A preparation method of ketorolac tromethamine impurity E

Abstract

The present invention discloses a method for preparing ketorolac tromethamine impurity E. The method for preparing compound E comprises the following steps: subjecting compound I to an amino acid condensation reaction in the absence of a solvent to produce compound E; the amino acid condensation reaction is carried out at a temperature of 120°C to 180°C. The method utilizes a solvent-free reaction, is simple to operate, and avoids the production of ester byproducts. High-purity compound E is obtained in good yield and meets the requirements for use as an impurity reference substance (purity greater than 95%).

Description

Technical Field

[0001] The present invention relates to a method for preparing ketorolac tromethamine impurity E. Background Art

[0002] Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug that inhibits prostaglandin biosynthesis and has analgesic effects without sedative or anxiolytic effects. Therefore, it is widely used for postoperative analgesia.

[0003] In order to control product quality, the Chinese Pharmacopoeia (ChP) 2020 edition, the United States Pharmacopoeia (USP) 2023 edition, and the European Pharmacopoeia (EP) 11.0 edition all include its quality standards. In the process of researching product quality, it was found that the pharmacopoeias of various countries included several related substances. For example, the European Pharmacopoeia 11.0 version included its related impurity E (named: (1RS)-5-benzoyl-N-[2-hydroxy-1,1-bis(hydroxymethyl)-ethyl]-2,3-dihydro-1H-pyrrolidine-1-carboxamide). Therefore, it is necessary to study and control the quality of impurity E in ketorolac tromethamine. However, relevant impurity reference substances are difficult to obtain, which seriously affects the research and detection of impurities in ketorolac tromethamine. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a method for preparing a high-purity ketorolac impurity E. The preparation method provided by the present invention adopts a solvent-free reaction, is simple to operate, avoids the production of ester by-products, and has a high product purity, meeting the requirements for use as an impurity reference substance.

[0005] The present invention solves the above technical problems through the following technical solutions.

[0006] The present invention provides a method for preparing compound E, comprising the following steps: subjecting compound I to an amino acid condensation reaction in the absence of a solvent to generate compound E;

[0007]

[0008] Wherein, the temperature of the amino acid condensation reaction is 120°C to 180°C.

[0009] The temperature of the amino acid condensation reaction is preferably 140°C to 180°C, more preferably 160°C to 180°C.

[0010] The raw materials for the amino acid condensation reaction may not include a condensing agent.

[0011] The raw material for the amino acid condensation reaction can be compound I.

[0012] In the preparation method, the amino acid condensation reaction time can be 5 to 8 hours, preferably 5 hours.

[0013] In the preparation method, the amino acid condensation reaction can be heated in an oven.

[0014] In the preparation method, the temperature of the amino acid condensation reaction is 160° C. to 180° C.; the reaction time of the amino acid condensation reaction is 5 to 8 hours; preferably, the temperature of the amino acid condensation reaction is 160° C.; the reaction time of the amino acid condensation reaction is 5 hours.

[0015] In the preparation method, the amino acid condensation reaction includes post-reaction treatment, which includes the following steps: after the reaction is completed, the reaction is cooled to room temperature and directly slurried.

[0016] In the preparation method, in the post-treatment, the slurrying solvent may be a mixed solvent of dichloromethane and methanol.

[0017] In the post-treatment, the volume ratio of the dichloromethane to methanol may be 15:1.

[0018] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0019] The term "condensing agent" refers to a condensing agent used in the art to promote the reaction in the amino acid condensation reaction, such as DCC (1,3-dicyclohexylcarbodiimide), EDCI (1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride) or HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate).

[0020] The reagents and raw materials used in the present invention are commercially available.

[0021] The positive and progressive effects of the present invention are one or more of the following:

[0022] (1) The present invention creatively adopts a solvent-free reaction to prepare impurity E. This preparation method simplifies the post-processing steps and is economical and environmentally friendly.

[0023] (2) The preparation method of the present invention avoids the production of ester by-products, and impurity E can be obtained with high purity through simple post-treatment;

[0024] (3) The yield of impurity E prepared under the preparation conditions of the present invention can reach more than 75% and the purity can reach more than 97%, both of which meet the requirements for use as an impurity reference substance. DETAILED DESCRIPTION

[0025] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0026] Example 1:

[0027]

[0028] 8.0 g of ketorolac tromethamine was added to a watch glass, placed in an oven, and heated at 160°C for 5 hours. HPLC monitoring indicated that the reaction was complete. After cooling to room temperature, the glassy solid in the watch glass was purified by slurrying with approximately 50 mL of dichloromethane / methanol (volume ratio 15 / 1) to obtain 6.9 g of off-white solid Compound E, with a yield of 90.6% and a purity of 98.2%; no ester byproducts were present. generate.

[0029] MS: 359.16 (M+H + );

[0030] 1 HNMR (400MHz, DMSO-d6): δ2.65-2.78(m,2H),3.55-3.63(q,6H),4.08-4.12(m,1H),4.25-4.30(m,1H),4.37-4.43(m,1H), 4.70(bs,3H),6.04-6.05(d,1H),6.75-6.76(d,1H),7.49-7.52(m,2H),7.53(s,1H),7.56-7.61(m,1H),7.73-7.75(m,2H).

[0031] 13 CNMR (100MHz, DMSO-d6): δ30.95,43.34,47.81,60.46,62.44,102.59,124.56,126.01,128.39,128.46,131.45,139.02,145.72,171.41,183.49.

[0032] HPLC: retention time 22.142 min; liquid phase method: octadecylsilane bonded silica gel as filler (YMC-Pack C18, 4.6 mm × 250 mm, 5 μm); 0.05 mol / L ammonium dihydrogen phosphate aqueous solution (pH adjusted to 3.3 with phosphoric acid) as mobile phase A, tetrahydrofuran as mobile phase B, gradient elution; flow rate 1.0 mL / min; detection wavelength 313 nm; column temperature 20°C; injection volume 20 μL.

[0033] Example 2:

[0034] 8.0 g of ketorolac tromethamine was added to a watch glass, placed in an oven, and heated at 120° C. for 5 hours. HPLC monitoring showed that only 2% of compound E was generated, and no ester by-product was generated; MS: 359.16 (M+H+ ).

[0035] Example 3:

[0036] 8.0 g of ketorolac tromethamine was added to a watch glass, and the dish was placed in an oven and heated at 140° C. for 5 hours. HPLC monitoring showed that only 13% of compound E was generated, and no ester by-product was generated; MS: 359.16 (M+H + ).

[0037] Example 4:

[0038] 8.0 g of ketorolac tromethamine was added to a watch glass, placed in an oven, and heated at 160°C for 8 hours. HPLC monitoring indicated the reaction was complete. After cooling to room temperature, the glassy solid in the watch glass was slurried and purified with approximately 50 mL of dichloromethane / methanol (15 / 1 by volume) to afford 6.5 g of Compound E as an off-white solid in an 85.3% yield and 98.1% purity. No ester byproducts were produced.

[0039] MS, 1 HNMR, 13 The CNMR results were the same as those in Example 1.

[0040] Example 5:

[0041] 8.0 g of ketorolac tromethamine was added to a watch glass, placed in an oven, and heated at 180°C for 5 hours. HPLC monitoring indicated the reaction was complete. After cooling to room temperature, the glassy solid in the watch glass was slurried and purified with approximately 50 mL of dichloromethane / methanol (15 / 1 by volume) to afford 6.3 g of Compound E as an off-white solid in an 82.7% yield and 97.8% purity. No ester byproducts were produced.

[0042] MS, 1 HNMR, 13 The CNMR results were the same as those in Example 1.

[0043] Example 6:

[0044] 8.0 g of ketorolac tromethamine was added to a watch glass, placed in an oven, and heated at 180°C for 8 hours. HPLC monitoring indicated the reaction was complete. After cooling to room temperature, the glassy solid in the watch glass was slurried and purified with approximately 50 mL of dichloromethane / methanol (15 / 1 by volume) to afford 5.8 g of Compound E as an off-white solid in a 76.1% yield and 97.5% purity. No ester byproducts were produced.

[0045] MS, 1 HNMR, 13 The CNMR results were the same as those in Example 1.

[0046] Comparative Example 1:

[0047] The following solvents were added to ketorolac tromethamine, and the reactions were carried out at the following temperatures and times. The reaction results are shown in the following table:

[0048]

[0049] Note: ND means no corresponding substance was generated.

Claims

1. A method for preparing compound E, characterized in that: The method comprises the following steps: subjecting compound I to an amino acid condensation reaction in the absence of a solvent to generate compound E; Wherein, the temperature of the amino acid condensation reaction is 120°C to 180°C.

2. The preparation method according to claim 1, wherein The raw materials for the amino acid condensation reaction do not include a condensing agent.

3. The preparation method according to claim 1, wherein The raw material of the amino acid condensation reaction is compound I.

4. The preparation method according to any one of claims 1 to 3, characterized in that The temperature of the amino acid condensation reaction is 140°C to 180°C; And / or, the amino acid condensation reaction time is 5 to 8 hours.

5. The preparation method according to claim 4, wherein The temperature of the amino acid condensation reaction is 160°C to 180°C; And / or, the amino acid condensation reaction time is 5 hours.

6. The preparation method according to claim 1, wherein The amino acid condensation reaction is carried out by oven heating.

7. The preparation method according to claim 1, wherein The temperature of the amino acid condensation reaction is 160° C. to 180° C.; and the reaction time of the amino acid condensation reaction is 5 to 8 hours.

8. The preparation method according to claim 7, wherein The temperature of the amino acid condensation reaction is 160° C.; the reaction time of the amino acid condensation reaction is 5 hours.

9. The preparation method according to claim 1, wherein The amino acid condensation reaction includes post-processing of the reaction, which includes the following steps: after the reaction is completed, the reaction is cooled to room temperature and directly slurried.

10. The preparation method according to claim 9, characterized in that In the post-treatment, the slurrying solvent is a mixed solvent of dichloromethane and methanol.

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