Synthesis method of relebactam intermediate impurity
By optimizing the preparation route of levobatane intermediates and using inexpensive and readily available (2S,5R)-phenoxyaminopiperidine-2-carboxylic acid ethyl oxalate as a raw material, the problems of difficult-to-obtain starting materials and numerous side reaction impurities were solved, achieving efficient and safe preparation of intermediate impurities, optimizing the production process and reducing costs.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- CHONGQING SHENGHUAXI PHARMA CO LTD
- Filing Date
- 2026-02-05
- Publication Date
- 2026-05-19
AI Technical Summary
Existing synthetic routes for relebactam intermediates suffer from problems such as difficulty in obtaining starting materials and numerous side reaction impurities, especially in synthetic routes using hydroxypiperacic acid as the starting material, which is commercially difficult to obtain and generates a large number of side reaction impurities.
Using (2S,5R)-phenoxyaminopiperidine-2-carboxylic acid ethyl oxalate as a raw material, a multi-step reaction was conducted, including solvent selection, control of alkaline conditions, and optimization of purification methods, to prepare the intermediate impurity of lelebactam. This process avoided the use of irritating chemicals, employed inexpensive and readily available raw materials, and purified the impurity through extraction and silica gel column chromatography.
This method enables the efficient preparation of intermediate impurities in levobatane, reduces production costs, minimizes safety and environmental risks, optimizes the production process, and improves product purity.
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Figure CN122059958A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical manufacturing, specifically to a method for synthesizing impurities in an important intermediate of relebactam. More specifically, this invention relates to the synthesis of impurities in the synthetic route of 4-[[[(1R,2S,5R)-7-oxo-6-(phenylmethoxy)-1,6-diazabicyclo[3.2.1]octane-2-yl]carbonyl]amino]-1-piperidinecarboxylic acid tert-butyl ester. Background Technology
[0002] Relebactam, developed by Merck & Co., is a novel β-lactamase inhibitor that can be used in combination with imipenem / cilastatin to treat complicated urinary tract infections and complicated intra-abdominal infections caused by susceptible Gram-negative bacteria. It restores the antibacterial activity of carbapenem antibiotics by inhibiting class A and C β-lactamases. It was approved by the US FDA in July 2019. Its chemical structure is as follows: .
[0003] Relebactam possesses broad-spectrum enzyme inhibitory activity, favorable pharmacokinetic characteristics, and a low risk of drug resistance induction. It exhibits significant clinical efficacy and has a promising market prospect, making it worthy of in-depth development and quality control research.
[0004] In the industrial production of relebactam, the synthesis of its key intermediate, 4-[[[(1R,2S,5R)-7-oxo-6-(phenylmethoxy)-1,6-diazabicyclo[3.2.1]octane-2-yl]carbonyl]amino]-1-piperidinecarboxylic acid tert-butyl ester, is the core step of the entire process route. Several synthetic strategies have been reported, typically starting with hydroxypiperacic acid, and proceeding through several steps to obtain the key intermediate, 1-tert-butoxycarbonyl-4-[(2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxamido]piperidine p-toluenesulfonate.
[0005] However, existing synthetic routes still have significant drawbacks. For example, although the scheme reported in the original patent CN114206851A is feasible, the starting material hydroxypiperacic acid A1 is commercially difficult to obtain.
[0006] .
[0007] The synthetic route starting from (2S,5R)-phenoxyaminopiperidine-2-carboxylic acid ethyl oxalate (compound 2 oxalate) shortens the process and avoids commercially unavailable starting materials. However, the reaction generates many side reaction impurities in the amide condensation step. The structure of these impurities is characterized and their synthesis is described below. Summary of the Invention
[0008] To address the above problems, this invention provides a method for preparing a relebactam intermediate impurity (compound 1): .
[0009] Its characteristics include the following steps: (1) (2S,5R)-phenoxyaminopiperidine-2-carboxylate oxalate was freed by passing it through an aqueous solution of base A in solvent A to obtain (2S,5R)-phenoxyaminopiperidine-2-carboxylate oxalate (compound 2). (2) The compound 2 obtained in step (1) was reacted with an aqueous solution of base B in solvent B to obtain sodium (2S,5R)-phenoxyaminopiperidine-2-carboxylate (compound 3); the pH of compound 3 was adjusted by hydrochloric acid to obtain (2S,5R)-phenoxyaminopiperidine-2-carboxylic acid (compound 4). (3) The compound 4 obtained in step (2) is reacted in solvent C under the catalysis of alkali, activator and condensing agent. Two molecules crosslink and two molecules of water are removed to obtain the crude product of impurity (compound 1); the purified product of compound 1 is obtained by purification method A.
[0010] The solvent A used in step (1) is any one of ethyl acetate, dichloromethane, dichloroethane, diethyl ether, and methyl tert-butyl ether, preferably ethyl acetate; the base A is any one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate, preferably sodium bicarbonate; the reaction temperature is 15~40℃, preferably 30~40℃.
[0011] The solvent B used in step (2) is any one of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, acetone, butanone, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone, preferably methanol; the base B used is any one of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, preferably sodium hydroxide; the reaction temperature is 15~40℃, preferably 30~40℃.
[0012] The solvent C used in step (3) is any one of acetonitrile, dichloromethane, chloroform, tetrachloromethane, dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and 1,4-dioxane, preferably acetonitrile; the base used is any one of N,N-diisopropylethylamine, triethylamine, pyridine, 2,6-dimethylpyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and N-methylmorpholine, preferably N,N-diisopropylethylamine; the activator used is 2-hydroxypyridine-N-oxide, 1-hydroxybenzotriazole, or 1-hydroxy The reaction mixture is selected from any one of α-7-azobenzotriazole and 4-dimethylaminopyridine, preferably 2-hydroxypyridine-N-oxide; the condensing agent is selected from any one of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and dicyclohexylcarbodiimide, preferably 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; the reaction temperature is 15~60℃, preferably 35~45℃.
[0013] In step (3), purification method A can be any one or a combination of extraction, silica gel column chromatography purification, and water filtration, with extraction and silica gel column chromatography purification being preferred.
[0014] The discovery of reactive impurities in the key intermediate of levobatane helps to further optimize the production process of this intermediate. The route uses relatively inexpensive and readily available (2S,5R)-phenoxyaminopiperidine-2-carboxylic acid ethyl oxalate as a raw material, effectively reducing production costs. The process avoids the use of highly odorous and irritating chemicals such as mercaptoacetic acid, reducing safety and environmental risks during production. Attached Figure Description
[0015] Figure 1 This is the mass spectrum of compound 1. ESI-MS-Pos m / z theoretical value 465.2496 [M+H] + Measured value: 465.2498 [M+H] + Error 0.4 ppm. Detailed Implementation
[0016] The present invention will be further illustrated by way of embodiments below, but the present invention is not limited to the scope of the embodiments described herein.
[0017] Example 1 A pre-prepared solution of (2S,5R)-phenoxyaminopiperidine-2-carboxylic acid ethyl oxalate (36.8 g), ethyl acetate (200 mL), sodium bicarbonate (42 g), and water (200 mL) was added to a 1000 mL three-necked flask. The mixture was heated to 30-40 °C and reacted for 2 hours. The upper ethyl acetate phase was collected by separation. The aqueous phase was back-extracted three times with ethyl acetate (100 mL). The ethyl acetate was combined, washed with 10% NaCl aqueous solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to remove ethyl acetate, yielding 27.4 g of a light brown oily liquid, with a yield of 99%.
[0018] Example 2 A pre-prepared solution of (2S,5R)-phenoxyaminopiperidine-2-carboxylate (27.4 g), methanol (200 mL), sodium hydroxide (8 g), and water (100 mL) was added to a 500 mL three-necked flask. The mixture was heated to 30-40 °C and reacted for 2 hours. After the reaction was completed, the pH of the reaction solution was measured to be 9 using HPLC, yielding a methanol-water mixture of sodium (2S,5R)-phenoxyaminopiperidine-2-carboxylate, which was directly used for pH adjustment in the next step. At -5 to 5 °C, 5 N hydrochloric acid (40 mL) was slowly added dropwise over 2 hours to neutralize the pH to 5-6, resulting in the precipitation of a large amount of white solid. After stirring for another 2-3 hours at the same temperature, the mixture was filtered through a Buchner funnel. The filter cake was washed 2-3 times with water (20 mL) and dried under vacuum at 40 °C to obtain 24.0 g of white solid, with a yield of 97%.
[0019] Example 3 In a 500 mL three-necked flask, (2S,5R)-phenoxyaminopiperidine-2-carboxylic acid (12.5 g), 2-hydroxypyridine-N-oxide (5.6 g), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (14.8 g), and acetonitrile (100 mL) were added dropwise. N,N-diisopropylethylamine (19.4 g) was added dropwise at -5 to 5 °C. The temperature was raised to 35 to 45 °C and the reaction was carried out for 10 hours. After the reaction of the starting material was confirmed to be complete by HPLC, 4 N sodium hydroxide aqueous solution (50 mL) was added and the mixture was washed twice. The organic phase was collected and separated by column chromatography to obtain 8.2 g of white solid compound 1, with a yield of 71%.
Claims
1. A method for synthesizing a relebactam intermediate impurity (compound 1), characterized in that... Includes the following steps: ； (1) In solvent A, (2S,5R)-phenoxyaminopiperidine-2-carboxylate oxalate was released by passing it through an aqueous solution of base A to obtain (2S,5R)-phenoxyaminopiperidine-2-carboxylate oxalate (compound 2). (2) The compound 2 obtained in step (1) was reacted with an aqueous solution of base B in solvent B to obtain sodium (2S,5R)-phenoxyaminopiperidine-2-carboxylate (compound 3); the pH of compound 3 was adjusted by hydrochloric acid to obtain (2S,5R)-phenoxyaminopiperidine-2-carboxylic acid (compound 4). (3) The compound 4 obtained in step (2) is reacted in solvent C under the catalysis of alkali, activator and condensing agent. Two molecules crosslink and two molecules of water are removed to obtain the crude product of impurity (compound 1); the purified product of compound 1 is obtained by purification method A.
2. The method according to claim 1, characterized in that: The solvent A used in step (1) is any one of ethyl acetate, dichloromethane, dichloroethane, diethyl ether, and methyl tert-butyl ether, preferably ethyl acetate; the base A is any one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate, preferably sodium bicarbonate; the reaction temperature is 15~40℃, preferably 30~40℃.
3. The method according to claim 1, characterized in that: The solvent B used in step (2) is any one of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, acetone, butanone, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone, preferably methanol; the base B is any one of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, preferably sodium hydroxide; the reaction temperature is 15~40℃, preferably 30~40℃.
4. The method according to claim 1, characterized in that: The solvent C used in step (3) is any one of acetonitrile, dichloromethane, trichloromethane, tetrachloromethane, dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and 1,4-dioxane, preferably acetonitrile; the base used is any one of N,N-diisopropylethylamine, triethylamine, pyridine, 2,6-dimethylpyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and N-methylmorpholine, preferably N,N-diisopropylethylamine; the activator used is 2-hydroxypyridine-N-oxide, 1-hydroxybenzotriazole, 1- The reaction mixture comprises any one of hydroxy-7-azobenzotriazole and 4-dimethylaminopyridine, preferably 2-hydroxypyridine-N-oxide; the selected condensing agent is any one of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboronic acid, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and dicyclohexylcarbodiimide, preferably 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; the reaction temperature is 15~60℃, preferably 35~45℃.
5. The method according to claim 1, characterized in that: In step (3), purification method A can be any one or a combination of extraction, silica gel column chromatography purification, and water filtration, with extraction and silica gel column chromatography purification being preferred.