HK1235396B - Process for large scale production of 1-isopropyl-3-{5- [1-(3-methoxypropyl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}- 1h-indazole oxalate - Google Patents

Description

Method for large-scale production of 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]- [1,3,4]oxadiazol-2-yl}-1H-indazole oxalate

Technical Field

The present invention comprises a method for synthesizing 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate of formula (I) that is suitable for large-scale preparation.

Background Art

Alzheimer's disease (AD) is an advanced age-related neurodegenerative disease characterized by memory loss, accumulation of amyloid beta protein (Aβ) deposits, and decreased levels of the neurotransmitter acetylcholine. Approximately 40% of AD patients suffer from significant depression. 5-HT4 receptor partial agonists have benefits for both symptomatic and disease-modifying treatment of AD and may provide improved clinical efficacy and/or tolerability relative to acetylcholinesterase inhibitors. 5-HT4 receptor agonists also have antidepressant-like properties (Expert Review of Neurotherapeutics, 2007, 7, 1357-1374; Experimental Neurology, 2007, 203(1), 274-278; Neuroscience & Medicine, 2011, 2, 87-92; Schizophrenia Bulletin, 2007, 33(5), 1100-1119).

1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate of formula (I) is a promising agent that is a potent, selective, and orally bioavailable 5-HT4 receptor partial agonist intended for both disease-modifying and symptomatic treatment of Alzheimer's disease and other memory and cognitive disorders such as attention deficit hyperactivity disorder, _Parkinson 's disease, and schizophrenia. In addition to its pro-cognitive effects, the compound also exhibits dose-dependent antidepressant-like effects in the forced swim test in mice. 1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate and its synthesis were disclosed by Ramakrishna et al. in WO2013042135.

At present, 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazole-2-yl}-1H-indazole oxalate of formula (I) has completed preclinical research and is ready to enter human clinical trials. 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazole-2-yl}-1H-indazole oxalate of formula (I) will significantly improve as the demand for drug substance increases with the emergence of its human clinical trials. Due to the expected commercialization of 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazole-2-yl}-1H-indazole oxalate of formula (I), it is estimated that far greater amounts will be needed in the future.

For those skilled in the art, it is a well-known fact that multiple parameters change during the large-scale preparation of compounds compared to the synthetic operations carried out in the laboratory. Therefore, it is necessary to establish and optimize large-scale preparation methods. It has been shown that the preparation method of 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazole-2-yl}-1H-indazole oxalate of formula (I) disclosed in WO2013042135 cannot meet large-scale synthesis. Ultimately, it is highly desirable to establish an optimized preparation method of 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazole-2-yl}-1H-indazole oxalate capable of large-scale preparation of formula (I).

SUMMARY OF THE INVENTION

The main object of the present invention is to provide a large-scale well-optimized preparation method of 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate of formula (I).

Another object of the present invention is to provide a process for obtaining substantially pure 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate of formula (I).

Another object of the present invention is to demonstrate the compatibility of a process for the large-scale production of 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate of formula (I) using standard larger-scale chemical process equipment.

Another object of the present invention is to provide a commercial process for the larger scale production of 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate of formula (I).

Detailed Description of the Invention

The large-scale preparation method of the present invention for preparing 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate of formula (I) is exemplified in Scheme-1:

Plan-1

Step (i): 1-(3-methoxypropyl)piperidine-4-carboxylic acid hydrazide of Formula 1 is coupled with 1-isopropyl-1H-indazole-3-carbonyl chloride of Formula 2 in the presence of 1,2 -dichloroethane to obtain N-[1-(3-methoxypropyl)piperidine-4-carbonyl]N′-(1-isopropyl-1H-indazole-3-carbonyl)hydrazine of Formula 3. The reaction temperature may be 20° C. to 35° C., preferably 25° C. to 30° C. The reaction duration may be 1.5 hours to 2.5 hours, preferably 2 hours.

Step (ii): N-[1-(3-methoxypropyl)piperidin-4-carbonyl]N′-(1-isopropyl-1H-indazole-3-carbonyl)hydrazine of Formula 3 is cyclized in the presence of a cyclizing agent such as phosphorus oxychloride, cyanuric chloride or thionyl chloride, preferably thionyl chloride, in a solvent such as dichloromethane, 1,2-dichloroethane or chlorobenzene, preferably 1,2-dichloroethane, to obtain 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole of Formula 4. The reaction temperature may be 60° C. to 95° C., preferably 70° C. to 85° C. The reaction duration may be 8 to 10 hours, preferably 9 hours.

Step (iii): Purify 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole of Formula 4 using a mixture of acetic acid and water (preferably in a ratio of 1:9). The reaction temperature may be 20° C. to 35° C., preferably 25° C. to 30° C.

Step (iv): 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole of Formula 4 is reacted with oxalic acid in the presence of isopropyl alcohol to obtain 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate of Formula (I). The reaction temperature may be 20° C. to 35° C., preferably 25° C. to 30° C. The reaction duration may be 1 to 4 hours, preferably 2 hours.

Step (v): Recrystallize the compound of formula (I) using a mixture of isopropyl alcohol and water (preferably in a ratio of 5:1). The reaction temperature may be 70°C to 80°C, preferably 74°C to 78°C. The reaction duration may be 15 hours to 17 hours, preferably 16 hours.

The present invention is illustrated in detail in the examples given below.

Preparation 1: Preparation of 1-isopropyl-1H-indazole-3-carboxylic acid

In 15 minutes, under nitrogen atmosphere, sodium tert-butoxide (6.0 Kg, 62.43 mol) was added to a stirred solution of dimethylformamide (DMF) (50 L) at 25 to 30 ° C. The reaction mixture was stirred for 10 minutes, after which it was cooled to 0 to 5 ° C. A solution of indazole-3-carboxylic acid (4.0 Kg, 24.67 mol) in DMF (50 L) was slowly added to the reactor over 45 minutes while maintaining the temperature of the reaction mass at 0 to 5 ° C. The cooling was removed and the reaction temperature was gradually increased to 25 to 30 ° C over 30 minutes. After stirring at this temperature for 1 hour, the reaction mixture was cooled to 0 ° C and isopropyl iodide (6.32 Kg, 37.18 mol) was added over 30 minutes. The cooling was removed and the reaction temperature was increased to 25 to 30 ° C. After stirring for 17 hours, HPLC analysis of the reaction mixture revealed a residual ≤10% indazole-7-carboxylic acid. The reaction mass was carefully diluted with water (200 L) and washed with ethyl acetate (2 × 100 L). The gained aqueous layer was acidified to pH 4.0 to 4.5 with aqueous hydrochloride solution (6.0 N, 21.5 L) and extracted with ethyl acetate (2 × 144 L). The combined organic layer was washed with water (2 × 100 L), brine solution (200 L) and dried over anhydrous sodium sulfate (4.0 Kg). At 50 ℃ to 60 ℃, under reduced pressure (＞500 mm Hg), the filtered organic layer was subjected to solvent removal to obtain a crude material. The obtained crude material was diluted with dichloromethane (DCM) (28.0 L) and stirred for 15 minutes. The precipitated solid (unreacted indazole-7-carboxylic acid) was filtered through a nutsche filter and the filter bed was washed once with DCM (8.0 L). The combined filtrates were distilled at 45-55°C under reduced pressure (>500 mm Hg) to obtain a crude material which was stirred with ether (7.0 L) for 30 minutes and filtered through a nutsche filter to obtain a wet solid which was further dried in a vacuum oven at 45-55°C under reduced pressure (>500 mm Hg) to obtain the above title compound (3.0 Kg) as an off-white crystalline powder.

Yield: 59.5%

Purity: 99.86%;

IR (cm ^-1 ): 2980, 1729, 1682, 1487, 1287, 1203, 1170, 1127, 1085, 754;

¹ H-NMR (δppm, CDCl ₃ ): 8.27 (d, J=8.1Hz, 1H), 7.55 (d, J=8.4Hz, 1H), .7.46 (t, J=7.6Hz, 1H), 7.34 (t, J=7.4Hz, 1H), 5.01-4.95 (m, 1H), 1.68 (d, J=6.65 Hz, 6H);

Mass (m/z): 205.1 (M+H) ⁺ .

Preparation 2: Preparation of 1-(3-methoxypropyl)piperidine-4-carboxylic acid hydrazide

Step (i): Preparation of ethyl 1-(3-methoxypropyl)piperidine-4-carboxylate

At 25 ℃ to 30 ℃ under nitrogen atmosphere, add ethyl isonipecotate (6.5Kg, 41.35mol) to the stirred solution of acetonitrile (97.5L). The content was stirred for 10 minutes, after which potassium carbonate powder (7.35Kg, 53.2mol) and 1-bromo-3-methoxypropane (6.89Kg, 45.0mol) were added in succession. Over a period of 30 minutes, the reaction mixture was gradually heated to reflux (82 ℃ to 85 ℃), and maintained at this temperature for 7 hours. At this point, TLC revealed that ethyl isonipecotate was completely exhausted. Volatiles were distilled out at 50 ℃ to 60 ℃ under reduced pressure (＞500mm mercury). The crude material was cooled to 25 ℃ to 30 ℃ and diluted with water (71.5L) and DCM (136.5L). After the content was stirred, the two layers were separated. The organic layer was washed with water (71.5 L), dried over anhydrous sodium sulfate (6.5 Kg) and volatiles were removed at 50-55°C under reduced pressure (>500 mm Hg) to obtain the desired product (9.3 Kg) as a pale yellow liquid.

Yield: 98%

Purity: 98.8%;

IR (cm ^-1 ): 2949, 1732, 1449, 1376, 1179, 1119, 1048;

¹ H-NMR (δppm, CDCl3): 4.06 (q, J=7.1Hz, 2H), 3.37-3.34 (t, J=6.4Hz, 2H), 3.27 (s, 3H), 2.83-2.80 (m, 2H), 2.34 (t, J=7.5Hz, 2H), 2.22-2.18 (m, 1H), 1.96-1.94(m, 2H), 1.85-1.82(m, 2H), 1.74-1.68(m, 4H), 1.19(t, J=7.04 Hz, 3H);

Mass (m/z): 230.4 (M+H) ⁺ .

Step (ii): Preparation of 1-(3-methoxypropyl)piperidine-4-carboxylic acid hydrazide

To a stirred solution of methanol (38 L) at 25°C to 30°C under a nitrogen atmosphere was added ethyl 1-(3-methoxypropyl)piperidine-4-carboxylate (5.0 Kg, 21.8 mol, obtained in the above step). After the reaction mixture was stirred for 15 minutes, hydrazine hydrate (80% w/v, 4.1 Kg, 65.4 mol) was added over a 15-minute period. The reaction mixture was gradually heated to reflux (70°C) over 30 minutes and stirring continued for 4 hours. An additional amount of hydrazine hydrate (80% w/v, 4.1 Kg, 65.4 mol) was added and stirring continued for another 4 hours. Another portion of hydrazine hydrate (80% w/v, 4.1 Kg, 65.4 mol) was added and stirring continued at 70°C for 16 hours, at which point thin layer chromatography (TLC) revealed ≤5% ester. Volatiles were distilled off at 60°C under reduced pressure (>500mm Hg) until a syrupy material appeared. After the syrupy material was cooled to room temperature (25°C to 30°C), it was diluted with DCM (38.0L) and stirred for 15 minutes. Then, the two layers observed were separated. The organic layer was dried over anhydrous sodium sulfate (5.0Kg) and the solvent was evaporated at 55°C under reduced pressure (>500mm Hg) until dry. The isolated solid product was cooled to 25°C to 30°C, diluted with hexane (15.0L) and the resulting slurry was filtered on a nutsche filter. The filter bed was washed once with hexane (15.0L) and ethyl acetate (2×10.0L). The product cake was vacuum dried, and the solid material thus separated was further dried in a vacuum oven at 50°C under reduced pressure (>500mm Hg) for 6 hours to obtain the above-mentioned title compound (4.1Kg) as an off-white crystalline powder.

Yield: 87%

Purity: 99.79%;

IR (cm ^-1 ): 3290, 3212, 2948, 2930, 1637, 1530, 1378, 1124, 1113, 986, 948, 789, 693;

¹ H-NMR (δppm, CDCl ₃ ): 6.83 (s, 1H), 3.86 (bs, 2H), 3.41 (t, J=6.4Hz, 2H), 3.32(s, 3H), 2.99-2.96(m, 2H), 2.42(t, J=7.44Hz, 2H), 2.11-1.96(m, 3H), 1.82-1.73(m, 6H);

Mass (m/z): 216.3 (M+H) ⁺ .

Example 1: Preparation of 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate

Step (i): Preparation of N-[1-(3-methoxypropyl)piperidine-4-carbonyl]N′-(1-isopropyl-1H-indazole-3-carbonyl)hydrazine

At 25 ℃ to 30 ℃ under nitrogen atmosphere, 1-isopropyl-1H-indazole-3-carboxylic acid (3.0 Kg, 14.69 mol, obtained in Preparation 1) was added to a stirred solution of 1,2-dichloroethane (19.8 L), and the reaction mixture was stirred for 15 minutes to completely dissolve. Then, thionyl chloride (3.6 Kg, 30.25 mol) was added to the reaction mixture over a period of 15 minutes by maintaining the temperature of the reaction mixture below 30 ℃. Then, the reaction temperature was gradually raised to 75 ℃ over a period of 30 minutes and stirred at this temperature for 2 hours. TLC revealed that the acid was completely converted into the acid chloride. The solvent 1,2-dichloroethane and excess thionyl chloride were removed under reduced pressure (＞500 mm Hg) at a temperature below 60 ℃. The obtained residual material was cooled to 25 ℃ to 30 ℃ and diluted with DCM (15.6 L). The contents were further cooled to 0 ℃ to 5 ℃. To the reaction mass was added a solution of 1-(3-methoxypropyl)piperidine-4-carboxylic acid hydrazide (3.0 Kg, 13.94 mol, obtained in Preparation 2) in DCM (18.0 L) over a period of 30 minutes. The reaction temperature was then gradually raised to 25°C to 30°C and the reaction mixture was stirred for 2 hours. The progress of the reaction was monitored by TLC, which showed that hydrazide was absent (≤1.0%). The reaction mixture was then diluted with water (30.0 L), stirred for 15 minutes and separated into two layers. The aqueous layer was washed with DCM (1 × 30.0 L), cooled to 0°C to 5°C, and carefully basified to pH 7.6 with aqueous sodium bicarbonate solution (10% w/v, 46.5 L). The basified aqueous layer was then extracted with DCM (2 × 30.0 L). The combined organic layers were dried over anhydrous sodium sulfate (6.0 Kg) and desolvated under reduced pressure (>500 mm Hg) at a temperature below 55°C. The residue was then cooled to 25°C to 30°C and diluted with hexane (9.0 L). The slurry thus obtained was centrifuged at room temperature under a nitrogen atmosphere, and the wet product cake was washed with hexane (6.0 L). The wet product was then dried in an oven at 55°C to 60°C until the loss on drying was <1.0% to obtain the above-mentioned title compound (4.4 Kg) as an off-white crystalline powder.

Yield: 74.5%

Purity: 98.75%;

IR (cm ^-1 ): 3506, 3233, 2943, 1703, 1637, 1523, 1487, 1195, 1116, 750;

¹ H-NMR (δppm, CDCl ₃ ): 9.35 (bs, 1H), 8.70 (bs, 1H), 8.30 (d, J=8.1Hz, 1H), 7.48 (d, J=8.4Hz, 1H), 7.42 (t, J=8.2Hz, 1H), 7.29 (t, J=7.6Hz, 1H), 4.90- 4.85(m, 1H), 3.40(t, J=6.4Hz, 2H), 3.33(s, 3H), 2.94-2.85(m, 2H), 2.39- 2.31 (m, 3H), 1.92-1.88 (m, 4H), 1.76-1.65 (m, 4H), 1.59 (d, J=6.6Hz, 6H);

Mass (m/z): 402.2 (M+H) ⁺ .

Step (ii): Preparation of 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole

To a stirred solution of 1,2-dichloroethane (60 L) was added N-[1-(3-methoxypropyl)piperidine-4-carbonyl]N'-(1-isopropyl-1H-indazole-3-carbonyl)hydrazine (3.0 Kg, 7.47 mol, obtained in the above step) at 25°C to 30°C under a nitrogen atmosphere and the contents were stirred for 15 minutes, after which thionyl chloride (1.77 Kg, 15.0 mol) was added over a period of 15 minutes. The reaction mixture was then gradually raised to 79°C to 83°C over a period of 30 minutes, at which point the reaction mixture began to reflux. After 9 hours, the reaction mass showed complete consumption of the starting material when checked by TLC. Excess thionyl chloride and the solvent 1,2-dichloroethane were distilled off under reduced pressure (>500 mm Hg) at below 60°C. The reaction mass was cooled to 25°C to 30°C, diluted with water (39.0 L) and solvent ether (19.5 L). The resulting material was stirred for 15 minutes and the two layers were separated. The pH of the aqueous layer was adjusted to 9 to 10 by adding an aqueous solution of sodium hydroxide (2.5 N, 3.0 L). The alkalized aqueous layer was then extracted with DCM (2 x 54.0 L). The combined organic layers were washed with a cold (5°C to 10°C) aqueous sodium hydroxide solution (0.6 N, 54.0 L), dried over anhydrous sodium sulfate (6.0 Kg) and removed from the solvent under reduced pressure (> 500 mm Hg) at a temperature below 55°C to give the above-mentioned title compound (2.6 Kg) as a brown syrupy material.

Yield: 90.5%

Purity: 99.3%;

IR (cm ^-1 ): 3054, 2946, 2808, 1599, 1563, 1462, 1389, 1211, 1120, 1069, 999, 749;

¹ H-NMR (δppm, CDCl ₃ ): 8.34 (d, J=8.12Hz, 1H), 7.53 (d, J=8.44Hz, 1H), 7.45 (t, J=7.58Hz, 1H), 7.32 (t, J=7.44Hz, 1H), 4.98-4.93 (m, 1H), 3.44 (t, J =6.44Hz, 2H), 3.03-3.00 (m, 3H), 3.34 (s, 3H), 2.46 (t, J = 7.54Hz, 2H), 2.20- 2.02 (m, 6H), 1.80 (t, J = 7.27Hz, 2H), 1.66 (d, J = 6.72Hz, 6H);

Mass (m/z): 384.3 (M+H) ⁺ .

Step (iii): Purification of 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole

The crude step (ii) product obtained above was dissolved in a stirred aqueous solution of acetic acid (10% w/v, 26.0 L) and washed with ethyl acetate (2×26.0 L). The pH of the resulting aqueous layer was adjusted to 9.0 to 10.0 by adding an aqueous sodium hydroxide solution (0.5 N, 52.0 L). The basified aqueous layer was extracted with ether (2×26.0 L) and the combined organic layers were dried over anhydrous sodium sulfate (3.0 Kg). Volatiles were removed under reduced pressure (>500 mm Hg) at a temperature below 55° C. to obtain a brown syrupy material (2.19 Kg).

Yield: 84%

Purity: 99.72%;

IR (cm ^-1 ): 3054, 2978, 2946, 2808, 2772, 1599, 1563, 1462, 1389, 1194, 1177, 1120, 1069, 999, 749;

¹ H-NMR (δppm, CDCl ₃ ): 8.34 (d, J=8.12Hz, 1H), 7.53 (d, J=8.44Hz, 1H), 7.45 (t, J=7.58Hz, 1H), 7.32 (t, J=7.44Hz, 1H), 4.98-4.93 (m, 1H), 3.44 (t, J =6.44Hz, 2H), 3.03-3.00 (m, 3H), 3.34 (s, 3H), 2.46 (t, J = 7.54Hz, 2H), 2.20- 2.02 (m, 6H), 1.80 (t, J = 7.27Hz, 2H), 1.66 (d, J = 6.72Hz, 6H);

Mass (m/z): 384.4 (M+H) ⁺ .

Step (iv): Preparation of 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate

To a stirred solution of isopropyl alcohol (60.8 L) at 25° C. to 30° C. under a nitrogen atmosphere was added 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole (6.08 Kg, 15.86 mol, obtained in step (iii)), followed by oxalic acid (1.46 Kg, 16.2 mol). The reaction mixture was stirred for 2 hours, and the precipitated solid product was filtered through a nutsche filter under a nitrogen atmosphere. The wet product bed was washed with isopropyl alcohol (10.0 L) and solvent ether (60.8 L) to obtain a technical grade product.

IR (cm ^-1 ): 3437, 2975, 2932, 2890, 1703, 1604, 1564, 1458, 1391, 1281, 1217, 1192, 1114, 992, 750;

¹ H-NMR (δppm, DMSO-d ₆ ): 10.72, (bs, 2H), 8.16 (d, J=8.1Hz, 1H), 7.85 (d, J =8.5Hz, 1H), 7.51 (t, J = 7.4Hz, 1H), 7.35 (t, J = 7.7Hz, 1H), 5.20-5.07 (m, 1H), 3.55-3.43(m, 3H), 3.36(t, J=5.9Hz, 2H), 3.21(s, 3H), 3.18-2.98(m, 4H), 2.40-2.30(m, 2H), 2.26-2.12(m, 2H), 1.96-1.85(m, 2H), 1.53(d, J=6.6 Hz, 6H);

Mass (m/z): 384.4 (M+H) ⁺ .

Step (v): Recrystallization of 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate

The product obtained above was suspended in a mixture of isopropanol (35.26 L) and water (7.3 L) and refluxed (76° C.) for 4 hours until completely dissolved. The homogeneous solution thus obtained was gradually cooled to 25° C. to 30° C. and maintained at this temperature for 16 hours with slow stirring. The precipitated oxalate salt was centrifuged under a nitrogen atmosphere. The product cake was washed with isopropanol (15.0 L) and ether (60.8 L). The drained product was then dried in a vacuum oven at 25° C. to 30° C. for 2 hours and at 65° C. for 1 hour to obtain the above-mentioned title compound (4.24 Kg) as a light cream-colored crystalline material.

Yield: 60%

Purity: 99.92%;

Salt content (oxalate): 20.37%;

Heavy metals: <20ppm;

IR (cm ^-1 ): 3437, 2975, 2932, 2890, 1703, 1604, 1564, 1458, 1391, 1281, 1217, 1192, 1114, 992, 750;

¹ H-NMR (δppm, DMSO-d ₆ ): 10.72, (bs, 2H), 8.16 (d, J=8.1Hz, 1H), 7.85 (d, J =8.5Hz, 1H), 7.51 (t, J = 7.4Hz, 1H), 7.35 (t, J = 7.7Hz, 1H), 5.20-5.07 (m, 1H), 3.55-3.43(m, 3H), 3.36(t, J=5.9Hz, 2H), 3.21(s, 3H), 3.18-2.98(m, 4H), 2.40-2.30(m, 2H), 2.26-2.12(m, 2H), 1.96-1.85(m, 2H), 1.53(d, J=6.6 Hz, 6H);

Mass (m/z): 384.4 (M+H) ⁺ .

Advantages of the present invention

1. The process is very simple and starts from commercially available and easily available raw materials, which makes the process economically and industrially feasible.

2. This method does not require silica gel column chromatography purification, otherwise it is not feasible for large-scale synthesis.

3. The present method avoids the use of highly corrosive, hazardous and toxic phosphorus oxychloride, which avoids laborious post-processing operations to remove it, making the method cheaper, simpler and safer.

4. The HPLC purity of the final compound obtained in this method is >99.9%.

Claims (15)

1. A method for large-scale production of 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate of formula (I), The method includes the following steps: Step (i): In the presence of dichloroethane, 1-(3-methoxypropyl)piperidine-4-carboxylic acid hydrazide of Formula 1 is coupled with 1-isopropyl-1H-indazole-3-carbonyl chloride of Formula 2 for 1.5 to 2.5 hours at a temperature of 20°C to 35°C to obtain N-[1-(3-methoxypropyl)piperidine-4-carbonyl]N′-(1-isopropyl-1H-indazole-3-carbonyl)hydrazide of Formula 3 ; Step (ii): In the presence of thionyl chloride, N-[1-(3-methoxypropyl)piperidin-4-carbonyl]N′-(1-isopropyl-1H-indazole-3-carbonyl)hydrazine of Formula 3 is cyclized for 8 to 10 hours in a solvent selected from dichloromethane, 1,2-dichloroethane and chlorobenzene at a temperature of 60°C to 95°C to obtain 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole of Formula 4 ; Step (iii): Purify 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole of Formula 4 at a temperature of 20°C to 35°C using a mixture of acetic acid and water; Step (iv): In the presence of isopropanol, 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole of Formula 4 is reacted with oxalic acid for 1 to 4 hours at a temperature of 20°C to 35°C to obtain 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate of Formula (I); Step (v): Recrystallize compound (I) using a mixture of isopropanol and water at a temperature of 70°C to 80°C for 15 to 17 hours. 2. The method of claim 1, wherein the temperature used in step (i) is 25°C to 30°C. 3. The method of claim 1, wherein the reaction in step (i) lasts for 2 hours. 4. The method of claim 1, wherein the temperature used in step (ii) is 70°C to 85°C. 5. The method of claim 1, wherein the reaction in step (ii) lasts for 9 hours. 6. The method of claim 1, wherein the ratio of acetic acid to water in step (iii) is 1:9. 7. The method of claim 1, wherein the temperature used in step (iii) is 25°C to 30°C. 8. The method of claim 1, wherein the temperature used in step (iv) is 25°C to 30°C. 9. The method of claim 1, wherein the reaction in step (iv) lasts for 2 hours. 10. The method of claim 1, wherein the temperature used in step (v) is 74°C to 78°C. 11. The method of claim 1, wherein the reaction in step (v) lasts for 16 hours. 12. The method of claim 1, wherein the ratio of isopropanol to water in step (v) is 5:1. 13. The method of claim 1, wherein the purity of 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate of formula (I) is >99.9%. 14. A method for preparing a compound of formula 3, wherein the method comprises reacting 1-isopropyl-1H-indazole-3-carboxylic acid with thionyl chloride to obtain 1-isopropyl-1H-indazole-3-carbonyl chloride, which, without separation, is further reacted with 1-(3-methoxypropyl)piperidine-4-carboxylic acid hydrazide in dichloromethane at a temperature of 20°C to 30°C for 1 hour to 3 hours to obtain a compound of formula 3 . 15. The method of claim 14, wherein the method for preparing 1-isopropyl-1H-indazole-3-carboxylic acid comprises reacting indazole-3-carboxylic acid with isopropyl iodine at a temperature of 25°C to 30°C for 16 to 18 hours in the presence of sodium tert-butoxide and dimethylformamide.