CN112898307A - Ketorolac impurity C and preparation method and application thereof - Google Patents
Ketorolac impurity C and preparation method and application thereof Download PDFInfo
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- CN112898307A CN112898307A CN202110177675.3A CN202110177675A CN112898307A CN 112898307 A CN112898307 A CN 112898307A CN 202110177675 A CN202110177675 A CN 202110177675A CN 112898307 A CN112898307 A CN 112898307A
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- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a ketorolac impurity C and a preparation method and application thereof, the method takes pyrrole as a starting raw material, and the ketorolac impurity C is prepared through a series of reactions such as substitution, oxidation, alkaline hydrolysis and the like, and the ketorolac impurity C is one of important impurities of ketorolac medicines or preparations thereof, can be used for toxicological and pharmacological researches such as absorption, metabolism and the like of ketorolac in vivo, and also can be used for researches on stability and quality control of ketorolac preparations. The method for preparing the ketorolac impurity C has the advantages of simple operation, safe reaction and high purity and yield, and can be widely applied to the fields of impurity analysis, toxicological research, safety detection, stability judgment and the like of ketorolac bulk drugs and preparations thereof.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method and application of ketorolac impurities.
Background
Ketorolac (Ketorolic) is a derivative of pyrrole acid, and belongs to nonsteroidal anti-inflammatory analgesics. Is a prostaglandin synthetase inhibitor, has strong analgesic effect and moderate anti-inflammatory and antipyretic effects, and mainly plays a role in reducing synthesis of prostaglandin by blocking cyclooxygenase of arachidonic acid metabolism. In a standard analgesic animal model, the analgesic activity of the product is 800 times of that of aspirin, is stronger than that of indomethacin and naproxen, and is equivalent to or superior to that of phenylbutazone. In multiple tests, the anti-inflammatory activity of the compound is equivalent to or stronger than that of indometacin and that of naproxen, and the compound is obviously superior to phenylbutazone. Multiple tests on eye diseases show that the product has strong anti-inflammatory activity and does not aggravate potential eye infection. The medicine has the advantages of no toxic and side effect such as damage to the central nervous system, addiction and the like, and no adverse reaction such as respiratory depression or constipation and the like. Chemical name: (+/-) -5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylic acid of formula (formula III):
the impurities of the medicine refer to substances which have no treatment effect or influence the stability and the curative effect of the medicine and are even harmful to the health of human bodies. In the aspects of research, production, storage, clinical application and the like of the medicine, the purity of the medicine must be maintained, and the impurities of the medicine are reduced, so that the effectiveness and the safety of the medicine can be ensured. The purity of a drug can be generally evaluated by integrating the structure, appearance, physicochemical constants, impurity inspection, content measurement, and the like of the drug into a whole. Impurities contained in the medicine are main factors influencing the purity of the medicine, and if the medicine contains more than limited amount of impurities, the physicochemical constants can be changed, the appearance character can be changed, and the stability of the medicine can be influenced; the increase of impurities also inevitably causes the content of the medicine to be lower or the activity to be reduced, and the toxic and side effects are obviously increased. Therefore, the impurity inspection of the medicine is a very important link for controlling the purity of the medicine and improving the quality of the medicine. However, no research on the analysis of the synthesis method of the impurities in the ketorolac bulk drug and the preparation thereof exists at present, and a detection method and a judgment basis for the production and medication safety of the ketorolac are lacked.
Disclosure of Invention
The invention mainly solves the technical problem of providing the preparation method of the ketorolac impurity C, which has the advantages of simple process, specific reaction, high product yield and low cost.
In order to achieve the above object, the present invention provides a ketorolac impurity C and a preparation method thereof, wherein the preparation method comprises the following steps:
step 1: pyrrole, tetrabutylammonium hydrogen sulfate, dissolved in 50% NaOH solution: slowly dripping benzene sulfonyl chloride into a mixed solution of dichloromethane (1:2.5v/v) under stirring at 0 ℃, continuing stirring and raising the temperature to room temperature for reaction for 2-6 h after dripping is finished within 10-30 min; adding dichloromethane, splitting phases, washing an organic phase with water, drying with a drying agent, filtering, and concentrating a filtrate to obtain a white solid, namely a compound 3;
step 2: adding anhydrous aluminum trichloride and dichloroethane into a reaction bottle, slowly adding benzoyl chloride while stirring, stirring at room temperature for 10-30 min, finally adding a compound 3, and reacting at room temperature for 1-3 h; adding dichloromethane, carrying out phase separation, washing an organic phase with water and alkali water respectively, drying with a drying agent, filtering, and concentrating a filtrate to obtain a white solid, namely a compound 4;
and step 3: compound 4 and sodium hydroxide were added to the reaction flask followed by dioxane: stirring and reacting the mixed solvent of water (4:1v/v) for 8-16 h at room temperature; adding ethyl acetate, carrying out phase separation, washing an organic phase with water, drying with a drying agent, filtering, and concentrating a filtrate to obtain a white solid, namely a compound 5;
and 4, step 4: and sequentially adding the compound 5, potassium carbonate, tetrabutylammonium bromide and dichloroethane into a reaction bottle, and heating and raising the temperature for reflux reaction for 3-6 hours under stirring. Cooling to room temperature, filtering, and concentrating the filtrate to obtain oily substance, namely compound 6;
and 5: and sequentially adding the compound 6, potassium carbonate, tetrabutylammonium bromide, diethyl malonate and toluene into a reaction bottle, and stirring and reacting at 75-85 ℃ for 8-16 h. Cooling to room temperature, filtering, washing filter residue with ethyl acetate, concentrating the filtrate, adding ethyl acetate and water, separating phases, washing the organic phase with water, drying with a drying agent, filtering, and concentrating the filtrate to obtain an oily substance, namely the compound 7;
step 6: under the protection of nitrogen, adding manganese acetate tetrahydrate and hot acetic acid into a reaction bottle, adding potassium permanganate under stirring, reacting for 30min, then slowly dropwise adding acetic anhydride, adding compound 7 and sodium acetate after dropwise adding is completed within 10-30 min, and reacting for 20-36 h under stirring at 55-75 ℃; cooling to room temperature, adding ethyl acetate, separating phases, washing the organic phase with water and alkali water, drying with a drying agent, filtering, concentrating the filtrate, and purifying with a chromatographic column to obtain an oily substance, namely a precursor of ketorolac impurity C;
and 7: ketorolac impurity v and sodium hydroxide were added to the reaction flask, followed by methanol: heating a water (4:1v/v) mixed solvent until reflux reaction lasts for 1-3 hours; removing the methanol under reduced pressure, adding water, extracting with diethyl ether, adjusting the pH of a water layer to 3-4 with dilute hydrochloric acid, separating out a solid, filtering, and drying to obtain a white solid, namely the ketorolac impurity C.
The reaction formula of the preparation method is shown in figure 1;
synthesis of compound 3 described in the above preparation: the inorganic base is preferably a strong base, more preferably sodium hydroxide; the organic base is preferably a quaternary ammonium salt, more preferably tetrabutylammonium hydrogen sulfate; the solvent is preferably 50% sodium hydroxide: dichloromethane (1:2.5v/v) mixed solvent.
Synthesis of compound 4 described in the above preparation: the acid is preferably aluminum trichloride; the solvent is preferably an aprotic solvent, more preferably dichloroethane.
Synthesis of compound 5 described in the above preparation: the inorganic base is preferably a strong base, more preferably sodium hydroxide; the solvent is preferably a mixed solvent of water, more preferably dioxane: water (4:1v/v) mixed solvent.
Synthesis of compound 6 described in the above preparation: the inorganic base is preferably a weak base, more preferably potassium carbonate; the organic base is preferably a quaternary ammonium salt, more preferably tetrabutylammonium bromide; the reaction temperature is preferably at reflux.
Synthesis of compound 7 described in the above preparation: the inorganic base is preferably a weak base, more preferably potassium carbonate; the organic base is preferably a quaternary ammonium salt, more preferably tetrabutylammonium bromide; the solvent is preferably an aprotic solvent, more preferably toluene; the reaction temperature is preferably 80 ℃.
Synthesis of the ketorolac impurity C precursor in the above preparation method: the inorganic base is preferably a weak base, more preferably sodium acetate; the metal catalyst is preferably potassium permanganate and manganese acetate tetrahydrate; the solvent is preferably a protic solvent, more preferably acetic acid and acetic anhydride; the reaction temperature is preferably 65 ℃.
The synthesis of the ketorolac impurity C in the preparation method comprises the following steps: the inorganic base is preferably a strong base, more preferably sodium hydroxide; the solvent is preferably a water-mixed solvent, more preferably methanol: water (4:1v/v) mixed solvent; the reaction temperature is preferably at reflux.
The preparation method of the ketorolac impurity has the beneficial effects that: according to the invention, cheap and easily available pyrrole is used as an initial reactant, and the technical scheme has the advantages of specific reaction, few byproducts, simple operation, stable process, good reproducibility, product total yield increased to over 70 percent, cost reduction and contribution to commercial production and batch supply.
Drawings
FIG. 1 is a reaction scheme of the preparation method of the present invention;
FIG. 2 is a MS spectrum of the precursor compound of ketorolac impurity C of example 6;
FIG. 3 is an HNMR spectrum of the precursor compound of ketorolac impurity C of example 6;
FIG. 4 is a CNMR spectrum of a precursor compound of the ketorolac impurity C of example 6;
FIG. 5 is a COYS spectrum of a precursor compound of ketorolac impurity C of example 6;
FIG. 6 is an HNMR spectrum of the ketorolac impurity C of example 7;
FIG. 7 is a CNMR spectrum of ketorolac impurity C of example 7.
Detailed Description
The specific embodiments described herein are merely illustrative of the invention and are not intended to be limiting, for the purposes of promoting an understanding of the invention.
Example 1: preparation of Compound 3
Pyrrole (10.0g, 149mmoL), tetrabutylammonium hydrogen sulfate (5.0g, 14.9mmoL) was added to a reaction flask, and 200ml of a naoh 50% solution was added: adding benzenesulfonyl chloride (29.0g, 164mmoL) slowly into a mixed solution of dichloromethane (1:2.5v/v) under stirring at 0 ℃, after dropwise addition is finished within 15min, heating to room temperature and reacting for 3 h; adding 200mL of dichloromethane, separating phases, washing an organic phase with water, drying anhydrous NaSO4, filtering, and concentrating a filtrate to obtain a white solid, namely the compound 3, 28.5g, with the yield of 93%.
Example 2: preparation of Compound 4
Dissolving anhydrous aluminum trichloride (20.0g, 150mmoL) in 100mL dichloroethane, slowly dropwise adding benzoyl chloride (21.0g, 150mmoL) while stirring, stirring at room temperature for 10min, finally adding compound 3(25.0g, 120mmoL), and reacting at room temperature for 1 h; adding 200mL of dichloromethane, separating phases, washing an organic phase with water, washing the organic phase with 10% NaHCO3 for 2-4 times, drying with anhydrous NaSO4, filtering, and concentrating a filtrate to obtain a white solid, namely the compound 4, 36.0g, with the yield of 95.8%.
EXAMPLE 3 preparation of Compound 5
Compound 4(35.0g, 112mmoL), sodium hydroxide (18.0g, 450mmoL) were added to a reaction flask followed by 200mL of dioxane: the reaction was stirred at room temperature for 12 hours with the solvent mixture of water (4:1 v/v). Adding 200mL of equivalent ethyl acetate, separating phases, washing an organic phase with water, drying with anhydrous NaSO4, filtering, and concentrating a filtrate to obtain a white solid, namely the compound 5, 18.0g, and the yield is 93.3%.
Example 4: preparation of Compound 6
Adding compound 5(15.0g, 87mmoL), potassium carbonate (53.0g, 386mmoL), tetrabutylammonium bromide (7.0g, 22mmoL) and 300mL dichloroethane in turn into a reaction flask, heating while stirring, heating, and carrying out reflux reaction for 4 h; cooled to room temperature, filtered, and the filtrate was concentrated to give compound 6 as an oil in a yield of 93.3%, 18.0 g.
EXAMPLE 5 preparation of Compound 7
Adding a compound 6(15.0g, 65mmoL), potassium carbonate (40g, 286mmoL), tetrabutylammonium bromide (10.0g, 32mmoL), diethyl malonate (15.5g, 97.5mmoL) and toluene into a reaction bottle in sequence, and stirring at 75-85 ℃ for reaction for 12 hours; cooling to room temperature, filtering, washing filter residues with ethyl acetate, concentrating the filtrate, adding ethyl acetate and water, carrying out phase separation, washing an organic phase with water, drying with a drying agent, filtering, and concentrating the filtrate to obtain an oily substance, namely the compound 7, 21g, with the yield of 91%.
Example 6: synthesis of ketorolac impurity C precursor compound
Under the protection of nitrogen, adding 17g of manganese acetate tetrahydrate (70 mmoL) and 100mL of hot acetic acid into a reaction bottle, adding 3g of potassium permanganate (18.5 mmoL) under stirring, reacting for 30min, then slowly dropwise adding 28.5g of acetic anhydride (280 mmoL), after dropwise addition within 10-30 min, finally adding 7(10g of compound, 28mmoL) and 9g of sodium acetate (112 mmoL), and stirring and reacting for 24h at 55-75 ℃. Cooling to room temperature, adding ethyl acetate, separating phases, washing an organic phase with water and alkali water, drying with a drying agent, filtering, concentrating a filtrate, and purifying with a chromatographic column to obtain an oily substance, namely the ketorolac impurity C precursor, 7.5g, wherein the yield is 76%.
Example 7: synthesis of ketorolac impurity C
The precursor of ketorolac impurity C (5g, 14mmoL) and sodium hydroxide (1.4g, 35mmoL) were added to a reaction flask, followed by addition of methanol: mixing a water (5:1v/v, 50mL) mixed solvent, heating and raising the temperature until reflux reaction is carried out for 3 hours; removing the methanol under reduced pressure, adding water, extracting twice with diethyl ether, removing a diethyl ether layer, adjusting the pH of a water layer to 3-4 with dilute hydrochloric acid, separating out a solid, filtering, and drying to obtain a white solid, namely ketorolac impurity C, 3.4g, and the yield is 95%.
The technical features mentioned above are combined with each other to form various embodiments which are not listed above, and all the embodiments are regarded as the scope of the present invention described in the specification; also, modifications and variations may be suggested to those skilled in the art in light of the above teachings, and it is intended to cover all such modifications and variations as fall within the true spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. A ketorolac impurity C, wherein the structural formula of the ketorolac impurity C compound is shown in formula (I):
the structural formula of the ketorolac impurity C precursor compound is shown as a formula (II):
2. a process for the preparation of ketorolac impurity C according to claim 1, characterized by the steps of:
step 1: adding pyrrole and tetrabutylammonium hydrogen sulfate into a reaction bottle, dissolving in a 50% NaOH solution: dropwise adding benzene sulfonyl chloride into a mixed solution with the volume ratio of dichloromethane of 1:2.5 under stirring at 0 ℃, continuously stirring and raising the temperature to room temperature for reacting for 2-6 h after dropwise adding is finished within 10-30 min; adding dichloromethane, splitting phases, washing an organic phase with water, drying with a drying agent, filtering, and concentrating a filtrate to obtain a white solid, namely a compound 3;
step 2: adding anhydrous aluminum trichloride and dichloroethane into a reaction bottle, slowly adding benzoyl chloride while stirring, stirring at room temperature for 10-30 min, finally adding a compound 3, and reacting at room temperature for 1-3 h; adding dichloromethane, carrying out phase separation, washing an organic phase with water and alkali water respectively, drying with a drying agent, filtering, and concentrating a filtrate to obtain a white solid, namely a compound 4;
and step 3: compound 4 and sodium hydroxide were added to the reaction flask followed by dioxane: mixing the solvent with the water volume ratio of 4:1, and stirring and reacting for 8-16 h at room temperature; adding ethyl acetate, carrying out phase separation, washing an organic phase with water, drying with a drying agent, filtering, and concentrating a filtrate to obtain a white solid, namely a compound 5;
and 4, step 4: adding the compound 5, potassium carbonate, tetrabutylammonium bromide and dichloroethane into a reaction bottle in sequence, and heating and carrying out reflux reaction for 3-6 h under stirring; cooling to room temperature, filtering, and concentrating the filtrate to obtain oily substance, namely compound 6;
and 5: adding a compound 6, potassium carbonate, tetrabutylammonium bromide, diethyl malonate and toluene into a reaction bottle in sequence, and stirring and reacting at 75-85 ℃ for 8-16 h; cooling to room temperature, filtering, washing filter residue with ethyl acetate, concentrating the filtrate, adding ethyl acetate and water, separating phases, washing the organic phase with water, drying with a drying agent, filtering, and concentrating the filtrate to obtain an oily substance, namely the compound 7;
step 6: under the protection of nitrogen, adding manganese acetate tetrahydrate and hot acetic acid into a reaction bottle, adding potassium permanganate under stirring, reacting for 30min, then slowly dropwise adding acetic anhydride, adding compound 7 and sodium acetate after dropwise adding is completed within 10-30 min, and reacting for 20-36 h under stirring at 55-75 ℃; cooling to room temperature, adding ethyl acetate, separating phases, washing the organic phase with water and alkali water, drying with a drying agent, filtering, concentrating the filtrate, and purifying with a chromatographic column to obtain an oily substance, namely a precursor of ketorolac impurity C;
and 7: ketorolac impurity v and sodium hydroxide were added to the reaction flask, followed by methanol: heating a mixed solvent with the water volume ratio of 4:1 until reflux reaction lasts for 1-3 hours; removing the methanol under reduced pressure, adding water, extracting with diethyl ether, adjusting the pH of a water layer to 3-4 with dilute hydrochloric acid, separating out a solid, filtering, and drying to obtain a white solid, namely the ketorolac impurity C.
3. The method of claim 2, wherein the inorganic base in step 1 is sodium hydroxide; the organic base is tetrabutylammonium hydrogen sulfate.
4. The process according to claim 2, wherein the solvent in step 2 is preferably an aprotic solvent, more preferably dichloroethane.
5. The process for the preparation of ketorolac impurity C according to claim 2, characterized in that in step 3 the inorganic base is preferably a strong base, more preferably sodium hydroxide; the solvent is preferably a mixed solvent of water, more preferably dioxane: the volume ratio of water is 4: 1.
6. The process for the preparation of ketorolac impurity C according to claim 2, wherein in step 4 the inorganic base is preferably a weak base, more preferably potassium carbonate; the organic base is preferably a quaternary ammonium salt, more preferably tetrabutylammonium bromide; the reaction temperature is preferably at reflux.
7. The process for the preparation of ketorolac impurity C according to claim 2, characterized in that step 5 the inorganic base is preferably a weak base, more preferably potassium carbonate; the organic base is preferably a quaternary ammonium salt, more preferably tetrabutylammonium bromide; the solvent is preferably an aprotic solvent, more preferably toluene; the reaction temperature is preferably 80 ℃.
8. The process for the preparation of ketorolac impurity C according to claim 2, characterized in that step 6 the inorganic base is preferably a weak base, more preferably sodium acetate; the metal catalyst is preferably potassium permanganate and manganese acetate tetrahydrate; the solvent is preferably a protic solvent, more preferably acetic acid and acetic anhydride; the reaction temperature is preferably 65 ℃.
9. The process for the preparation of ketorolac impurity C according to claim 2, characterized in that step 7 the inorganic base is preferably a strong base, more preferably sodium hydroxide; the solvent is preferably a water-mixed solvent, more preferably methanol: water (4:1v/v) mixed solvent; the reaction temperature is preferably at reflux.
10. The use of the ketorolac impurity C as claimed in claims 1 to 9, wherein said ketorolac impurity C is used in the toxicological and pharmacological studies of absorption and metabolism of ketorolac in vivo or in the study of stability and quality control of ketorolac preparations.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113603625A (en) * | 2021-08-12 | 2021-11-05 | 南京卓康医药科技有限公司 | Synthetic method of ketorolac intermediate |
| CN114181215A (en) * | 2021-12-27 | 2022-03-15 | 四川仁安药业有限责任公司 | Preparation method of related impurities of ketorolac or ketorolac salt |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0275092A1 (en) * | 1987-01-14 | 1988-07-20 | Syntex (U.S.A.) Inc. | Process for preparing (+)-1,2-dihydro-3H-pyrrolo(1,2-a)pyrrole-1,7-dicarboxylates |
| US6197976B1 (en) * | 1998-12-14 | 2001-03-06 | Syntex (U.S.A.) Llc | Preparation of ketorolac |
| US20020137945A1 (en) * | 1998-07-10 | 2002-09-26 | Caskey Douglas C. | Synthesis of compounds useful in the manufacture of ketorolac |
| CN108152418A (en) * | 2018-01-10 | 2018-06-12 | 成都倍特药业有限公司 | The HPLC detection methods of ketorolac tromethamine or/and impurity in ketorolac tromethamine or its preparation |
| CN108191876A (en) * | 2018-01-18 | 2018-06-22 | 上海仁实医药科技有限公司 | A kind of synthesis technology of ketorolac |
| CN111454271A (en) * | 2019-09-12 | 2020-07-28 | 南京海融医药科技股份有限公司 | Sodium salt and crystal form of pyrrolidine carboxylic acid compound and preparation method thereof |
-
2021
- 2021-02-07 CN CN202110177675.3A patent/CN112898307A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0275092A1 (en) * | 1987-01-14 | 1988-07-20 | Syntex (U.S.A.) Inc. | Process for preparing (+)-1,2-dihydro-3H-pyrrolo(1,2-a)pyrrole-1,7-dicarboxylates |
| US20020137945A1 (en) * | 1998-07-10 | 2002-09-26 | Caskey Douglas C. | Synthesis of compounds useful in the manufacture of ketorolac |
| US6197976B1 (en) * | 1998-12-14 | 2001-03-06 | Syntex (U.S.A.) Llc | Preparation of ketorolac |
| CN108152418A (en) * | 2018-01-10 | 2018-06-12 | 成都倍特药业有限公司 | The HPLC detection methods of ketorolac tromethamine or/and impurity in ketorolac tromethamine or its preparation |
| CN108191876A (en) * | 2018-01-18 | 2018-06-22 | 上海仁实医药科技有限公司 | A kind of synthesis technology of ketorolac |
| CN111454271A (en) * | 2019-09-12 | 2020-07-28 | 南京海融医药科技股份有限公司 | Sodium salt and crystal form of pyrrolidine carboxylic acid compound and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| NIKOLAOS PAPASTAVROU: "Enhancing activity and selectivity in a series of pyrrol-1-yl-1-hydroxypyrazole-based aldose reductase inhibitors: The case of trifluoroacetylation", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 2020, pages 1729 - 335 * |
| XU, RU XUN: "Pyrrole chemistry. XXV. A simplified synthesis of some 3-substituted pyrroles", TETRAHEDRON LETTERS, vol. 22, no. 49, pages 4899 - 4900 * |
| 王华: "镇痛药酮咯酸合成工艺的改进", 中国药物化学杂志, vol. 2020, no. 4, pages 1729 - 229 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113603625A (en) * | 2021-08-12 | 2021-11-05 | 南京卓康医药科技有限公司 | Synthetic method of ketorolac intermediate |
| CN113603625B (en) * | 2021-08-12 | 2023-03-10 | 南京卓康医药科技有限公司 | Synthetic method of ketorolac intermediate |
| CN114181215A (en) * | 2021-12-27 | 2022-03-15 | 四川仁安药业有限责任公司 | Preparation method of related impurities of ketorolac or ketorolac salt |
| CN114181215B (en) * | 2021-12-27 | 2024-03-01 | 四川仁安药业有限责任公司 | Preparation method of ketorolac or related impurities of ketorolac salt |
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