Synthetic method of empagliflozin
Through the catalytic coupling reaction of FeCl3 and bipyridine complex, combined with green solvents and supported palladium catalysts, the precious metal dependence and solvent toxicity problems in engaliflozin synthesis were solved, and efficient, environmentally friendly and economical engaliflozin synthesis was achieved, improving product yield and stereoselectivity.
Patent Information
- Application Number
- CN202510665863.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-22
- Publication Date
- 2025-08-29
AI Technical Summary
The existing engagliflozin synthesis methods have problems such as precious metal dependence, high cost, metal residue risk, high solvent toxicity, harsh reaction conditions, low product yield and insufficient stereoselectivity.
The coupling reaction of FeCl3 and bipyridine complex was catalyzed, 2-methyltetrahydrofuran and cyclopentylmethyl ether were used as green solvents, and the supported Pd@MOF-808 catalyst was synergistically carried out the glycosylation reaction with (R)-BINAP chiral ligand, and the steps were integrated in a continuous flow reactor to combine with ion exchange resin deprotection.
It realizes efficient, environmentally friendly and economical synthesis of engagliflozin, reduces raw material costs, avoids heavy metal residues, improves product yield and three-dimensional selectivity, and is suitable for industrial applications.
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Figure CN120554343A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to a method for synthesizing empagliflozin, and belongs to the field of raw material medicine preparation. Background Art
[0002] Empagliflozin, a Boehringer Ingelheim innovation, is a selective SGLT-2 inhibitor designed specifically for patients with type 2 diabetes. Its unique mechanism of action precisely targets the renal tubules, promoting glucose excretion and effectively regulating blood sugar levels. Clinical trials have demonstrated that Empagliflozin not only demonstrates excellent efficacy but also offers excellent safety and tolerability, bringing benefits to patients with diabetes.
[0003] In the existing technology, the synthesis of empagliflozin mainly relies on palladium- or nickel-catalyzed coupling reactions and low-temperature glycosylation reactions. The traditional method uses palladium / nickel catalysts, such as Pd(PPh3)4 and NiCl2, which are prone to precious metal dependence, high cost and the risk of metal residues, and require complex purification steps. The commonly used homogeneous palladium catalysts are difficult to recover, have low reuse rates, and cause serious waste of resources. In addition, the reaction often uses solvents such as dioxane and toluene, which are carcinogenic or highly volatile and do not meet the requirements of green chemistry. The glycosylation reaction needs to be carried out at -78°C, the reaction conditions are harsh, the operation is complicated, there are many side reactions, and the product yield is low. At the same time, the existing methods lack effective chiral control means and insufficient stereoselectivity, resulting in an unsatisfactory α / β configuration ratio.
[0004] These drawbacks severely limit the efficiency and cost control of industrial production of empagliflozin. Therefore, developing an efficient, environmentally friendly, and economical synthesis method has become a technical challenge that needs to be addressed urgently. Summary of the Invention
[0005] The present invention addresses the above-mentioned defects in the prior art and provides a method for synthesizing empagliflozin, which solves the problem of how to achieve an efficient, environmentally friendly and economical method for preparing empagliflozin.
[0006] The object of the present invention is achieved through the following technical solution, a method for synthesizing empagliflozin, comprising the following steps:
[0007] S1: In the presence of an iron catalyst, a base, and a first solvent, coupling the compound of formula 4 with pinacol diboron to produce a compound of formula 3;
[0008] S2: In the presence of a supported palladium catalyst, a chiral ligand, a base, and a second solvent, the compound of formula 3 undergoes a glycosylation reaction with acetyl bromide-α-D-glucose to produce a compound of formula 2;
[0009] S3: In the presence of a methanol solution of sodium methoxide and an ion exchange resin, the compound of formula 2 is deprotected to produce empagliflozin, i.e., the compound of formula 1;
[0010] Preferably, in step S1, the iron catalyst is a complex of FeCl3 and bipyridine;
[0011] Preferably, in step S1, the first solvent is 2-methyltetrahydrofuran (2-MeTHF);
[0012] Preferably, in step S2, the supported palladium catalyst is Pd@MOF-808;
[0013] Preferably, in step S2, the chiral ligand is (R)-BINAP;
[0014] Preferably, in step S2, the second solvent is a mixed solvent of cyclopentyl methyl ether and N,N-dimethylformamide.
[0015] In the prior art, although there have been reports on coupling reactions using iron catalysts (such as iron triacetylacetonate), there has been no mention of the use of bipyridine ligands in borate coupling. Partially switching to iron-based catalysts can avoid dependence on precious metals, reduce costs, and avoid the risk of metal residues. In addition, the prior art mostly uses dioxane or toluene, and 2-MeTHF as a green solvent alternative. Its boiling point is suitable for the reaction temperature and its toxicity is low. It is also derived from renewable resources and is more convenient to recycle. MOF-supported palladium catalysts have a high recovery rate in glycosylation reactions and can be recycled more than 5 times. The recovery rate of homogeneous palladium catalysts used in conventional technologies is low, and resource waste is relatively serious. The combination of iron catalyst / green solvent and supported palladium catalyst / chiral ligand can greatly improve the product yield and reduce the difficulty of the reaction.
[0016] Furthermore, in step S1:
[0017] The molar ratio of FeCl3 to bipyridine in the iron catalyst is 1:2-3;
[0018] The base is cesium carbonate, and the amount used is 2.3 to 2.8 eq of the molar amount of the compound of formula 4. Cesium carbonate can enhance the reaction stability of borate esters;
[0019] The reaction temperature is 80-95° C. and the reaction time is 4-8 hours to avoid deboronation caused by high temperature reaction.
[0020] Furthermore, in step S1:
[0021] Ascorbic acid is added to the reaction system as a reducing agent in an amount of 1 to 1.5 equivalents of the molar amount of the iron catalyst. Ascorbic acid acts as a reducing agent to simultaneously inhibit oxidative deactivation and side reactions of the iron catalyst.
[0022] The reaction is carried out under nitrogen protection, and the moisture content is controlled to be ≤0.1%. Nitrogen protection prevents hydrolysis of borate ester.
[0023] Furthermore, in step S2:
[0024] The carrier of the supported palladium catalyst is MOF-808, and the loading amount is 1.5% to 4.5% (w / w);
[0025] The amount of the chiral ligand (R)-BINAP is 0.8 to 1.2 eq of the molar amount of the compound of formula 3. The chiral ligand (R)-BINAP improves the α-configuration selectivity of glycosylation;
[0026] The volume ratio of CPME to DMF is 9:1, and the mixture of CPME and DMF enhances the reaction activity.
[0027] Furthermore, in step S2:
[0028] The base is potassium phosphate, and the amount used is 2.2 to 2.5 equivalents of the molar amount of the compound of formula 3;
[0029] The reaction temperature is 80-90° C., and the reaction time is 8-12 hours.
[0030] Furthermore, in step S3:
[0031] The concentration of the sodium methoxide methanol solution is 5% to 10% (w / v);
[0032] The ion exchange resin is Amberlyst 15, and the amount is adjusted according to the pH of the reaction solution;
[0033] The deprotection reaction is carried out at 0-5°C for 20-40 minutes.
[0034] Furthermore, the step S1 and the step S2 are integrated and performed in a continuous flow reactor;
[0035] The inner diameter of the reaction channel of the continuous flow reactor is 1 to 3 mm, the flow rate is 0.5 to 2 mL / min, and the total residence time is 2 to 4 hours.
[0036] Furthermore, the supported palladium catalyst (Pd@MOF-808) can be recycled, with the number of cycles being ≥5 times and the activity retention rate being ≥90%.
[0037] In summary, the present invention has the following advantages compared with the prior art:
[0038] 1. In the scheme of the present invention, FeCl3 and bipyridine complex are used to catalyze the coupling reaction. Iron catalyst replaces part of the precious metal catalyst, which greatly reduces the cost of raw materials and avoids the risk of heavy metal residues. 2-methyltetrahydrofuran (2-MeTHF) and cyclopentyl methyl ether (CPME) are used to replace dioxane and toluene, which significantly reduces toxicity. They are derived from renewable resources, improve recycling rate, and improve cost and safety. Compared with the existing technology, the synthesis of empagliflozin is more efficient, environmentally friendly and economical through iron / palladium synergistic catalysis, green solvent substitution and process integration, which has significant industrial application value.
[0039] 2. In the scheme of the present invention, by optimizing the loading amount of the supported palladium catalyst, the yield of the glycosylation reaction is improved, the catalyst can be recycled more than 5 times, and the activity retention rate is improved. The (R)-BINAP ligand is introduced. Under the synergistic effect of the chiral ligand, the α-configuration selectivity reaches a high level, which is significantly better than the unspecified selectivity of the prior art. BRIEF DESCRIPTION OF THE DRAWINGS
[0040] Figure 1 This is the synthetic route of the present invention. DETAILED DESCRIPTION
[0041] The technical solution of the present invention is further specifically described below through specific embodiments, but the present invention is not limited to these embodiments.
[0042] Example 1
[0043] a. Preparation of the compound of formula 3 (step S1):
[0044] Under nitrogen protection, FeCl3 (9.73 g, 0.06 mol), bipyridine (18.74 g, 0.12 mol) and 2-MeTHF (500 mL) were added to the reactor and stirred until completely dissolved.
[0045] The compound of formula 4 (36.6 g, 0.1 mol), pinacol diboron (30.5 g, 0.12 mol), cesium carbonate (74.9 g, 0.23 mol) and ascorbic acid (5.3 g, 0.03 mol) were added in sequence.
[0046] The temperature was raised to 85°C and the mixture was stirred for 6 hours. The end point of the reaction was monitored by TLC.
[0047] The reaction solution was cooled to room temperature, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure.
[0048] The residue was recrystallized from ethanol to obtain 32 g of compound 3 as a white solid (yield 78%, HPLC purity 98.5%).
[0049] b. Preparation of the compound of formula 2 (step S2):
[0050] The compound of formula 3 (30.77 g, 0.075 mol), Pd@MOF-808 (2 g, loading 3.0%), (R)-BINAP (46.7 g, 0.075 mol) and potassium phosphate (35 g, 0.165 mol) were added to a CPME / DMF (9:1, 600 mL) mixed solvent and replaced with nitrogen three times.
[0051] A CPME solution of acetyl bromide-α-D-glucose (30.84 g, 0.075 mol) was added dropwise, and the temperature was raised to 85° C. The mixture was stirred for 10 hours and the reaction progress was monitored by HPLC.
[0052] The reaction solution was cooled, filtered to recover the catalyst, the filtrate was washed three times with saturated brine, and the organic phase was concentrated.
[0053] The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 38.2 g of compound 2 as a white solid (yield 82.4%, HPLC purity 99.1%, α / β selectivity 99.3:0.7).
[0054] c. Synthesis of Empagliflozin (Step S3):
[0055] The compound of formula 2 (37.1 g, 0.06 mol) was dissolved in a solution of sodium methoxide in methanol (7% w / v, 150 mL), cooled to 0° C. in an ice bath, stirred for 30 minutes, and the deprotection progress was monitored by HPLC.
[0056] Amberlyst 15 resin was added, stirred and neutralized to pH = 7, and the resin was removed by filtration.
[0057] The filtrate was concentrated under reduced pressure, and the residue was extracted with ethyl acetate / water (1:1). The organic phase was dried and concentrated.
[0058] The crude product was recrystallized from ethanol to obtain 25.52 g of white crystalline empagliflozin (yield 94.5%, HPLC purity 99.6%).
[0059] The total yield of the three-step reaction of steps S1 to S3 is 60.7%.
[0060] Example 2
[0061] Continuous flow reactor integrating steps S1 and S2:
[0062] The reaction solution in step S1 (compound of formula 4, FeCl3 / bipyridine, biboronic acid ester) is allowed to stay in the first reaction zone for 1.5 hours to generate a compound of formula 3.
[0063] In step S2, the raw materials (compound of formula 3, Pd@MOF-808, (R)-BINAP, acetyl bromide-α-D-glucose) were injected into the second reaction zone and stayed for 1.5 hours.
[0064] The inner diameter of the reaction channel was 2 mm, the flow rate was 1.5 mL / min, and the temperature was controlled at 85°C in the first reaction zone and 85°C in the second reaction zone.
[0065] The outlet liquid was post-treated (same as in Example 2) to obtain 45.5 g of the compound of formula 2 (total yield 73.6%, HPLC purity 98.4%).
[0066] Example 3
[0067] Catalyst cycle performance test:
[0068] The Pd@MOF-808 catalyst recovered in Example 1 was reused in the reaction of step S2 under the same conditions as in Example 1.
[0069] After 5 cycles, the catalyst activity and product yield were measured.
[0070] Number of cycles: 5 times
[0071] Yield retention rate: 81.3% for the first time, 74% for the fifth time
[0072] Activity retention rate: ≥90%.
[0073] Example 4
[0074] Solvent ratio optimization (step S2):
[0075] Condition comparison
[0076] Group 1: CPME / DMF = 9:1 (volume ratio);
[0077] Group 2: CPME / DMF = 8:2 (volume ratio);
[0078] result
[0079] Group 1: yield 82.6%, α selectivity 99.3%;
[0080] Group 2: yield 77.4%, α selectivity 98.5%.
[0081] Example 5
[0082] Effect of ascorbic acid dosage on step S1:
[0083] Condition comparison
[0084] Group 1: 1.0 equivalent of ascorbic acid (relative to FeCl3);
[0085] Group 2: no ascorbic acid;
[0086] Test results
[0087] Group 1: yield 78.1%, no deactivation of Fe catalyst;
[0088] Group 2: yield 52.7%, Fe 3+ Aggregation leads to stagnation of the reaction.
[0089] Example 6
[0090] Preparation of the compound of formula 3 (step S1)
[0091] Raw materials and conditions:
[0092] Compound of formula 4: 36.6 g (0.1 mol);
[0093] Pinacol diborate: 30.5 g (0.12 mol);
[0094] FeCl3: 9.73 g (0.06 mol);
[0095] Bipyridine: 28.11 g (0.18 mol, molar ratio 1:3);
[0096] Cesium carbonate: 74.9 g (0.23 mol);
[0097] 2-MeTHF: 500 mL;
[0098] Ascorbic acid: 5.3 g (0.03 mol);
[0099] Reaction temperature: 85°C;
[0100] Reaction time: 6 hours;
[0101] The operation is the same as step S1 of Example 1.
[0102] Test results:
[0103] 31.5 g of white solid compound 3 was obtained (yield 76.8%, HPLC purity 98.3%).
[0104] Example 7
[0105] Preparation of the compound of formula 3 (step S1)
[0106] Raw materials and conditions:
[0107] Compound of formula 4: 36.6 g (0.1 mol);
[0108] Pinacol diborate: 30.5 g (0.12 mol);
[0109] FeCl3: 9.73 g (0.06 mol);
[0110] Bipyridine: 18.74 g (0.12 mol, molar ratio 1:2);
[0111] Cesium carbonate: 74.9 g (0.23 mol);
[0112] 2-MeTHF: 500 mL;
[0113] Ascorbic acid: 5.3 g (0.03 mol);
[0114] Reaction temperature: 95°C;
[0115] Reaction time: 6 hours;
[0116] The operation is the same as step S1 of Example 1.
[0117] Test results:
[0118] 30.2 g of white solid compound 3 was obtained (yield 73.7%, HPLC purity 97.9%).
[0119] Example 8
[0120] Preparation of the compound of formula 2 (step S2)
[0121] Raw materials and conditions:
[0122] Compound of formula 3: 30.77 g (0.075 mol);
[0123] Acetyl bromide-α-D-glucose: 30.84 g (0.075 mol);
[0124] Pd@MOF-808 (loading 1.5%): 4.0 g (actual palladium content 0.06 g);
[0125] (R)-BINAP: 46.7g (0.075mol, 1.0eq);
[0126] Potassium phosphate (K3PO4): 35 g (0.165 mol);
[0127] Solvent: CPME / DMF (9:1, 600 mL);
[0128] Reaction temperature: 85°C;
[0129] Reaction time: 10 hours;
[0130] The operation is the same as step S2 of Example 1.
[0131] Test results:
[0132] 36.8 g of white solid compound 2 was obtained (yield 79.5%, HPLC purity 98.8%, α / β selectivity 99.1:0.9).
[0133] Example 9
[0134] Preparation of the compound of formula 2 (step S2)
[0135] Raw materials and conditions:
[0136] Compound of formula 3: 30.77 g (0.075 mol);
[0137] Acetyl bromide-α-D-glucose: 30.84 g (0.075 mol);
[0138] Pd@MOF-808 (loading 3.0%): 2.0 g;
[0139] (R)-BINAP: 37.4g (0.06mol, 0.8eq);
[0140] Potassium phosphate: 35 g (0.165 mol);
[0141] Solvent: CPME / DMF (9:1, 600 mL);
[0142] Reaction temperature: 85°C;
[0143] Reaction time: 10 hours;
[0144] The operation is the same as step S2 of Example 1.
[0145] Test results:
[0146] 36.0 g of the compound of formula 2 as a white solid was obtained (yield 77.6%, HPLC purity 98.5%, α / β selectivity 98.8:1.2).
[0147] Example 10
[0148] Preparation of the compound of formula 2 (step S2)
[0149] Raw materials and conditions:
[0150] Compound of formula 3: 30.77 g (0.075 mol);
[0151] Acetyl bromide-α-D-glucose: 30.84 g (0.075 mol);
[0152] Pd@MOF-808 (loading 3.0%): 2.0 g;
[0153] (R)-BINAP: 46.7g (0.075mol, 1.0eq);
[0154] Potassium phosphate: 35 g (0.165 mol);
[0155] Solvent: CPME / DMF (8:2, 600 mL);
[0156] Reaction temperature: 85°C;
[0157] Reaction time: 10 hours;
[0158] The operation is the same as step S2 of Example 1.
[0159] Test results:
[0160] 35.2 g of the compound of formula 2 as a white solid was obtained (yield 75.9%, HPLC purity 98.2%, α / β selectivity 98.5:1.5).
[0161] Example 11
[0162] Step S3: Synthesis of Empagliflozin
[0163] Raw materials and conditions:
[0164] Compound of formula 2: 37.1 g (0.06 mol);
[0165] Sodium methoxide solution concentration: 5% w / v (150 mL);
[0166] Amberlyst 15 resin: 15g;
[0167] Reaction temperature: 0–5°C;
[0168] Reaction time: 30 minutes;
[0169] The operation is the same as step S3 of Example 1.
[0170] Test results:
[0171] 24.1 g of white crystalline empagliflozin was obtained (yield 89.3%, HPLC purity 99.3%).
[0172] Example 12
[0173] Continuous flow reactor integrating steps S1 and S2
[0174] Device parameters:
[0175] Reaction channel inner diameter: 2mm;
[0176] Flow rate: 1.5 mL / min;
[0177] Total stay time: 3 hours;
[0178] Temperature control: S1 zone 85℃, S2 zone 85℃.
[0179] Steps:
[0180] Step S1: The compound of formula 4 (36.6 g), FeCl3 (9.73 g), bipyridine (18.74 g), bipyridyl ...
[0181] Step S2: The reaction solution was mixed with acetyl bromide-α-D-glucose (30.84 g), Pd@MOF-808 (2.0 g), (R)-BINAP (46.7 g) and potassium phosphate (35 g), and injected into the second zone for 1.5 hours;
[0182] The outlet liquid was post-treated (same as in Example 1) to obtain 34.8 g of the compound of formula 2 (total yield 75.2%, HPLC purity 98.6%).
[0183] The above examples cover all key parameter ranges specified in the claims (e.g., catalyst loading, ligand ratio, solvent ratio, etc.), demonstrating the feasibility and superiority of the technical solution. Each example exhibits stable yields, high selectivity for the α-configuration, and total yields exceeding 60%, significantly outperforming existing technologies.
[0184] The embodiments of the present invention are not limited to the above embodiments. Without departing from the spirit and scope of the present invention, ordinary technicians in this field can make various changes and improvements to the present invention in form and details, and these are all considered to fall within the scope of protection of the present invention.
Claims
1. A method for synthesizing empagliflozin, characterized in that: The following steps are involved: S1: In the presence of an iron catalyst, a base, and a first solvent, coupling the compound of formula 4 with pinacol diboron to produce a compound of formula 3; S2: In the presence of a supported palladium catalyst, a chiral ligand, a base, and a second solvent, the compound of formula 3 undergoes a glycosylation reaction with acetyl bromide-α-D-glucose to produce a compound of formula 2; S3: In the presence of a methanol solution of sodium methoxide and an ion exchange resin, the compound of formula 2 is deprotected to produce empagliflozin, i.e., the compound of formula 1; In the step S1, the iron catalyst is a complex of FeCl3 and bipyridine; In the step S1, the first solvent is 2-methyltetrahydrofuran (2-MeTHF); In the step S2, the supported palladium catalyst is Pd@MOF-808; In step S2, the chiral ligand is (R)-BINAP; In step S2, the second solvent is a mixed solvent of cyclopentyl methyl ether and N,N-dimethylformamide.
2. The method for synthesizing empagliflozin according to claim 1, wherein: In the step S1: The molar ratio of FeCl3 to bipyridine in the iron catalyst is 1:2-3; The base is cesium carbonate, and the amount used is 2.3 to 2.8 eq of the molar amount of the compound of formula 4; The reaction temperature is 80-95° C., and the reaction time is 4-8 hours.
3. The method for synthesizing empagliflozin according to claim 2, wherein: In the step S1: Ascorbic acid is added to the reaction system as a reducing agent in an amount of 1 to 1.5 equivalents of the molar amount of the iron catalyst; The reaction was carried out under nitrogen protection, and the moisture content was controlled to be ≤0.1%.
4. The method for synthesizing empagliflozin according to claim 1, wherein: In the step S2: The carrier of the supported palladium catalyst is MOF-808, and the loading amount is 1.5% to 4.5% (w / w); The amount of the chiral ligand (R)-BINAP used is 0.8 to 1.2 eq of the molar amount of the compound of formula 3; The volume ratio of the CPME to DMF is 9:
1.
5. The method for synthesizing empagliflozin according to claim 4, wherein: In the step S2: The base is potassium phosphate, and the amount used is 2.2 to 2.5 equivalents of the molar amount of the compound of formula 3; The reaction temperature is 80-90° C., and the reaction time is 8-12 hours.
6. The method for synthesizing empagliflozin according to claim 1, wherein: In the step S3: The concentration of the sodium methoxide methanol solution is 5% to 10% (w / v); The ion exchange resin is Amberlyst 15, and the amount is adjusted according to the pH of the reaction solution; The deprotection reaction is carried out at 0-5°C for 20-40 minutes.
7. A method for synthesizing empagliflozin according to the compound of formula 1, characterized in that: Step S1 and step S2 are integrated and performed in a continuous flow reactor; The inner diameter of the reaction channel of the continuous flow reactor is 1 to 3 mm, the flow rate is 0.5 to 2 mL / min, and the total residence time is 2 to 4 hours.
8. The method for synthesizing empagliflozin according to claim 5, wherein: The supported palladium catalyst can be recycled, the number of cycles is ≥5 times, and the activity retention rate is ≥90%.