Preparation method of ketorolac impurity D

Abstract

The invention discloses a preparation method of a ketorolac impurity D. According to the method, 2-benzoylpyrrole is used as a main raw material, and the ketorolac impurity D is obtained through condensation, ring closing deacidification and esterification. The method is simple, raw materials are convenient and easy to obtain, the cost is low, the yield is high, and the prepared impurity D meets the requirement of serving as an impurity reference substance.

Description

Technical Field

[0001] The invention belongs to the field of organic chemistry, and particularly relates to a method for preparing ketorolac impurity D. Background Art

[0002] Ketorolac tromethamine is a new type of injectable non-steroidal strong analgesic and moderate anti-inflammatory antipyretic drug. Its mechanism of action is to inhibit the production of peripheral and central prostaglandins (PG) in the body, thereby reducing PG in the periphery and central nervous system. The chemical structure of its main ingredient ketorolac is as follows:

[0003]

[0004] In order to control the quality of the product, the United States Pharmacopoeia (USP) 43rd edition, the European Pharmacopoeia (EP) 10.0 edition and the Chinese Pharmacopoeia (ChP) 2020 edition all clearly stipulate in the quality standards of ketorolac tromethamine raw materials that multiple impurities need to be studied. In the European Pharmacopoeia (EP) 10.0 edition, impurity D (name: 5-benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolazine-1-carboxylic acid) is included in the scope of necessary research. However, under normal circumstances, relevant impurity reference substances are difficult to obtain and expensive, which greatly increases the research and development costs of enterprises.

[0005] At present, there are few reports on the synthesis method of impurity D in the European Pharmacopoeia (EP) (hereinafter referred to as "impurity EP-D" in this text). CN116120325A and CN118561854A both use ketorolac as a starting material, and obtain impurity EP-D after esterification, hydroxylation, esterification and hydrolysis. However, these methods inevitably use hydroxylation reactions, resulting in a low yield in CN116120325A, while CN118561854A uses oxygen as an oxidant, which is inconvenient to operate, has a greater safety risk, and has a low total yield of four steps (about 51%). Summary of the invention

[0006] The invention provides a method for preparing ketorolac impurity D, wherein the method uses cheap and readily available 2-benzoylpyrrole as a starting material, and obtains impurity D (EP-D) through condensation, cyclization decarboxylation and esterification reactions. The method is simple to synthesize, the raw materials are convenient and readily available, the cost is low, and the yield is high. The obtained ketorolac impurity D fully meets the requirements for being used as an impurity reference substance (purity is greater than 95%).

[0007] To achieve the purpose of the present invention, the following embodiments are provided.

[0008] In one embodiment, a method for preparing ketorolac impurity D (5-benzoyl-1-methoxy-2,3-dihydro-1H-pyrrolazine-1-carboxylic acid) of the present invention is as follows:

[0009]

[0010] The preparation method comprises the following steps:

[0011] 1) adding 2-benzoylpyrrole, diethyl malonate, manganese acetate dihydrate (trivalent), sodium acetate, and acetic anhydride to toluene, and heating until the reaction is complete to obtain compound am-1;

[0012] 2) Add compound am-1, phase transfer catalyst a, potassium carbonate and water to 1,2-dichloroethane, heat and reflux until the reaction is complete, separate the organic phase, add phase transfer catalyst b and alkali solution, heat to 35-45°C to complete the reaction, and obtain compound am-2;

[0013] 3) Compound am-2 is added to an organic solvent, an alkali reagent and methyl iodide are added, and the mixture is stirred at room temperature to react. After the reaction is completed, the mixture is quenched with a sodium sulfite solution to separate impurity D (EP-D).

[0014] In some embodiments, preferably, in the above preparation method, in step 1), the molar ratio of 2-benzoylpyrrole: diethyl malonate: manganese acetate dihydrate (trivalent): sodium acetate: acetic anhydride is about 1:1.5:2.5:2.0:7.5.

[0015] In some embodiments, preferably, in the above preparation method, in step 2), the molar ratio of compound am-1: phase transfer catalyst a: phase transfer catalyst b is about 1:0.5:0.05.

[0016] In some embodiments, preferably, in the above preparation method, in step 3), the molar ratio of compound am-2: base reagent: iodomethane is about 1:(1.0-1.5):(2.0-4.0).

[0017] In some embodiments, preferably, in the above preparation method, in step 3), the molar ratio of compound am-2: base reagent: iodomethane is about 1:1.2:2.0.

[0018] In some embodiments, preferably, in the above preparation method, in step 2), the phase transfer catalyst a and the phase transfer catalyst b are both tetrabutylammonium bromide.

[0019] In some embodiments, preferably, in the above preparation method, the organic solvent in step 3) is tetrahydrofuran or 2-methyltetrahydrofuran, more preferably tetrahydrofuran.

[0020] In some embodiments, preferably, in the above preparation method, the alkaline reagent is sodium hydride or potassium hydride, preferably sodium hydride.

[0021] In a specific embodiment, the method for preparing ketorolac impurity D of the present invention comprises the following steps:

[0022] 1) Condensation reaction: 2-benzoylpyrrole, diethyl malonate, manganese acetate dihydrate (trivalent), sodium acetate, and acetic anhydride are added to toluene and heated until the reaction is complete; sodium bisulfite aqueous solution is added to the system, the liquids are separated, and the obtained organic phase is concentrated under reduced pressure to obtain am-1;

[0023] 2) Cyclization and decarboxylation reaction: add am-1, phase transfer catalyst a, potassium carbonate and appropriate amount of water to 1,2-dichloroethane, heat and reflux until the reaction is complete, add water to separate, wash the separated organic phase with water twice, add phase transfer catalyst b and alkali solution again, continue to heat to 35-45°C to complete the reaction, separate the liquids, wash the aqueous phase with ethyl acetate, cool, adjust the pH value to 1-2 with hydrochloric acid, filter, wash the filter cake with water, and dry to obtain am-2;

[0024] 3) Esterification reaction: add am-2 to an organic solvent, cool, add an alkaline reagent and methyl iodide, stir at room temperature until the reaction is complete, quench with sodium sulfite solution, adjust the pH value with hydrochloric acid, add ethyl acetate to extract, concentrate under reduced pressure, and recrystallize with ethyl acetate / n-heptane to obtain a light yellow solid impurity D (i.e., EP-D).

[0025] Preferably, in the above specific embodiment, in the preparation method of impurity D of the present invention, the condensation reaction of step 1), the molar ratio of 2-benzoylpyrrole: diethyl malonate: manganese acetate dihydrate (trivalent): sodium acetate: acetic anhydride is about 1:1.5:2.5:2.0:7.5; in the cyclization decarboxylation reaction of step 2), the phase transfer catalyst a is tetrabutylammonium bromide, the phase transfer catalyst b is tetrabutylammonium bromide, and the molar ratio of am-1: phase transfer catalyst a: phase transfer catalyst b is about 1:0.5:0.05. The alkali solution is one of sodium hydroxide aqueous solution and potassium hydroxide aqueous solution, preferably sodium hydroxide aqueous solution; in the esterification reaction of step 3), the molar ratio of am-2: alkaline reagent: methyl iodide is about 1:(1.0-1.5):(2.0-4.0), preferably 1:1.2:2.0. The alkaline reagent is one of sodium hydride and potassium hydride, preferably sodium hydride.

[0026] The preparation method of the invention has the advantages of convenient and easily available raw materials, simple synthesis, low cost, and can obtain impurity D with relatively high purity (purity greater than 95%) under the condition of high yield. The obtained ketorolac impurity D fully meets the requirements of being used as an impurity reference substance, can be used as a reference for the preparation of impurity reference substances in the detection standard of ketorolac tromethamine finished products, can improve the location analysis and qualitative detection of impurities in the detection analysis of ketorolac tromethamine finished products, effectively control the quality of ketorolac tromethamine finished products, and ensure the safety of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 is the HPLC spectrum of am-1;

[0028] Figure 2 For am-1 1 H-NMR spectrum;

[0029] Figure 3 For am-1 13 C-NMR spectrum;

[0030] Figure 4 is the HPLC spectrum of am-2;

[0031] Figure 5 For am-2 1 H-NMR spectrum;

[0032] Figure 6 For am-2 13 C-NMR spectrum;

[0033] Figure 7 is the HPLC chart of impurity EP-D;

[0034] Figure 8 is the mass spectrum of impurity EP-D;

[0035] Fig. 9 For impurity EP-D 1 H-NMR spectrum. DETAILED DESCRIPTION

[0036] The following examples are representative and are used to further explain and understand the essence of the present invention, but are not intended to limit the scope of the present invention.

[0037] Example 1 Preparation of Impurity D

[0038] Step a): 5.0 g of 2-benzoylpyrrole, 7.0 g of diethyl malonate, 19.6 g of manganese acetate dihydrate (trivalent), 4.8 g of sodium acetate, and 22.4 g of acetic anhydride were added to 50 mL of toluene. After heating for complete reaction, about 50 mL of 5% sodium bisulfite aqueous solution was added, the liquids were separated, and the obtained organic phase was concentrated under reduced pressure to obtain 10.8 g of am-1, with a yield of 95.5% and a purity of 96.757%.

[0039] HPLC: retention time is 29.478min; liquid phase method: octadecylsilane bonded silica gel is used as filler (Inertsil ODS-3C18, 4.6mm×250mm, 5μm); 0.05mol / L diammonium phosphate aqueous solution (pH adjusted to 3.0 with phosphoric acid) is used as mobile phase A, tetrahydrofuran is used as mobile phase B, gradient elution; flow rate is 1.0mL / min; detection wavelength is 313nm; column temperature is 40℃; injection volume is 10μL. The test results are shown in Table 1 and Figure 1 .

[0040] Table 1. HPLC data of am-1 compound

[0041] Peak name Retention time area Peak height area% 1 12.845 19405 1235 0.058 2 15.067 719 35 0.002 3 16.735 2455 60 0.007 4 17.901 69467 2815 0.207 5 19.224 7253 361 0.022 6 20.297 14671 727 0.044 7 23.553 689 33 0.002 8 24.335 51115 2384 0.152 9 24.987 4257 190 0.013 10 27.36 856416 40295 2.55 11 28.592 7719 381 0.023 12 29.478 32493821 1535560 96.757 13 30.206 5929 411 0.018 14 31.561 8380 231 0.025 15 33.711 4646 144 0.014 16 36.434 9260 260 0.028 17 39.141 2381 60 0.007 18 40.573 1495 47 0.004 19 41.926 4930 108 0.015 20 44.917 10683 242 0.032 21 49.2 7384 145 0.022 total 33583075 1585723 100

[0042] 1 H-NMR (400MHz, CDCl3) δ10.294 (s, 1H), 7.868 (dd, J1=4.8Hz, J2=0.8Hz, 2H), 7.568 (t, J1=J2=4.8Hz, 1H), 7.479 (t, J1=5.2Hz, J2=4.8Hz, J=, 2H) , 6.781 (dd, J1=1.6Hz, J2=2.4Hz, 1H), 6.399 (dd, J1=1.6Hz, J2=2.4Hz, 1H), 4.332 (m, 4H), 2.241 (t, J=4.8Hz, 3H), 2.241 (t, J1=J2=4.8Hz, 6H), see Figure 2 .

[0043] 13 C-NMR (400 MHz, CDCl3) δ 184.67, 169.43, 164.46, 138.00, 132.01, 131.64, 130.63, 128.92, 128.36, 118.60, 110.61, 78.51, 63.28, 20.76, 13.88, see Figure 3 .

[0044] Step b): 5.0 g of am-1 is directly added to 15 mL of 1,2-dichloroethane, and then 3.6 g of potassium carbonate, 3.6 g of water, and 2.1 g of tetrabutylammonium bromide are added, and the mixture is heated to reflux until the reaction is complete. Water is added to separate the mixture, and the organic phase is washed twice with water. 0.2 g of tetrabutylammonium bromide and about 14 mL of a 20% aqueous sodium hydroxide solution are added again, and the mixture is heated to 35 to 45° C. until the reaction is complete. The mixture is separated, and the aqueous phase is washed with ethyl acetate, cooled, and the pH value is adjusted to 1 to 2 with hydrochloric acid, filtered, and the filter cake is washed with water and dried to obtain 3.38 g of am-2 with a yield of 96.5% and a purity of 97.934%.

[0045] HPLC: retention time is 11.221min; liquid phase method: octadecylsilane bonded silica gel is used as filler (Inertsil ODS-3 C18, 4.6mm×250mm, 5μm); 0.05mol / L ammonium dihydrogen phosphate aqueous solution (pH adjusted to 3.0 with phosphoric acid) is used as mobile phase A, tetrahydrofuran is used as mobile phase B, gradient elution; flow rate is 1.0mL / min; detection wavelength is 313nm; column temperature is 40℃; injection volume is 10μL. The test results are shown in Table 2 and Figure 4 .

[0046] Table 2. HPLC data of am-2 compound

[0047] Peak name Retention time area Peak height area% 1 2.756 43935 7930 0.896 2 11.221 4804642 506908 97.934 3 11.843 19840 1849 0.404 4 16.235 5563 511 0.113 5 16.46 21463 1020 0.437 6 17.062 10577 779 0.216 total 4906020 518997 100

[0048] 1 H-NMR (400MHz, CDCl3) δ7.786 (d, J=4.8Hz, 2H), 7.542 (t, J1=J2=4.8Hz, 1H), 7.446 (t, J1=4.8Hz, J2=5.2Hz, 2H), 6.836(s, 1H), 6.102(d, 1H), 5.700(br, 2H), 4.631(s, 1H), 4.524(s, 1H), 3.116(s, 1H), 2.739(s, 1H), see Figure 5 .

[0049] 13 C-NMR (400 MHz, CDCl3) δ 186.04, 176.13, 144.57, 138.57, 131.89, 129.03, 128.28, 127.33, 125.56, 102.21, 76.38, 47.09, 41.40, see Figure 6 .

[0050] Step c): 3.0 g of am-2 was added to 12 mL of tetrahydrofuran, the temperature was lowered, 0.53 g of sodium hydride (60%) and 3.14 g of methyl iodide were added, and the reaction was stirred at room temperature until completion, quenched with sodium sulfite solution, the pH value was adjusted with hydrochloric acid, ethyl acetate was added for extraction, and after concentrating under reduced pressure, recrystallized from ethyl acetate / n-heptane to obtain 2.78 g of light yellow solid impurity EP-D, with a yield of 88.1% and a purity of 96.903%.

[0051] HPLC: retention time is 20.825min; liquid phase method: octadecylsilane bonded silica gel is used as filler (Shimadzu ShimNex CS C18, 4.6mm×250mm, 5μm); 0.05mol / L ammonium dihydrogen phosphate aqueous solution (pH adjusted to 3.0 with phosphoric acid) is used as mobile phase A, tetrahydrofuran is used as mobile phase B, gradient elution; flow rate is 1.0mL / min; detection wavelength is 313nm; column temperature is 40℃; injection volume is 20μL. The test results are shown in Table 4 and Figure 7 .

[0052] Table 3. HPLC data of impurity EP-D

[0053] Peak name Retention time area Peak height area% 1 17.02 458472 42506 2.651 2 20.825 16760135 1313633 96.903 3 22.437 1928 118 0.011 4 25.924 8330 434 0.048 5 29.005 1838 97 0.011 6 33.031 50789 3094 0.294 7 33.801 6470 471 0.037 8 35.913 4203 107 0.024 9 36.483 1763 94 0.01 10 40.594 1778 103 0.01 total 17295706 1360657 100

[0054] MS (m / z): 286.0 [M+H] + ,See Figure 8 .

[0055] 1 H-NMR (CDCl3, 400Hz) δ (ppm): 7.916 (s, 1H), 7.777~7.801 (m, 2H), 7.546~7.585 (m, 1H), 7.463~7.522 (m, 2H), 6.809 (d, J=4.0 Hz, 1H), 6.206 (t, J1=8.8Hz, J2=4.0Hz, 1H), 4.459~4.542(m, 2H), 3.332(s, 3H), 3.053~3.123(m, 1H), 2.701~2.763(m, 1H), see Fig. 9 .

[0056] Example 2

[0057] The "about 14 mL of 20% sodium hydroxide aqueous solution" in step b) of Example 1 was replaced with "about 14 mL of 20% potassium hydroxide aqueous solution", and other conditions and operations were the same as step b) in Example 1 to obtain 3.32 g of am-2 with a yield of 94.8%.

[0058] The "3.14 g of iodomethane" in step c) of Example 1 was replaced with 6.28 g of iodomethane. Other conditions and operations were the same as those in step c) of Example 1 to obtain 2.71 g of impurity EP-D with a yield of 85.9% and a purity of 96.764%.

[0059] The above embodiments are typical, and any simple adaptation, modification and change of the technical solution of the present invention by anyone within the spirit of the present invention also falls within the scope of the present invention.

Claims

1. A method for preparing ketorolac impurity D, comprising the following steps: 1) adding 2-benzoylpyrrole, diethyl malonate, manganese acetate dihydrate (trivalent), sodium acetate, and acetic anhydride to toluene, and heating until the reaction is complete to obtain compound am-1; 2) Compound am-1, phase transfer catalyst a, potassium carbonate and water are added to 1,2-dichloroethane, heated to reflux until the reaction is complete, the organic phase is separated, phase transfer catalyst b and alkali solution are added, and the reaction is completed at 35-45°C to obtain compound am-2; 3) Add compound am-2 to an organic solvent, add an alkali reagent and methyl iodide, stir and react at room temperature, and after the reaction is completed, quench with a sodium sulfite solution to separate impurity D (EP-D). Among them, the reaction formula is as follows:

2. The preparation method according to claim 1, wherein in step 1), the molar ratio of 2-benzoylpyrrole: diethyl malonate: manganese acetate dihydrate (trivalent): sodium acetate: acetic anhydride is about 1:1.5:2.5:2.0:7.

5.

3. The preparation method according to claim 1, wherein in step 2), the molar ratio of compound am-1: phase transfer catalyst a: phase transfer catalyst b is about 1:0.5:0.

05.

4. The preparation method according to claim 1, in step 3), the molar ratio of compound am-2: alkaline reagent: iodomethane is about 1:(1.0-1.5):(2.0-4.0).

5. The preparation method according to claim 4, wherein in step 3), the molar ratio of compound am-2: alkaline reagent: iodomethane is about 1:1.2:2.

0.

6. The preparation method according to claim 3, wherein the phase transfer catalyst a and the phase transfer catalyst b in step 2) are both tetrabutylammonium bromide.

7. The preparation method according to claim 1, wherein the organic solvent in step 3) is tetrahydrofuran or 2-methyltetrahydrofuran.

8. The preparation method according to claim 7, wherein the organic solvent is tetrahydrofuran.

9. The preparation method according to claim 4 or 5, wherein the alkaline reagent is sodium hydride or potassium hydride, preferably sodium hydride.

10. The preparation method according to claim 1, wherein the alkali solution in step 2) is an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution, preferably an aqueous sodium hydroxide solution.

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