Method for manufacturing R-ketrolac and its applications

Abstract

The present invention provides a method for preparing R-ketorolac and its application in the technical field of organic synthesis. The method includes: preparing ketorolac in step 1; dividing R-ketorolac into chiral amine division or enzymatic division in step 2; in this application, glacial acetic acid is used as reaction solvent, which is clean and environmentally friendly, and easy to remove; it can greatly improve the conversion rate of raw material SM1, and improve the yield and purity of ketorolac; the yield of the obtained ketorolac can reach up to more than 70%, and the purity can reach more than 99%; by using chiral amine or enzyme to divide ketorolac into chiral parts, R-ketorolac can be obtained with high purity and high yield; and the obtained R-ketorolac can prevent chemotherapy drug resistance and improve the efficacy and cure rate of chemotherapy.

Description

Cross-reference to Related Applications

[0001] This application claims the priority of a Chinese patent application with application number CN202211032611.5 and title of invention "Method for Producing R-Ketorolac and Its Applications", which was filed with the Chinese Patent Office on August 26, 2022, and all of its contents are incorporated herein by reference.

Technical Field

[0002] This application belongs to the technical field of organic synthesis, and specifically relates to a method for producing R-ketorolac and its applications.

Background Art

[0003] In recent years, a series of activities of drugs in vivo have been closely related to their structures, and it has been recognized that there are significant differences in the pharmacological activities, metabolic processes, and pharmacokinetics shown by different enantiomers. Therefore, the research on the synthesis and preparation of single enantiomers has become a hot topic in the academic circles at home and abroad. In nature, most of the amino acids used in the pharmaceutical, pesticide, and food industries are chiral substances. In many cases, they exist as racemates of two or more enantiomers at the same time. From the perspective of biological activity, these are some completely different substances. Generally, only one of the enantiomers has the required biological activity, and the other enantiomers are redundant, and they affect the exertion of the activity of the active substance and even cause adverse effects in reverse. According to statistics, among the drugs currently on the market, except for some natural drugs such as hormonal agents and antibiotics that mainly exist as single isomers, most of the other synthetic drugs are supplied as racemates, which clearly causes some serious problems in the treatment of diseases and other applications. Therefore, how to perform chiral resolution and provide a single chiral drug to control the quality of pharmaceutical production has become a major concern.

[0004] Ketrolac (5-benzoyl-1,2-dihydro-3Hpyrrolo[1,2-a]pyrrole-1-carboxylic acid) is a new type of nonsteroidal anti-inflammatory drug (NSAID) that is potent, non-addictive, and non-narcotic, and exerts a strong analgesic effect by inhibiting prostaglandin synthesis. Racemic ketrolac has been on the market in the United States since 1991 and is sold as ketrolac trishydroxymethylaminomethane. JPEG0007904631000001.jpg3979 Formula I

[0005] As shown in formula I, the structure of the ketrolac molecule contains a chiral carbon atom, and a pair of enantiomers exist. Studies have shown that S-ketrolac has an analgesic effect 230 times stronger and an anti-inflammatory effect 60 times stronger than R-ketrolac, so ever since ketrolac was released to the market, people have been constantly searching for ways to obtain its S isomer.

[0006] Patent Document 1 discloses a method for producing optically active ketrolac, the first step of which is a kinetic splitting reaction, in which the two amides produced by the reaction appear one after the other, rather than simultaneously. The most ideal situation is that one isomer of racemic ketrolac is completely converted to the amide product before the other isomer begins to react. In the case of a kinetic splitting reaction, in principle, the reaction product and unreacted starting material should be optically active, as long as the reaction is terminated before the racemic starting material is completely converted to the product; that is, the reaction exhibits selectivity and splitting can be achieved, and in this application, the final product obtained by splitting is the S-isomer.

[0007] However, there are few reports on the production of R-isomers, and Patent Document 2 discloses the application of R-ketrolac in the prevention and treatment of aortic dissection and aortic aneurysm. Oral administration of R-ketrolac can inhibit pathological dilation of the aorta, reducing the incidence and mortality of aortic dissection and aortic aneurysm. Furthermore, R-ketrolac can suppress the development of inflammatory responses in the vascular wall, reduce the rupture of aortic aneurysms, suppress the development of intramural hematomas, maintain the integrity of elastic fibers in the vascular wall, and treat aortic dissection and aortic aneurysm. This invention opens up a new field of application for R-ketrolac and provides meaningful references regarding the prevention and treatment of aortic dissection and aortic aneurysm diseases, as well as the improvement of vascular disease conditions. This application discloses the application of R-ketrolac in the prevention and treatment of aortic dissection and aortic aneurysm, but does not relate to the production of R-isomers.

[0008] Patent Document 3 discloses R-ketrolac for the treatment of cachexia and provides a method for treating cachexia to reduce morbidity and mortality from chronic diseases and generally improve the therapeutic effect of chronic diseases. However, this application also does not relate to the manufacture of R-ketrolac.

[0009] Therefore, it is necessary to provide a method for manufacturing R-ketrolac. [Prior art documents] [Patent Documents]

[0010] [Patent Document 1] Chinese Patent No. 02102547.9 Specification [Patent Document 2] Chinese Patent No. 202111115983 Specification [Patent Document 3] Chinese Patent No. 201880084997 Specification [Overview of the Initiative] [Problems that the invention aims to solve]

[0011] This application aims to provide a method for producing R-ketrolac and its applications, which, by optimizing the manufacturing method based on the shortcomings of the prior art, can be obtained to produce R-ketrolac of higher purity, and which, when used in combination with chemotherapy, can significantly enhance the effect of chemotherapy and improve the cure rate of tumors. [Means for solving the problem]

[0012] To solve the above technical problems, this application is realized by the following technical solutions.

[0013] The method for manufacturing R-ketrolac includes the following steps: Step 1, Manufacturing of Ketrolac: (1) Add glacial acetic acid, manganese acetate dihydrate (trivalent), triethyl methanetricarboxylate (SM2), 2-benzoyl pyrrole (SM1), and sodium acetate to the reaction vessel, raise the temperature until the reaction is complete, then lower the temperature, add methyl tert-butyl ether to the reaction system, filter to obtain the filtrate, add aqueous potassium carbonate solution to the filtrate to adjust the pH to 4-8, collect the organic phase by liquid-liquid separation, concentrate, recrystallize, filter, and dry to obtain (5-benzoyl-1H-pyrrole-2-yl)methanetricarboxylate. The reaction equation is, The filename is JPEG0007904631000002.jpg42152. (2) Add 1,2-dichloroethane, product A, potassium carbonate, and tetrabutylammonium bromide to the reaction vessel and raise the temperature once until the reaction is complete to obtain a mixture containing product B, which is 5-benzoyl-2,3-dihydro-1H-pyrrolidine-1,1-dicarboxylate diethyl ester. Filter the mixture containing product B, transfer the filtrate to the reaction vessel and concentrate it. Next, add the tetrahydrofuran solution and the sodium hydroxide solution to the reaction vessel in order and raise the temperature a second time until the reaction is complete. Separate the product and collect the organic phase. Add the HCl tetrahydrofuran solution to the organic phase to adjust the pH to 3, concentrate it, add methyl tert-butyl ether to the concentrate, add water and wash, separate the solution, collect the organic phase, decolorize it, recrystallize it, filter it, and dry it to obtain product C, which is ketrolac. The reaction equation is, The filename is JPEG0007904631000003.jpg34152.

[0014] Step 2, the division of R-ketrolac by chiral amine division or enzymatic division, wherein the chiral amine division step is: Ketrolac and isopropyl alcohol are added to the reaction vessel, the temperature is raised to dissolve the ketrolac, then chiral amine and seed crystals are added, and after homogeneous stirring, ethyl acetate is added dropwise, the temperature is lowered to crystallize, and the mixture is filtered to obtain a first solid and a filtrate. The first solid is acidified with hydrochloric acid and filtered to obtain the product FP, which is R-ketrolac. The reaction equation is The filename is JPEG0007904631000004.jpg32152. The aforementioned enzyme splitting step is (1) Add ketrolac and methanol to the reaction vessel, lower the temperature to -5 to 5°C, add SOCl2, raise the temperature to 40 to 50°C until the reaction is complete, concentrate, add water to crystallize, filter, and dry to obtain product D, which is ketrolac methyl ester. The reaction equation is, The filename is JPEG0007904631000005.jpg54150. (2) The product D, tert-butanol, buffer solution, and enzyme are added to the reaction kettle in sequence, reacted while monitoring the chiral purity. After the reaction is completed, filtration is carried out, methyl tert-butyl ether and water are added for washing, then liquid separation is performed, the organic phase is concentrated, liquid separation is carried out again, the organic phase is collected, methyl tert-butyl ether is added, the temperature is lowered to -5 to 5 °C, isopropylamine is added, stirred, filtered, the filtered solid is added to the reaction kettle, water and 4 mol / L hydrochloric acid aqueous solution are added for acidification, and filtration is carried out to obtain the product FP which is R-ketorolac. The reaction equation is JPEG0007904631000006.jpg31152.

[0015] The molar ratio of 2-benzoylpyrrole, triethyl methanetricarboxylate, manganese(II) acetate dihydrate, sodium acetate, and glacial acetic acid described in step (1) is 0.99 - 1.01:1.09 - 1.12:1.9 - 2.1:2.8 - 3.2:28 - 32. Preferably, the molar ratio of 2-benzoylpyrrole, triethyl methanetricarboxylate, manganese(II) acetate dihydrate, sodium acetate, and glacial acetic acid described in step (1) is 1:1.1:3:2:30.

[0016] Preferably, the mass ratio of the addition amount of methyl tert-butyl ether described in step (1) to the mass of 2-benzoylpyrrole is 18:1. Preferably, the temperature-raising reaction temperature described in step (1) is 65 - 75 °C, preferably 70 °C, and the reaction time is 14 - 20 hours, preferably 16 hours.

[0017] Preferably, the temperature-lowering temperature described in step (1) is 35 - 45 °C, preferably 40 °C.

[0018] Preferably, the steps of the recrystallization operation described in step (1) are as follows: ethanol with a mass ratio of 4:1 to 2-benzoylpyrrole is added to the concentrated organic phase, the temperature is raised to 40 °C and stirred to dissolve the solid, then the temperature is lowered to -10 °C to crystallize the solid, filtered, and dried to obtain the product A, and the cooling and temperature-lowering time is 6 - 10 hours.

[0019] Preferably, the criterion for determining the complete reaction in step (1) is SM1 / A ≤ 5%.

[0020] Preferably, the molar ratio of 1,2-dichloroethane, product A, potassium carbonate, and tetrabutylammonium bromide described in step (2) is 85-95:0.99-1.01:8.7-11.6:0.75-1.25, Preferably, the molar ratio of 1,2-dichloroethane, product A, potassium carbonate, and tetrabutylammonium bromide described in step (2) above is 90:1:10:1.

[0021] Preferably, the first temperature increase in step (2) is 75-85 °C, preferably 80 °C, the reaction time is 14-20 hours, preferably 18 hours, and the criterion for determining the complete reaction is product A / product B ≤ 5%.

[0022] Preferably, the mass ratio of the addition amount of the tetrahydrofuran solution described in step (2) to product A is 8:1. Preferably, the mass fraction of the sodium hydroxide solution described in step (2) is 20%, and the mass ratio of the addition amount of the sodium hydroxide solution to product A is 4:1. Preferably, the second temperature increase in step (2) is 50-60 °C, preferably 55 °C, the reaction time is 1-5 hours, preferably 5 hours, and the criterion for determining the complete reaction is B / C ≤ 5%.

[0023] Preferably, the mass fraction of the tetrahydrofuran solution of HCl described in step (2) is 11%, and the mass ratio of the addition amount to product A is 1.45:1. Preferably, the mass ratio of the addition amount of methyl tert-butyl ether in step (2) to product A is 7:1.

[0024] Preferably, the decolorization described in step (2) uses a CUNO filter. Preferably, the recrystallization step described in step (2) involves concentrating the decolorized organic phase, adding n-heptane, raising the temperature to 40°C, stirring to dissolve the solid, then slowly lowering the temperature to -10°C to crystallize the solid, filtering, and vacuum drying to obtain product C.

[0025] Preferably, the mass ratio of the amount of isopropyl alcohol added in the chiral amine resolution step to product C (ketrolac) is 4.2:1 to 8.0:1, preferably 4.75:1.

[0026] Preferably, the heating temperature described in the chiral amine splitting step is 50 to 60°C, preferably 55°C.

[0027] Preferably, the chiral amine described in the chiral amine resolution step is one of dehydroabiethylamine, (s)-1-phenylethylamine, (1S,2S)-(+)-1,2-diaminocyclohexane, L-(-)-epinephrine, (R)-(+)-1-(1-naphthyl)ethylamine, and synconine, and is preferably synconine.

[0028] Preferably, the molar ratio of product C (ketrolac) to chiral amine is 1:0.82 to 1:1.73. Preferably, the molar ratio of the product C (ketrolac) to the seed crystal is 1:0.0005 to 1:0.05. Preferably, the chiral amine is added in batches. Specifically, the method of addition is as follows: first, a chiral amine with a molar ratio of 0.52 to 0.86:1 with product C is added and stirred to dissolve the solid; then, a chiral amine with a molar ratio of 0.04 to 0.17:1 with product C is added and stirred to dissolve the solid; then, a chiral amine with a molar ratio of 0.04 to 0.17:1 with product C is added and stirred for another hour; after that, ketrolac with a molar ratio of 0.04 to 0.17:1 with product C is added; and finally, after stirring for 1.5 hours, a chiral amine with a molar ratio of 0.17 to 0.35:1 with product C is added.

[0029] Preferably, the method of adding the chiral amine involves first adding synconin with a molar ratio of 0.68:1 to product C, stirring to dissolve the solid, then adding synconin with a molar ratio of 0.07:1 to product C, stirring to dissolve the solid, then adding synconin with a molar ratio of 0.13:1 to product C, stirring for another hour, then adding synconin with a molar ratio of 0.1:1 to product C, and finally stirring for 1.5 hours, then adding synconin with a molar ratio of 0.25:1 to product C.

[0030] Preferably, the seed crystal is added after the second batch of chiral amine is added.

[0031] Preferably, the amount of ethyl acetate added in the chiral amine resolution step described above is in a mass ratio of 5:1 with ketrolac, and stirring is continued at 50-60°C for 6-12 hours after the dropwise addition is complete, preferably stirring is continued at 55°C for 9 hours after the dropwise addition is complete.

[0032] Preferably, the temperature reduction described in the chiral amine splitting step is reduced to 15°C.

[0033] Preferably, after the chiral amine is divided, the filtrate is further concentrated, ethyl acetate is added, the mixture is stirred, cooled, crystallized, filtered to obtain a second solid, the filtrate is discarded, the first and second solids are mixed, acidified with hydrochloric acid, and filtered to obtain the product FP, which is R-ketrolac.

[0034] Preferably, both the first and second solids are cinchonine salts of R-ketrolac, where the first solid is the cinchonine salt of R-ketrolac obtained by the first chlorination, and the second solid is the cinchonine salt of R-ketrolac obtained by filtering the mother liquor after the first chlorination and recrystallizing it.

[0035] Preferably, the amount of ethyl acetate added is in a mass ratio of 8:1 with ketrolac, and the cooling temperature is 20°C.

[0036] Preferably, the enzyme described above for enzyme resolution is Novozym 435, and the mass ratio of the enzyme to product D is 10:1.

[0037] Preferably, the buffering component described above for the enzyme decomposition is potassium phosphate buffer solution, pH = 7.0.

[0038] This application also provides an application of R-ketrolac described in the above-mentioned solution in the preparation of cancer therapeutics, preferably the cancer being colon cancer and / or breast cancer. [Effects of the Invention]

[0039] Compared to the prior art, the beneficial effects of this application are as follows: (1) In the prior art, high-boiling-point toluene is used as the solvent, but it has the disadvantage of being difficult to remove and inconvenient for crystallization. In this application, glacial acetic acid is used as the reaction solvent, which is not only clean and environmentally friendly but also easy to remove, significantly improving the conversion rate of the raw material SM1, improving the yield and purity of ketrolac, with the yield of the obtained ketrolac reaching up to 70% or more and the purity reaching 99% or more. (2) In this application, by performing chiral resolution of ketrolac using chiral amines or enzymes, R-ketrolac can be obtained in high purity and high yield, and the obtained R-ketrolac can prevent resistance to chemotherapy drugs and improve the effectiveness and cure rate of chemotherapy. [Brief explanation of the drawing]

[0040] [Figure 1] This is a liquid chromatogram of product A prepared in Example 1. [Figure 2] This is a liquid chromatogram of product C prepared in Example 1. [Figure 3] This is a liquid chromatogram of the product FP prepared by the chiral amine resolution method of Example 1. [Figure 4] This is the chiral purity HPLC chromatogram of the product FP prepared by the chiral amine resolution method of Example 1. [Figure 5] This is the liquid chromatogram of product D prepared in Example 1. [Figure 6] This is a liquid chromatogram of the product FP prepared by the enzymatic resolution method of Example 1. [Figure 7] This is the chiral purity HPLC chromatogram of the product FP prepared by the enzymatic resolution in Example 1. [Figure 8] This is the liquid chromatogram of product A prepared in Example 2. [Figure 9] This is a liquid chromatogram of product C prepared in Example 2. [Figure 10] This is a liquid chromatogram of the product FP prepared by the chiral amine resolution in Example 2. [Figure 11] This is the chiral purity HPLC chromatogram of the product FP prepared by the chiral amine resolution method of Example 2. [Figure 12] This is a liquid chromatogram of product A prepared in Example 3. [Figure 13] This is a liquid chromatogram of product C prepared in Example 3. [Figure 14] This is a liquid chromatogram of the product FP prepared by the chiral amine resolution in Example 3. [Figure 15] This is the chiral purity HPLC chromatogram of the product FP prepared by the chiral amine resolution method of Example 3. [Figure 16] This is a tumor growth curve diagram for the colon cancer model Colon-26, induced by the combined use of R-ketrolac and gemcitabine. [Figure 17] This is a tumor growth curve diagram for the colon cancer model Colon-26, induced by the combined use of R-ketrolac and cyclophosphamide. [Figure 18] This is a tumor growth curve diagram for a 4T1 breast cancer model treated with the combined use of R-ketrolac and cyclophosphamide. [Modes for carrying out the invention]

[0041] The following further limits the technical solutions of the present invention in relation to specific embodiments, but the scope of the claimed protection is not limited to that description.

[0042] The manufacturers and model numbers of the raw material components used in this invention are as follows: JPEG0007904631000007.jpg40130

[0043] Example 1: Method for producing R-ketrolac The following steps are included. Step 1, Manufacturing of Ketrolac: (1) Add glacial acetic acid (11015 g), manganese acetate dihydrate (trivalent) (4087 g), triethyl methanetricarboxylate (SM2) (1300 g), 2-benzoyl pyrrole (SM1) (870 g), and sodium acetate (835 g) to the reaction vessel, raise the temperature until the reaction is complete (65-75°C), then lower the temperature (35-45°C), add methyl tert-butyl ether (7000 ml) to the reaction system, filter to obtain the filtrate, add potassium carbonate aqueous solution to the filtrate to adjust the pH to 4-8, collect the organic phase by liquid-liquid separation, concentrate, recrystallize, filter, and dry to obtain product A (1220 g, yield 59.80%, purity 99.59% (shown in Figure 1)), The reaction equation is, The filename is JPEG0007904631000008.jpg42152. (2) Add 1,2-dichloroethane (28767g), product A (1144g), potassium carbonate (3939g), and tetrabutylammonium bromide (918.74g) to the reaction vessel and raise the temperature to (75~85°C) until the reaction is complete to obtain a mixture containing product B. Filter the mixture containing product B, transfer the filtrate to the reaction vessel and concentrate it, then add tetrahydrofuran solution (6800mL) and sodium hydroxide solution (20%, 4.0kg) to the reaction vessel. The ingredients were added in order, the temperature was raised to 55°C until the reaction was complete, the product was separated, the organic phase was collected, a solution of HCl tetrahydrofuran was added to the organic phase to adjust the pH to 3, the solution was concentrated, methyl tert-butyl ether (5000 mL) was added to the concentrate, water was added to wash, the solution was separated, the organic phase was collected, decolorized, recrystallized, filtered, and dried to obtain product C (303 g, yield 41.8%, purity 99.54% (shown in Figure 2)), which is ketrolac. The reaction equation is, The filename is JPEG0007904631000009.jpg34152.

[0044] Step 2: R-Ketrolak splitting 2.1 Chiral amine resolution Product C (286 g) and isopropyl alcohol (1610 ml) were added to the reaction vessel, and the temperature was raised (55°C) to dissolve product C. Then chiral amine (386.76 g) and seed crystal (4.0 g) were added, and after homogeneous stirring, ethyl acetate (1610 ml) was added dropwise, the temperature was lowered to allow crystallization, and the mixture was filtered to obtain the first solid and filtrate. The first solid was acidified with hydrochloric acid (4 mol / L, 1275 ml), filtered, and product FP (211.98 g), which is R-ketrolac, with a yield of 74%, a purity of 98.58% (shown in Figure 3), and a chiral purity of 98.84% (shown in Figure 4). The reaction equation is, The filename is JPEG0007904631000010.jpg32152.

[0045] 2.2 Enzyme Decomposition: (1) Add product C (180g) and methanol (2844g) to the reaction vessel, reduce the temperature (-5 to 5°C), add SOCl2 (126g), raise the temperature until the reaction is complete (40 to 50°C), concentrate, add process water (900g) to crystallize, filter, and dry to obtain product D (178.69g, yield 94%, purity 99.45% (shown in Figure 5)), The reaction equation is, The filename is JPEG0007904631000011.jpg54150. (2) Product D (100 g), tert-butanol (400 mL), buffer solution (100 mL), and enzyme (10 g) were heated to a temperature of 25-35°C until the reaction was complete, filtered, washed with methyl tert-butyl ether (100 mL) and process water (150 mL), separated, concentrated, separated again, chlorinated with methyl tert-butyl ether (150 mL) and isopropylamine (12.2 g), filtered to obtain a solid, and the solid was acidified with hydrochloric acid (45 mL, 4 mol / L) to obtain product FP (35.91 g, yield 39.6%, purity 97.27% (shown in Figure 6) and chiral purity 87.47% (shown in Figure 7). The reaction equation is, The filename is JPEG0007904631000012.jpg31152.

[0046] Example 2: Method for producing R-ketrolac The following steps are included. Step 1, Manufacturing of Ketrolac: (1) Add glacial acetic acid (18980g), manganese acetate dihydrate (trivalent) (4700g), triethyl methanetricarboxylate (SM2) (1500g), 2-benzoyl pyrrole (SM1) (1000g), and sodium acetate (960g) to the reaction vessel, raise the temperature until the reaction is complete (65-75°C), then lower the temperature (35-45°C), add methyl tert-butyl ether (7000ml) to the reaction system, filter to obtain the filtrate, add potassium carbonate aqueous solution to the filtrate to adjust the pH to 4-8, collect the organic phase by liquid-liquid separation, concentrate, recrystallize, filter, and dry to obtain product A (1740g, yield 74%, purity 99.69% (shown in Figure 8)), The reaction equation is, The filename is JPEG0007904631000013.jpg42152. (2) Add 1,2-dichloroethane (36.04 kg), product A (1.72 kg), potassium carbonate (6.14 kg), and tetrabutylammonium bromide (1.4 kg) to the reaction vessel and raise the temperature to 80°C until the reaction is complete to obtain a mixture containing product B. Filter the mixture containing product B, transfer the filtrate to the reaction vessel and concentrate it, then add tetrahydrofuran solution (12.02 kg) and sodium hydroxide solution (7.00 kg) to the reaction vessel in order. The mixture was heated to 54°C until the reaction was complete, the product was separated, the organic phase was collected, 2.5 kg of HCl tetrahydrofuran solution was added to the organic phase to adjust the pH to 3, and the mixture was concentrated. 6.10 kg of methyl tert-butyl ether was added to the concentrate, water was added for washing, the mixture was separated, the organic phase was collected, decolorized, recrystallized, filtered, and dried to obtain product C, which is ketrolac (0.64 kg, yield 56%, purity 98.34% (shown in Figure 9)). The reaction equation is, The filename is JPEG0007904631000014.jpg34152.

[0047] Step 2: R-Ketrolak splitting Product C (0.56 kg) and isopropyl alcohol (2.50 kg) were added to the reaction vessel, and the temperature was raised (55°C) to dissolve product C. Then chiral amine (0.70 kg) and seed crystal (0.011 kg) were added, and after homogeneous stirring, ethyl acetate (2.88 kg) was added dropwise, and the temperature was lowered to crystallize. The mixture was filtered to obtain the first solid and filtrate. The first solid was acidified with hydrochloric acid (4 mol / L, 2.10 kg), filtered, and product FP, which is R-ketrolac (0.32 kg, yield 54%, purity 99.56% (shown in Figure 10), chiral purity 98.97% (shown in Figure 11)). The reaction equation is, The filename is JPEG0007904631000015.jpg32152.

[0048] Example 3: Method for producing R-ketrolac The following steps are included. Step 1, Manufacturing of Ketrolac: (1) Add glacial acetic acid (28.74 kg), manganese acetate dihydrate (trivalent) (8.01 kg), triethyl methanetricarboxylate (SM2) (2.56 kg), 2-benzoyl pyrrole (SM1) (1.71 kg), and sodium acetate (1.64 kg) to the reaction vessel, raise the temperature until the reaction is complete (65-70°C), then cool the temperature and add methyl tert-butyl ether (13.0 kg) to the reaction system, filter to obtain the filtrate, add aqueous potassium carbonate solution to the filtrate to adjust the pH to 4-8, collect the organic phase by liquid-liquid separation, concentrate, recrystallize, filter, and dry to obtain product A (2.84 kg, yield 70%, purity 99.73% (shown in Figure 12)), The reaction equation is, The filename is JPEG0007904631000016.jpg42152. (2) Add 1,2-dichloroethane (59.0 kg), product A (2.82 kg), potassium carbonate (10.0 kg), and tetrabutylammonium bromide (2.28 kg) to the reaction vessel and raise the temperature until the reaction is complete (75-80°C) to obtain a mixture containing product B. Filter the mixture containing product B, transfer the filtrate to the reaction vessel and concentrate it, then add tetrahydrofuran solution (16.02 kg) and sodium hydroxide solution (8.60 kg) to the reaction vessel in sequence and complete the reaction. The mixture was heated until the reaction was complete (50-60°C), the product was separated, the organic phase was collected, a solution of tetrahydrofuran in HCl (4.15 kg) was added to the organic phase to adjust the pH to 3, and the mixture was concentrated. Methyl tert-butyl ether (20.10 kg) was added to the concentrate, water was added for washing, the mixture was separated, the organic phase was collected, the color was removed, the mixture was recrystallized, filtered, and dried to obtain product C, which is ketrolac (1.06 kg, yield 56%, purity 94.97% (shown in Figure 13)). The reaction equation is, The filename is JPEG0007904631000017.jpg34152.

[0049] Step 2: R-Ketrolak splitting Product C (1.06 kg) and isopropyl alcohol (4.64 kg) were added to the reaction vessel, and the temperature was raised (50-60°C) to dissolve product C. Then chiral amine (1.50 kg) and seed crystal (0.018 kg) were added, and after homogeneous stirring, ethyl acetate (5.42 kg) was added dropwise, and the temperature was lowered to crystallize. The mixture was filtered to obtain the first solid and filtrate. The first solid was acidified with hydrochloric acid (6.20 kg), filtered, and product FP (0.452 kg), which is R-ketrolac, was obtained with a yield of 42%, a purity of 99.50% (shown in Figure 14), and a chiral purity of 99.58% (shown in Figure 15). The reaction equation is, The filename is JPEG0007904631000018.jpg32152.

[0050] Application Example: Application of R-ketrolac in the preparation of therapeutic drugs for colon cancer or breast cancer. 1. Therapeutic efficacy of combination therapy with R-ketrolac and gemcitabine for the colon cancer model Colon-26. A colon cancer tumor model was established using adult male BALB / C mice by subcutaneous inoculation of 106 well-growing Colon-26 tumor cells. From day 7 after tumor inoculation, the two largest diameters of the tumor were measured twice a week using calipers, and the tumor size was expressed as area (square millimeters). After the tumors had grown to a certain size, the mice were randomly divided into four groups, including one control group (n=5) and three treatment groups. In the R-ketrolac monotherapy group (n=5), 0.1 mg was administered intragastricly daily for a total of 12 days. In the gemcitabine monotherapy group (n=4), 2 mg was administered intraperitoneally every three days for a total of four doses. In the combination therapy group (n=5), two drugs were used in combination, with the same dosage and frequency as the monotherapy groups. Tumor measurements were continued twice a week after the start of treatment, and tumor growth curves were created using the mean tumor area ± SEM. From the growth curve figure 16 below, it was found that R-ketrolac did not affect the growth of colon cancer tumors when administered alone, but when used in combination with gemcitabine, the inhibitory effect on tumor growth was significantly enhanced (*p=0.021).

[0051] 2. Therapeutic effects of combination therapy with cyclophosphamide on the colon cancer model Colon-26 The colon cancer tumor model was established as described above. After the tumors grew to a certain size, they were randomly divided into three groups, including one control group (n=6) and two treatment groups. In the cyclophosphamide monotherapy group (n=6), 3 mg was administered intraperitoneally once every 6 days for a total of 3 times. In the combination therapy group (n=7), the dose and frequency of cyclophosphamide administration were the same as in the monotherapy group, and based on this, R-ketrolac was administered intragastricly once daily at a dose of 0.1 mg for a total of 18 times.

[0052] Tumor measurements were continued twice a week after the start of treatment, and tumor growth curves were created using the mean tumor area ± SEM. From the growth curve figure 17 below, it was found that the combination of R-ketrolac and cyclophosphamide significantly increased the inhibitory effect on tumor growth (***p=0.0002). More importantly, 4 out of 7 mice in the combination therapy group were completely cured (cure rate 57.1%), compared to only 1 out of 6 mice in the cyclophosphamide group (cure rate 16.7%). Furthermore, the cure rate in the combination therapy group was found to be 3.4 times higher than that of the cyclophosphamide monotherapy group.

[0053] 3. Therapeutic efficacy of combination therapy with cyclophosphamide for breast cancer model 4T1 The breast cancer tumor model uses adult female BALB / C mice, with a 5×10⁶ size. 5 This was established by subcutaneous inoculation of highly proliferative 4T1 tumor cells. From day 7 after tumor inoculation, the two largest diameters of the tumor were measured twice a week using calipers, and the tumor size was expressed as area (square millimeters). After the tumors had grown to a certain size, the mice were randomly divided into three groups, including one control group (n=5) and two treatment groups. In the cyclophosphamide monotherapy group (n=6), 3 mg was administered intraperitoneally once every 6 days for a total of 4 doses. In the combination therapy group (n=6), the dose and frequency of cyclophosphamide administration were the same as in the monotherapy group, and based on this, R-ketrolac was administered intragastricly once daily at a dose of 0.1 mg for a total of 24 doses.

[0054] Tumor measurements were continued twice a week after the start of treatment, and tumor growth curves were created using the mean tumor area ± SEM. From the growth curve figure 18 below, it was found that the combination of R-ketrolac and cyclophosphamide significantly enhanced the inhibitory effect of cyclophosphamide on breast cancer 4T1 tumor growth (**p=0.0075).

[0055] Finally, it should be noted that the above embodiments are used solely to illustrate the technical solutions of the present invention and do not limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art will understand that the technical solutions of the present invention can be modified or replaced with equivalents without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A method for manufacturing R-ketrolac, Ketrolac manufacturing step 1, The process includes a second step of resolving R-ketrolac by chiral amine resolving, The chiral amine resolution step is, The reaction involves adding ketrolac and isopropyl alcohol to a reaction vessel, raising the temperature to dissolve the ketrolac, then adding chiral amine and seed crystals, stirring uniformly, adding ethyl acetate dropwise, cooling to crystallize, filtering to obtain a first solid and filtrate, acidifying the first solid with hydrochloric acid, filtering to obtain product FP, which is R-ketrolac. The reaction equation is, A manufacturing method characterized by the following:

2. The manufacturing of ketrolac as described in Step 1 is Glacial acetic acid, manganese acetate dihydrate, triethyl methanetricarboxylate (SM2), 2-benzoyl pyrrole (SM1), and sodium acetate are added to the reaction vessel, the temperature is raised until the reaction is complete, then the temperature is lowered, methyl tert-butyl ether is added to the reaction system, the mixture is filtered to obtain a filtrate, an aqueous potassium carbonate solution is added to the filtrate to adjust the pH to 4-8, the organic phase is collected by liquid-liquid separation, concentrated, recrystallized, filtered, and dried to obtain product A, which is (5-benzoyl-1H-pyrrole-2-yl)methanetricarboxylate. The reaction equation is, Step (1) is, 1,2-dichloroethane, product A, potassium carbonate, and tetrabutylammonium bromide are added to the reaction vessel, and the temperature is raised once until the reaction is complete to obtain a mixture containing product B, which is 5-benzoyl-2,3-dihydro-1H-pyrrolidine-1,1-dicarboxylate diethyl ester. The mixture containing product B is filtered, and the filtrate is transferred to the reaction vessel and concentrated. Next, tetrahydrofuran solution and sodium hydroxide solution are added to the reaction vessel in sequence, and the temperature is raised a second time until the reaction is complete to separate the products, collect the organic phase, add HCl tetrahydrofuran solution to the organic phase to adjust the pH to 3, concentrate, add methyl tert-butyl ether to the concentrate, wash with water, separate, collect the organic phase, decolorize, recrystallize, filter, and dry to obtain product C, which is ketrolac. The reaction equation is, The manufacturing method according to claim 1, characterized in that it is the same.

3. The mass ratio of the amount of isopropyl alcohol added to ketrolac as described in the chiral amine resolution step is 4.2:1 to 8.0:

1. The heating temperature described in the chiral amine splitting step is 50 to 60°C. The chiralamine described in the chiralamine resolution step is one of dehydroabiethylamine, (s)-1-phenylethylamine, (1S,2S)-(+)-1,2-diaminocyclohexane, L-(-)-epinephrine, (R)-(+)-1-(1-naphthyl)ethylamine, and synconine. The molar ratio of ketrolac to chiralamine described in the chiralamine resolution step is 1:0.82 to 1:1.

73. The molar ratio of ketrolac to seed crystal described in the chiral amine splitting step is 1:0.0005 to 1:0.

05. The chiral amine addition method described in the chiral amine splitting step is batch addition, and the batch addition step is as follows: first, add a chiral amine with a molar ratio of 0.52 to 0.86:1 with ketrolac, stir to dissolve the solid, then add a chiral amine with a molar ratio of 0.04 to 0.17:1 with ketrolac, stir again to dissolve the solid, then add a chiral amine with a molar ratio of 0.04 to 0.17:1 with ketrolac, stir for a further 1 hour, then add ketrolac with a molar ratio of 0.04 to 0.17:1 with ketrolac, and finally, stir for 1.5 hours, then add a chiral amine with a molar ratio of 0.17 to 0.35:1 with ketrolac. After the second addition of the chiral amine, a seed crystal was added. The amount of ethyl acetate added in the chiral amine splitting step is in a mass ratio of 5:1 with ketrolac, and further includes continuing stirring at 50-60°C for 6-12 hours after the dropwise addition is complete. The step of reducing the temperature to crystallize the chiral amine described above means reducing the temperature to 15°C. The manufacturing method according to claim 1, characterized by the above.

4. The molar ratio of 2-benzoyl pyrrole, triethyl methanetricarboxylate, manganese acetate dihydrate, sodium acetate, and glacial acetic acid described in step (1) is 0.99 to 1.01: 1.09 to 1.12: 1.9 to 2.1: 2.8 to 3.2: 28 to 32. In step (1), the mass ratio of methyl tert-butyl ether to 2-benzoyl pyrrole is 18:

1. The molar ratio of 1,2-dichloroethane, product A, potassium carbonate, and tetrabutylammonium bromide after obtaining product A is 85-95:0.99-1.01:8.7-11.6:0.75-1.

25. The mass ratio of the tetrahydrofuran solution to product A after obtaining product A is 8:1, and the mass ratio of the sodium hydroxide solution to product A is 4:

1. The mass fraction of the sodium hydroxide solution is 20%. The mass fraction of the HCl tetrahydrofuran solution after obtaining product A is 11%, and the mass ratio of the amount of HCl tetrahydrofuran solution added to product A is 1.45:

1. The mass ratio of methyl tert-butyl ether to product A after obtaining product A is 7:

1. The manufacturing method according to claim 2, characterized in that the recrystallization step after obtaining product A involves concentrating the decolorized organic phase, adding n-heptane, raising the temperature to 40°C, stirring to dissolve the solid, then slowly lowering the temperature to -10°C to crystallize the solid, filtering, and vacuum drying to obtain product C.

5. The use of R-ketrolac manufactured by the manufacturing method described in any one of claims 1 to 4 in the preparation of cancer therapeutic drugs, The aforementioned cancer treatment drug comprises R-ketrolac and a chemotherapeutic agent, wherein the chemotherapeutic agent comprises gemcitabine or cyclophosphamide.

6. The use according to claim 5, characterized in that the cancer is selected from colon cancer and / or breast cancer.

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