased costs but also severely impacting process stability and yield. Furthermore, the HgCl2 used in this route is a highly toxic substance that easily sublimates, exhibiting high environmental toxicity. Its use and disposal pose significant safety hazards and environmental pressures, further increasing the environmental remediation costs and operational risks of industrial production, severely restricting the large-scale application prospects of this process.

[0007] Of course, diethyl 3-hydroxycyclobutane-1,1-dicarboxylate can also be prepared by other methods besides the above-mentioned methods. In 2021, A. Malashchuk et al. reported a method for preparing diisopropyl 3-hydroxycyclobutane-1,1-dicarboxylate (compound 4) in 93% yield by reducing diisopropyl 3-oxo-1-cyclobutanecarboxylate (compound 3) with sodium borohydride (A. Malashchuk, AV Chernykh, AV Dobrydnev, et al. Fluorine-iabelled spiro[3.3]heptane-derived building blocks: is single fluorine the best?[J]. Eur.J. Org. Chem., 2021, 35: 4897-4910). Theoretically, this strategy can be extended to the reduction of diethyl 3-oxo-1-cyclobutanecarboxylate for the synthesis of diethyl 3-hydroxycyclobutane-1,1-dicarboxylate. However, the practical application of this route still faces significant challenges: First, the synthesis and acquisition of the key starting material, diethyl 3-oxo-1-cyclobutanecarboxylate, is difficult, which restricts the feasibility of the overall route; Second, the reducing agent sodium borohydride used is a controlled chemical that is prone to explosives. Its use in scale-up production is not only accompanied by high operational safety risks, but its market procurement and compliance management are also relatively strict, which further limits the applicability of this process in large-scale production.

[0008]

[0009] If the reduction-based route described above is used to prepare diethyl 3-hydroxycyclobutane-1,1-dicarboxylate, the synthesis of the key intermediate diethyl 3-oxo-1-cyclobutanecarboxylate still needs to be solved. In 2009, DS Radchenko et al. reported a method for synthesizing a similar structure from diisopropyl malonate and 1,3-dibromo-2,2-dimethoxypropane (compound 5) (DS Radchenko, PK Mykhailiuk, AV Bezdudny, et al. Trifluoromethyl-substituted analogues of 1-aminocyclobutane-1-carboxylic acid[J]. Synlett.,2009, 11: 1827-1829). This process requires a reaction at 140°C for 48 hours with NaH as the base and DMF as the solvent. Scale-up is risky, has poor selectivity, and yields only 53%. Furthermore, 10%-20% of the residual 1,3-dibromo-2,2-dimethoxypropane (compound 5, melting point 65°C) in the product is prone to condensation and clogging of the vacuum distillation equipment during subsequent vacuum distillation, severely limiting its feasibility for industrial scale-up. In 2020, Nanjing Yaoshi Technology disclosed a patent entitled "A Method for Preparing an Intermediate for the Synthesis of 3-oxo-1-cyclobutanecarboxylic Acid" (CN 113443986 A), which describes the preparation of the corresponding intermediate by cyclization of 1,3-dibromo-2,2-dimethoxypropane (compound 5) and diisopropyl malonate under the action of potassium isopropoxide. However, the potassium isopropoxide relied upon by this route has a limited supply and high price in the market, resulting in a significant increase in production costs and lacking a competitive advantage for large-scale production.

[0010]

[0011] Theoretically, the starting material 1,1-bis(prop-2-yl)-3,3-dimethoxycyclobutane-1,1-dicarboxylic acid diethyl ester (compound 9), used to prepare 3-oxo-1-cyclobutanecarboxylic acid diethyl ester, can also be prepared using the above-mentioned ring-closure strategy, simply by replacing the starting material with diethyl malonate. Based on this idea, the patent "A method for preparing 3-oxocyclobutanecarboxylic acid" (CN 113527081 A) published by Shanghai Riyi Biotechnology in 2021 describes a method using 1,3-dihydroxyacetone (compound 7) as the starting material, which, after carbonyl protection, yields 1,3-dihydroxy-2,2-dimethoxypropane (compound 8), which is then cyclically cyclically closed with diethyl malonate via the Mitsunobu reaction to construct 3,3-dimethoxycyclobutane-1,1-dicarboxylic acid diethyl ester (compound 9). Subsequently, the hydrolysis of compound 9 yields 3-oxo-1-cyclobutanecarboxylic acid diethyl ester. However, this route inevitably generates a large amount of triphenylphosphine oxide byproducts in the Mitsunobu cyclization step. These byproducts have similar physicochemical properties to the target product, are difficult to separate and purify, and are very likely to remain in the final product. This not only affects the purity of the product but also increases the post-processing costs and environmental burden, making it difficult to apply to industrial-scale production.

[0012]

[0013] In summary, 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester, as a key pharmaceutical intermediate with significant application prospects, still faces significant limitations in terms of safety, efficiency, cost, and feasibility for large-scale production with existing synthetic methods, severely hindering its industrial production and application. Therefore, developing a novel and efficient synthetic route that is safe, mild, simple to operate, cost-controllable, and has good scalability is of urgent practical significance for promoting the research and development and industrialization of related drugs. Summary of the Invention

[0014] Given the significant application value of 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester as a key pharmaceutical intermediate in drug development, existing synthetic methods generally suffer from low yields, numerous side reactions, harsh conditions, use of high-risk reagents, or complex post-processing, severely limiting its industrial production. This invention aims to overcome these technical deficiencies and provide an efficient, safe, and scalable synthetic method for preparing 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester. Specifically, this method uses readily available and inexpensive diethyl malonate as a starting material. First, it reacts with allyl bromide to prepare 2-propenyl malonate diethyl ester, which is then oxidized to obtain 2-epoxypropyl malonate diethyl ester. Subsequently, a ring-opening halogenation reaction is performed to generate 2-(3-X-2-hydroxypropyl)malonate diethyl ester (X being a halogen). After further protecting its hydroxyl group, an intramolecular substitution reaction is performed under mild conditions to construct a 3-hydroxy-protected cyclobutane skeleton. Finally, the protecting group is removed, and the product is purified by vacuum distillation to obtain the high-purity target product. The route design of this invention is reasonable, the reaction conditions of each step are mild, the selectivity is high, and the byproducts are few. It avoids the use of high-risk reagents, and the intermediates are easy to separate and purify. The overall process has outstanding advantages such as low raw material cost, simple operation, stable yield, good reproducibility, and strong scalability, and has significant potential for industrial application.

[0015] To address the issue of the industrial-scale preparation of diethyl 3-hydroxycyclobutane-1,1-dicarboxylic acid, this invention achieves this through the following six steps:

[0016]

[0017] (1) Substitution reaction: Under alkaline conditions, diethyl malonate is subjected to a monosubstitution reaction with allyl bromide to give diethyl 2-propenyl malonate (intermediate 1).

[0018] (2) Oxidation reaction: In a solvent, intermediate 1 is oxidized to its olefin double bond by an oxidizing agent to obtain diethyl 2-epoxypropylmalonate (intermediate 2);

[0019] (3) Ring-opening reaction: In a solvent, intermediate 2 undergoes epoxide ring-opening under the action of acid and LiX (X is a halogen) to obtain diethyl 2-(3-X-2-hydroxypropyl)malonate (intermediate 3);

[0020] (4) Hydroxyl protection: In a solvent, the 3-hydroxyl group of intermediate 3 is protected to obtain diethyl 2-(3-X-2-hydroxypropyl)malonate with the hydroxyl group protected (intermediate 4);

[0021] (5) Ring-closing reaction: In a solvent, intermediate 4 undergoes an intramolecular substitution reaction under alkaline conditions, and generates 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester (intermediate 5) with 3-hydroxy protected.

[0022] (6) Deprotection reaction: In a solvent, intermediate 5 removes the hydroxyl protecting group at the 3-position under acidic conditions to obtain crude 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester, which is then purified by vacuum distillation to obtain the target product 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester.

[0023] Step (1) is a selective monosubstituted reaction of diethyl malonate with allyl bromide. The solvent used in the reaction is one of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), acetone, acetonitrile, tetrahydrofuran, ethyl acetate, or 1,4-dioxane. The base used in the reaction is one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction temperature is 25℃~60℃.

[0024] Step (2) is the epoxidation reaction of the olefin double bond in intermediate 1. The solvent used in the reaction is one of dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, toluene, acetonitrile, and acetone; the oxidant is one of 3-chloroperoxybenzoic acid (m-CPBA), 4-nitroperoxybenzoic acid, peracetic acid, hydrogen peroxide, peroxyacetone (DMDO), and potassium persulfate (Oxone).

[0025] Step (3) is a selective ring-opening reaction of intermediate 2. The solvent used in the reaction is one of ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, acetone, tetrahydrofuran, acetonitrile, or toluene; the acid is one of glacial acetic acid, trifluoroacetic acid, formic acid, citric acid, oxalic acid, or silica gel; and LiX is one of lithium bromide, lithium chloride, or lithium iodide. To ensure the selectivity of the ring-opening reaction, the reaction temperature is between -10℃ and 30℃.

[0026] Step (4) is the reaction for protecting the hydroxyl group in intermediate 3. The solvent used in the reaction is one of dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, ethyl acetate, acetonitrile, and acetone. The protecting group reagent is one of vinyl ethyl ether, MOMCl, MOMBr, 3,4-dihydro-2H-pyran, TBSCl, and TBDPSCl. The catalyst is one of p-toluenesulfonic acid, p-toluenesulfonic acid pyridinium salt (PPTS), trifluoroacetic acid, camphorsulfonic acid (CSA), imidazole, and triethylamine. To avoid the decomposition of the hydroxyl protecting reagent, the reaction temperature is between -5 and 25°C.

[0027] Step (5) is the reaction in which intermediate 4 is substituted to achieve cyclization. The solvent used in the reaction is one of methanol, ethanol, isopropanol, tert-butanol, DMF, DMA, 1,4-dioxane, and tetrahydrofuran; the base is one of sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide, and potassium hydroxide.

[0028] Step (6) is the reaction of removing the 3-hydroxy protecting group from intermediate 5. The solvent used in the reaction is one of methanol, ethanol, isopropanol, dichloromethane, chloroform, tetrahydrofuran, and ethyl acetate. The deprotecting agent is one of p-toluenesulfonic acid and its hydrate, p-toluenesulfonic acid pyridinium salt (PPTS), tetrabutylammonium fluoride and its hydrate, hydrochloric acid, hydrobromic acid, and hydrofluoric acid.

[0029] This invention aims to provide an industrially producible method for synthesizing diethyl 3-hydroxycyclobutane-1,1-dicarboxylate, which has the following advantages over existing technologies:

[0030] (1) The route design is more industrially feasible. This invention uses inexpensive and readily available diethyl malonate as the starting material and precisely constructs key intermediates through steps such as highly selective mono-substitution, olefin epoxidation and epoxide ring opening. This effectively avoids byproducts such as di-substitution caused by excessive alkylation in traditional processes, and significantly improves reaction selectivity and overall yield.

[0031] (2) Significantly reduced safety risks and production costs. In the hydroxyl protection and deprotection process, this invention introduces a protecting group that is stable under alkaline conditions and can be efficiently removed under weakly acidic conditions. This successfully avoids the dependence on precious metal catalysts (such as Pd / C) and high-risk operations such as high-pressure hydrogenation found in traditional synthesis routes. Compared to existing technologies, this invention not only significantly reduces catalyst costs and the risk of "catalyst poisoning," but also greatly reduces equipment investment and safety risks, making it more suitable for large-scale industrial production.

[0032] (3) Simplified process and purification flow. By constructing the cyclobutane skeleton through intramolecular nucleophilic substitution ring closure and combining it with a protecting group removal strategy under mild conditions, the entire process conditions are made milder and more controllable, which helps to reduce the occurrence of side reactions, simplify post-processing and purification steps, thereby improving the purity of the target product and the overall production efficiency.

[0033] (4) Provides a novel and efficient synthetic route. Under the premise of ensuring product quality, this invention provides a novel, low-cost, safe, simple-to-operate and easily scale-up synthetic route for 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester, providing a practical technical solution for the industrial production of this important pharmaceutical intermediate. Attached Figure Description

[0034] Figure 1 For intermediate 1 1 H NMR spectrum

[0035] Figure 2 For intermediate 2 1 H NMR spectrum

[0036] Figure 3 For intermediate 3 1 H NMR spectrum

[0037] Figure 4 For intermediate 4 1 H NMR spectrum

[0038] Figure 5 For intermediate 5 1 H NMR spectrum

[0039] Figure 6 It is diethyl 3-hydroxycyclobutane-1,1-dicarboxylic acid ester. 1 H NMR spectrum

[0040] Figure 7 It is diethyl 3-hydroxycyclobutane-1,1-dicarboxylic acid ester. 13 C NMR spectrum

[0041] Figure 8 It is 3-hydroxycyclobutane-1,1-dicarboxylic acid 1 H NMR spectrum

[0042] Figure 9 It is 3-hydroxycyclobutane-1,1-dicarboxylic acid 13 C NMR spectrum Detailed Implementation

[0043] The present invention will be further described in detail below through examples. The method of the present invention has been described in considerable detail for the preparation of diethyl 3-hydroxycyclobutane-1,1-dicarboxylic acid. Any modifications, appropriate alterations, or combinations of the method described herein without departing from the content, spirit, and scope of the present invention, particularly equivalent substitutions and adjustments to the starting materials, functional groups, or protecting groups based on the synthetic route disclosed in the present invention, as well as related intermediates obtained by further hydrolysis and decarboxylation reactions of the products prepared using the method of the present invention, are all considered to fall within the protection scope of the present invention. The protection scope of the present invention is not limited to the specific content described above. Unless otherwise specified in the examples, the methods used are conventional methods, and the reagents used are commercially available reagents or reagents prepared by conventional methods.

[0044] Example 1

[0045] Step (1): Add 100g of diethyl malonate, 500ml of acetonitrile, and 26.2g of sodium hydroxide to a 1L three-necked round-bottom flask and stir at room temperature for 30min; then add 79.3g of allyl bromide dropwise to the system, and continue stirring for 8h after the addition is complete. After confirming the complete reaction of the raw material diethyl malonate by TLC monitoring, add 1L of water to the reaction solution for dilution and extract with ethyl acetate 3 times; combine the organic phases, wash with water 3 times and saturated brine 1 time, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 142.4g of colorless oily crude product; the crude product is further purified by reduced pressure distillation to finally obtain 111.2g of colorless oily substance (intermediate 1).

[0046] 1 H NMR (500 MHz, CDCl3) δ 5.68-5.77 (m, 1H), 4.98-5.09 (m, 2H), 4.11-4.17 (m, 4H), 3.34-3.38 (m, 1H), 2.56-2.60 (m, 2H), 1.19-1.23 (m, 6H).

[0047] 13 C NMR (125 MHz, CDCl3) δ 168.80, 134.07, 117.36, 61.27, 51.61,32.75, 13.99.

[0048] ESI-MS: m / z Calcd for C 10 H 16 O4 [M+H] + : 201.1, Found: 201.1.

[0049] Step (2): Add 110g of intermediate 1 and 500ml of dichloromethane to a 1L three-necked round-bottom flask. Add 123.8g of 3-chloroperoxybenzoic acid in portions while stirring at room temperature. After the addition is complete, continue stirring at room temperature for 24h. After confirming that intermediate 1 has reacted completely by TLC monitoring, filter the solution and wash the filter cake with excess dichloromethane. Combine the filtrates and wash them once with sodium sulfite solution, three times with water, and once with saturated saline solution. Dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 112.28g of pale yellow oil (intermediate 2). This intermediate is used directly in the next step of the reaction without purification.

[0050] 1H NMR (500 MHz, CDCl3) δ 4.14-4.21 (m, 4H), 3.47-3.51 (m, 1H), 2.95-2.99 (m, 1H), 2.72 (t, J = 4.38 Hz, 1H), 2.47 (q, J = 2.65, 4.90 Hz, 1H),2.18-2.25 (m, 1H), 1.93-1.99 (m, 1H), 1.21-1.26 (m, 6H).

[0051] 13 C NMR (125 MHz, CDCl3) δ 168.84, 168.75, 61.57, 61.54, 49.73, 48.96,47.13, 31.62, 13.98, 13.95.

[0052] ESI-MS: m / z Calcd for C 10 H 16 O5 [M+H] + Found: 216.1.

[0053] Step (3): Add 112.28g of intermediate 2, 400ml of dichloromethane and 20g of silica gel powder (200-300 mesh) to a 1L three-necked round-bottom flask, and stir at 10℃ for 30min; then add 54.2g of lithium bromide in batches, and continue stirring for 30min after the addition is complete; after confirming that intermediate 2 has reacted completely by TLC monitoring, filter the reaction solution and wash the filter cake thoroughly with dichloromethane; combine the filtrate and the eluent, concentrate under reduced pressure to obtain 145.84g of pale yellow oil (intermediate 3); this intermediate is used directly in the next step of the reaction without purification.

[0054] 1 H NMR (500 MHz, CDCl3) δ 4.11-4.21 (m, 4H), 3.80-3.81 (m, 1H), 3.52-3.64 (m, 1H), 3.42-3.50 (m, 1H), 3.33-3.40 (m, 1H), 2.85 (br s, 1H), 2.13-2.21 (m, 1H), 1.95-2.08 (m, 1H), 1.19-1.27 (m, 6H).

[0055] 13C NMR (125 MHz, CDCl3) δ 169.48, 169.23, 68.88, 68.82, 61.62, 48.78,48.75, 39.17, 33.91, 13.98, 13.95.

[0056] ESI-MS: m / z Calcd for C 10 H 17 BrO5 [M+H] + Found: 297.0

[0057] Step (4): Add 145.84 g of intermediate 3, 450 ml of dichloromethane and 12.4 g of p-toluenesulfonic acid pyridine salt to a 1 L three-necked round-bottom flask. After stirring at room temperature for 10 min, add 53.3 g of vinyl ethyl ether dropwise to the system. After the addition is complete, continue stirring for 24 h. After confirming that intermediate 3 has reacted completely by TLC monitoring, concentrate under reduced pressure to remove dichloromethane. Dissolve the residue in 1.2 L of ethyl acetate, wash with water 3 times and saturated brine once, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 174.14 g of colorless oil (intermediate 4). This intermediate is used directly in the next reaction without purification.

[0058] 1 H NMR (500 MHz, CDCl3) δ 4.65-4.75 (m, 1H), 4.11-4.20 (m, 4H), 3.38-3.86 (m, 6H), 2.01-2.33 (m, 2H), 1.20-1.28 (m, 9H), 1.11-1.17 (m, 3H).

[0059] 13 C NMR (125 MHz, CDCl3) δ 169.39, 169.12, 100.95, 98.90, 74.45,74.40, 71.50, 61.44, 61.42, 61.33, 61.02, 60.14, 48.33, 48.06, 35.29, 35.06,33.05, 32.57, 20.02, 19.90, 19.87, 15.20, 15.13, 14.01, 13.99.

[0060] ESI-MS: m / z Calcd for C 14 H 25 BrO6 [M+H] +: 369.1, Found: 369.1.

[0061] Step (5): Add 38.5g sodium ethoxide and 350ml ethanol to a 500ml three-necked round-bottom flask. Stir at room temperature until the system is clear, then add 174.14g intermediate 4. Heat to reflux and stir overnight. After confirming that intermediate 4 has reacted completely by TLC monitoring, stop heating, cool the reaction solution to room temperature, and concentrate under reduced pressure to remove ethanol. Dissolve the residue in 1.2L ethyl acetate, wash with water three times and saturated brine once, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 118.29g brown oily substance (intermediate 5). This intermediate is used directly in the next reaction without purification.

[0062] 1 H NMR (500 MHz, CDCl3) δ 4.61-4.66 (m, 1H), 4.23-4.28 (m, 1H), 4.14-4.22 (m, 4H), 3.55-3.63 (m, 1H), 3.38-3.46 (m, 1H), 2.77-2.81 (m, 2H), 2.47-2.56 (m, 2H), 1.20-1.26 (m, 9H), 1.13-1.18 (m, 3H).

[0063] 13 C NMR (125 MHz, CDCl3) δ 171.74, 170.89, 98.90, 63.67, 61.59, 61.42,61.06, 61.05, 46.40, 38.99, 38.12, 20.39, 15.21, 13.98.

[0064] ESI-MS: m / z Calcd for C 14 H 24 O6 [M+H] + Found: 289.6.

[0065] Step (6): Add 118.29 g of intermediate 5 and 300 ml of methanol to a 500 ml three-necked round-bottom flask. After stirring evenly at room temperature, slowly add 34 ml of concentrated hydrochloric acid to the system. After the addition is complete, continue stirring for 20 min. After confirming that intermediate 5 has reacted completely by TLC monitoring, add 1.2 L of water to the reaction solution for dilution and extract with ethyl acetate three times. Combine the ethyl acetate extracts, wash once with water and once with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 86.24 g of brownish-red oily crude product. The crude product is further purified by reduced pressure distillation to finally obtain 63.54 g of colorless oily substance (diethyl 3-hydroxycyclobutane-1,1-dicarboxylic acid). Based on this, the overall yield of the above six steps is 47.1%.

[0066] 1 H NMR (500 MHz, CDCl3) δ 4.24-4.39 (m, 1H), 4.10-4.21 (m, 4H), 3.21(br s, 1H), 2.75-2.89 (m, 2H), 2.36-2.47 (m, 2H), 1.17-1.26 (m, 6H).

[0067] 13 C NMR (125 MHz, CDCl3) δ 171.70, 171.41, 61.89, 61.61, 61.60, 45.79,40.24, 40.13, 13.90.

[0068] ESI-MS: m / z Calcd for C 10 H 16 O5 [M+H] + Found: 217.1.

[0069] Example 2

[0070] Step (1): Add 100g of diethyl malonate, 300ml of DMF and 138g of potassium carbonate to a 1L three-necked round-bottom flask and stir at room temperature for 30min; then add 79.3g of allyl bromide dropwise to the system. After the addition is complete, continue stirring at room temperature for 16h; after confirming by TLC that the reaction of the raw material diethyl malonate is complete, add 1L of water to the reaction solution for dilution and extract with ethyl acetate 3 times; combine the organic phases, wash with water 3 times and saturated brine 1 time, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain 132.1g of colorless oily crude product; the crude product is further purified by reduced pressure distillation to obtain 115.8g of colorless oily substance (intermediate 1).

[0071] Step (2): Add 115g of intermediate 1 and 500ml of dichloromethane to a 1L three-necked round-bottom flask. Add 119g of 3-chloroperoxybenzoic acid in portions while stirring at room temperature. After the addition is complete, continue stirring at room temperature for 24h. After confirming that intermediate 1 has reacted completely by TLC monitoring, filter the solution and wash the filter cake with excess dichloromethane. Combine the filtrates and wash them once with sodium thiosulfate solution, three times with water, and once with saturated saline solution. Dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 121.4g of pale yellow oil (intermediate 2). This intermediate is used directly in the next step of the reaction without purification.

[0072] Step (3): Add 121.4g of intermediate 2, 500ml of tetrahydrofuran and 40.5g of glacial acetic acid to a 1L three-necked round-bottom flask and stir at room temperature for 30min; then add 28.6g of lithium chloride in batches at 30℃. After the addition is complete, continue stirring for 30min; after confirming that intermediate 2 has reacted completely by TLC monitoring, filter the reaction solution and wash the filter cake thoroughly with dichloromethane; combine the filtrate and the eluent, concentrate under reduced pressure to obtain 135.9g of pale yellow oil (intermediate 3); this intermediate is used directly in the next step of the reaction without purification.

[0073] Step (4): Add 135.9 g of intermediate 3, 450 ml of dichloromethane and 13.5 g of p-toluenesulfonic acid pyridine salt to a 1 L three-necked round-bottom flask. After stirring at room temperature for 10 min, add 58.3 g of vinyl ethyl ether dropwise to the system. After the addition is complete, continue stirring for 24 h. After confirming that intermediate 3 has reacted completely by TLC monitoring, concentrate under reduced pressure to remove dichloromethane. Dissolve the residue in 1.2 L of ethyl acetate, wash with water 3 times and saturated brine once, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 162.4 g of colorless oil (intermediate 4). This intermediate is used directly in the next reaction without purification.

[0074] Step (5): Add 40.0 g sodium ethoxide and 350 ml ethanol to a 500 ml three-necked round-bottom flask. Stir at room temperature until the system is clear, then add 162.4 g intermediate 4. Heat to reflux and stir overnight. After confirming that intermediate 4 has reacted completely by TLC monitoring, stop heating, cool the reaction solution to room temperature, and concentrate under reduced pressure to remove ethanol. Dissolve the residue in 1.2 L ethyl acetate, wash with water three times and saturated brine once, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 121.5 g of brown oily substance (intermediate 5). This intermediate is used directly in the next reaction without purification.

[0075] Step (6): Add 121.5g of intermediate 5 and 300ml of methanol to a 500ml three-necked round-bottom flask. After stirring evenly at room temperature, add 10.6g of p-toluenesulfonic acid pyridine salt, then heat to reflux and stir for 1h. After confirming that intermediate 5 has reacted completely by TLC monitoring, concentrate under reduced pressure to remove methanol. Dissolve the residue in 1L of ethyl acetate, wash with water 3 times and saturated brine once, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 83.2g of brownish-red oily crude product. The crude product is further purified by reduced pressure distillation to obtain 60.5g of colorless oily substance (diethyl 3-hydroxycyclobutane-1,1-dicarboxylic acid). Based on this, the overall yield of the above six steps is 44.8%.

[0076] Example 3

[0077] Step (1): Add 3500g of diethyl malonate, 5L of DMF and 4832g of potassium carbonate to a 20L reactor. Add 3172g of allyl bromide slowly dropwise to the system while stirring at room temperature. The addition is completed in about 3 hours. Continue stirring for 4 hours. The reaction of the raw material diethyl malonate is confirmed to be complete by TLC monitoring. Filter the reaction solution and wash the filter cake thoroughly with 12L of ethyl acetate. Combine the filtrate and the eluent, wash with water 3 times and saturated brine once, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 4410g of colorless oily crude product. The crude product is further purified by reduced pressure distillation to obtain 4078g of colorless oily substance (intermediate 1).

[0078] Step (2): Add 14L of dichloromethane and 4551g of 3-chloroperoxybenzoic acid to a 20L reactor. Under stirring at room temperature, slowly add 4078g of intermediate 1 dropwise to the system. The addition is completed in about 3 hours. Continue stirring for 24 hours. After confirming that intermediate 1 has reacted completely by TLC monitoring, filter the reaction solution and wash the filter cake thoroughly with 10L of dichloromethane. Combine the filtrate and the eluent, and wash once with sodium thiosulfate solution, once with saturated sodium bicarbonate solution, three times with water, and once with saturated brine. Dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 4443g of colorless oily substance (intermediate 2). This intermediate is used directly in the next reaction without purification.

[0079] Step (3): Add 4443g of intermediate 2 and 9L of tetrahydrofuran to a 20L reactor, add 1467g of glacial acetic acid while stirring at -10℃, and then add 2121g of lithium bromide in batches; after the addition is complete, gradually heat the reaction system to room temperature and continue stirring for 2.5h; after confirming that intermediate 2 has reacted completely by TLC monitoring, add 5L of water to the reactor, stir thoroughly and let stand to separate the layers, and separate the upper organic phase; extract the lower aqueous phase twice with ethyl acetate, combine all organic phases, wash twice with water and once with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain 5889g of pale yellow oil (intermediate 3); this intermediate is used directly in the next step of the reaction without purification.

[0080] Step (4): Add 5889g of intermediate 3 and 10.5L of dichloromethane to a 20L reactor. Add 500g of p-toluenesulfonic acid pyridine salt while stirring at -5℃. After stirring for 30min, slowly add 2152g of vinyl ethyl ether dropwise to the system, controlling the system temperature to not exceed 25℃ during the dropwise addition. After the dropwise addition is complete, continue stirring for 16h. After confirming that intermediate 3 has reacted completely by TLC monitoring, wash the reaction solution twice with water and once with saturated saline solution. Dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 7189g of pale yellow oil (intermediate 4). This intermediate is used directly in the next step of the reaction without purification.

[0081] Step (5): Add 9L of ethanol and 1590g of sodium ethoxide to a 20L reactor. Stir at room temperature until completely dissolved, then add 7189g of intermediate 4. Heat to reflux and stir for 16h. After confirming that intermediate 4 has reacted completely by TLC monitoring, concentrate under reduced pressure to remove ethanol. Add 5L of ethyl acetate and 5L of water to the residue, stir, and allow to stand for separation. Separate the upper organic phase. Extract the lower aqueous phase twice with ethyl acetate. Combine all organic phases, wash three times with water and once with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 4817g of reddish-brown oil (intermediate 5). This intermediate is used directly in the next reaction without purification.

[0082] Step (6): Add 8.5L of methanol, 4817g of intermediate 5 and 420g of p-toluenesulfonic acid pyridine salt to a 20L reactor, heat to reflux and stir for 1.5h; after confirming that intermediate 5 has reacted completely by TLC monitoring, concentrate under reduced pressure to remove methanol; dissolve the residue in 8L of ethyl acetate, wash with water 3 times and saturated brine once, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain 3406g of reddish-brown oily crude product; further purify the crude product by reduced pressure distillation to obtain 2280g of colorless oily substance (diethyl 3-hydroxycyclobutane-1,1-dicarboxylic acid); based on this, the overall yield of the above six steps is 48.3%.

[0083] Example 4

[0084] Further hydrolysis verification: 50g of diethyl 3-hydroxycyclobutane-1,1-dicarboxylic acid and 300ml of ethanol were added to a three-necked round-bottom flask. After stirring evenly at room temperature, 23g of sodium hydroxide was added, followed by heating to reflux and stirring for 8 hours. After confirming the complete reaction of diethyl 3-hydroxycyclobutane-1,1-dicarboxylic acid by TLC monitoring, the ethanol was removed by concentration under reduced pressure. The residue was dissolved in 200ml of water, and the pH was adjusted to 1-2 by adding concentrated hydrochloric acid. Then, it was extracted four times with ethyl acetate. The ethyl acetate extract was washed twice with water and once with saturated brine. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 38.6g of crude product. The crude product was further pulped to obtain 35.2g of white solid (3-hydroxycyclobutane-1,1-dicarboxylic acid), with a yield of 95.2%.

[0085] 1 H NMR (500 MHz, CD3OD) δ 4.23-4.29 (m, 1H), 2.76-2.80 (m, 2H), 2.38-2.42 (m, 2H).

[0086] 13 C NMR (125 MHz, CD3OD) δ 173.88, 173.37, 60.94, 45.31, 39.82.

[0087] ESI-MS: m / z Calcd for C6H8O5 [M+H] + Found: 161.0

Claims

1. This invention provides a method for preparing the pharmaceutical intermediate 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester, characterized in that, Includes the following steps: (1) In a solvent, under alkaline conditions, diethyl malonate is reacted with allyl bromide to give diethyl 2-propenyl malonate. (2) In a solvent, the 2-propenyl malonate diethyl ester obtained in step (1) is oxidized with an oxidizing agent to obtain 2-epoxypropyl malonate diethyl ester; (3) In a solvent, under acidic conditions, the 2-epoxypropylmalonate diethyl ester obtained in step (2) is reacted with LiX (where X is a halogen) to obtain 2-(3-X-2-hydroxypropyl)malonate diethyl ester; (4) In a solvent, the 2-(3-X-2-hydroxypropyl)malonic acid diethyl ester obtained in step (3) is reacted with a hydroxyl protecting agent to obtain 2-(3-X-2-hydroxypropyl)malonic acid diethyl ester with 3-hydroxy protected. (5) In a solvent, under alkaline conditions, the hydroxyl-protected diethyl 2-(3-X-2-hydroxypropyl)malonic acid obtained in step (4) is subjected to a cyclization reaction to obtain 3-hydroxy-protected 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester. (6) In a solvent, the 3-hydroxy-protected 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester obtained in step (5) is deprotected and distilled under reduced pressure to obtain the target product 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester.

2. The method for preparing the pharmaceutical intermediate 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester according to claim 1, characterized in that: The solvent in step (1) is acetonitrile, tetrahydrofuran, N , N- Dimethylformamide (DMF) N , N- The ingredients are dimethylacetamide (DMA), acetone, and 1,4-dioxane; the base is one of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate.

3. The method for preparing the pharmaceutical intermediate 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester according to claim 1, characterized in that: The solvent used in step (2) is one of dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, toluene, acetonitrile, or acetone; the oxidant is 3-chloroperoxybenzoic acid (...). m One of the following: -CPBA), 4-nitroperoxybenzoic acid, peracetic acid, hydrogen peroxide, peroxyacetone (DMDO), and potassium persulfate (Oxone).

4. The method for preparing the pharmaceutical intermediate 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester according to claim 1, characterized in that: The solvent used in step (3) is one of ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, acetone, tetrahydrofuran, acetonitrile, or toluene; the reagent providing acidic conditions is one of glacial acetic acid, trifluoroacetic acid, formic acid, citric acid, oxalic acid, or silica gel; LiX is one of lithium bromide, lithium chloride, or lithium iodide; and the reaction temperature is between -10°C and 30°C.

5. The method for preparing the pharmaceutical intermediate 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester according to claim 1, characterized in that: The solvent used in step (4) is one of dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, ethyl acetate, acetonitrile, or acetone; the hydroxyl protecting group reagent is vinyl ether, MOMCl, MOMBr, or 3,4-dihydro- 2H - One of pyran, TBSCl, TBDPSCl; the catalyst is one of p-toluenesulfonic acid, p-toluenesulfonic acid pyridinium salt (PPTS), trifluoroacetic acid, camphorsulfonic acid (CSA), imidazole, triethylamine; the reaction temperature is -5℃ to room temperature.

6. The method for preparing the pharmaceutical intermediate 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester according to claim 1, characterized in that: The solvent used in step (5) is one of methanol, ethanol, isopropanol, tert-butanol, DMF, DMA, 1,4-dioxane, and tetrahydrofuran; the base is one of sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide, and potassium hydroxide.

7. The method for preparing the pharmaceutical intermediate 3-hydroxycyclobutane-1,1-dicarboxylic acid diethyl ester according to claim 1, characterized in that: The solvent used in step (6) is one of methanol, ethanol, isopropanol, dichloromethane, chloroform, tetrahydrofuran, and ethyl acetate; the hydroxyl deprotecting agent is one of p-toluenesulfonic acid and its hydrate, p-toluenesulfonic acid pyridinium salt (PPTS), tetrabutylammonium fluoride and its hydrate, hydrochloric acid, hydrobromic acid, and hydrofluoric acid.

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