4-oxopyrrolidine derivative as well as preparation method and application thereof
By using an aprotic solvent under alkaline conditions and performing post-treatment, the problem of high proportion of by-products in the preparation of 4-oxopyrrolidine derivatives in the prior art is solved, and the preparation effect of high yield and low by-products is achieved.
Patent Information
- Application Number
- CN202411786637.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-06
- Publication Date
- 2025-04-01
AI Technical Summary
In the prior art, when preparing 4-oxopyrrolidine derivatives, there is a problem of high proportion of by-products, which affects the yield and production efficiency of the product.
The reaction was performed under alkaline conditions using an aprotic solvent such as dimethyl sulfoxide for 20 to 28 hours, and the 4-oxopyrrolidine derivative was obtained by post-treatment such as under reduced pressure distillation, hydrolysis and washing.
It increases the yield of 4-oxopyrrolidine derivatives, reduces the proportion of by-products, reduces production costs, and is suitable for large-scale process production.
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Figure CN119735539A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of pharmaceutical intermediate synthesis, and in particular to a 4-oxopyrrolidine derivative and a preparation method and application thereof. Background Art
[0002] Moxifloxacin, chemical name is 1-cyclopropyl-7-{(S,S)-2,8-diazo-bicyclo[4.3.0]non-8-yl{-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, molecular formula is C 21 H 24 FN 3 O 4 . Moxifloxacin is a fourth-generation quinolone antibacterial drug. It has strong antibacterial activity against common respiratory pathogens, such as Streptococcus pneumoniae, Haemophilus influenzae, Morahanella catarrhalis, and some Staphylococcus aureus, especially against Streptococcus pneumoniae. It has a strong antibacterial effect. It can be used clinically to treat acute sinusitis, acute exacerbation of chronic bronchitis, community-acquired pneumonia, and uncomplicated skin infections and skin and soft tissue infections. (4aS,7aS)-Octahydro-1H-pyrrolo[3,4-b]pyridine, i.e., Moxifloxacin, is a key intermediate in the synthesis of Moxifloxacin. Ethyl 3-(3-chloropropyl)-4-oxopyrrolidine-1-carboxylate is a raw material for the preparation of Moxifloxacin, which can be prepared from 4-oxopyrrolidine derivatives.
[0003]
[0004] In the prior art, the method for preparing 4-oxopyrrolidine derivatives such as 3-(3-chloropropyl)-4-oxopyrrolidine-1,3-dicarboxylic acid diethyl ester (B) has the following problems: 4-oxopyrrolidine-1,3-dicarboxylic acid diethyl ester (A) undergoes substitution reaction with 1,3-halochloropropane under alkaline conditions to prepare compound 3-(3-chloropropyl)-4-oxopyrrolidine-1,3-dicarboxylic acid diethyl ester (B), and the reaction conditions usually use toluene or alkane as solvent or solvent-free reaction. However, when B is generated, a byproduct B' is generated, accounting for about 50%, and compound B' needs to be recovered and converted into A.
[0005] Therefore, there is an urgent need for a preparation method for 4-oxopyrrolidine derivatives with high yield and low by-product ratio.
[0006] Summary of the invention
[0007] The purpose of the present invention is to provide a 4-oxopyrrolidine derivative and a preparation method and application thereof. The preparation method of the 4-oxopyrrolidine derivative has a high product yield and a low proportion of by-products.
[0008] The purpose of the present invention can be achieved by the following technical solutions:
[0009] In one aspect, the present invention provides a 4-oxopyrrolidine derivative having the structural formula:
[0010]
[0011] in:
[0012] R 1 and R 2 Each independently selected from a linear or branched C 1 ~C 18 The alkyl group;
[0013] Y is selected from a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br), a methanesulfonyl group (Ms), a p-toluenesulfonyl group (Ts), a nitrobenzenemethylsulfonyl group (Ns), and a trifluoromethanesulfonyl group (Tf).
[0014] Preferably, the R 1 and R 2 Each independently selected from a linear or branched C 1 ~C 8 of alkyl.
[0015] More preferably, the R 1 and R 2 Each independently selected from a linear or branched C 1 ~C 4 of alkyl.
[0016] More preferably, the R 1 and R 2 Each independently selected from a linear C 1 or C 2 of alkyl.
[0017] Preferably, the compound represented by formula (I) is selected from any one of the compounds represented by the following structural formulas:
[0018]
[0019]
[0020]
[0021] Further preferably, the compound represented by formula (I) is selected from any one of the compounds represented by the following structural formulas:
[0022]
[0023] More preferably, the compound represented by formula (I) has the structural formula:
[0024]
[0025] In a second aspect, the present invention also provides a method for preparing a 4-oxopyrrolidine derivative, wherein the compound represented by formula (II) and the compound represented by formula (III) are reacted in an aprotic solvent under alkaline conditions for 20 to 28 hours, and after post-treatment, a compound represented by formula (I) is obtained, and the reaction route is as follows:
[0026]
[0027] in:
[0028] X is selected from a chlorine atom (Cl), a bromine atom (Br), and an iodine atom (I).
[0029] Preferably, the compound represented by formula (II) is selected from any one of 4-oxopyrrolidine-1,3-dicarboxylic acid dimethyl ester, 3-ethyl-1-methyl-4-oxopyrrolidine-1,3-dicarboxylate, 3-methyl-4-oxopyrrolidine-1,3-dicarboxylic acid ethyl ester, and 4-oxopyrrolidine-1,3-dicarboxylic acid diethyl ester.
[0030] Preferably, the compound represented by formula (III) is selected from any one of the compounds represented by the following structural formulas:
[0031]
[0032]
[0033] Further preferably, the compound represented by formula (III) is selected from any one of the compounds represented by the following structural formulas:
[0034]
[0035] Preferably, the base is selected from an inorganic base or an organic base.
[0036] Further preferably, the organic base comprises triethylamine or pyrrole or tetrahydropyrrole.
[0037] Further preferably, the inorganic base comprises potassium carbonate or sodium carbonate.
[0038] Further preferably, the base is selected from triethylamine or pyrrole or tetrahydropyrrole.
[0039] Preferably, the aprotic solvent is selected from a combination of one or more of dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone, cyclopentane, and methyl ethyl ketone.
[0040] Further preferably, the reaction solvent is selected from dimethyl sulfoxide, dimethylformamide or sulfolane.
[0041] Preferably, the reaction temperature is 10-30°C, more preferably 25°C.
[0042] Preferably, the molar ratio of the compound represented by formula (II) to the compound represented by formula (III) is 1:1.2-2, and more preferably 1:1.2.
[0043] Preferably, the molar ratio of the compound represented by formula (II) to the base is 1:1.2 to 1.8, more preferably 1:1.2.
[0044] Preferably, the post-treatment includes reduced pressure distillation, hydrolysis, washing, and reduced pressure concentration in sequence.
[0045] Further preferably, in the vacuum distillation, the working pressure is -0.090 to 0.098 MPa, and the temperature is the boiling point of the solvent corresponding to the pressure selected for the vacuum distillation.
[0046] Further preferably, in the hydrolysis, concentrated hydrochloric acid is used for hydrolysis, and the concentration of the concentrated hydrochloric acid is 36% to 38%, and the concentration is mass fraction.
[0047] More preferably, the weight ratio of the concentrated hydrochloric acid to the compound represented by formula (II) is 1:5-8, and more preferably 1:5.
[0048] More preferably, in the washing, washing with washing liquid is performed 3 to 5 times.
[0049] Further preferably, the washing liquid is an aqueous solution of potassium carbonate.
[0050] Further preferably, in the potassium carbonate aqueous solution, the weight ratio of potassium carbonate to water is 1-1.2:10, and further preferably 1:10.
[0051] More preferably, during the reduced pressure concentration, the temperature is 35-55°C.
[0052] In a third aspect, the present invention also provides a use of the 4-oxopyrrolidine derivative, wherein the 4-oxopyrrolidine derivative is used to prepare a moxifloxacin intermediate.
[0053] Preferably, one of the compounds represented by formula (I) has a structure of It can be used to prepare moxifloxacin intermediates.
[0054] Preferably, the moxifloxacin intermediate is a moxifloxacin mini-ring.
[0055] Compared with the prior art, the present invention has the following beneficial effects:
[0056] (1) The present invention provides a 4-oxopyrrolidine derivative and a preparation method thereof. The preparation method has a high yield and a low proportion of by-products.
[0057] (2) In the preparation process of the present invention, aprotic solvents such as dimethyl sulfoxide are used to reduce the generation of by-products, which only account for about 15%.
[0058] (3) In the preparation process of the present invention, the amount of 1,3-disubstituted propane (the compound represented by formula (III)) is reduced, which greatly reduces the production cost.
[0059] (4) The preparation process of the present invention has high yield, high recovery rate and low cost, and is more suitable for large-scale process production. BRIEF DESCRIPTION OF THE DRAWINGS
[0060] Figure 1 This is the nuclear magnetic resonance spectrum of the 4-oxopyrrolidine derivative prepared in Example 1. DETAILED DESCRIPTION
[0061] The present invention is described in detail below in conjunction with the accompanying drawings and specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the protection scope of the present invention is not limited to the following embodiments.
[0062] Unless otherwise specified, the reagents, methods, instruments and equipment used in the present invention are conventional reagents, methods, instruments and equipment in the art. Unless otherwise specified, the reagents and materials used in the following examples are commercially available.
[0063] Embodiment 1:
[0064]
[0065] (a): Add 4-oxopyrrolidine-1,3-dicarboxylic acid diethyl ester (5g, 21.81mmol), 1-iodo-3-chloropropane (6.69g, 32.72mmol) and dimethyl sulfoxide (10mL) to a 50mL flask, stir to dissolve, and control the temperature to below 20°C. Add triethylamine (2.65g, 26.17mmol) dropwise, and control the temperature at 25°C to react for 20h after the addition is complete. HPLC (high performance liquid chromatography) monitors the reaction to be complete. After the reaction is completed, the reaction solution is subjected to reduced pressure distillation, and the fractions are collected until no more fractions are distilled out. Add concentrated hydrochloric acid (1g) to the material after reduced pressure distillation, and react at 20-30°C for 1h. TLC (thin layer chromatography) monitors the end point, and distilled water (2.70g) and toluene (6.74g) are added to wash. The mixture was washed for 0.5 h and allowed to stand for stratification. Potassium carbonate (1.35 g) and distilled water (13.5 g) were weighed in a 25 mL beaker, stirred to dissolve, and the upper organic phase was washed with potassium carbonate aqueous solution three times, kept at 30-35 ° C for 30 min, and separated. TLC confirmed that 4-oxopyrrolidine-1,3-dicarboxylic acid diethyl ester was completely salted; the upper organic phase was concentrated under reduced pressure to obtain 6.49 g of the target compound (yield 97.36%), and its nuclear magnetic resonance spectrum is shown as follows: Figure 1 shown.
[0066] (b): Dissolve the compound (5g) prepared in step (a) in sulfuric acid solution (10g distilled water + 18.38g 98% concentrated sulfuric acid) and 95% ethanol (0.70g), stir and control the temperature to 50-60°C, and react for 24h. The reaction solution is cooled to 20-30°C, toluene (4.79g) and distilled water (4.47g) are added, the layers are separated, the organic phase is extracted 3 times with toluene, and the organic phases are combined. Wash twice with distilled water (1.28g*2). The organic phase is concentrated under reduced pressure at 55-60°C and -0.095MPa to obtain an oily substance, which is 3-(3-chloropropyl)-4-oxopyrrolidine-1-carboxylic acid ethyl ester, i.e., Moxi ring intermediate, 3.25g (yield 85.03%)
[0067] Embodiment 2:
[0068]
[0069] Add 3-ethyl-1-methyl-4-oxopyrrolidine-1,3-dicarboxylate (5 g, 23.23 mmol), 1-fluoro-3-chloropropane (3.14 g, 32.53 mmol) and dimethylformamide (10 mL) into a 50 mL flask, stir to dissolve, and control the temperature to below 20°C. Triethylamine (3.06 g, 30.20 mmol) was added dropwise, and the temperature was controlled at 25°C for 24 h after the addition was completed. The reaction was monitored by HPLC to be complete. After the reaction was completed, the reaction solution was subjected to reduced pressure distillation, and the fractions were collected until no more fractions were distilled out. Concentrated hydrochloric acid (1.5 g) was added to the material after reduced pressure distillation, and the reaction was carried out at 20-30°C for 1 h. The end point was monitored by TLC. Distilled water (2.70 g) and toluene (6.74 g) were added for washing for 0.5 h, and the mixture was allowed to stand for stratification. Potassium carbonate (1.35 g) and distilled water (13.5 g) were weighed in a 25 mL beaker, stirred to dissolve, and the upper organic phase was washed with potassium carbonate aqueous solution 4 times, kept at 30-35°C for 30 min, and separated. TLC confirmed that 3-ethyl-1-methyl-4-oxopyrrolidine-1,3-dicarboxylate was completely salified. The upper organic phase was concentrated under reduced pressure to obtain 6.45 g of the target compound (yield 95.13%).
[0070] Embodiment 3:
[0071]
[0072] Add dimethyl 4-oxopyrrolidine-1,3-dicarboxylate (10 g, 49.71 mmol), 1-bromo-3-chloropropane (9.78 g, 62.13 mmol) and dimethyl sulfoxide (20 mL) into a 100 mL flask, stir to dissolve, and control the temperature to below 20°C. Tetrahydropyrrole (4.67 g, 65.16 mmol) was added dropwise, and the temperature was controlled at 25°C for 26 hours after the addition was completed. The reaction was monitored by HPLC. After the reaction was completed, the reaction solution was distilled under reduced pressure, and the fractions were collected until no more fractions were evaporated. Concentrated hydrochloric acid (3.5 g) was added to the material after reduced pressure distillation, and the reaction was carried out at 20-30°C for 1 hour. The end point was monitored by TLC. Distilled water (5.40 g) and toluene (13.48 g) were added for washing for 0.5 hours, and the mixture was allowed to stand for stratification. Potassium carbonate (2.70 g) and distilled water (27.0 g) were weighed in a 50 mL beaker, stirred to dissolve, and the upper organic phase was washed with potassium carbonate aqueous solution for 3 times, and kept at 30-35°C for 30 minutes. The mixture was separated and TLC confirmed that diethylmethyl 4-oxopyrrolidine-1,3-dicarboxylate was completely salified. The upper organic phase was concentrated under reduced pressure to obtain 12.35 g of the target compound (yield 89.56%).
[0073] Embodiment 4:
[0074]
[0075] Add ethyl 3-methyl-4-oxopyrrolidine-1,3-dicarboxylate (10 g, 46.47 mmol), 1-iodo-3-fluoropropane (10.39 g, 55.30 mmol) and dimethylformamide (20 mL) into a 100 mL flask, stir to dissolve, and control the temperature to below 20°C. Pyrrole (3.83 g, 57.15 mmol) was added dropwise, and the temperature was controlled at 25°C for 22 hours after the addition was completed. The reaction was monitored by HPLC. After the reaction was completed, the reaction solution was subjected to reduced pressure distillation, and the fractions were collected until no more fractions were distilled out. Concentrated hydrochloric acid (3.5 g) was added to the material after reduced pressure distillation, and the reaction was carried out at 20-30°C for 1 hour. The end point was monitored by TLC. Distilled water (5.40 g) and toluene (13.48 g) were added for washing for 0.5 hours, and the mixture was allowed to stand for stratification. Potassium carbonate (2.70 g) and distilled water (27.0 g) were weighed in a 50 mL beaker, stirred to dissolve, and the upper organic phase was washed with potassium carbonate aqueous solution for 5 times, and kept at 30-35°C for 30 minutes. The upper organic phase was separated, and TLC confirmed that 3-methyl-4-oxopyrrolidine-1,3-dicarboxylic acid 1-ethyl ester was completely salted. The upper organic phase was concentrated under reduced pressure to obtain 12.91 g of the target compound. (yield 96.77%).
[0076] Embodiment 5:
[0077]
[0078] Add diethyl 4-oxopyrrolidine-1,3-dicarboxylate (5 g, 21.81 mmol), 1-bromo-3-iodopropane (7.27 g, 29.23 mmol) and dimethyl sulfoxide (10 mL) into a 50 mL flask, stir to dissolve, and control the temperature to below 20°C. Triethylamine (2.65 g, 26.17 mmol) was added dropwise, and the temperature was controlled at 25°C for 27 hours after the addition was completed. The reaction was monitored by HPLC to be complete. After the reaction was completed, the reaction solution was subjected to reduced pressure distillation, and the fractions were collected until no more fractions were evaporated. Concentrated hydrochloric acid (1.5 g) was added to the material after reduced pressure distillation, and the reaction was carried out at 20-30°C for 1 hour. The end point was monitored by TLC, and distilled water (2.70 g) and toluene (6.74 g) were added for washing for 0.5 hour, and the mixture was allowed to stand for stratification. Potassium carbonate (1.35 g) and distilled water (13.5 g) were weighed in a 25 mL beaker, stirred to dissolve, and the upper organic phase was washed with potassium carbonate aqueous solution for 3 times, and kept at 30-35°C for 30 minutes. The mixture was separated and TLC confirmed that the 4-oxopyrrolidine-1,3-dicarboxylic acid diethyl ester was completely salified. The upper organic phase was concentrated under reduced pressure to obtain 7.56 g of the target compound (yield 87.30%).
[0079] Embodiment 6:
[0080]
[0081] Add ethyl 3-methyl-4-oxopyrrolidine-1,3-dicarboxylate (10 g, 46.47 mmol), 1-bromo-3-fluoropropane (10.48 g, 74.35 mmol) and 1,3-dimethyl-2-imidazolidinone (20 mL) into a 100 mL flask, stir to dissolve, and control the temperature to below 20°C. Pyrrole (4.68 g, 69.70 mmol) was added dropwise, and the temperature was controlled at 25°C for 21 hours after the addition was completed. The reaction was monitored by HPLC. After the reaction was completed, the reaction solution was subjected to reduced pressure distillation, and the fractions were collected until no more fractions were distilled out. Concentrated hydrochloric acid (3.5 g) was added to the material after reduced pressure distillation, and the reaction was carried out at 20-30°C for 1 hour. The end point was monitored by TLC. Distilled water (5.40 g) and toluene (13.48 g) were added for washing for 0.5 hours, and the mixture was allowed to stand for stratification. Potassium carbonate (2.70 g) and distilled water (27.0 g) were weighed in a 50 mL beaker, stirred to dissolve, and the upper organic phase was washed with potassium carbonate aqueous solution for 4 times, and kept at 30-35°C for 30 minutes. The upper organic phase was separated, and TLC confirmed that 3-methyl-4-oxopyrrolidine-1,3-dicarboxylic acid ethyl ester was completely salted. The upper organic phase was concentrated under reduced pressure to obtain 11.91 g of the target compound. (yield 93.12%).
[0082] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.
Claims
1. A 4-oxopyrrolidine derivative, characterized in that: Its structural formula is: in: R1 and R2 are each independently selected from a linear or branched C1-C 18 The alkyl group; Y is selected from a fluorine atom, a chlorine atom, a bromine atom, a methanesulfonyl group, a p-toluenesulfonyl group, a nitrobenzenemethylsulfonyl group, and a trifluoromethanesulfonyl group.
2. A 4-oxopyrrolidine derivative according to claim 1, characterized in that: The compound represented by formula (I) is selected from any one of the compounds represented by the following structural formulas:
3. A 4-oxopyrrolidine derivative according to claim 2, characterized in that: The compound represented by formula (I) is selected from any one of the compounds represented by the following structural formulas:
4. A 4-oxopyrrolidine derivative according to claim 3, characterized in that: The compound represented by the formula (I) has the structural formula:
5. A method for preparing a 4-oxopyrrolidine derivative according to any one of claims 1 to 4, characterized in that: The compound represented by formula (II) and the compound represented by formula (III) are reacted in an aprotic solvent under alkaline conditions for 20 to 28 hours, and after post-treatment, a compound represented by formula (I) is obtained. The reaction route is as follows: in: X is selected from a chlorine atom, a bromine atom and an iodine atom.
6. The method for preparing a 4-oxopyrrolidine derivative according to claim 5, characterized in that: The compound represented by formula (II) is selected from any one of 4-oxopyrrolidine-1,3-dicarboxylic acid dimethyl ester, 3-ethyl-1-methyl-4-oxopyrrolidine-1,3-dicarboxylate, 3-methyl-4-oxopyrrolidine-1,3-dicarboxylic acid ethyl ester, and 4-oxopyrrolidine-1,3-dicarboxylic acid diethyl ester; The compound represented by formula (III) is selected from any one of the compounds represented by the following structural formulas:
7. The method for preparing a 4-oxopyrrolidine derivative according to claim 5, characterized in that: The base is selected from an inorganic base or an organic base; The organic base includes triethylamine or pyrrole or tetrahydropyrrole; The inorganic base includes potassium carbonate or sodium carbonate; The aprotic solvent is selected from a combination of one or more of dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone, cyclopentane, and methyl ethyl ketone; The reaction temperature of the reaction is 10 to 30°C; The molar ratio of the compound represented by formula (II) to the compound represented by formula (III) is 1:1.2-2; The molar ratio of the compound represented by the formula (II) to the base is 1:1.2-1.
8.
8. The method for preparing a 4-oxopyrrolidine derivative according to claim 5, characterized in that: The post-treatment includes reduced pressure distillation, hydrolysis, washing and reduced pressure concentration in sequence.
9. The method for preparing a 4-oxopyrrolidine derivative according to claim 8, characterized in that: In the vacuum distillation, the working pressure is -0.090 to 0.098 MPa, and the temperature is the boiling point of the solvent corresponding to the pressure selected for the vacuum distillation; In the hydrolysis, concentrated hydrochloric acid is used for hydrolysis, and the concentration of the concentrated hydrochloric acid is 36% to 38%; The weight ratio of the concentrated hydrochloric acid to the compound represented by the formula (II) is 1:5-8; In the washing, washing with a washing liquid is performed 3 to 5 times; The washing liquid is an aqueous solution of potassium carbonate; In the potassium carbonate aqueous solution, the weight ratio of potassium carbonate to water is 1 to 1.2:10; During the reduced pressure concentration, the temperature is 35-55°C.
10. A use of a 4-oxopyrrolidine derivative as claimed in any one of claims 1 to 4, characterized in that: The 4-oxopyrrolidine derivative is used for preparing a moxifloxacin intermediate.