Process for the preparation of xanthine oxidase inhibitors

Abstract

The present invention relates to a novel process of preparation which can be advantageously used for the synthesis of xanthine oxidase inhibitors of formula (1).

Description

Technical Field

[0001] This invention relates to a novel method for preparing xanthine oxidase inhibitors, and more specifically, to a novel method for synthesizing xanthine oxidase inhibitors of formula 1 more efficiently using compounds of formula 2 as starting materials through a simple method:

[0002] [Chemical Formula 1]

[0003]

[0004] [Chemical Formula 2]

[0005]

[0006] in

[0007] R1 is hydrogen, halogen, C1-C7 alkyl, C1-C7 alkoxy-C1-C7 alkyl, or phenyl;

[0008] R2 is hydrogen; an unsubstituted or substituted C1-C7 alkyl group selected from halogens, C3-C7 cycloalkyl groups, or O-R6 substituents, wherein R6 represents a C1-C4 alkyl group; a C3-C7 cycloalkyl group; or (W represents O or S, R7 represents hydrogen or C1-C4 alkyl, and n is an integer from 0 to 3);

[0009] R3 is hydrogen, halogen, or C1-C7 alkyl; and

[0010] X is F, Cl, Br, or I. Background Technology

[0011] Xanthine oxidase is known to be an enzyme that converts hypoxanthine into xanthine, which in turn converts xanthine into uric acid. Since uricase, an enzyme present in most mammals, is not found in humans and chimpanzees, uric acid is considered the final product of purine metabolism (SPBruce, Ann. Pharm., 2006, 40, 2187-2194). High levels of uric acid in the blood can cause various diseases, with gout being a prime example.

[0012] As mentioned above, gout is a disease caused by excessively high levels of uric acid in the body, specifically the accumulation of uric acid crystals in the articular cartilage, ligaments, and surrounding tissues, leading to severe inflammation and pain. Gout is an inflammatory joint disease, and its incidence has been steadily increasing over the past 40 years (NLEdwards, Arthritis & Rheumatism, 2008, 58, 2587-2590).

[0013] From the 1960s to the mid-1990s, the number of gout patients in Western countries increased dramatically by approximately 200% to 300%, with men being the predominantly affected. Obesity, aging, declining kidney function, and hypertension are considered contributing factors to this increase. The incidence of gout is approximately 1.4 per 1000 people, but this varies depending on uric acid levels. In other words, the incidence of gout is 0.5% in patients with blood uric acid levels above 7.0 mg / dL, and 5.5% in patients with blood uric acid levels above 9.0 mg / dL (G. Nuki, Medicine, 2006, 34, 417-423). As the incidence rate shows, high blood uric acid concentration is a significant contributing factor to gout. In addition, dietary habits, alcohol, lipids, and obesity may also be important contributing factors. Recently, many researchers have actively studied the correlation between uric acid and heart failure, hypertension, diabetes, kidney disease, and cardiovascular disease, and the importance of uric acid management is increasing (DIFeig et al., N.Eng.J.Med, 2008, 23, 1811-1821). Furthermore, the xanthine oxidase inhibitor allopurinol is known to be effective in treating ulcerative colitis (Aliment. Pharmacol. Ther. 2000, 14, 1159-1162; WO 2007 / 043457).

[0014] Allopurinol was the only drug used to treat gout for the past 40 years, until febuxostat was approved as a gout medication in the United States in 2009 (Brain Tomlinson, Current Opin. Invest. Drugs, 2005, 6, 1168-1178). Allopurinol is known to be a non-specific inhibitor of multiple enzymes involved in purine and pyrimidine metabolism, and its Ki for xanthine oxidase is 700 nM (Y. Takano et al., Life Sciences, 2005, 76, 1835-1847). Allopurinol is directly oxidized by xanthine oxidase to oxopurinol, a known potent xanthine oxidase inhibitor.

[0015] However, allopurinol is known to cause gastrointestinal side effects and skin rashes, and adherence to long-term use is poor. In particular, unpredictable fatal side effects of Stevens-Johnson syndrome have been reported at a low rate in patients taking allopurinol (Felix Arellano et al., Ann. Pharm., 1993, 27, 337-43). This side effect is known to be serious, causing necrosis of skin and oral mucosal cells, and can lead to death in approximately 25% of cases if not treated properly.

[0016] Therefore, various studies have been conducted to develop new xanthine oxidase inhibitors. Korean Patent Publication No. 10-2011-0037883 discloses a novel compound of the following chemical formula 1, which is an effective xanthine oxidase inhibitor:

[0017] [Chemical Formula 1]

[0018]

[0019] In chemical formula 1,

[0020] A is selected from the following substituents Ai, A-ii, A-iii, A-iv, Av, A-vi, A-vii, and A-viii.

[0021]

[0022] in

[0023] J represents hydrogen, halogen, or an unsubstituted or halogenated C1-C6 alkyl group.

[0024] X is O or S, and

[0025] Z is C or N.

[0026] E represents hydrogen, halogen, cyano, nitro, substituted or unsubstituted C1-C6-alkyl, or substituted or unsubstituted C1-C6-alkoxy.

[0027] D represents hydrogen, halogen, cyano, nitro, unsubstituted or halogenated C1-C6-alkyl, -CHO, or -CH=N-OH.

[0028] Q is selected from the following substituents Qi, Q-ii, and Q-iii-1 to Q-iii-9.

[0029] (Qi) Hydrogen;

[0030] (Q-ii) Substituted or unsubstituted straight-chain, branched or cyclic saturated or unsaturated alkyl groups;

[0031] (Q-iii-1)

[0032]

[0033] (W represents O or S, R7 represents hydrogen or a substituted or unsubstituted lower alkyl group, and n is an integer from 0 to 3);

[0034] (Q-iii-2)

[0035]

[0036] (W represents O or S, R8 and R9 each independently represent hydrogen or lower alkyl groups, and m is an integer from 1 to 3);

[0037] (Q-iii-3)

[0038]

[0039] (where R8 and R9 each independently represent hydrogen or lower alkyl groups, and m is an integer from 1 to 3);

[0040] (Q-iii-4)

[0041]

[0042] (where R10 and R11 each independently represent hydrogen, halogen, lower alkoxy or lower alkyl, and m is an integer from 1 to 3);

[0043] (Q-iii-5)

[0044]

[0045] (Where R12 represents a substituted or unsubstituted lower alkyl or aromatic group, and n is an integer from 0 to 3);

[0046] (Q-iii-6)

[0047]

[0048] (where R13 and R14 each independently represent substituted or unsubstituted lower alkyl groups, or can form N-containing 3- to 7-membered heterocycles, where n is an integer from 0 to 3);

[0049] (Q-iii-7)

[0050]

[0051] (Where R15 represents a substituted or unsubstituted lower alkyl group, and m is an integer from 1 to 3);

[0052] (Q-iii-8)

[0053]

[0054] (where m is an integer from 1 to 3); and

[0055] (Q-iii-9)

[0056]

[0057] (Where R15 represents a substituted or unsubstituted lower alkyl group, and m is an integer from 1 to 3),

[0058] Y represents hydrogen, halogen, substituted or unsubstituted straight-chain, branched or cyclic saturated or unsaturated alkyl group, substituted or unsubstituted C1-C6-alkoxy group, substituted or unsubstituted aromatic or heteroaromatic group, and

[0059] G represents hydrogen or a substituted or unsubstituted straight-chain, branched, or cyclic saturated or unsaturated alkyl group.

[0060] In one specific embodiment of this document, the preparation of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid according to Scheme 1 is disclosed.

[0061] [Option 1]

[0062]

[0063] A more detailed description of Option 1 is as follows.

[0064] (1) 1H-pyrazole-4-carboxylate and 1H-indol-5-ylboronic acid were dissolved in N,N-dimethylformamide (DMF), and copper(II) acetate and pyridine were added. The mixture was stirred at room temperature for 3 days, and then the solvent was distilled off under reduced pressure. The mixture was separated by column chromatography to prepare 1-(1H-indol-5-yl)pyrazole-4-carboxylate.

[0065] (2) Ethyl 1-(1H-indol-5-yl)pyrazole-4-carboxylate was added to the reaction solution of oxaloyl chloride and N,N-dimethylformamide, and then reacted. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure to prepare ethyl 1-(3-formyl-1H-indol-5-yl)pyrazole-4-carboxylate.

[0066] (3) Ethyl 1-(3-formyl-1H-indol-5-yl)pyrazole-4-carboxylate was dissolved in pyridine, and ammonium hydroxychloride was added. The mixture was heated and stirred under reflux. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and filtered through silica gel to prepare ethyl 1-[3-[(E,Z)-hydroxyiminomethyl]-1H-indol-5-yl]pyrazole-4-carboxylate.

[0067] (4) Ethyl 1-[3-[(E,Z)-hydroxyiminomethyl]-1H-indol-5-yl]pyrazole-4-carboxylate was dissolved in anhydrous tetrahydrofuran, and di(imidazol-1-yl)methylthione was added. The reaction was carried out at room temperature with stirring, the reaction mixture was concentrated under reduced pressure, and the resulting solid compound was separated by column chromatography to prepare ethyl 1-(3-cyano-1H-indol-5-yl)pyrazole-4-carboxylate.

[0068] (5) Ethyl 1-(3-cyano-1H-indol-5-yl)pyrazole-4-carboxylate was dissolved in acetonitrile, and then cesium carbonate and 2-iodopropane were added. The mixture was heated and stirred under reflux. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the resulting solid compound was separated by column chromatography to prepare ethyl 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-carboxylate.

[0069] (6) Ethyl 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid was added to tetrahydrofuran, methanol and 6N sodium hydroxide solution and reacted at room temperature. The organic solvent was then removed under reduced pressure. The remaining aqueous layer was washed with ethyl acetate. Concentrated hydrochloric acid was added to acidify the aqueous solution to pH 1. The precipitated solid compound was filtered, washed with distilled water and dried to prepare 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid.

[0070] However, this method involves several synthetic steps and may not be preferred for the large-scale synthesis of xanthine oxidase inhibitors in high yields. Summary of the Invention

[0071] Technical issues

[0072] Therefore, the technical objective of this invention is to provide a method suitable for more efficient mass production of a compound of Formula 1, which is an excellent xanthine oxidase inhibitor.

[0073] Technical solution

[0074] To achieve the aforementioned objective, the present invention provides a method for preparing a xanthine oxidase inhibitor of the following chemical formula 1, the method comprising the following steps:

[0075] i) To prepare compounds of formula 3 by introducing an R2 substituent into compounds of formula 2.

[0076] ii) Reacting the compound of formula 3 with a compound of formula 4 to prepare a compound of formula 5, and

[0077] iii) To prepare the compound of formula 1 by removing the R4 substituent from the compound of formula 5:

[0078] [Chemical Formula 1]

[0079]

[0080] [Chemical Formula 2]

[0081]

[0082] [Chemical Formula 3]

[0083]

[0084] [Chemical Formula 4]

[0085]

[0086] [Chemical Formula 5]

[0087]

[0088] in,

[0089] R1 is hydrogen, halogen, C1-C7 alkyl, C1-C7 alkoxy-C1-C7 alkyl, or phenyl;

[0090] R2 is hydrogen; an unsubstituted or substituted C1-C7 alkyl group selected from halogens, C3-C7 cycloalkyl groups, or O-R6 substituents, wherein R6 represents a C1-C4 alkyl group; a C3-C7 cycloalkyl group; or (W represents O or S, R7 represents hydrogen or C1-C4 alkyl, and n is an integer from 0 to 3);

[0091] R3 is hydrogen, halogen, or C1-C7 alkyl; and

[0092] R4 is a C1-C7 alkyl or a C3-C7 cycloalkyl; and

[0093] X is F, Cl, Br, or I.

[0094] The invention will be described in more detail below.

[0095] In the method for preparing the xanthine oxidase inhibitor of Formula 1 according to the present invention, firstly, the compound of Formula 2 is reacted with a suitable substituent in an organic solvent to prepare the compound of Formula 3.

[0096] In one embodiment of the invention, R2 is an unsubstituted C1-C7 alkyl group, for example, isopropyl, and the compound of formula 3 can be prepared by reacting the compound of formula 2 with 2-iodopropane and CS2CO3.

[0097] In the method for preparing the xanthine oxidase inhibitor of Formula 1 according to the present invention, the compound of Formula 5 is prepared by reacting the compound of Formula 3 with the compound of Formula 4 in an organic solvent in the presence of a copper catalyst, a base and a ligand.

[0098] In one embodiment of the invention, one or more of, for example, selected from toluene, xylene, dimethylformamide (DMF) or dimethyl sulfoxide (DMSO) can be used as the organic solvent in this step.

[0099] In another embodiment of the invention, one or more of the following can be used as the copper catalyst in this step: for example, CuI, Cu(OAc)2, Cu, Cu2O or CuO.

[0100] In one embodiment of the invention, one or more of the following can be used as the base in this step: potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), tripotassium phosphate (K3PO4), triethylamine (Et3N) or sodium tert-butoxide (NaOtBu).

[0101] In one embodiment of the invention, one or more of the following can be used as the ligand in this step: for example, 1,2-cyclohexanediamine, N,N'-dimethyl-1,2-cyclohexanediamine, N,N'-dimethylethylenediamine, 1,10-phenanthroline, proline, oxime ligands or tetradentate ligands.

[0102] In the method for preparing the xanthine oxidase inhibitor of Formula 1 according to the present invention, the compound of Formula 1 can be prepared by removing the R4 substituent from the compound of Formula 5.

[0103] In one embodiment of the invention, R4 is a C1-C7 alkyl group. For example, a xanthine oxidase inhibitor of formula 1 can be prepared by hydrolyzing the ester with a base.

[0104] In one embodiment of the invention, the alkali in this step may be one or more selected from sodium hydroxide (NaOH), lithium hydroxide (LiOH), calcium hydroxide (Ca(OH)2), or potassium hydroxide (KOH).

[0105] Beneficial effects

[0106] In the preparation method of the present invention, since the compound of chemical formula 2 with cyano group introduced is used as the starting material to prepare the compound of chemical formula 3, and then the compound of chemical formula 5 is prepared by CN coupling reaction of the compound of chemical formula 3 and the compound of chemical formula 4, the xanthine oxidase inhibitor of chemical formula 1 can be prepared in a simpler way under mild conditions with high yield. Detailed Implementation

[0107] The invention will now be described in more detail with reference to embodiments. However, the following embodiments are merely illustrative and intended to aid in understanding the invention, and the scope of the invention is not limited thereto.

[0108] Example 1-1: Synthesis of 5-bromo-3-cyano-1-isopropyl-indole

[0109] 5-Bromo-3-cyano-1H-indole (20 g, 90.5 mmol) was dissolved in 100 mL of acetone, followed by the addition of Cs₂CO₃ (50.1 g, 153.8 mmol) and 2-iodopropane (26.1 g, 153.8 mmol). The mixture was stirred under reflux for 2 hours. After the reaction was complete, the reaction solution was removed by vacuum distillation, and EtOAc (100 mL) was added, followed by washing with purified water. The organic layer was separated, and the solvent was removed to give 23.5 g (98% yield) of the title compound.

[0110] 1 H-NMR(CDCl3)δ7.90(1H,d),7.70(1H,s),7.43(1H,dd),7.32(1H,d),4.72-4.62(1H,m),1.57(6H,d)

[0111] Examples 1-2: Synthesis of ethyl 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylate

[0112] 5-Bromo-3-cyano-1-isopropylindole (23.5 g, 89.3 mmol) and ethyl 1H-pyrazole-4-carboxylate (12.5 g, 89.3 mmol) were added to 107 mL of toluene. CuI, 1,2-cyclohexanediamine, and K₂CO₃ were added, and the mixture was stirred under reflux for 2 days. The solvent was distilled off under reduced pressure, ethyl acetate (EtOAc) was added, and the mixture was washed with aqueous NH₄OH solution. The organic layer was filtered through Na₂SO₄ / silica gel. The solvent was distilled off under reduced pressure, and the mixture was crystallized with isopropanol (IPA) to give 16.1 g (56% yield) of the title compound.

[0113] 1 H-NMR(CDCl3)δ8.45(1H,s),8.13(1H,s),8.03(1H,d),7.80(1H,s),7.75(1H ,dd),7.54(1H,d),4.79-4.69(1H,m),4.36(2H,q),1.61(6H,d),1.40(3H,t)

[0114] Examples 1-3: Synthesis of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid

[0115] Ethyl 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylate (16 g, 49.6 mmol) was dissolved in a mixture of 25 mL tetrahydrofuran (THF) and 25 mL methanol (MeOH), followed by the addition of 25 mL of 10 N NaOH aqueous solution. The mixture was stirred at room temperature for 2 hours, and then 25 mL of purified water was added. The solid produced by the addition of concentrated HCl was filtered to give 12.9 g (88% yield) of the title compound.

[0116] 1 H-NMR(DMSO-d6)δ12.56(1H,br),9.10(1H,s),8.53(1H,s),8.16(1H,d),8.06(1H,s),7.91-7.85(2H,m),4.92-4.86(1H,m),1.48(6H,d)

Claims

1. A method for preparing a xanthine oxidase inhibitor of the following chemical formula 1, the method comprising the following steps: i) To prepare compounds of formula 3 by introducing an R2 substituent and Cs2CO3 into compounds of formula 2. ii) Reacting the compound of formula 3 with a compound of formula 4 to prepare a compound of formula 5, and iii) To prepare the compound of formula 1 by removing the R4 substituent from the compound of formula 5: [Chemical Formula 1] [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] in, R1 is hydrogen; R2 is an unsubstituted C1-C7 alkyl group; R3 is hydrogen; R4 is a C1-C7 alkyl group; and X is F, Cl, Br, or I. The organic solvent in step (ii) is selected from one or more of toluene, xylene, dimethylformamide (DMF), or dimethyl sulfoxide (DMSO). The copper catalyst in step (ii) is selected from one or more of CuI, Cu(OAc)2, Cu, Cu2O, or CuO. The base in step (ii) is selected from one or more of potassium carbonate, cesium carbonate, tripotassium phosphate, triethylamine, or sodium tert-butoxide. The ligand in step (ii) is selected from 1,2-cyclohexanediamine, N,N' -Dimethyl-1,2-cyclohexanediamine, N,N' -Dimethylethylenediamine, 1,10-phenanthroline, proline, oxime ligands, or one or more tetradentate ligands, Step (iii) is carried out by hydrolyzing the ester with an alkali, wherein the alkali is one or more selected from sodium hydroxide (NaOH), lithium hydroxide (LiOH), calcium hydroxide (Ca(OH)2) or potassium hydroxide (KOH).

2. The preparation method according to claim 1, wherein R2 is isopropyl.

3. The preparation method according to claim 2, wherein in step (i), the compound of chemical formula 2 is reacted with 2-iodopropane and Cs2CO3.

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