A preparation method of ketorolac EP impurity D

Abstract

The invention discloses a preparation method of ketorolac EP impurity D, comprising the following steps: using free ketorolac as a raw material, adding methanol to dissolve, then dropping thionyl chloride, purifying to obtain 5-benzoyl-2,3-dihydro-1H-pyrrolazine-1-carboxylic acid methyl ester; dissolving 5-benzoyl-2,3-dihydro-1H-pyrrolazine-1-carboxylic acid methyl ester with a solvent twice, adding sodium methoxide and stirring, then adding an oxidant to react, to obtain 5-benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolazine-1-carboxylic acid methyl ester; dissolving 5-benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolazine-1-carboxylic acid methyl ester with a solvent three times, then adding a sodium hydroxide aqueous solution, to obtain 5-benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolazine-1-carboxylic acid. The preparation method of ketorolac EP impurity D of the invention is simple to operate, and the raw materials are convenient and easy to obtain, and meets the requirements of being used as an impurity reference substance.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing ketorolac EP impurity D. Background Art

[0002] Ketorolac is a new generation of powerful analgesic non-steroidal anti-inflammatory drugs. With the continuous development of drug delivery systems and formulation technologies, in addition to conventional oral and injection administration, new routes and dosage forms of ketorolac administration through the skin, eyes, nasal cavity and oral mucosa have been developed, making ketorolac have two main characteristics: long-term analgesia and local administration and local effect. The new ketorolac preparation has good analgesic effect, can improve patient compliance and drug safety, and has a good market prospect.

[0003] Ketorolac tromethamine is a salt form of ketorolac. In order to control its product quality, its quality standards are included in the United States Pharmacopoeia (USP) 43rd edition and the European Pharmacopoeia (EP) 10.0 edition.

[0004] During the investigation of product quality research, it was found that several related substances were included in the pharmacopoeias of various countries. For example, the European Pharmacopoeia (abbreviated as EP) version 10.0 included its related impurity D (named: 5-benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid). Therefore, it is necessary to study and control the quality of impurity D in ketorolac. However, it is difficult to obtain related impurity reference substances, which seriously affects the research and detection of impurities related to ketorolac tromethamine. Summary of the invention

[0005] In view of the problems existing in the prior art, the present invention provides a method for preparing ketorolac EP impurity D.

[0006] In order to achieve the above object, the present invention provides a method for preparing ketorolac EP impurity D, comprising the following steps:

[0007] Step S1: using free ketorolac as a raw material, adding methanol to dissolve, then adding thionyl chloride dropwise, passing nitrogen gas for protection, reacting for a period of time, and then vacuum concentrating to obtain 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid methyl ester;

[0008] Step S2: dissolving 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid methyl ester in solvent II, adding sodium methoxide and stirring, and then adding an oxidant to react, extracting and concentrating the reaction solution, and then passing a mixture of PE and EA through a column to obtain 5-benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid methyl ester, wherein the oxidant is iodophenyldiacetic acid;

[0009] Step S3: dissolving 5-benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid methyl ester with a solvent, adding a sodium hydroxide solution to react for a period of time, and then concentrating and extracting the reaction solution to obtain 5-benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid;

[0010] The reaction equations in the above steps are as follows:

[0011] .

[0012] Preferably, the solvent 2 in step S2 and the solvent 3 in step S3 are both selected from one or more of methanol, tetrahydrofuran, acetonitrile, N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0013] Preferably, the oxidant in step S2 is selected from one of 2-iodoacylbenzoic acid, manganese dioxide, iodophenyldiacetic acid, lead hydroxide, and tetramethylpiperidinoxide.

[0014] Preferably, the amount ratio of ketorolac to thionyl chloride in step S1 is 1:1.1.

[0015] Preferably, the amount ratio of benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid methyl ester to sodium methoxide in step 2 is 1:4.

[0016] Preferably, the amount ratio of 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid methyl ester to the oxidant in step 2 is 1:1.1-4.

[0017] Preferably, the specific steps of extraction and concentration in step S2 are: pouring the reaction solution into a mixed solution of ammonium chloride:ethyl acetate=1:2, extracting the organic phase, washing twice with sodium bicarbonate solution, washing once with sodium chloride solution, and concentrating the organic phase.

[0018] Preferably, the amount ratio of EA to PE in step S2 is 1:5.

[0019] Preferably, the specific steps of concentrated extraction in step S3 are: adding water and ethyl acetate, extracting in layers, adding ethyl acetate to the aqueous phase, adding dilute hydrochloric acid to adjust the pH to weak acidity under stirring at room temperature, and standing and extracting in layers twice.

[0020] The technical solution of the present invention has the following beneficial effects:

[0021] (1) The method for preparing ketorolac EP impurity D of the present invention is simple to operate and the raw materials are readily available. The purity of the prepared 5-benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolazine-1-carboxylic acid reaches more than 96%, which meets the requirements of being used as an impurity reference substance and plays a positive role in the research and inspection of impurities related to ketorolac tromethamine.

[0022] (2) The present invention found that the compounds derived from the ketorolac raw material are sensitive to light sources, which affects the yield. The yield is higher when protected from light than when not protected from light. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 It is the reaction equation diagram of the present invention;

[0024] Figure 2 This is a schematic diagram of the nuclear magnetic resonance of the ketorolac EP impurity D of the present invention;

[0025] Figure 3 is the mass spectrum of ketorolac EP impurity D of the present invention;

[0026] Figure 4 It is the HPLC chromatogram of the impurity D of ketorolac EP of the present invention. DETAILED DESCRIPTION

[0027] The present invention is further described below in conjunction with the accompanying drawings and specific embodiments.

[0028] Reference Figure 1-Figure 4 The present invention provides a method for preparing ketorolac EP impurity D, which is simple to operate and has readily available raw materials, meets the requirements of being an impurity reference substance, and plays a positive role in the research and inspection of impurities related to ketorolac tromethamine.

[0029] Embodiment 1:

[0030] Step 1:

[0031] Without light protection, add 40 ml of methanol to 4 g of free ketorolac to dissolve, stir in an ice-water bath, add 2.1 g of thionyl chloride (equivalent ratio is 1.1), after the dripping, protect with nitrogen, return to room temperature for reaction for 30 minutes, directly vacuum concentrate the reaction solution to remove methanol, add 40 ml of water and dichloromethane, add sodium bicarbonate solution under stirring at room temperature, adjust the pH to weak alkalinity, extract the organic phase twice, concentrate the organic phase, and obtain (5-benzoyl-2,3-dihydro-1H-pyrrolazine-1-carboxylic acid methyl ester) as a brown solid 3.82 g (yield 90.53%). In the above step S1, thionyl chloride is selected, and sulfuric acid and methanol solutions have the same effect, but the stability of the product will affect the purification.

[0032] Step 2:

[0033] Under the condition of not shielding from light, add 40 ml of methanol to 4 g of 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid methyl ester to dissolve it, then add 6.4 g of sodium methoxide (equivalent ratio is 4), add 5.27 g, 5.75 g, 6.22 g, 6.70 g, 7.18 g, 9.58 g of iodophenyl diacetic acid (equivalent ratios are 1.1, 1.2, 1.3, 1.4, 1.5, 2, respectively) under stirring at room temperature, react for 5 minutes after addition, and the result shows that iodine is preferred. The yield is the largest when the equivalent of phenylenediacetic acid is 1.3. The reaction solution is poured into a 160 ml mixed solution of ammonium chloride: ethyl acetate = 1:2, the organic phase is extracted, washed once with sodium thiosulfate solution, washed twice with sodium bicarbonate solution, and washed once with sodium chloride solution. The organic phase is concentrated and passed through a column with PE:EA = 5:1. The product is collected to obtain (5-benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid methyl ester) as a black solid 0.53 g (yield 11.70%)

[0034] Step 3:

[0035] Without shielding from light - 40 ml of methanol was added to 4 g of 5-benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid methyl ester to dissolve it, 20 ml of 3N sodium hydroxide solution was added under stirring at room temperature, the reaction was reacted at room temperature for 30 min, the reaction solution was concentrated to remove methanol, 20 ml of water and 40 ml of ethyl acetate were added, the layers were extracted, 40 ml of ethyl acetate was added to the aqueous phase, dilute hydrochloric acid was added under stirring at room temperature to adjust the pH to weak acidity, the layers were allowed to stand and extracted twice, and the organic layer was concentrated to obtain 1.0 g (yield 26.22%) of (5-benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid) as a yellow solid.

[0036] Embodiment 2:

[0037] Step 1:

[0038] Under light-proof conditions, add 40 ml of methanol to 4 g of free ketorolac to dissolve it, stir in an ice-water bath, and add 2.1 g of thionyl chloride dropwise (equivalent ratio is 1.1). After the dropwise addition, protect with nitrogen and return to room temperature for reaction for 30 min. The reaction solution is directly concentrated in vacuo to remove methanol to obtain (5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid methyl ester) as a brown solid 4.14 g (yield 98.11%).

[0039] Step 2:

[0040] Under light-proof conditions, add 40 ml of methanol to 4 g of 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid methyl ester to dissolve it, then add 6.4 g of sodium methoxide (equivalent ratio is 4), add 9.58 g of iodophenyl diacetic acid (equivalent ratio is 2) under stirring at room temperature, react for 5 minutes after the addition, pour the reaction solution into 160 ml of a mixed solution of ammonium chloride: ethyl acetate = 1:2, extract the organic phase, wash twice with sodium bicarbonate solution, wash once with sodium chloride solution, concentrate the organic phase, pass through a column with PE:EA = 5:1, collect the product to obtain (5-benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid methyl ester) yellow solid 1.21 g (yield 27.21%)

[0041] Step 3:

[0042] Under light-proof conditions, 40 ml of methanol was added to 4 g of 5-benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid methyl ester to dissolve it, 20 ml of 3N sodium hydroxide solution was added under stirring at room temperature, and the reaction was carried out at room temperature for 30 min. The reaction solution was concentrated to remove methanol, 20 ml of water and 40 ml of ethyl acetate were added, and the layers were extracted. 40 ml of ethyl acetate was added to the aqueous phase, and dilute hydrochloric acid was added under stirring at room temperature to adjust the pH to weak acidity. The layers were allowed to stand and extracted twice, and the organic layer was concentrated to obtain 1.82 g (yield 47.74%) of (5-benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid) as a yellow solid with a purity of 96.3%.

[0043] See also Figure 2-Figure 4 : 5-Benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolazine-1-carboxylic acid impurity was confirmed by NMR, mass spectrometry and HPLC:

[0044] MS (m / z): 286 (M+H)+

[0045] 1H NMR (400 MHz, DMSO-d6) δ 7.85 – 7.74 (m, 2H), 7.64 (t, J = 7.3 Hz, 1H), 7.55 (t, J = 7.5 Hz, 2H), 6.83 (d, J = 4.1 Hz, 1H), 6.26 (d, J = 3.9 Hz, 1H), 4.53 – 4.35 (m, 2H), 3.28 (s, 3H), 3.08 – 2.96 (m, 1H), 2.71 (ddd, J =13.4, 7.0, 4.3 Hz, 1H).

[0046] It can be seen from the above-mentioned Embodiment 1 and Embodiment 2 that:

[0047] 1. The preparation method of ketorolac EP impurity D of the present invention is simple to operate and the raw materials are convenient and easy to obtain. The purity of the prepared 5-benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolazine-1-carboxylic acid reaches more than 96%, which meets the requirements of being used as an impurity reference substance and plays a positive role in the research and inspection of impurities related to ketorolac tromethamine.

[0048] 2. It was found that the compounds derived from ketorolac raw materials are sensitive to light sources, which affects the yield. The yield is higher when protected from light than when not protected from light.

[0049] The above description is only a preferred embodiment of the present invention, and does not limit the patent scope of the present invention. All equivalent structural changes made by using the contents of the present invention specification and drawings under the inventive concept of the present invention, or directly / indirectly applied in other related technical fields are included in the patent protection scope of the present invention.

Claims

1. A method for preparing ketorolac EP impurity D, characterized in that: The steps include: Step S1: using free ketorolac as a raw material, adding methanol to dissolve, then adding thionyl chloride dropwise, passing nitrogen gas for protection, reacting for a period of time, and then vacuum concentrating to obtain 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid methyl ester; Step S2: dissolving 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid methyl ester in solvent II, adding sodium methoxide and stirring, and then adding an oxidant to react, extracting and concentrating the reaction solution, and then passing a mixture of PE and EA through a column to obtain 5-benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid methyl ester, wherein the oxidant is iodophenyldiacetic acid; Step S3: dissolving 5-benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid methyl ester with a solvent, adding a sodium hydroxide solution to react for a period of time, and then concentrating and extracting the reaction solution to obtain 5-benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid; The reaction equations in the above steps are as follows: 。 2. The method for preparing ketorolac EP impurity D according to claim 1, characterized in that: The amount ratio of ketorolac to thionyl chloride in step S1 is 1:1.

1.

3. The method for preparing ketorolac EP impurity D according to claim 1, characterized in that: The solvent 2 in step S2 and the solvent 3 in step S3 are both selected from one or more of methanol, ethanol, tetrahydrofuran, acetonitrile, N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide.

4. The method for preparing ketorolac EP impurity D according to claim 3, characterized in that: The amount ratio of benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid methyl ester to sodium methoxide in step S2 is 1:

4.

5. The method for preparing ketorolac EP impurity D according to claim 4, characterized in that: The amount ratio of 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid methyl ester to the oxidant in step S2 is 1:1.1-4.

6. The method for preparing ketorolac EP impurity D according to claim 5, characterized in that: The specific steps of extraction and concentration in step S2 are: pouring the reaction solution into a mixed solution of ammonium chloride:ethyl acetate = 1:2, extracting the organic phase, washing it twice with sodium bicarbonate solution and once with sodium chloride solution, and concentrating the organic phase.

7. The method for preparing ketorolac EP impurity D according to claim 6, characterized in that: The amount ratio of EA to PE in step S2 is 1:

5.

8. The method for preparing ketorolac EP impurity D according to claim 1, characterized in that: The specific steps of concentrated extraction in step S3 are: adding water and ethyl acetate, extracting in layers, adding ethyl acetate to the aqueous phase, adding dilute hydrochloric acid to adjust the pH to weak acidity under stirring at room temperature, and standing and extracting in layers twice.

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