Method for preparing benzamide derivative, novel intermediate used in preparation of benzamide, and method for preparing novel intermediate

Abstract

The present invention relates to a method for preparing N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide, which is a novel benzamide derivative as a 5-HT4 receptor agonist, or a pharmaceutically acceptable salt thereof; to a novel intermediate capable of being used in the preparation of the compounds; and to a method for preparing the same. The preparation methods of the present invention can be useful for mass production since a low-priced reagent and intermediate are used and the number of reaction processes is decreased, thereby saving preparation costs and improving the yield.

Claims

1. A method for preparing a compound of Formula 3: ##STR00023## or a pharmaceutically acceptable salt thereof, the method comprising: reacting a compound of Formula 1: ##STR00024## with a compound of Formula 2: ##STR00025## or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the reaction of the compound of Formula 1 with the compound of Formula 2 or the pharmaceutically acceptable salt thereof is conducted in the presence of at least one compound selected from the group consisting of isobutyl chloroformate, ethyl chloroformate, carbonyldiimidazole, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole.

3. The method of claim 1, wherein the reaction of the compound of Formula 1 with the compound of Formula 2 or the pharmaceutically acceptable salt thereof is conducted in the presence of a base.

4. The method of claim 3, wherein the base is a tertiary amine.

5. The method of claim 4, wherein the tertiary amine is at least one selected from the group consisting of N-methylmorpholine, isopropylethylamine, triethylamine and pyridine.

6. The method of claim 1, wherein the preparation of salt of the compound of Formula 3 further comprises reacting the compound of Formula 3 with an acid.

7. The method of claim 6, wherein the acid is hydrochloric acid.

8. The method of claim 6, wherein the reaction between the compound of Formula 3 and the acid is conducted in the presence of at least one solvent selected from the group consisting of an alcohol, a ketone and an ether.

9. The method of claim 6, wherein the reaction between the compound of Formula 3 and the acid is conducted in the presence of at least one solvent selected from the group consisting of a C.sub.1-C.sub.5 alcohol, a C.sub.3-C.sub.10 ketone and a C.sub.2-C.sub.10 ether.

10. The method of claim 1, wherein the compound of Formula 2 or the pharmaceutically acceptable salt thereof is prepared by a method comprising: preparing a compound of Formula 6: ##STR00026## wherein X is an amine protecting group, by reacting a compound of Formula 4: ##STR00027## wherein X is an amine protecting group, with a compound of Formula 5: ##STR00028## wherein Y is Cl, Br, I, —OTs (tosylate) or —OMs (mesylate); and removing the protecting group X from the compound of—Formula 6—to yield a compound of Formula 2: ##STR00029## or a pharmaceutically acceptable salt thereof.

11. The method of claim 10, wherein the compound of Formula 5 is prepared by a method comprising: preparing a compound of Formula 8: ##STR00030## wherein Y.sub.1 is Cl, Br, I or OH, by reacting a compound of Formula 7: ##STR00031## wherein Y.sub.1 and Z each independently is Cl, Br, I or OH, with an azide compound; and cyclizing the azido group of the compound of Formula 8.

12. The method of claim 11, wherein the cyclization of the compound of Formula 8 comprises reacting the compound of Formula 8 with a carbide compound in the presence of sodium ascorbate and copper iodide.

13. A compound of Formula 6: ##STR00032## wherein X is an amine protecting group and the amine protecting group is butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl or 9-fluorenylmethylcarbonyl (Fmoc), or a pharmaceutically acceptable salt thereof; or a compound of Formula 2: ##STR00033## or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13, wherein the pharmaceutically acceptable salt is hydrochloride, sulfate, phosphate, oxalate, adipate, citrate, di-p-toluoyl-L-tartarate, di-p-toluoyl-D-tartarate, citrate, lactate, maleate, fumarate, gluconate, methanesulfonate, acetate, glycolate, succinate, L- or D-tartarate, tartarate, 4-toluenesulfonate, trifluoroacetate, galacturonate, embonate, glutamate or aspartate.

15. A compound selected from the group consisting of: 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine hydrochloride; 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine; 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine oxalate; 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine succinate; 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine adipate; 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine citrate; 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine L-tartarate; 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine D-tartarate; 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine fumarate; and 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine maleate.

16. A method for preparing a compound of Formula 6: ##STR00034## or a pharmaceutically acceptable salt thereof, the method comprising: reacting a compound of Formula 4: ##STR00035## wherein X is an amine protecting group, with a compound of Formula 5: ##STR00036## wherein Y is Cl, Br, I, —OTs (tosylate) or —OMs (mesylate).

17. The method of claim 16, wherein the reaction between the compound of Formula 4 and the compound of Formula 5 is conducted in the presence of at least one compound selected from the group consisting of sodium iodide and potassium iodide.

18. The method of claim 16, wherein the reaction between the compound of Formula 4 and the compound of Formula 5 is conducted in the presence of a base.

19. The method of claim 18, wherein the base is at least one selected from the group consisting of sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, N-methyl morpholine, isopropylethylamine, triethylamine and pyridine.

20. A method for preparing a compound of Formula 2: ##STR00037## or the pharmaceutically acceptable salt thereof, the method comprising: preparing a compound of Formula 6: ##STR00038## wherein X is an amine protecting group, by reacting a compound of Formula 4: ##STR00039## wherein X is an amine protecting group, with a compound of Formula 5: ##STR00040## wherein Y is Cl, Br, I, —OTs (tosylate) or —OMs (mesylate); and removing the amine protecting group X from the compound—of Formula 6.

21. The method of claim 20, wherein removing the amine protecting groups comprises reacting the compound of Formula 6 with an acid.

22. The method of claim 20, wherein removing the amine protecting groups comprises performing a hydrogenation of the compound of Formula 6 in the presence of palladium/carbon.

Description

MODE FOR INVENTION

(1) The present disclosure will be described more fully hereinafter with reference to the accompanying examples. However, the present disclosure may be embodied in many different forms, and should not be construed as being limited to the embodiments set forth herein. Additionally, .sup.1HNMR data were measured by using a NMR 400 Spectrometer (Varian Instrument).

Example 1

Preparation of 1-(3-chloroproryl)-1H-1,2,3-triazole (Formula 5)

Step 1. Preparation of 1-azido-3-chloropropane (Formula 8)

(2) Dimethyl sulfoxide (126 L) was added to a reaction part, and then 3-bromo-1-chloropropanol (14 kg) was added thereto at room temperature. A reaction solution was prepared by adding sodium azide (5.8 kg) thereto, washing the reaction part with dimethyl sulfoxide (14 L) and performing the stirring for 3 hours. Water (560 L) was added to the reaction solution and then was extracted with dichloromethane (420 L). An organic layer was dehydrated with anhydrous sodium sulfate (25 kg) and concentrated under reduced pressure to quantitatively obtain the titled compound as pale yellow oil (11.04 kg).

(3) .sup.1H NMR (CDCl.sub.3, 400 MHz) δ3.62 (t, 2H), 3.49 (t, 2H), 2.05 (m, 2H)

(4) ##STR00011##

Step 2. Preparation of 1-(3-chloropropyl)-1H-1,2,3-triazole (Formula 5)

(5) Acetonitrile (96 L) and potable water (53.0 L) were added to a reactor. 1-azido-3-chloropropane (10.6 kg) was added thereto at a room temperature. The reaction solution was prepared by adding copper iodide (8.52 kg) and sodium ascorbate (8.8 kg) thereto and then performing the stirring for 2 hours. The reaction solution was cooled to 0-10° C. Potassium carbide (9.7 kg) was slowly added to the reaction solution while not exceeding 20° C. of an internal temperature and then resulting solution was filtered using diatomite and concentrated under reduced pressure. A mixed solution was prepared by adding water (266 L) and charcoal (4.3 kg) to the concentrated residue and performing the stirring for 4 hours. The mixed solution was filtered using diatomite and extracted with dichloromethane. An organic layer was washed with 5% NaCl aqueous solution, and dehydrated and filtered by using anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain the titled compound as pale yellow oil (8.86 kg; yield: 69%).

(6) .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.63 (s, 1H), 7.58 (s, 1H), 4.55 (t, 2H), 3.47 (t, 2H), 2.38 (quintet, 2H)

(7) ##STR00012##

Example 2

Preparation of 3-(1H-1,2,3-triazol-1-yl) propyl methanesulfonate (Formula 5)

Step 1. Preparation of 3-azido propan-1-ol (Formula 8)

(8) Dimethyl sulfoxide (1.3 L) was added to the reaction part, and then 3-bromo-1-propanol (0.14 kg) was added thereto at a room temperature. A reaction solution was prepared by adding sodium azide (58 g) thereto, washing the reaction part with dimethyl sulfoxide (0.2 L) and performing the stirring for 3 hours. Water (5.6 L) was added to the reaction solution and the resulting solution was extracted with dichloromethane (4.2 L). An organic layer was dehydrated with anhydrous sodium sulfate (0.5 kg) and concentrated under reduced pressure to quantitatively obtain the titled compound as oil (0.11 kg).

(9) .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 3.72 (m, 2H), 3.42 (m, 2H), 1.81 (m, 2H)

(10) ##STR00013##

Step 2. Preparation of 3-(1H-1,2,3-triazol-1-yl)propan-1-ol (Formula 5)

(11) Acetonitrile (303 mL) and potable water (190 mL) were added to a reaction part. 1-azido-3-chloropropane (38 g) was added thereto at a room temperature. A reaction solution was prepared by adding copper iodide (35.7 g) and sodium ascorbate (37.1 g) thereto and performing the stirring for 2 hours. The reaction solution was cooled to 0-10° C. Potassium carbide (48 g) was slowly added to the reaction solution while not exceeding 20° C. of an internal temperature. The resulting solution was filtered through diatomite and concentrated under reduced pressure. A mixed solution was prepared by adding water (950 mL) and charcoal (15 g) to the concentrated residue and performing the stirring for 4 hours. The mixed solution was filtered through diatomite and extracted with dichloromethane. An organic layer was washed with 5% NaCl aqueous solution, and dehydrated by using anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the titled compound as pale yellow oil (10 g; yield: 21%).

(12) .sup.1H NMR (DMSO d.sub.6, 400 MHz) δ 8.08 (s, 1H), 7.67 (s, 1H), 4.39 (t, 2H), 3.34 (t, 2H), 1.91 (quintet, 2H)

(13) ##STR00014##

Step 3. Preparation of 3-(1H-1,2,3-triazol-1-yl) propyl methanesulfonate (Formula 5)

(14) Dichloromethane (51 mL) was added to a reaction part, and then 3-(1H-1,2,3-triazol-1-yl)propan-1-ol (5.1 g) was added thereto. The reaction solution was cooled to 0-10° C., triethylamine (11.3 mL) was added to the reaction solution and methanesulfonyl chloride (4.7 mL) was slowly added thereto. The temperature of the resulting solution was elevated to the room temperature and then the solution was stirred for 2 hours. Potable water (102 mL) was added and then was extracted with dichloromethane (255 mL) and concentrated under reduced pressure. Potable water (75 mL) and charcoal (2.0 g) were added to the concentrated residue and stirred for 2 hours. The mixed solution was filtered through diatomite and extracted with dichloromethane (102 mL). An organic layer was washed with 5% NaCl aqueous solution, and dehydrated by using anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the titled compound as pale yellow oil (4.06 g; yield: 50%).

(15) .sup.1H NMR (CDCl.sub.3, 600 MHz) δ 7.68 (s, 1H), 7.61 (s, 1H), 4.52 (t, 2H), 3.0 (s, 3H), 2.36 (quintet, 2H)

(16) ##STR00015##

Example 3

Preparation of 3-(1H-1,2,3-triazol-1-yl)propyl 4-methylbenzenesulfonate (Formula 5)

(17) Dichloromethane (49 mL) was added to a reaction part, and then 3-(1H-1,2,3-triazol-1-yl)propan-1-ol (4.9 g) was added thereto. The reaction solution was cooled to 0-10° C., triethylamine (10.8 mL) was added to the reaction solution and 4-methyl benzenesulfonate (11.0 g) was slowly added thereto. The temperature of the resulting solution was elevated to a room temperature and the solution was stirred for 2 hours. Potable water (98 mL) was added to the resulting solution, and then was extracted with dichloromethane (146 mL) and concentrated under reduced pressure. Potable water (75 mL) and charcoal (2.0 g) were added to the concentrated residue and stirred for 2 hours to prepare a mixed solution. The mixed solution was filtered through diatomite and extracted with dichloromethane (200 mL). An organic layer was washed with 5% NaCl aqueous solution, and dehydrated by using anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the titled compound as oil (0.97 g; yield: 9%).

(18) .sup.1H NMR (CDCl.sub.3, 600 MHz) δ 7.77 (d, 2H), 7.65 (s, 1H), 7.49 (s, 1H), 7.33 (d, 2H), 4.44 (t, 2H), 3.97 (t, 2H), 2.43 (s, 3H), 2.29 (quintet, 2H)

(19) ##STR00016##

Example 4

Preparation of [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine and its hydrochloride (Formula 2) from tert-butyl(piperidin-4-ylmethyl)carbamate

Step 1. Preparation of tert-butyl[[1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]carbamate (Formula 6)

(20) Acetonitrile (IL) was added to a 2 L flask, and then tert-butyl(piperidin-4-ylmethyl)carbamate (35.2 g) was added thereto. A reaction solution was prepared by sequentially adding potassium iodide (19.1 g), calcium carbonate (227.1 g) and 1-(3-chloropropyl)-1H-1,2,3-triazole (35.9 g) thereto and performing the stirring under reflux for 7 hours. The reaction solution was cooled to a room temperature, and water (1.4 L) and 5% sodium thiosulfate solution were sequentially added to the reaction solution.

(21) The resulting solution was extracted with dichloromethane (1.5 L), and then an organic layer was dehydrated by using magnesium sulfate and filtered. The organic layer was concentrated under reduced pressure to obtain the titled compound (88.0 g; yield: quantitative).

(22) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.68 (s, 1H), 7.55 (s, 1H), 4.59 (br s, 1H), 4.45 (t, 2H), 3.01 (t, 2H), 2.85 (d, 2H), 2.82 (t, 2H), 2.07 (m, 2H), 1.89 (m, 2H), 1.67 (d, 2H), 1.43 (s, 9H & m, 1H), 1.23 (m, 2H)

(23) ##STR00017##

Step 2. Preparation of 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine hydrochloride (Formula 2)

(24) A reaction solution was prepared by dissolving tert-butyl[[1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]carbamate (16.5 g) in methanol (83 mL) and performing the stirring at a room temperature for 7 hours. 2N hydrochloric acid diethyl ether (124 mL) was added to the reaction solution and stirred for 30 minutes. The resulting solution was filtered and dried under reduced pressure to obtain the titled compound (14.9 g; yield: quantitative).

(25) .sup.1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 8.17 (br s, 4H), 7.76 (s, 1H), 4.49 (t, 2H), 3.46 (d, 2H), 2.99 (m, 2H), 2.86 (m, 2H), 2.68 (m, 2H), 2.33 (m, 2H), 1.84-1.92 (m, 3H), 1.58 (m, 2H)

(26) ##STR00018##

Step 3. Preparation of 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine (Formula 2)

(27) A reaction solution was prepared by dissolving 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine hydrochloride (5.0 g) in water (50 mL) and pH of the reaction solution was adjusted to about 10 using 2N sodium hydroxide. The reaction solution was extracted with dichloromethane/2-propanol=4/1 (volumetric ratio, 250 mL), and then dehydrated by using anhydrous magnesium sulfate and filtered. An organic layer was concentrated under reduced pressure to obtain the titled compound (3.1 g; yield: 81%).

(28) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.67 (s, 1H), 7.55 (s, 1H), 4.44 (t, 2H), 2.86 (d, 2H), 2.58 (m, 2H), 2.28 (t, 2H), 2.07 (m, 2H), 1.89 (t, 2H), 1.71 (d, 2H), 1.17-1.30 (m, 3H)

(29) ##STR00019##

Example 5

Preparation of [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine (Formula 2) from benzyl(piperidin-4-ylmethyl)carbamate

Step 1. Preparation of benzyl[[1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]carbamate (Formula 6)

(30) A reaction solution was prepared by dissolving benzyl(piperidin-4-ylmethyl)carbamate (300 g) in acetonitrile (9 L); sequentially adding potassium iodide (201 g), calcium carbonate (1680 g) and 1-(3-chloropropyl)-1H-1,2,3-triazole (264 g) thereto; and performing the stirring under reflux for 16 hours. The reaction solution was cooled to a room temperature, and water (12 L) and 5% sodium thiosulfate solution (9 L) were sequentially added to the reaction solution. The resulting solution was extracted with dichloromethane (15 L). 2N hydrochloric acid (1.2 L) and water (12 L) were added to an organic layer, and then the layer was separated. 2N sodium hydroxide (1.8 L) was added to an aqueous layer and the resulting solution was extracted with dichloromethane (12 L). An organic layer was treated with charcoal, and then filtered and concentrated under reduced pressure. A reaction solution was prepared by adding hexane (6 L) to the concentrated residue. The reaction solution was stirred for 16 hours. The resulting solids were filtered and dried to obtain the titled compound (285 g; yield: 66%).

(31) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.66 (s, 1H), 7.52 (s, 1H), 7.34-7.28 (m, 5H), 5.07 (s, 2H), 4.44 (t, 2H), 3.08 (t, 2H), 2.83 (d, 2H), 2.28 (d, 2H), 2.08-2.01 (m, 2H), 1.90 (t, 2H), 1.67 (d, 2H), 1.46 (m, 1H), 1.26-1.17 (m, 2H)

(32) ##STR00020##

Step 2. Preparation of 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine (Formula 2)

(33) Benzyl[[1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]carbamate (270 g) was added to a hydrogen reactor and was dissolved by adding methanol (1.35 L). A reaction solution was prepared by adding 10 wt % of palladium/carbon (containing 56 wt % of water) (61 g) to the reactor, applying a pressure with hydrogen (10 bar) thereto, and performing the stirring at 50° C. for 18 hours. The reaction solution was cooled to a room temperature and filtered through diatomite. The filtrate was concentrated under reduced pressure to obtain the titled compound (168.7 g; yield: quantitative).

(34) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.67 (s, 1H), 7.55 (s, 1H), 4.44 (t, 2H), 2.86 (d, 2H), 2.58 (m, 2H), 2.28 (t, 2H), 2.07 (m, 2H), 1.89 (t, 2H), 1.71 (d, 2H), 1.17-1.30 (m, 3H)

(35) ##STR00021##

Example 6

Preparation of 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine oxalate (Formula 2)

(36) A solution prepared by adding oxalic acid dihydrate (0.57 g) to acetone (10 mL) was slowly added into a solution, which was prepared by dissolving 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine (1.0 g) in acetone (10 mL) to prepare a reaction solution. The reaction solution was stirred for 4 hours, and then the resulting solids were filtered and dried to obtain the titled compound (1.30 g; yield: 93%).

(37) .sup.1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.71 (s, 1H), 4.39 (t, 2H), 2.90 (d, 2H), 2.68 (d, 2H), 2.49 (s, 4H), 2.21 (t, 2H), 1.98 (m, 2H), 1.82 (t, 2H), 1.66 (d, 2H), 1.46 (m, 1H), 1.18-1.09 (m, 2H)

Example 7

Preparation of 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine succinate (Formula 2)

(38) A solution prepared by adding succinic acid (0.53 g) into ethanol (20 mL) was slowly added into a solution, which was prepared by dissolving 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine (1.0 g) in ethanol (10 mL) to prepare a reaction solution. The reaction solution was stirred for 4 hours and cooled to around 0° C., and then diethylether (60 mL) was added thereto. The resulting solution was further stirred for 16 hours. The resulting solids were filtered and dried to obtain the titled compound (1.44 g; yield: 94%).

(39) .sup.1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.71 (s, 1H), 4.39 (t, 2H), 2.90 (d, 2H), 2.68 (d, 2H), 2.49 (s, 4H), 2.21 (t, 2H), 1.98 (m, 2H), 1.82 (t, 2H), 1.66 (d, 2H), 1.46 (m, 1H), 1.18-1.09 (m, 2H)

Example 8

Preparation of 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine adipate (Formula 2)

(40) A solution prepared by adding adipic acid (0.65 g) to ethanol (20 mL) was slowly added into a solution which was prepared by dissolving 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine (1.0 g) in ethanol (10 mL) to prepare a reaction solution. The reaction solution was stirred for 4 hours and cooled to around 0° C., and then diethylether (60 mL) was added thereto. The resulting solution was further stirred for 16 hours. The resulting solids were filtered and dried to obtain the titled compound (1.39 g; yield: 84%).

(41) .sup.1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.69 (s, 1H), 4.38 (t, 2H), 2.80 (d, 2H), 2.52-2.49 (m, 2H), 2.20-2.12 (m, 6H), 1.97 (m, 2H), 1.80 (t, 2H), 1.66 (d, 2H), 1.46 (m, 4H), 1.33 (m, 1H), 1.13-1.05 (m, 2H)

Example 9

Preparation of 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine citrate (Formula 8)

(42) A solution prepared by adding citric acid (0.94 g) to acetone (10 mL) was slowly added into a solution which was prepared by dissolving 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine (1.0 g) in acetone (10 mL) to prepare a reaction solution. The reaction solution was stirred for 4 hours, and then the resulting solids were filtered and dried to obtain the titled compound (1.59 g; yield: 86%).

(43) .sup.1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.71 (s, 1H), 4.39 (t, 2H), 2.89 (d, 2H), 2.69 (d, 2H), 2.56-2.45 (m, 4H), 2.29-2.27 (m, 2H), 2.01-1.88 (m, 6H), 1.68 (d, 2H), 1.52-1.51 (m, 1H), 1.22-1.14 (m, 2H)

Example 10

Preparation of 1-[{3-(1H-1,2,3-trizol-1-yl)propyl}piperidin-4-yl]methanamine L-tartrate (Formula 2)

(44) A solution prepared adding L-tartaric acid (0.67 g) to ethanol (10 mL) was slowly added to a solution which was prepared by dissolving 1-[{3-(1H-1,2,3-trizol-1-yl)propyl}piperidin-4-yl]methanamine (1.0 g) in ethanol (10 mL), and then diethylether (40 mL) was added to prepare a reaction solution. The reaction solution was stirred for 4 hours, and then the resulting solids were filtered and dried to obtain the titled compound (1.64 g; yield: 98%).

(45) .sup.1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.70 (s, 1H), 4.39 (t, 2H), 3.89 (s, 2H), 2.87 (d, 2H), 2.68 (d, 2H), 2.28 (t, 2H), 2.00-1.85 (m, 4H), 1.68 (d, 2H), 1.53 (m, 1H), 1.21-1.13 (m, 2H)

Example 11

Preparation of 1-[{3-(1H-1,2,3-trizol-1-yl)propyl}piperidin-4-yl]methanamine D-tartrate (Formula 2)

(46) A solution prepared by adding D-tartaric acid (0.67 g) to ethanol (10 mL) was slowly added to a solution which was prepared by dissolving 1-[{3-(1H-1,2,3-trizol-1-yl)propyl}piperidin-4-yl]methanamine (1.0 g) in ethanol (10 mL), and then diethylether (40 mL) was added to prepare a reaction solution. The reaction solution was stirred for 4 hours, and then the resulting solids were filtered and dried to obtain the titled compound (1.65 g; yield: 99%).

(47) .sup.1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.70 (s, 1H), 4.39 (t, 2H), 3.83 (s, 2H), 2.84 (d, 2H), 2.68 (d, 2H), 2.24 (t, 2H), 1.99-1.92 (m, 2H), 1.85 (t, 2H), 1.67 (d, 2H), 1.49 (m, 1H), 1.20-1.12 (m, 2H)

Example 12

Preparation of 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine fumarate (Formula 2)

(48) A solution prepared by adding fumaric acid (0.52 g) to ethanol (10 mL) was slowly added to a solution which was prepared by dissolving 1-[{3-(1H-1,2,3-trizol-1-yl)propyl}piperidin-4-yl]methanamine (1.0 g) in ethanol (10 mL), and then diethylether (40 mL) was added to prepare a reaction solution. The reaction solution was stirred for 4 hours, and then the resulting solids were filtered and dried to obtain the titled compound (1.49 g; yield: 98%).

(49) .sup.1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.70 (s, 1H), 6.44 (s, 2H), 4.38 (t, 2H), 2.83 (d, 2H), 2.66 (d, 2H), 2.24 (t, 2H), 1.99-1.92 (m, 2H), 1.85 (t, 2H), 1.68 (d, 2H), 1.50 (m, 1H), 1.19-1.11 (m, 2H)

Example 13

Preparation of 1-[{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine maleate (Formula 2)

(50) A solution prepared by adding maleic acid (0.52 g) to ethanol (10 mL) was slowly added to a solution which was prepared by dissolving 1-[{3-(1H-1,2,3-trizol-1-yl)propyl}piperidin-4-yl]methanamine (1.0 g) in ethanol (10 mL), and then diethylether (40 mL) was added to prepare a reaction solution. The reaction solution was stirred for 4 hours, and then the resulting solids were filtered and dried to obtain the titled compound (0.96 g; yield: 63%).

(51) .sup.1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.76 (s, 1H), 6.02 (s, 2H), 4.48 (t, 2H), 2.96 (bs, 2H), 2.74 (bs, 2H), 2.24 (m, 2H), 1.88-1.84 (m, 2H), 1.85 (t, 2H), 1.68 (d, 2H), 1.50 (m, 1H), 1.19-1.11 (m, 2H)

Example 14

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (Formula 3)

(52) 4-amino-5-chloro-2-methoxybenzoic acid (1.0 g) was dissolved in dichloromethane (50 mL) and cooled to 0° C. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.14 g) and 1-hydroxybenzotriazole hydrate (0.80 g) were sequentially added to the solution and stirred for 3.5 hours. A reaction solution was prepared by sequentially adding diisopropylethylamine (3.21 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine (1.33 g) thereto and performing the stirring for 5 minutes. The temperature of the reaction solution was elevated to a room temperature. The reaction solution was further stirred for 14 hours. Water (40 mL) was added to the reaction solution and stirred for 5 minutes, and then an organic layer was separated. Dichloromethane (20 mL) was added to a aqueous layer and the organic layer was extracted again. The aqueous layer was extracted by collecting the organic layers and adding water (30 mL) and 1N hydrochloric acid (15 mL) thereto. 2N sodium hydroxide (7.5 mL) was added to the aqueous layer and stirred for 14 hours. The resulting solids were filtered and washed with water, and then was concentrated under reduced pressure at 19-22° C. for 6 hours to obtain the titled compound (1.68 g; yield: 84%).

(53) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)

(54) ##STR00022##

Example 15

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (Formula 3)

(55) 4-Amino-5-chloro-2-methoxybenzoic acid (1.0 g) was dissolved in tetrahydrofuran (50 mL) and cooled to 0-5° C. Diisopropylethylamine (0.76 g) and ethyl chloroformic acid (0.64 g) were sequentially added to the solution and stirred for 1 hour. A reaction solution was prepared by sequentially adding diisopropylethylamine (2.56 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine (1.33 g) and performing the stirring for 3.5 hours. The temperature of the reaction solution was elevated and the solution was stirred under reflux. The reaction solution was further stirred for 4 hours. Water (40 mL) was added thereto and stirred for 5 minutes and an organic layer was separated. Dichloromethane (20 mL) was added to a aqueous layer and the organic layer was extracted again. The aqueous layer was extracted by collecting the organic layers and adding water (30 mL) and 1N hydrochloric acid (15 mL). 2N sodium hydroxide (7.5 mL) was added to the aqueous layer and stirred for 11 hours. The resulting solids were filtered, washed with water and then dried under reduced pressure at 19-22° C. for 24 hours to obtain the titled compound (1.28 g; yield: 63%).

(56) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)

Example 16

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (Formula 3)

(57) 4-Amino-5-chloro-2-methoxybenzoic acid (1.0 g) was dissolved in dichloromethane (50 mL) at 20° C. Carbonyldiimidazole (0.96 g) was added to the solution and stirred for 2.5 hours at the same temperature. A reaction solution was prepared by sequentially adding isopropylamine (2.56 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine (1.33 g) and performing the stirring for 3.5 hours, and then the temperature of the reaction solution was elevated to 40° C. The reaction solution was further stirred for 7 hours and cooled to 20° C. Water (40 mL) was added thereto. The stirring was performed for 5 minutes and an organic layer was separated. Dichloromethane (20 mL) was added to an aqueous layer and the organic layer was extracted again. The aqueous layer was extracted by collecting the organic layers and adding water (30 mL) and 1N hydrochloric acid (15 mL) thereto. 2N sodium hydroxide (7.5 mL) was added to the aqueous layer and stirred for 15 hours. The resulting solids were filtered, washed with water and dried under reduced pressure at 19-22° for 24 hours to obtain the titled compound (1.90 g; yield: 95%).

(58) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)

Example 17

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (Formula 3)

(59) 4-Amino-5-chloro-2-methoxybenzoic acid (0.20 g) was dissolved in dichloromethane (10 mL) and cooled to 0° C. N-methyl morpholine (0.12 g) and isobutyl chloroformate (0.16 g) were sequentially added to the solution and stirred for 3 hours. A reaction solution was prepared by sequentially adding triethylamine (0.20 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine (0.27 g) thereto, and the temperature of the reaction solution was elevated to 20° C. The stirring was performed for 14 hours, water (10 mL) was added thereto and stirred for 5 minutes, and layers were separated. Dichloromethane (10 mL) was added to an aqueous layer and an organic layer was extracted. The aqueous layer was extracted by adding water (10 mL) and 1N hydrochloric acid (3 mL) to the collected organic layers. 1N sodium hydroxide (4 mL) was added to the aqueous layer and the extraction was performed twice using a mixed solvent of dichloromethane (8 ml) and 2-propanol (2 ml). The collected organic layers were dried with sodium sulfate and filtered, and then washed with dichloromethane (10 mL). The solvent was removed by concentrating the filtered organic solution under the reduced pressure. The resulting solids were dried under reduced pressure at 19-22° C. for 18 hours to obtain the titled compound (0.41 g; yield: quantitative).

(60) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)

Example 18

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (Formula 3)

(61) 4-Amino-5-chloro-2-methoxybenzoic acid (0.20 g) was dissolved in dichloromethane (10 mL) and cooled to ° C. N-methyl morpholine (0.12 g) and isobutyl chloroformate (0.16 g) were sequentially added to the solution and stirred for 3 hours. A reaction solution was prepared by sequentially adding triethylamine (0.20 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine hydrochloride (0.31 g) thereto. The temperature of the reaction solution was elevated and the solution was stirred under reflux. After 4 hours of stirring, water (10 mL) was added thereto, stirred for 5 minutes and a layer was separated. Dichloromethane (10 mL) was added to an aqueous layer and an organic layer was extracted. Water (10 mL) and 1N hydrochloric acid (3 mL) were added to the collected organic layers to extract the aqueous layer. 1N sodium hydroxide (4 mL) was added to the aqueous layer, and the extraction was performed twice with a mixed solvent of dichloromethane (8 mL) and 2-propanol (2 mL). The collected organic layers were dried with sodium sulfate and filtered, and then washed with dichloromethane (10 mL). The solvent was removed by concentrating the filtered organic solution under reduced pressure. The resulting solids were dried under reduced pressure at 19-22° C. for 18 hours to obtain the titled compound (0.39 g; yield: 98%).

(62) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)

Example 19

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (Formula 3)

(63) 4-Amino-5-chloro-2-methoxybenzoic acid (0.2 g) was dissolved in dichloromethane (10 mL) and cooled to ° C. N-methyl morpholine (0.12 g) and isobutyl chloroformate (0.16 g) were sequentially added to the solution and stirred for 3 hours. A reaction solution was prepared by sequentially adding triethylamine (0.2 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine oxalate (0.37 g) thereto, and the temperature of the reaction solution was elevated. The reaction solution was stirred under reflux. After 4 hours of stirring, water (10 ml) was added thereto, stirred for 5 minutes, and layers were separated. Dichloromethane (10 mL) was added to an aqueous layer and an organic layer was extracted. Water (10 mL) and 1N hydrochloric acid (3 mL) were added to the collected organic layers to extract the aqueous layer. 1N sodium hydroxide (4 mL) was added to the aqueous layer and the extraction was performed twice with a mixed solvent of dichloromethane (8 mL) and 2-propanol (2 mL). The collected organic layers were dried with sodium sulfate and filtered, and then washed with dichloromethane (10 mL). The solvent was removed by concentrating the filtered organic solution under reduced pressure. The resulting solids were dried under reduced pressure at 19-22° C. for 18 hours to obtain the titled compound (0.36 g; yield: 90%).

(64) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)

Example 20

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (Formula 3)

(65) 4-Amino-5-chloro-2-methoxybenzoic acid (0.20 g) was dissolved in dichloromethane (10 mL) and cooled to ° C. N-methyl morpholine (0.12 g) and isobutyl chloroformate (0.16 g) were sequentially added to the solution and stirred for 3 hours. A reaction solution was prepared by sequentially adding triethylamine (0.20 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine citrate (0.49 g) thereto. The temperature of the reaction solution was elevated and the reaction solution was stirred under reflux. After 14 hours of stirring, water (10 mL) was added thereto, stirred for 5 minutes and layers were separated. Dichloromethane (10 mL) was added to an aqueous layer and an organic layer was extracted. Water (10 mL) and 1N hydrochloric acid (3 mL) were added to the collected organic layers to extract the aqueous layer. 1N sodium hydroxide (4 mL) was added to the aqueous layer and the extraction was performed twice with a mixed solvent of dichloromethane (8 mL) and 2-propanol (2 mL). The collected organic layers were dried with sodium sulfate and filtered, and then washed with dichloromethane (10 mL). The solvent was removed by concentrating the filtered organic solution under reduced pressure. The resulting solids were dried under reduced pressure at 19-22° C. for 18 hours to obtain the titled compound (0.35 g; yield: 88%).

(66) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)

Example 21

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (Formula 3)

(67) 4-Amino-5-chloro-2-methoxybenzoic acid (0.20 g) was dissolved in dichloromethane (10 mL) and cooled to ° C. N-methyl morpholine (0.12 g) and isobutyl chloroformate (0.16 g) were sequentially added to the solution and stirred for 3 hours. A reaction solution was prepared by sequentially adding triethylamine (0.20 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine succinate (0.41 g) thereto. The temperature of the reaction solution was elevated and the stirring was performed under reflux. After 14 hours of stirring, water (10 mL) was added thereto, stirred for 5 minutes and layers were separated. Dichloromethane (10 mL) was added to an aqueous layer and an organic layer was extracted. Water (10 mL) and 1N hydrochloric acid (3 mL) were added to the collected organic layers to extract the aqueous layer. 1N sodium hydroxide (4 mL) was added to the aqueous layer and the extraction was performed twice with a mixed solvent of dichloromethane (8 mL) and 2-propanol (2 mL). The collected organic layers were dried with sodium sulfate and filtered, and then washed with dichloromethane (10 mL). The solvent was removed by concentrating the filtered organic solution under reduced pressure. The resulting solids were dried under reduced pressure at 19-22° C. for 18 hours to obtain the titled compound (0.36 g; yield: 90%).

(68) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)

Example 22

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (Formula 3)

(69) 4-Amino-5-chloro-2-methoxybenzoic acid (0.20 g) was dissolved in dichloromethane (10 mL) and cooled to ° C. N-methyl morpholine (0.12 g) and isobutyl chloroformate (0.16 g) were sequentially added to the solution and stirred for 3 hours. A reaction solution was prepared by sequentially adding triethylamine (0.20 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine L-tartrate (0.44 g) thereto. The temperature of the reaction solution was elevated and the solution was stirred under reflux. After 14 hours of stirring, water (10 mL) was added thereto, stirred for 5 minutes and layers were separated. Dichloromethane (10 mL) was added to an aqueous layer and an organic layer was extracted. Water (10 mL) and 1N hydrochloric acid (3 mL) were added to the collected organic layers to extract the aqueous layer. 1N sodium hydroxide (4 mL) was added to the aqueous layer and the extraction was performed twice with a mixed solvent of dichloromethane (8 mL) and 2-propanol (2 mL). The collected organic layers were dried with sodium sulfate and filtered, and then washed with dichloromethane (10 mL). The solvent was removed by concentrating the filtered organic solution under reduced pressure. The resulting solids were dried under reduced pressure at 19-22° C. for 18 hours to obtain the titled compound (0.40 g; yield: 100%).

(70) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.08 δ (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)

Example 23

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (Formula 3)

(71) 4-Amino-5-chloro-2-methoxybenzoic acid (0.20 g) was dissolved in acetonitrile (10 mL). Carbonyldiimidazole (0.19 g) was added to the solution and stirred at 19-22° C. for 4 hours. After triethylamine (0.20 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine (0.27 g) were sequentially added thereto, the temperature of the resulting solution was elevated. Then the solution was stirred under reflux. After 21 hours of stirring, water (10 mL) was added thereto, stirred for 5 minutes, and layers were separated. Dichloromethane (10 mL) was added to an aqueous layer and an organic layer was extracted. Water (10 mL) and 1N hydrochloric acid (4 mL) were added to the collected organic layers to extract the aqueous layer. 2N sodium hydroxide (about 4 mL) was added to the aqueous layer to adjust pH of about 10. The extraction was performed twice with a mixed solvent of dichloromethane (8 mL) and 2-propanol (2 mL). The collected organic layers were dried with anhydrous magnesium sulfate and filtered, and then washed with dichloromethane (10 mL). The solvent was removed by concentrating the filtered organic solution under reduced pressure. The resulting solids were dried under reduced pressure at 19-22° C. for 17 hours to obtain the titled compound (0.41 g; yield: 100%).

(72) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)

Example 24

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (Formula 3)

(73) 4-Amino-5-chloro-2-methoxybenzoic acid (0.20 g) was dissolved in acetonitrile (10 mL). Carbonyldiimidazole (0.19 g) was added to the solution and stirred at 19-22° C. for 4 hours. After triethylamine (0.20 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine hydrochloride (0.31 g) were sequentially added thereto, the temperature of the resulting solution was elevated, and the solution was stirred under reflux. After 18 hours of stirring, water (10 mL) was added thereto, stirred for 5 minutes, and layers were separated. Dichloromethane (10 mL) was added to an aqueous layer and an organic layer was extracted. Water (10 mL) and 1N hydrochloric acid (4 mL) were added to the collected organic layers to extract the aqueous layer. 2N sodium hydroxide (about 4 mL) was added to the aqueous layer adjust pH of about 10. The extraction was performed twice with a mixed solvent of dichloromethane (8 mL) and 2-propanol (2 mL). The collected organic layers were dried with anhydrous magnesium sulfate and filtered and then washed with dichloromethane (10 mL). The solvent was removed by concentrating the filtered organic solution under reduced pressure. The resulting solids were dried under reduced pressure at 19-22° C. for 17 hours to obtain the titled compound (0.39 g; yield: 98%).

(74) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)

Example 25

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (Formula 3)

(75) 4-Amino-5-chloro-2-methoxybenzoic acid (0.20 g) was dissolved in acetonitrile (10 mL). Carbonyldiimidazole (0.19 g) was added to the solution and stirred at 19-22° C. for 4 hours. After triethylamine (0.20 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine oxalate (0.37 g) were sequentially added, the temperature of the resulting solution was elevated. Then the solution was stirred under reflux. After 21 hours of stirring, water (10 mL) was added thereto, stirred for 5 minutes, and layers were separated. Dichloromethane (10 mL) was added to an aqueous layer and an organic layer was extracted. Water (10 mL) and 1N hydrochloric acid (4 mL) were added to the collected organic layers to extract the aqueous layer. 2N sodium hydroxide (about 4 mL) was added into the aqueous layer to adjust pH of about 10. The extraction was performed twice with a mixed solvent of dichloromethane (8 mL) and 2-propanol (2 mL). The collected organic layers were dried with anhydrous magnesium sulfate and filtered, and then washed with dichloromethane (10 mL). The solvent was removed by concentrating the filtered organic solution under reduced pressure. The resulting solids were dried under reduced pressure at 19-22° C. for 17 hours to obtain the titled compound (0.25 g; yield: 63%).

(76) 1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)

Example 26

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (Formula 3)

(77) 4-Amino-5-chloro-2-methoxybenzoic acid (0.20 g) was dissolved in acetonitrile (10 mL). Carbonyldiimidazole (0.19 g) was added to the solution and stirred at 19-22° C. for 3 hours. After triethylamine (0.20 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine citrate (0.49 g) were sequentially added thereto, the temperature of the resulting solution was elevated. Then the solution was stirred under reflux. After 16 hours of stirring, water (10 mL) was added thereto, stirred for 5 minutes, and layers were separated. Dichloromethane (10 mL) was added to an aqueous layer and an organic layer was extracted. Water (10 mL) and 1N hydrochloric acid (4 mL) were added to the collected organic layers to extract the aqueous layer. 2N sodium hydroxide (about 4 mL) was added into the aqueous layer to adjust pH of about 10. The extraction was performed twice with a mixed solvent of dichloromethane (8 mL) and 2-propanol (2 mL). The collected organic layers were dried with anhydrous magnesium sulfate and filtered, and then washed with dichloromethane (10 mL). The solvent was removed by concentrating the filtered organic solution under reduced pressure. The resulting solids were dried under reduced pressure at 19-22° for 17 hours to obtain the titled compound (0.39 g; yield: 98%).

(78) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)

Example 27

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (Formula 3)

(79) 4-Amino-5-chloro-2-methoxybenzoic acid (0.20 g) was dissolved in acetonitrile (10 mL). Carbonyldiimidazole (0.19 g) was added to the solution and stirred at 19-22° C. for 3 hours. After triethylamine (0.20 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine succinate (0.41 g) were sequentially added, the temperature of the resulting solution was elevated. Then the solution was stirred under reflux. After 16 hours of stirring, water (10 mL) was added thereto, stirred for 5 minutes, and layers were separated. Dichloromethane (10 mL) was added to an aqueous layer and an organic layer was extracted. Water (10 mL) and 1N hydrochloric acid (4 mL) were added to the collected organic layers to extract the aqueous layer. 2N sodium hydroxide (about 4 mL) was added into the aqueous layer to adjust pH of about 10. The extraction was performed twice with a mixed solvent of dichloromethane (8 mL) and 2-propanol (2 mL). The collected organic layers were dried with anhydrous magnesium sulfate and filtered, and then washed with dichloromethane (10 mL). The solvent was removed by concentrating the filtered organic solution under reduced pressure. The resulting solids were dried under reduced pressure at 19-22° C. for 17 hours to obtain the titled compound (0.39 g; yield: 98%).

(80) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)

Example 28

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidine-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (Formula 3)

(81) 4-Amino-5-chloro-2-methoxybenzoic acid (0.20 g) was dissolved in acetonitrile (10 mL). Carbonyldiimidazole (0.19 g) was added to the solution and stirred at 19-22° C. for 3 hours. After triethylamine (0.20 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidine-4-yl]methanamine L-tartrate (0.44 g) were sequentially added thereto, the temperature of the resulting solution was elevated. Then, the solution was stirred under reflux. After 16 hours of stirring, water (10 mL) was added thereto, stirred for 5 minutes, and layers were separated. Dichloromethane (10 mL) was added to an aqueous layer and an organic layer was extracted. Water (10 mL) and 1N hydrochloric acid (4 mL) were added to the collected organic layers to extract the aqueous layer. 2N sodium hydroxide (about 4 mL) was added into the aqueous layer to adjust pH of about 10. The extraction was performed twice with a mixed solvent of dichloromethane (8 mL) and 2-propanol (2 mL). The collected organic layers were dried with anhydrous magnesium sulfate and filtered, and then washed with dichloromethane (10 mL). The solvent was removed by concentrating the filtered organic solution under reduced pressure. The resulting solids were dried under reduced pressure at 19-22° for 17 hours to obtain the titled compound (0.35 g; yield: 88%).

(82) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)

Example 29

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (Formula 3)

(83) 4-Amino-5-chloro-2-methoxybenzoic acid (0.20 g) was dissolved in tetrahydrofuran (10 mL). Carbonyldiimidazole (0.19 g) was added to the solution and stirred at 19-22° C. for 3 hours. After triethylamine (0.20 g) and [1-{3-(1H-1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methanamine succinate (0.41 g) were sequentially added, the temperature of the resulting solution was elevated. Then, the solution was stirred under reflux. After 6 hours of stirring, water (10 mL) was added thereto, stirred for 5 minutes, and layers were separated. Dichloromethane (10 mL) was added to an aqueous layer and an organic layer was extracted. Water (10 mL) and 1N hydrochloric acid (4 mL) were added to the collected organic layers to extract the aqueous layer. 2N sodium hydroxide (about 4 mL) was added into the aqueous layer to adjust pH of about 10. The extraction was performed twice with a mixed solvent of dichloromethane (8 mL) and 2-propanol (2 mL). The collected organic layers were dried with anhydrous magnesium sulfate and filtered, and then washed with dichloromethane (10 mL). The solvent was removed by concentrating the filtered organic solution under reduced pressure. The resulting solids were dried under reduced pressure at 19-22° C. for 17 hours to obtain the titled compound (0.37 g; yield: 92.5%).

(84) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (s, 1H), 7.72 (m, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 6.27 (s, 1H), 4.43 (t, 2H), 4.36 (s, 1H), 3.88 (s, 3H), 3.30 (t, 2H), 2.83 (d, 2H), 2.27 (t, 2H), 2.06 (t, 2H), 1.90 (t, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H)

Example 30

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide hydrochloride (Formula 3)

(85) N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (2.7 g) was dissolved in ethanol (13.5 mL) and methylethylketone (27 mL), and then 2N-hydrochloric acid diethyl-ether solution (4.98 mL) was slowly added thereto. The resulting solution was stirred at a room temperature for 4 hours. The resulting solids were filtered, washed with methylethylketone (13.5 mL) and dried under reduced pressure for 18 hours to obtain the titled compound (2.69 g; yield: 91%).

(86) .sup.1H NMR (400 MHz, DMSO-d6) δ 10.28 (br s, 1H), 8.19 and 8.17 (s, 1H), 8.00 (t, J=5.6 Hz, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 6.67 (s, 1H), 5.95 (br s, 2H), 4.48 (t, J=6.6 Hz, 2H), 3.81 (s, 3H), 3.43 (m, 2H), 3.15 (m, 2H), 2.97 (m, 2H), 2.83 (m, 2H), 2.30 (m, 2H), 1.70-1.90 (m, 3H), 1.52 (m, 2H)

Example 31

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide hydrochloride (Formula 3)

(87) N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (2.7 g) was dissolved in ethanol (13.5 mL) and methylethylketone (27 mL), and then concentrated hydrochloric acid (35%, 0.83 mL) was added thereto. The resulting solution was stirred for 4 hours. The resulting solids were filtered, washed with methylethylketone (13.5 mL), and dried under reduced pressure for 18 hours. 2-propanol (25 mL) was added to the dried solids and refluxed for 4 hours. The solids were filtered, washed with 2-propanol (14 mL), and dried under reduced pressure for 17 hours to obtain the titled compound (2.49 g; yield: 84%).

(88) .sup.1H NMR (400 MHz, DMSO-d6) δ 10.28 (br s, 1H), 8.19 and 8.17 (s, 1H), 8.00 (t, J=5.6 Hz, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 6.67 (s, 1H), 5.95 (br s, 2H), 4.48 (t, J=6.6 Hz, 2H), 3.81 (s, 3H), 3.43 (m, 2H), 3.15 (m, 2H), 2.97 (m, 2H), 2.83 (m, 2H), 2.30 (m, 2H), 1.70-1.90 (m, 3H), 1.52 (m, 2H)

Example 32

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide hydrochloride (Formula 3)

(89) A reaction solution was prepared by dissolving N-[[l-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (3.0 g) in 2-propanol (35 mL), adding concentrated hydrochloric acid (35%, 0.92 mL) thereto, and performing the stirring for 4 hours. The reaction solution was cooled to 0° C. and further stirred for 1 hour. The resulting solids were filtered. The solid was washed with 2-propanol (15 mL) and dried under reduced pressure for 16 hours to obtain the titled compound (3.08 g; yield: 94%).

(90) .sup.1H NMR (400 MHz, DMSO-d6) δ 10.28 (br s, 1H), 8.19 and 8.17 (s, 1H), 8.00 (t, J=5.6 Hz, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 6.67 (s, 1H), 5.95 (br s, 2H), 4.48 (t, J=6.6 Hz, 2H), 3.81 (s, 3H), 3.43 (m, 2H), 3.15 (m, 2H), 2.97 (m, 2H), 2.83 (m, 2H), 2.30 (m, 2H), 1.70-1.90 (m, 3H), 1.52 (m, 2H)

Example 33

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide hydrochloride (Formula 3)

(91) N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (3.0 g) was dissolved in ethanol (45 mL), concentrated hydrochloric acid (35%, 0.92 mL) was added thereto. The resulting solution was stirred for 4 hours. The resulting solids were filtered. The solid was washed with ethanol (15 mL), dried under reduced pressure for 15 hours to obtain the titled compound (2.02 g; yield: 62%).

(92) .sup.1H NMR (400 MHz, DMSO-d6) δ 10.28 (br s, 1H), 8.19 and 8.17 (s, 1H), 8.00 (t, J=5.6 Hz, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 6.67 (s, 1H), 5.95 (br s, 2H), 4.48 (t, J=6.6 Hz, 2H), 3.81 (s, 3H), 3.43 (m, 2H), 3.15 (m, 2H), 2.97 (m, 2H), 2.83 (m, 2H), 2.30 (m, 2H), 1.70-1.90 (m, 3H), 1.52 (m, 2H)

Example 34

Preparation of N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide hydrochloride (Formula 3)

(93) N-[[1-{3-(1,2,3-triazol-1-yl)propyl}piperidin-4-yl]methyl]-4-amino-5-chloro-2-methoxybenzamide (3.0 g) was dissolved in methanol (15 mL), concentrated hydrochloric acid (35%, 0.92 mL) was added thereto. The reaction solution was stirred for 1 hour. t-butyl methyl ether (15 mL) was added to the reaction solution and further stirred for 2.5 hours. The resulting solids were filtered, washed with t-butyl methyl ether (15 mL). Then, ethanol (30 mL) was added and refluxed for 4 hours. The solids were filtered, washed with ethanol (15 mL), and dried under reduced pressure for 17 hours to obtain the titled compound (2.48 g; yield: 73%).

(94) .sup.1H NMR (400 MHz, DMSO-d6) δ 10.28 (br s, 1H), 8.19 and 8.17 (s, 1H), 8.00 (t, J=5.6 Hz, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 6.67 (s, 1H), 5.95 (br s, 2H), 4.48 (t, J=6.6 Hz, 2H), 3.81 (s, 3H), 3.43 (m, 2H), 3.15 (m, 2H), 2.97 (m, 2H), 2.83 (m, 2H), 2.30 (m, 2H), 1.70-1.90 (m, 3H), 1.52 (m, 2H)

INDUSTRIAL APPLICABILITY

(95) The preparation methods of the present disclosure can be useful for mass production because a compound that could be purchased in large quantities are used and the number of reaction processes is decreased, thereby saving preparation costs and improving the yield and purity.