CN114349757B - Preparation method of ketorolac - Google Patents
Preparation method of ketorolac Download PDFInfo
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- CN114349757B CN114349757B CN202210064887.5A CN202210064887A CN114349757B CN 114349757 B CN114349757 B CN 114349757B CN 202210064887 A CN202210064887 A CN 202210064887A CN 114349757 B CN114349757 B CN 114349757B
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Abstract
The invention relates to the field of medicine, in particular to a method for preparing ketorolac, wherein in the process of preparing the ketorolac by using an alkaline hydrolysis intermediate A5, borohydride is added to obtain a ketorolac sample, and the sample is checked according to a Chinese pharmacopoeia solution color check method, so that the sample is obviously lighter than the sample obtained in the prior art.
Description
Technical Field
The invention relates to the field of medicines, in particular to a preparation method of ketorolac.
Background
Ketorolac tromethamine, a nonsteroidal anti-inflammatory drug for injection, was marketed in 1990. Ketorolac tromethamine injection is mainly suitable for short-term treatment of acute severe pain requiring analgesic drugs at opioid level, and is usually used for postoperative analgesia, as shown in fig. 2, china journal of pharmaceutical chemistry 2002, 12 (4): 228-229, obtaining ketorolac, and salifying with tromethamine to obtain ketorolac tromethamine as raw material.
Chinese patent application CN108191876A discloses a synthetic route, in which pyrrole and diethyl iodomalonate react under the action of iron salt and oxidant, the obtained intermediate reacts with 1, 2-dichloroethane, after ring closure, friedel-crafts acylation reaction, and benzoyl chloride, and then, after alkaline hydrolysis and decarboxylation, ketorolac is obtained. In the preparation method, hydrogen peroxide, peracetic acid, m-chloroperoxybenzoic acid and tert-butyl peroxy alcohol are used as oxidants.
In the prior art, a long conjugated system exists in the structure of ketorolac, so that the ketorolac is easy to oxidize to form colored impurities. The solution color of the raw material drug of ketorolac tromethamine is specified in the second part of the Chinese pharmacopoeia 2020 edition, 0.30g of ketorolac tromethamine is taken, 10ml of water is added for dissolving, and if the solution is developed, the solution cannot be darker than yellow or yellow-green No. 3 standard colorimetric solution. The color of the ketorolac tromethamine injection is also specified, and the preparation is taken out and is not darker than yellow or yellow-green No. 4 standard colorimetric solution.
In the existing ketorolac preparation method, oxidizing agents such as potassium permanganate are used, the color of ketorolac is darkened, the color of a finished ketorolac tromethamine product is affected, a reducing agent containing a low-valence sulfur atom is used in the process of salifying with tromethamine, and because inorganic salt is used as a reagent in the last step of salifying of ketorolac and tromethamine, the risk of bringing the inorganic salt into the finished ketorolac tromethamine product is increased, and the use is very inconvenient, so that the preparation method of ketorolac is urgently needed to be developed aiming at the current situation, and the defects in the current practical application are overcome.
Disclosure of Invention
The present invention aims to provide a method for preparing ketorolac, which solves the problems of the background art.
In order to achieve the purpose, the invention provides the following technical scheme:
a method for preparing ketorolac comprises the following steps:
step 1: dissolving the intermediate A5 in a solvent, and adding a sodium hydroxide or potassium hydroxide solution;
step 2: stirring the solution, adding borohydride, heating to 50-60 ℃, and stirring for reaction;
and step 3: the reaction was monitored by TLC to completion;
and 4, step 4: evaporating the solvent under reduced pressure, adding concentrated hydrochloric acid dropwise at 0-10 deg.C, adjusting pH, separating out white solid, vacuum filtering, and vacuum drying to obtain ketorolac.
Ketorolac is applied to the preparation method of ketorolac.
A process for the preparation of ketorolac tromethamine, for use in ketorolac as described above, which comprises the steps of:
adding ketorolac (50g, 0.196mol, 1.0eq.) into 95% ethanol (150 ml), stirring and heating, heating to 50-60 deg.C, dissolving solid, adding activated carbon (5 g), stirring at 50-60 deg.C for 45 min, and filtering to remove activated carbon;
adding tromethamine solid (28.5g, 0.235mol, 1.2eq.) into the filtrate, heating to 50-60 ℃, completely dissolving the solid, stopping heating, cooling the solution to below 40 ℃, adding a small amount of seed crystals, separating out the solid, cooling the temperature to below 20 ℃, stirring for crystallization for more than 8 hours, filtering, leaching the filter cake with absolute ethyl alcohol (25 ml multiplied by 2) to obtain a white-like solid, and drying in vacuum at 50 +/-5 ℃ to obtain the ketorolac tromethamine.
Compared with the prior art, the invention has the beneficial effects that:
when the ketorolac is prepared, in the process of preparing the ketorolac by using the alkaline hydrolysis intermediate A5, borohydride is added to obtain a ketorolac sample, the color of the ketorolac obtained by the technical scheme is obviously lighter than that of the sample obtained by the prior art, ketorolac from different sources is prepared into ketorolac tromethamine according to the method, the detection is carried out according to the first method of Chinese pharmacopoeia, the color of the solution is obviously lighter than that of the ketorolac tromethamine obtained according to the prior art, and the risk of unqualified detection of a finished product burning residue project can be avoided due to the fact that inorganic salts such as sodium thiosulfate are avoided being used in the final salifying and refining step, and the method is worthy of popularization.
Drawings
FIG. 1 is a schematic diagram of the preparation of ketorolac in an embodiment of the present invention.
FIG. 2 is a synthesis route of ketorolac disclosed in the journal of Chinese medicinal chemistry in the examples of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be described clearly and completely with reference to the accompanying drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Specific implementations of the present invention are described in detail below with reference to specific embodiments.
Comparative example 1: ketorolac tromethamine is prepared according to the method of 2019,50 (8): 868-870 in the Chinese medical industry, which is shown in figure 2.
Intermediate A3 (100g, 0.425mol, 1.0eq.), potassium carbonate (250g, 1.8mol, 4.25eq.), tetrabutylammonium bromide (18.7g, 0.058mol, 0.13eq.), and diethyl malonate (100g, 0.625mol, 1.47eq.) were added to toluene (830 ml) and N, N-dimethylformamide (170 ml), stirred at 85 ± 5 ℃ for 12 hours, then cooled to room temperature, filtered, the filtrate was concentrated to dryness under reduced pressure, ethyl acetate (830 ml) was added, washed with purified water (830 ml × 3), and washed with a saturated sodium chloride solution (830 ml) in this order. Adding anhydrous sodium sulfate and drying. After filtration, the filtrate was concentrated under reduced pressure to give intermediate A4 as an oily substance, which was dissolved in acetic acid (170 ml) for further use.
Manganese acetate tetrahydrate (195g, 0.79mol, 1.87eq.) was dissolved in acetic acid (1700 ml), heated to 75. + -. 5 ℃ and dissolved by stirring. Potassium permanganate (30g, 0.19mol, 0.45eq.) and acetic anhydride (210ml, 1.75mol, 4.12eq.) and sodium acetate (97.5g, 1.2mol, 2.8eq.) were added, the above-mentioned acetic acid solution of intermediate A4 was added, the reaction was controlled at 80 to 85 ℃ for 5 hours, the reaction solution was poured into purified water (830 ml), toluene (670 ml. Times.2) was used for extraction, the organic phases were combined, purified water (830 ml. Times.3) was used for washing, anhydrous sodium sulfate was added for drying, filtration was carried out, the filtrate was concentrated under reduced pressure to remove toluene, and a pale yellow oily substance was obtained as intermediate A5.
Adding methanol (850 ml) and 1.8mol/L potassium hydroxide solution (1420 ml, 2.56mol,6 eq.) into the oily intermediate A5 obtained in the previous step, heating to 60-65 ℃, stirring for reaction for 4 hours, reducing pressure to remove methanol, cooling to 0-10 ℃, adjusting pH to 2 with concentrated hydrochloric acid, separating out light yellow solid, filtering, adding wet filter cake into a reaction bottle, adding methanol (350 ml), stirring, adding purified water (350 ml), heating to dissolve, cooling to 0-10 ℃, crystallizing to obtain white-like solid, drying to obtain 68.3g of ketorolac with a yield of 63.0%.
Ketorolac (60g, 0.233mol, 1.0eq.) and tromethamine (28.4g, 0.233mol, 1.0eq.) and sodium thiosulfate (0.15g, 0.75mmol, 0.003eq.) were added to anhydrous ethanol (225 ml), heated to 80-85 ℃ and stirred to dissolve, cooled slightly, added with activated carbon (1.5 g), stirred for 30 minutes, filtered while hot, the filtrate was cooled to crystallize, filtered and dried to obtain a white solid, 78.2g in total, and the yield was 89.2%.
Example 1
As shown in fig. 1, intermediate A5 (50 g, 0.141mol, 1.0 eq.) was dissolved in methanol (500 ml), 30% sodium hydroxide solution (225 g, 1.69mol, 12 eq.) was added, sodium borohydride (53.2 mg, 1.407mmol, 0.01 eq.) was added with stirring, the reaction system was heated to 50-60 ℃, the reaction was stirred, and the reaction was monitored by TLC until completion of the reaction. Reducing pressure to evaporate the methanol, reducing the temperature, dripping concentrated hydrochloric acid under the condition of 0-10 ℃, adjusting the pH value to 2, separating out white solid, filtering, pulping and washing a filter cake by using 1mol/L diluted hydrochloric acid (250 ml), filtering, leaching the filter cake by using purified water (100 ml), and drying at the temperature of 40 +/-5 ℃ in vacuum to obtain ketorolac with 32.8g in total and the yield of 91.3%.
Example 2
As shown in fig. 1, intermediate A5 (50 g, 0.141mol, 1.0 eq.) was dissolved in methanol (500 ml), 30% sodium hydroxide solution (225 g, 1.69mol, 12 eq.) was added, sodium borohydride (532.2 mg, 14.07mmol, 0.1 eq.) was added with stirring, the reaction system was heated to 50-60 ℃, the reaction was stirred, and the reaction was monitored by TLC until the reaction was complete. Reducing pressure to evaporate the methanol, reducing the temperature, dripping concentrated hydrochloric acid under the condition of 0-10 ℃, adjusting the pH value to 2, separating out white solid, filtering, pulping and washing a filter cake by using 1mol/L diluted hydrochloric acid (250 ml), filtering, leaching the filter cake by using purified water (100 ml), and drying at the temperature of 40 +/-5 ℃ in vacuum to obtain the ketorolac with 31.2g in total and the yield of 86.9%.
Example 3
As shown in fig. 1, intermediate A5 (50 g, 0.141mol, 1.0 eq.) was dissolved in methanol (500 ml), 30% sodium hydroxide solution (225 g, 1.69mol, 12 eq.) was added, sodium borohydride (5.3 mg, 0.141mmol, 0.001 eq.) was added with stirring, the reaction system was heated to 50-60 ℃, the reaction was stirred, and the reaction was monitored by TLC until the reaction was complete. And (2) evaporating the methanol under reduced pressure, cooling, dropwise adding concentrated hydrochloric acid at the temperature of 0-10 ℃, adjusting the pH value to 2, separating out white solid, performing suction filtration, leaching a filter cake with purified water (100 ml), and drying at the temperature of 40 +/-5 ℃ in vacuum to obtain ketorolac with 30.7g in total and the yield of 85.5%.
Example 4
As shown in fig. 1, intermediate A5 (50 g, 0.141mol, 1.0 eq.) was dissolved in methanol (500 ml), 30% sodium hydroxide solution (225 g, 1.69mol, 12 eq.) was added, sodium borohydride (1.06 g, 28.1mmol, 0.2 eq.) was added with stirring, the reaction system was heated to 50-60 ℃, the reaction was stirred, and the reaction was monitored by TLC until completion of the reaction. Reducing pressure to evaporate methanol, reducing temperature, dripping concentrated hydrochloric acid under the condition of 0-10 ℃, adjusting the pH value to 2, separating out white solid, filtering, pulping and washing a filter cake by using 1mol/L dilute hydrochloric acid (250 ml), filtering, then leaching the filter cake by using purified water (100 ml), and drying at the temperature of 40 +/-5 ℃ in vacuum to obtain ketorolac, wherein the total yield is 32.1 g.
Example 5
As shown in fig. 1, intermediate A5 (50 g, 0.141mol, 1.0 eq.) was dissolved in methanol (500 ml), 30% sodium hydroxide solution (225 g, 1.69mol, 12 eq.) was added, sodium borohydride (1.06 g, 28.1mmol, 0.2 eq.) was added with stirring, the reaction system was heated to 50-60 ℃, the reaction was stirred, and the reaction was monitored by TLC until completion of the reaction. And (2) evaporating methanol under reduced pressure, cooling, dropwise adding concentrated hydrochloric acid at 0-10 ℃, adjusting the pH value to 2, separating out white solid, performing suction filtration, pulping and washing a filter cake by using 1mol/L dilute hydrochloric acid (250 ml), filtering, leaching the filter cake by using purified water (100 ml), and drying at the temperature of 40 +/-5 ℃ in vacuum to obtain ketorolac, wherein the total yield is 33.2 g.
Example 6
As shown in fig. 1, intermediate A5 (50 g, 0.141mol, 1.0 eq.) was dissolved in methanol (500 ml), 30% sodium hydroxide solution (225 g, 1.69mol, 12 eq.) was added, sodium cyanoborohydride (88.4 mg, 1.407mmol, 0.01 eq.) was added with stirring, the reaction system was heated to 50-60 ℃, the reaction was stirred, and the reaction was monitored by TLC until the reaction was complete. And (2) evaporating methanol under reduced pressure, cooling, dropwise adding concentrated hydrochloric acid at the temperature of 0-10 ℃, adjusting the pH value to 2, separating out white solid, performing suction filtration, pulping and washing a filter cake by using 1mol/L dilute hydrochloric acid (250 ml), filtering, leaching the filter cake by using purified water (100 ml), and drying at the temperature of 40 +/-5 ℃ in vacuum to obtain ketorolac, wherein the total yield is 32.8 g.
Example 7
As shown in fig. 1, intermediate A5 (50 g, 0.141mol, 1.0 eq.) was dissolved in methanol (500 ml), 30% sodium hydroxide solution (225 g, 1.69mol, 12 eq.) was added, sodium triacetoxyborohydride (298.19 mg, 1.407mmol, 0.01 eq.) was added with stirring, the reaction system was heated to 50-60 ℃, the reaction was stirred, and the reaction was monitored by TLC until the reaction was complete. Reducing pressure to evaporate methanol, reducing temperature, dripping concentrated hydrochloric acid under the condition of 0-10 ℃, adjusting the pH value to 2, separating out white solid, filtering, pulping and washing a filter cake by using 1mol/L dilute hydrochloric acid (250 ml), filtering, then leaching the filter cake by using purified water (100 ml), and drying at the temperature of 40 +/-5 ℃ in vacuum to obtain ketorolac, wherein the total yield is 32.5 g.
Example 8
As shown in fig. 1, intermediate A5 (50 g, 0.141mol, 1.0 eq.) was dissolved in methanol (500 ml), 30% potassium hydroxide solution (315 g, 1.69mol, 12 eq.) was added, sodium borohydride (53.2 mg, 1.407mmol, 0.01 eq.) was added with stirring, the reaction system was heated to 50-60 ℃, the reaction was stirred, and the reaction was monitored by TLC until the reaction was complete. And (2) evaporating methanol under reduced pressure, cooling, dropwise adding concentrated hydrochloric acid at the temperature of 0-10 ℃, adjusting the pH value to 2, separating out white solid, performing suction filtration, pulping and washing a filter cake by using 1mol/L dilute hydrochloric acid (250 ml), filtering, leaching the filter cake by using purified water (100 ml), and drying at the temperature of 40 +/-5 ℃ in vacuum to obtain ketorolac, wherein the total yield is 32.8 g.
Example 9 color check of solution
Ketorolac obtained in each example was prepared to ketorolac tromethamine according to the method described in the summary of the invention and tested according to the first method in the color examination method of the solution of the second 0901 edition of the chinese pharmacopoeia 2020.
Taking 0.30g of ketorolac tromethamine, adding 10ml of water, dissolving, placing in a 25ml Nashi colorimetric tube, taking 10ml of yellow-green standard colorimetric solution of each color number, placing in the Nashi colorimetric tube, placing on a white background at the same time, and performing perspective from top to bottom to determine the color of the solution. The results are as follows:
| examples | Yellow-green colorimetric liquid color number |
| Comparative example 1 | 4 |
| Example 1 | 1 |
| Example 2 | 1 |
| Example 3 | 2 |
| Example 4 | 1 |
| Example 5 | 1 |
| Example 6 | 2 |
| Example 7 | 2 |
| Example 8 | 2 |
Compared with the prior art, the ketorolac obtained by the invention has lighter color and is easier to meet the requirements of Chinese pharmacopoeia. The ketorolac tromethamine is prepared according to the same method, and the color of the product obtained by the method is lighter.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.
Claims (1)
1. A method for preparing ketorolac is characterized by comprising the following steps:
step 1: dissolving the intermediate A5 in a solvent, and adding a sodium hydroxide or potassium hydroxide solution, wherein the structural formula of the intermediate A5 is as follows:
step 2: stirring the solution, adding borohydride, heating to 50-60 ℃, and stirring for reaction;
and 3, step 3: the reaction was monitored by TLC until completion;
and 4, step 4: after the reaction is finished, decompressing to evaporate the solvent, dripping concentrated hydrochloric acid under the condition of 0-10 ℃, adjusting the pH value, separating out white solid, performing suction filtration, and performing vacuum drying to obtain ketorolac;
in step 1, the solvent is methanol or ethanol;
in step 2, the borohydride is sodium borohydride;
the molar ratio of the intermediate A5 to borohydride is 1;
in steps 1 and 2, the reaction is fed in the order of borohydride addition to the aqueous sodium or potassium hydroxide solution of intermediate A5;
in step 3, TLC monitoring conditions were GF254 silica gel plates, developing agent was n-heptane, ethyl acetate v/v was 1, observed with a 254nm UV lamp;
in step 4, the pH value is adjusted to 2, and a filter cake is formed after pulping, washing and suction filtration by using dilute hydrochloric acid.
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