Preparation of R-ketorolac and its application

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 priority to a Chinese patent application filed with the China Patent Office on August 26, 2022, with application number CN202211032611.5 and title "Method for preparing R-ketorolac and its application", the entire contents of which are incorporated herein by reference. [Technical field]

[0002] The present application belongs to the technical field of organic synthesis, and specifically relates to a preparation method of R-ketorolac and its application. [Background technology]

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

[0004] Ketorolac (5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid) is a new type of nonsteroidal anti-inflammatory analgesic that is potent, non-addictive, and non-narcotic, and exerts a strong analgesic effect by inhibiting the synthesis of prostaglandins. Racemic ketorolac has been on the market in the United States since 1991 and is sold as ketorolac trishydroxymethylaminomethane. JPEG2025516009000002.jpg3979 Formula I

[0005] The structure of the ketorolac molecule is shown in Formula I. There is a chiral carbon atom in the molecule, and a pair of enantiomers exists. Research has shown that the analgesic effect of S-ketorolac is 230 times stronger than that of R-ketorolac, and the anti-inflammatory effect is 60 times stronger. Therefore, since ketorolac was released on the market, people have always been looking for ways to obtain its S-isomer.

[0006] Patent document 1 discloses a method for preparing optically active ketorolac, the first step of which is kinetic resolution reaction, and the two amides produced by the reaction do not appear simultaneously, but appear one after another.The most ideal situation is that one isomer of racemic ketorolac is completely converted into amide product, and then the other isomer begins to react.In the case of kinetic resolution reaction, in principle, as long as the reaction is terminated before the racemic raw material is completely converted into product, the reaction product and unreacted raw material should be optically active, that is, the reaction shows selectivity and can achieve resolution, and in this application, the final resolution is S-isomer.

[0007] However, there are few reports on the preparation of R-isomers, and Patent Document 2 discloses the application of R-ketorolac in the prevention and treatment of aortic dissection and aortic aneurysm. Oral administration of R-ketorolac can inhibit the pathological dilation of the aorta, reduce the incidence and mortality of aortic dissection and aortic aneurysm, and R-ketorolac can inhibit the occurrence of inflammatory reaction in the vascular wall, reduce the rupture of aortic aneurysm, inhibit the occurrence of intraluminal intramural hematoma, maintain the integrity of elastic fiber in the vascular wall, and treat aortic dissection and aortic aneurysm. This invention opens up a new application field of R-ketorolac, provides a meaningful reference for the prevention and treatment of aortic dissection and aortic aneurysm disease, and improves vascular disease conditions, and although this application discloses the application of R-ketorolac in the prevention and treatment of aortic dissection and aortic aneurysm, it does not concern the preparation of R-isomers.

[0008] Although U.S. Patent No. 5,333,636 discloses R-ketorolac for the treatment of cachexia and provides a method for treating cachexia to reduce morbidity and mortality due to chronic diseases and generally improve the efficacy of treatment of chronic diseases, the application is also not directed to the manufacture of R-ketorolac.

[0009] Therefore, there is a need to provide a method for producing R-ketorolac. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] Chinese Patent No. 02102547.9 [Patent Document 2] Chinese Patent No. 202111115983 [Patent Document 3] Chinese Patent No. 201880084997 Summary of the Invention [Problem to be solved by the invention]

[0011] Based on the deficiencies of the prior art, the present application aims to provide a method for producing R-ketorolac and its application, which can obtain higher purity R-ketorolac by optimizing the production method, and by using the obtained R-ketorolac in combination with chemotherapy, can greatly enhance the effect of chemotherapy and improve the tumor cure rate. [Means for solving the problem]

[0012] In order to solve the above technical problems, the present application is realized by the following technical solutions.

[0013] The process for preparing R-ketorolac comprises the following steps: Step 1, Preparation of Ketorolac: (1) Add glacial acetic acid, manganese acetate dihydrate (trihydrate), triethyl methanetricarboxylate (SM2), 2-benzoylpyrrole (SM1), and sodium acetate to a reaction vessel, heat the vessel until the reaction is complete, then cool the vessel, add methyl tert-butyl ether to the reaction system, filter the vessel to obtain a filtrate, add an aqueous potassium carbonate solution to the filtrate to adjust the pH to 4-8, collect the organic phase by liquid separation, concentrate, recrystallize, filter, and dry to obtain (5-benzoyl-1H-pyrrol-2-yl)methanetricarboxylate; The reaction equation is: JPEG2025516009000003.jpg42152. (2) 1,2-dichloroethane, product A, potassium carbonate, and tetrabutylammonium bromide are added to the reaction vessel, and the mixture is heated for the first time until it is completely reacted to obtain a mixture containing product B, which is 5-benzoyl-2,3-dihydro-1H-pyrrolidine-1,1-dicarboxylic acid diethyl ester; the mixture containing product B is filtered, and the filtrate is transferred to the reaction vessel and concentrated; then, tetrahydrofuran solution and sodium hydroxide solution are added to the reaction vessel in sequence, and the mixture is heated for the second time until it is completely reacted; the product is separated; the organic phase is collected; HCl in tetrahydrofuran solution is added to the organic phase to adjust the pH to 3; the organic phase is concentrated; methyl tert-butyl ether is added to the concentrated liquid; water is added to wash and separate; the organic phase is collected, decolorized, recrystallized, filtered, and dried to obtain product C, which is ketorolac; The reaction equation is: JPEG2025516009000004.jpg34152.

[0014] Step 2: Resolution of R-ketorolac, which is divided into chiral amine resolution or enzymatic resolution, wherein the chiral amine resolution step is: Add ketorolac and isopropyl alcohol to the reactor, heat to dissolve ketorolac, then add chiral amine and seed crystals, stir uniformly, add ethyl acetate dropwise, cool to crystallize, filter to obtain a first solid and a filtrate, acidify the first solid with hydrochloric acid, filter to obtain product FP, which is R-ketorolac; The reaction equation is JPEG2025516009000005.jpg32152. The enzymatic resolution step comprises: (1) Ketorolac and methanol are added to a reactor, cooled to -5-5°C, SOCl2 is added, and the temperature is raised to 40-50°C until the reaction is complete. After concentration, water is added to crystallize, and the mixture is filtered and dried to obtain product D, which is ketorolac methyl ester. The reaction equation is: JPEG2025516009000006.jpg54150. (2) Product D, tert-butanol, buffer solution, and enzyme are added to the reactor in order, reacted, and the chiral purity is monitored. After the reaction is completed, the reaction is filtered, methyl tert-butyl ether and water are added to wash, and then the liquid is separated. The organic phase is concentrated and separated 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, and filtered. The filtered solid is added to the reactor, and water and 4 mol / L hydrochloric acid aqueous solution are added to acidify, and the mixture is filtered to obtain product FP, which is R-ketorolac. The reaction equation is: The image is JPEG2025516009000007.jpg31152.

[0015] The molar ratio of 2-benzoylpyrrole, triethyl methanetricarboxylate, manganese 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 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 amount of methyl tert-butyl ether added in step (1) to the amount of 2-benzoylpyrrole is 18:1; Preferably, the elevated 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 drop temperature described in step (1) is 35 to 45°C, preferably 40°C.

[0018] Preferably, the recrystallization step described in step (1) includes adding ethanol in a mass ratio of 4:1 with 2-benzoylpyrrole to the concentrated organic phase, heating to 40°C and stirring to dissolve the solid, then cooling to -10°C to crystallize the solid, filtering and drying to obtain product A, and the cooling and cooling time is 6-10 hours.

[0019] Preferably, the criterion for determining a 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 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 heating temperature 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 complete reaction is product A / product B≦5%.

[0022] Preferably, the mass ratio of the tetrahydrofuran solution added 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 amount of sodium hydroxide solution added to product A is 4:1; Preferably, the second heating temperature 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 complete reaction is B / C≦5%.

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

[0024] Preferably, the bleaching step (2) uses a CUNO filter, Preferably, the recrystallization step described in step (2) is to concentrate the organic phase after decolorization, add n-heptane, raise to 40° C., stir to dissolve the solid, then slowly lower the temperature to −10° C. to crystallize the solid, filter, and vacuum dry to obtain product C.

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

[0026] Preferably, the elevated temperature described in the chiral amine resolution step is 50-60°C, preferably 55°C.

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

[0028] Preferably, the molar ratio of the product C (ketorolac) to the chiral amine is 1:0.82 to 1:1.73; Preferably, the molar ratio of the product C (ketorolac) to the seed crystals is 1:0.0005 to 1:0.05; Preferably, the chiral amine is added in batches, and the specific addition method is: first, add chiral amine having a molar ratio with product C of 0.52-0.86:1, stir to dissolve solids, then add chiral amine having a molar ratio with product C of 0.04-0.17:1, stir to dissolve solids, add chiral amine having a molar ratio with product C of 0.04-0.17:1, stir for another hour, then add ketorolac having a molar ratio with product C of 0.04-0.17:1, and finally, stir for 1.5 hours, then add chiral amine having a molar ratio with product C of 0.17-0.35:1.

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

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

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

[0032] Preferably, the temperature reduction in the chiral amine resolution step is to reduce the temperature to 15°C.

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

[0034] Preferably, the first solid and the second solid are both cinchonine salt of R-ketorolac, of which the first solid is the cinchonine salt of R-ketorolac obtained by the first salification, and the second solid is the cinchonine salt of R-ketorolac obtained by filtering the mother liquor after the first salification and recrystallizing it.

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

[0036] Preferably, the enzyme mentioned in the enzymatic resolution is Novozym 435 and the mass ratio of said enzyme to product D is 10:1.

[0037] Preferably, the buffer component described in the enzymatic resolution above is potassium phosphate buffer, pH=7.0.

[0038] The present application also provides the application of R-ketorolac as described in the aforesaid solution in preparing a cancer treatment drug, preferably, the cancer is colon cancer or / and breast cancer. Effect of the Invention

[0039] Compared with the prior art, the beneficial effects of the present application are as follows: (1) In the prior art, toluene with a high boiling point is used as the solvent, which has the disadvantages of being difficult to remove and inconvenient for crystallization. In the present application, glacial acetic acid is used as the reaction solvent, which is not only clean and environmentally friendly, but also easy to remove, which greatly improves the conversion rate of the raw material SM1 and improves the yield and purity of ketorolac, and the yield of the obtained ketorolac reaches up to more than 70%, and the purity reaches more than 99%. (2) In the present application, by using chiral amines or enzymes to perform chiral resolution of ketorolac, 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. [Brief description of the drawings]

[0040] [Figure 1] 1 is a liquid chromatogram of the product A produced in Example 1. [Diagram 2] 1 is a liquid chromatogram of the product C produced in Example 1. [Diagram 3] 1 is a liquid chromatogram of the product FP produced by chiral amine resolution in Example 1. [Figure 4] 1 is a chiral purity HPLC chromatogram of product FP produced by chiral amine resolution in Example 1. [Diagram 5] 1 is a liquid chromatogram of product D produced in Example 1. [Figure 6] 1 is a liquid chromatogram of the product FP produced by enzymatic resolution in Example 1. [Figure 7] 1 is a chiral purity HPLC chromatogram of product FP produced by enzymatic resolution in Example 1. [Figure 8] 1 is a liquid chromatogram of the product A produced in Example 2. [Figure 9] 1 is a liquid chromatogram of the product C produced in Example 2. [Figure 10] 1 is a liquid chromatogram of the product FP produced by chiral amine resolution in Example 2. [Figure 11] 1 is a chiral purity HPLC chromatogram of product FP produced by chiral amine resolution in Example 2. [Figure 12] 1 is a liquid chromatogram of the product A produced in Example 3. [Figure 13] 1 is a liquid chromatogram of product C produced in Example 3. [Figure 14] 1 is a liquid chromatogram of the product FP produced by chiral amine resolution in Example 3. [Figure 15] 1 is a chiral purity HPLC chromatogram of product FP produced by chiral amine resolution in Example 3. [Figure 16] FIG. 1 is a graph showing the tumor growth curve in a colon cancer model, Colon-26, treated with a combination of R-ketorolac and gemcitabine. [Figure 17] FIG. 1 is a graph showing the tumor growth curve in a colon cancer model, Colon-26, treated with a combination of R-ketorolac and cyclophosphamide. [Figure 18] FIG. 1 is a graph showing the tumor growth curve in breast cancer model 4T1 treated with the combination of R-ketorolac and cyclophosphamide. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] The technical solution of the present invention will be further limited in relation to specific embodiments below, but the claimed scope of protection is not limited to that description.

[0042] The purchase manufacturers and model numbers of the raw material components used in the present invention are as follows. JPEG2025516009000008.jpg40130

[0043] Example 1: Method for manufacturing R-ketorolac It includes the following steps. Step 1, manufacturing of ketorolac: (1) Add glacial acetic acid (11015 g), manganese(II) acetate dihydrate (trivalent) (4087 g), triethyl methanetricarboxylate (SM2) (1300 g), 2-benzoylpyrrole (SM1) (870 g), and sodium acetate (835 g) to the reaction kettle, heat up to (65 - 75 °C) until complete reaction, cool down to (35 - 45 °C), add methyl tert-butyl ether (7000 ml) to the reaction system, filter to obtain a filtrate, add an aqueous potassium carbonate solution to the filtrate to adjust the pH to 4 - 8, collect the organic phase by 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 JPEG2025516009000009.jpg42152. (2) 1,2-dichloroethane (28767g), product A (1144g), potassium carbonate (3939g), and tetrabutylammonium bromide (918.74g) were added to the reaction vessel, and the temperature was raised to (75-85°C) until the reaction was complete, to obtain a mixture containing product B. The mixture containing product B was filtered, and the filtrate was transferred to the reaction vessel and concentrated. Then, tetrahydrofuran solution (6800mL) and sodium hydroxide solution (20%, 4.0kg) were added to the reaction vessel. and then the temperature was raised to 55°C until the reaction was complete, the product was separated, the organic phase was collected, and a solution of HCl in tetrahydrofuran was added to the organic phase to adjust the pH to 3, concentrated, methyl tert-butyl ether (5000mL) was added to the concentrated solution, and water was added to wash and separate the liquid, the organic phase was collected, decolorized, recrystallized, filtered, and dried to obtain product C, which is ketorolac (303g, yield 41.8%, purity 99.54% (shown in Figure 2)). The reaction equation is: The image is JPEG2025516009000010.jpg34152.

[0044] Step 2, Partitioning of R-Ketorolac 2.1 Chiral amine resolution Product C (286 g) and isopropyl alcohol (1610 ml) are added to the reactor, and the temperature is raised (55° C.) to dissolve Product C. Then, chiral amine (386.76 g) and seed crystals (4.0 g) are added. After uniform stirring, ethyl acetate (1610 ml) is added dropwise, and the temperature is lowered to crystallize. Filtered to obtain a first solid and a filtrate. The first solid is acidified with hydrochloric acid (4 mol / L, 1275 ml), and filtered to obtain product FP (211.98 g), which is R-ketorolac, with a yield of 74%, a purity of 98.58% (shown in FIG. 3), and a chiral purity of 98.84% (shown in FIG. 4). The reaction equation is: The image is JPEG2025516009000011.jpg32152.

[0045] 2.2 Enzymatic resolution: (1) Product C (180 g) and methanol (2844 g) were added to a reaction vessel, cooled (-5 to 5°C), SOCl2 (126 g) was added, and the temperature was raised (40 to 50°C) until the reaction was complete. After concentration, process water (900 g) was added to crystallize, filtered, and dried to obtain Product D (178.69 g, 94% yield, 99.45% purity (shown in Figure 5)). The reaction equation is: JPEG2025516009000012.jpg54150. (2) Product D (100 g), tert-butanol (400 mL), buffer solution (100 mL), and enzyme (10 g) were heated (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, salified 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, 39.6% yield, 97.27% purity (shown in Figure 6) and 87.47% chiral purity (shown in Figure 7). The reaction equation is: The image is JPEG2025516009000013.jpg31152.

[0046] Example 2: Method for the preparation of R-ketorolac The method includes the following steps: Step 1, Preparation of Ketorolac: (1) Add glacial acetic acid (18980g), manganese acetate dihydrate (trivalent) (4700g), triethyl methanetricarboxylate (SM2) (1500g), 2-benzoylpyrrole (SM1) (1000g), and sodium acetate (960g) to a reaction vessel, heat the vessel until the reaction is complete (65-75°C), then cool the vessel (35-45°C), add methyl tert-butyl ether (7000ml) to the reaction system, filter the vessel to obtain a filtrate, add an aqueous potassium carbonate solution to the filtrate to adjust the pH to 4-8, collect the organic phase by liquid separation, concentrate, recrystallize, filter, and dry the vessel to obtain product A (1740g, yield 74%, purity 99.69% (shown in Figure 8)). The reaction equation is: The image is JPEG2025516009000014.jpg42152. (2) 1,2-dichloroethane (36.04 kg), product A (1.72 kg), potassium carbonate (6.14 kg), and tetrabutylammonium bromide (1.4 kg) are added to the reaction vessel, and the temperature is raised to 80°C until the reaction is complete. A mixture containing product B is obtained, and the mixture containing product B is filtered. The filtrate is transferred to the reaction vessel and concentrated. Then, tetrahydrofuran solution (12.02 kg) and sodium hydroxide solution (7.00 kg) are added to the reaction vessel in order. The temperature was raised until the reaction was complete (54° C.), the product was separated, the organic phase was collected, a solution of HCl in tetrahydrofuran (2.5 kg) was added to the organic phase to adjust the pH to 3, concentrated, methyl tert-butyl ether (6.10 kg) was added to the concentrate, and the mixture was washed with water, separated, the organic phase was collected, decolorized, recrystallized, filtered, and dried to obtain ketorolac product C (0.64 kg, 56% yield, 98.34% purity (shown in FIG. 9 )). The reaction equation is: The image is JPEG2025516009000015.jpg34152.

[0047] Step 2, Partitioning of R-Ketorolac Product C (0.56 kg) and isopropyl alcohol (2.50 kg) are added to the reactor, and the temperature is raised (55° C.) to dissolve Product C; then, chiral amine (0.70 kg) and seed crystals (0.011 kg) are added; after uniform stirring, ethyl acetate (2.88 kg) is added dropwise; the temperature is lowered to crystallize; filtered to obtain a first solid and a filtrate; the first solid is acidified with hydrochloric acid (4 mol / L, 2.10 kg), and filtered to obtain product FP (0.32 kg, yield 54%, purity 99.56% (shown in FIG. 10), chiral purity 98.97% (shown in FIG. 11)), which is R-ketorolac. The reaction equation is: The image is JPEG2025516009000016.jpg32152.

[0048] Example 3: Method for the preparation of R-ketorolac The method includes the following steps: Step 1, Preparation of Ketorolac: (1) Add glacial acetic acid (28.74 kg), manganese acetate dihydrate (trivalent) (8.01 kg), triethyl methanetricarboxylate (SM2) (2.56 kg), 2-benzoylpyrrole (SM1) (1.71 kg), and sodium acetate (1.64 kg) to a reaction vessel, heat the vessel until the reaction is complete (65-70°C), lower the temperature, add methyl tert-butyl ether (13.0 kg) to the reaction system, filter the vessel to obtain a filtrate, add an aqueous potassium carbonate solution to the filtrate to adjust the pH to 4-8, collect the organic phase by 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 image is JPEG2025516009000017.jpg42152. (2) 1,2-dichloroethane (59.0 kg), product A (2.82 kg), potassium carbonate (10.0 kg), and tetrabutylammonium bromide (2.28 kg) are added to the reaction vessel, and the temperature is raised (75-80°C) until the reaction is complete. A mixture containing product B is obtained, and the mixture containing product B is filtered. The filtrate is transferred to the reaction vessel and concentrated. Next, tetrahydrofuran solution (16.02 kg) and sodium hydroxide solution (8.60 kg) are added to the reaction vessel in order, and the reaction is complete. The temperature was raised (50-60°C) until the reaction was complete, the product was separated, the organic phase was collected, a solution of HCl in tetrahydrofuran (4.15 kg) was added to the organic phase to adjust the pH to 3, concentrated, methyl tert-butyl ether (20.10 kg) was added to the concentrated solution, and water was added for washing and separation, the organic phase was collected, decolorized, recrystallized, filtered, and dried to obtain ketorolac product C (1.06 kg, yield 56%, purity 94.97% (shown in Figure 13)). The reaction equation is: The image is JPEG2025516009000018.jpg34152.

[0049] Step 2, Partitioning of R-Ketorolac Product C (1.06 kg) and isopropyl alcohol (4.64 kg) are added to the reactor, and the temperature is raised (50-60°C) to dissolve Product C. Then, chiral amine (1.50 kg) and seed crystals (0.018 kg) are added, and after uniform stirring, ethyl acetate (5.42 kg) is dropped, and 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 (6.20 kg), and filtered to obtain product FP (0.452 kg), which is R-ketorolac, 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 image is JPEG2025516009000019.jpg32152.

[0050] Application example: Application of R-ketorolac in the preparation of a drug for treating colon or breast cancer 1. Therapeutic effect of R-ketorolac and gemcitabine combination on colon cancer model Colon-26 Colon cancer tumor models were established using adult male BALB / C mice by subcutaneous inoculation with 106 well-growing Colon-26 tumor cells. From the 7th day after tumor inoculation, the two largest diameters of the tumor were measured twice a week with a vernier caliper, and the tumor size was expressed as an 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-ketorolac single agent group (n=5), 0.1 mg was administered intragastrically every day for a total of 12 days, in the gemcitabine single agent group (n=4), 2 mg was administered intraperitoneally once every 3 days for a total of 4 times, and in the combination treatment group (n=5), the two drugs were administered in combination, with the dosage and frequency of administration being the same as in the single agent group. After the start of treatment, tumor measurements were continued twice a week, and tumor growth curves were plotted using the mean tumor area ± SEM. The growth curves in Figure 16 below show that R-ketorolac had no effect on colon cancer tumor growth when administered alone, but when combined with gemcitabine, it could significantly enhance the inhibitory effect on tumor growth (*p=0.021).

[0051] 2. Therapeutic effect of combination therapy with cyclophosphamide on colon cancer model Colon-26 Colon cancer tumor models were 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), cyclophosphamide was intraperitoneally administered once every 6 days, 3 mg each time, for a total of three 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-ketorolac was intragastrically administered once a day, 0.1 mg each time, for a total of 18 times.

[0052] After the start of treatment, tumor measurements were continued twice a week, and tumor growth curves were drawn using the mean tumor area ± SEM. From the growth curves in Figure 17 below, we can see that the combination of R-ketorolac and cyclophosphamide can significantly enhance the inhibitory effect on tumor growth (***p=0.0002). More importantly, 4 out of 7 mice in the combination treatment group were completely cured (cure rate 57.1%), while only 1 out of 6 mice in the cyclophosphamide group were cured (cure rate 16.7%). We then found that the cure rate of the combination treatment group was 3.4 times that of the cyclophosphamide single agent group.

[0053] 3. Therapeutic effect of combination with cyclophosphamide on breast cancer model 4T1 The breast cancer tumor model was performed using adult female BALB / C mice with 5 × 10 5 Tumors were established by subcutaneous inoculation of well-growing 4T1 tumor cells. From the 7th day after tumor inoculation, the two largest diameters of the tumor were measured twice a week with a caliper, 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 single-agent cyclophosphamide group (n=6), cyclophosphamide was intraperitoneally administered once every 6 days, 3 mg each time, for a total of four times, while in the combination treatment group (n=6), the dose and frequency of cyclophosphamide administration were the same as in the single-agent group, and based on this, R-ketorolac was intragastrically administered once a day, 0.1 mg each time, for a total of 24 times.

[0054] After the start of treatment, tumor measurements were continued twice a week, and tumor growth curves were plotted using the mean tumor area ± SEM. From the growth curves shown below in Figure 18, it was found that the combination of R-ketorolac and cyclophosphamide could significantly enhance 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 only used to describe the technical solutions of the present invention, and do not limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention can be modified or replaced with equivalents, but without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. 1. A method for producing R-ketorolac, comprising: Step 1 of preparing ketorolac; Step 2: Resolution of R-ketorolac, which is resolved by chiral amine resolution or enzymatic resolution; The chiral amine resolution step comprises: Add ketorolac and isopropyl alcohol to the reactor, heat to dissolve ketorolac, then add chiral amine and seed crystals, stir uniformly, add ethyl acetate dropwise, cool to crystallize, filter to obtain a first solid and a filtrate, acidify the first solid with hydrochloric acid, and filter to obtain product FP, which is R-ketorolac; The reaction equation is: and The enzymatic resolution step comprises: (1) Ketorolac and methanol are added to a reaction vessel, the temperature is lowered to -5 to 5°C, and SOCl ２ and heating to 40-50°C until complete reaction, concentrated, then added with water to crystallize, filtered and dried to obtain product D, which is ketorolac methyl ester; The reaction equation is: and (2) Product D, tert-butanol, buffer solution, and enzyme are added to the reactor in order, reacted, and the chiral purity is monitored. After the reaction is completed, the reaction is filtered, methyl tert-butyl ether and water are added to wash, and then the liquid is separated. The organic phase is concentrated and separated 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, and filtered. The solid obtained by filtration is added to the reactor, and water and 4 mol / L hydrochloric acid aqueous solution are added to acidify, and filtered to obtain product FP, which is R-ketorolac. The reaction equation is: The manufacturing method according to claim 1,

2. The preparation of ketorolac described in step 1 comprises: Add glacial acetic acid, manganese acetate dihydrate, triethyl methanetricarboxylate (SM2), 2-benzoylpyrrole (SM1), and sodium acetate to the reactor, heat the reactor until it is completely reacted, then cool the reactor, add methyl tert-butyl ether to the reaction system, filter the reactor to obtain a filtrate, add potassium carbonate aqueous solution to the filtrate to adjust the pH value to 4-8, collect the organic phase by separation, concentrate, recrystallize, filter, and dry to obtain product A, which is (5-benzoyl-1H-pyrrol-2-yl)methanetricarboxylate; The reaction equation is: Step (1), Add 1,2-dichloroethane, product A, potassium carbonate, and tetrabutylammonium bromide to the reactor, heat the reaction mixture for the first time until it is completely reacted, to obtain a mixture containing product B, which is 5-benzoyl-2,3-dihydro-1H-pyrrolidine-1,1-dicarboxylic acid diethyl ester; filter the mixture containing product B, transfer the filtrate to the reactor and concentrate; then add tetrahydrofuran solution and sodium hydroxide solution to the reactor in sequence, heat the reaction mixture for the second time until it is completely reacted, separate the product, collect the organic phase, add HCl in tetrahydrofuran solution to the organic phase to adjust the pH to 3, concentrate, add methyl tert-butyl ether to the concentrate, add water to wash and separate; collect the organic phase, decolorize, recrystallize, filter, and dry to obtain product C, which is ketorolac; The reaction equation is: The method according to claim 1,

3. 2. The method according to claim 1, wherein the mass ratio of isopropyl alcohol to ketorolac in the chiral amine resolution step is 4.2:1 to 8.0:

1.

4. The method according to claim 1, wherein the temperature in the chiral amine resolution step is 50 to 60° C.

5. 2. The method according to claim 1, wherein the chiral amine in the chiral amine resolution step is one of dehydroabietylamine, (s)-1-phenylethylamine, (1S,2S)-(+)-1,2-diaminocyclohexane, L-(-)-epinephrine, (R)-(+)-1-(1-naphthyl)ethylamine, and cinchonine.

6. 2. The method according to claim 1, wherein the molar ratio of ketorolac to chiral amine in the chiral amine resolution step is 1:0.82 to 1:1.

73.

7. 2. The method according to claim 1, wherein the molar ratio of ketorolac to seed crystals in the chiral amine resolution step is 1:0.0005 to 1:0.

05.

8. The method of claim 1, characterized in that the chiral amine is added in batchwise manner in the chiral amine separation step, and the batchwise addition step is as follows: first, add chiral amine having a molar ratio with ketorolac of 0.52-0.86:1, stir to dissolve solids, then add chiral amine having a molar ratio with ketorolac of 0.04-0.17:1, stir again to dissolve solids, then add chiral amine having a molar ratio with ketorolac of 0.04-0.17:1, stir for another hour, then add ketorolac having a molar ratio with ketorolac of 0.04-0.17:1, and finally, stir for 1.5 hours, then add chiral amine having a molar ratio with ketorolac of 0.17-0.35:

1.

9. The process according to claim 8, characterized in that a seed crystal is added after the second addition of the chiral amine.

10. The method according to claim 1, characterized in that the amount of ethyl acetate added in the chiral amine resolution step is a mass ratio of 5:1 to ketorolac, and the method further comprises continuing stirring at 50-60°C for 6-12 hours after the dropwise addition is completed.

11. 2. The method according to claim 1, wherein the step of crystallizing the chiral amine by lowering the temperature comprises lowering the temperature to 15°C.

12. 2. The method according to claim 1, wherein the enzyme in the enzymatic resolution step is Novozym 435, and the mass ratio of the enzyme loading to product D is 10:

1.

13. The method according to claim 2, characterized in that the molar ratio of 2-benzoylpyrrole, triethyl methanetricarboxylate, manganese acetate dihydrate, sodium acetate, and glacial acetic acid in step (1) is 0.99-1.01:1.09-1.12:1.9-2.1:2.8-3.2:28-32.

14. 3. The method according to claim 2, wherein the mass ratio of methyl tert-butyl ether and 2-benzoylpyrrole in step (1) is 18:

1.

15. The method according to claim 2, wherein the molar ratio of 1,2-dichloroethane, product A, potassium carbonate and tetrabutylammonium bromide in step (2) is 85-95: 0.99-1.01: 8.7-11.6: 0.75-1.

25.

16. 3. The method according to claim 2, wherein the mass ratio of the tetrahydrofuran solution to product A in step (2) is 8:1, and the mass ratio of the sodium hydroxide solution to product A is 4:

1.

17. 17. The method according to claim 16, characterized in that the mass fraction of the sodium hydroxide solution is 20%.

18. 3. The method according to claim 2, wherein the mass fraction of the HCl tetrahydrofuran solution in step (2) is 11%, and the mass ratio of the HCl tetrahydrofuran solution to product A is 1.45:

1.

19. 3. The method according to claim 2, wherein the mass ratio of methyl tert-butyl ether to product A in step (2) is 7:

1.

20. The method according to claim 2, wherein the recrystallization step in step (2) is to concentrate the organic phase after decolorization, add n-heptane, raise the temperature to 40°C, stir to dissolve the solid, and then slowly lower the temperature to -10°C to crystallize the solid, filter, and vacuum dry to obtain product C.

21. Application of R-ketorolac produced by the process according to any one of claims 1 to 20 in the preparation of a cancer treatment drug.

22. 22. The application according to claim 21, wherein the cancer is selected from colon cancer and / or breast cancer.

23. The application of claim 21, wherein the cancer treatment drug comprises R-ketorolac and a chemotherapy drug, the chemotherapy drug comprises gemcitabine or cyclophosphamide.

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