| 92.1% |
With lithium hydroxide In methanol; water at 20℃; for 6h; |
6 Preparation of bilastine
To the reaction flask was added 500 mL of water, 500 mL of methanol, 11.3 g of lithium hydroxide and 43.2 g of the compound prepared in Example 4, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the mixture was adjusted to pH 7 with 6N aqueous hydrochloric acid to precipitate a white solid Filtered and dried at 50 ° C under reduced pressure to give 38.6 g of white powder than lustin in a yield of 92.1%. |
| 91.3% |
With methanol; sodium hydroxide at 0 - 20℃; for 3h; |
3 Example 3:
4- [2- [1- (2-ethoxyethyl) benzimidazolyl] piperidinyl] ethyl-phenyl tert-butyric acid methyl ester (477g) was dissolved in methanol (3L) and cooled to 0 , 4N sodium hydroxide (500mL) was added dropwise, stirred at room temperature for 3h, concentrated to remove methanol, 36% hydrochloric acid (200mL) was added dropwise, solid precipitated, filtered, the filter cake was slurried with ethanol (800mL) for 1 hour, filtered,Bilastine (423 g) was obtained, yield: 91.3%, purity 99.5%. |
| 90% |
Stage #1: methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methylpropanoate With sodium hydroxide In ethanol at 50 - 55℃; for 3h;
Stage #2: With acetic acid In ethanol; water |
16
Example 16 Preparation of 2-[4-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-piperidin-1-yl}-ethyl)-phenyl]-2-methyl-propionic acid In a reaction vessel, 2-[4-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-piperidin-1-yl}-ethyl)-phenyl]-2-methyl-propionic acid methylester (2.3 g) prepared in the Example 14, sodium hydroxide (0.6 g) and ethylalcohol (13 mL) were introduced, and the mixture was reacted at 50-55° C. for 3 hours. Distilled water (20 mL) was added thereto, and acetic acid was added to control the pH to 7. Ethylacetate (50 mL) was added thereto, and the mixture was stirred to separate a layer. The separated organic layer was condensed under reduced pressure. And, butanol (9 mL) was added thereto, and dissolved by'heating. And then, it was cooled to precipitate crystals, and the crystals were filtered under reduced pressure to obtain 2-[4-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-piperidin-1-yl}ethyl)-phenyl]-2-methyl-propionic acid (2.0 g, yield 90%, HPLC purity 99% or more). 1H-NMR, 400 MHz, CDCl3, ppm: 61.08 (t, 3H), 1.59 (s, 6H), 2.15-2.30 (m. 4H), 2.64-2.79 (m, 6H), 3.25 (s, 1H), 3.67 (q, 2H), 3.47 (m, 2H), 3.71 (t, 2H), 4.32 (t, 2H), 6.79 (d, 2H), 7.26 (m, 2H), 7.29-7.32 (m, 3H), 7.76 (t, 1H) |
| 89.3% |
With water; sodium hydroxide In ethanol for 1h; Reflux; |
9-11 Example 10 Preparation of Bilastine
Into a 250mL reaction flask, sequentially add 140mL of ethanol, 14.33g of the compound V obtained in Example 10,7mL water and 3.6g sodium hydroxide. Heat to reflux for 1h,TLC detected that the reaction of Compound V was complete, the ethanol was distilled off under reduced pressure at 40°C, and 70 mL of water was added.Stir to dissolve, wash three times with 30 mL of ethyl acetate, adjust pH to 6.5 with 1.2 mol/L hydrochloric acid, stir for 1 h, and filter.Add 150mL of isopropanol, stir and heat to reflux for 1h, drop to room temperature, stir for 1h, filter, and vacuum dry at 50,12.42 g derbystatin was obtained, the yield was 89.3%, the purity by HPLC detection was 99.9%, and the maximum single impurity was 0.06%. |
| 82.2% |
Stage #1: methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methylpropanoate With water; sodium hydroxide In ethanol for 3h; Reflux;
Stage #2: With hydrogenchloride In water at 20℃; |
1.2; 1.3; 2.2; 2.3; 3.2; 3.3
(2) Preparation of crude bilastineThe above-derived bilastine methyl ester (23.88 g, 0.05 mol) was added to ethanol (75 ml), followed by the addition of sodium hydroxide(3g, 0.075mol) of a 30% aqueous solution,After refluxing for 3 hours, the reaction solution was cooled to room temperature and concentrated hydrochloric acid was added.The solution has a pH between 5 and 6 and a pale yellow solid precipitates.The filter cake was washed twice with ice water and iced ethanol.The filter cake was dried to give a crude product (20.50 g, 88.5%).(3) Preparation of bilastineThe crudebilastine (23.2 g, 0.05 mol) obtained in the previous step was placed in n-butanol (500 ml), and then activated carbon (0.5 g) was added to reflux system for 5 hours.After hot filtration, the filtrate was naturally cooled to room temperature and filtered to dryness to give the crystalline form of bilastine (19.07 g, 82.2%). |
| 64% |
Stage #1: methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methylpropanoate With water; lithium hydroxide In tetrahydrofuran; methanol at 70℃; for 16h;
Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water |
|
|
Multi-step reaction with 2 steps
1: hydrogenchloride / diethyl ether / 0 - 5 °C
2: water; potassium hydroxide / methanol / 16 h / 100 °C / Inert atmosphere |
|
| 7 g |
With sodium hydroxide In ethanol at 65 - 70℃; for 4h; |
19; 20 Example-19: Preparation of 2-[4-(2-{4-[l-(2-ethoxyethyl)-lH-benzimidazoI-2-yl]-l- piperidinyl}ethyl)phenyl]-2-methylpropanoic acid (Formula-1)
Example-19: Preparation of 2-[4-(2-{4-[l-(2-ethoxyethyl)-lH-benzimidazoI-2-yl]-l- piperidinyl}ethyl)phenyl]-2-methylpropanoic acid (Formula-1) A mixture of methyl 2-(4-(2-(4-(l-(2-eth0xyethyl)-lH-benzo[d]imidazol-2-yl) piperidin-l-yl)ethyl)phenyl)-2-methylpropanoate compound of formula- 13 (3 gm), sodium hydroxide (0.5 gm) and ethanol (21 ml) was heated to 65-70°C and stirred for 4 hrs at the same temperature. Water and dichloromethane were added to the reaction mixture and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was neutralized using acetic acid. Extracted the aqueous layer with dichloromethane. Both the organic and aqueous layers were separated and the organic layer was washed with sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 1.3 gm. Example-20: Purification of 2-[4-(2-{4-[l-(2-ethoxyethyl)-lH-benzimidazoI-2-yl]-l- piperidinyl}ethyl)phenyI]-2-methylpropanoic acid (Formula-1) A mixture of 2-[4-(2-{4-[l-(2-ethoxyemyl)-lH-berizimidazol-2-yl]-l-piperidinyl} ethyl)phenyl]-2-methylpropanoic acid compound of formula-1 (8 gm) and n-butanol (75 ml) was heated to 110-115°C and stirred for 10 min at the same temperature. Carbon (0.8 gm) was added to the reaction mixture and stirred for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with n-butanol. Cooled the reaction mixture to 5-10°C and stirred for 30 min at the same temperature. Filtered the solid, washed with n-butanol and dried the material to get pure title compound. Yield: 7.0 gm; Purity by HPLC: 99.6%. |
|
With lithium hydroxide In tetrahydrofuran |
|
|
With hydrogenchloride In water |
|
| 8.2 g |
With water; sodium hydroxide In ethanol at 25 - 40℃; |
9-11 Example 9: Preparation of 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methylpropanoic acid (I)
15 g of compound (IV) was charged to 45 ml of ethanol at 25-30 °C. 3.8 g of sodium hydroxide dissolved in 45 ml of water was added to the reaction mixture. The reaction mixture was maintained at 35-40 °C. After completion of the reaction 45 ml of ethanol was added. The pH of the aqueous layer was adjusted to 6.5 to 7.5 using hydrochloric acid solution and then 100 ml of ethyl acetate was charged and stirred for Ihr at 25-30 °C. The solid was filtered and washed with 30 ml of ethyl acetate and dried at below 50 °C to obtain 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methylpropanoic acid (I). Yield: 8.2 g. Example 10: Purification of Bilastine (I) 10 g of Bilastine (I) was added to 50 ml of methanol and heated to 50-60 °C, stirred for 10 min. To the reaction mixture 50ml of acetone was added and stirred at 50-60 °C for 15 minutes. The reaction mass was cooled to 20-25 °C and stirred for 30 minutes. After completion of the reaction, the reaction mass was filtered and washed with 20 ml of methanol. To the filtrate, 30 ml of methanol was added and heated to 50-60 °C and stirred for 30 minutes. 1.0 g of activated carbon was added to the reaction mass and then stirred for 10 minutes. Then the reaction mass was filtered and washed with 10 ml of hot methanol. The filtrate was cooled to 20-22 °C and stirred for 40 minutes at 20-22 °C. The solid was filtered and washed with 10ml of cold methanol and dried at below 60-70 °C to obtain pure Bilastine (I). Yield: 7.0 g; Purity: 99.9%. Example 11: Purification of Bilastine (I) A mixture of 10 g of Bilastine(I) and 75 ml of isopropyl alcohol was heated to SO- 85 °C and stirred for 30 min at 80-85 °C. The reaction mixture was cooled to 5-10 °C and stirred for 30 min. The obtained solid was filtered, washed with 25 mL isopropyl alcohol, and dried the material to get pure Bilastine (I). Yield: 7.0 g; Purity: 99.89%. |
| 8.2 g |
With water; sodium hydroxide In ethanol at 25 - 40℃; |
9-11 Example 9: Preparation of 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methylpropanoic acid (I)
15 g of compound (IV) was charged to 45 ml of ethanol at 25-30 °C. 3.8 g of sodium hydroxide dissolved in 45 ml of water was added to the reaction mixture. The reaction mixture was maintained at 35-40 °C. After completion of the reaction 45 ml of ethanol was added. The pH of the aqueous layer was adjusted to 6.5 to 7.5 using hydrochloric acid solution and then 100 ml of ethyl acetate was charged and stirred for Ihr at 25-30 °C. The solid was filtered and washed with 30 ml of ethyl acetate and dried at below 50 °C to obtain 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methylpropanoic acid (I). Yield: 8.2 g. Example 10: Purification of Bilastine (I) 10 g of Bilastine (I) was added to 50 ml of methanol and heated to 50-60 °C, stirred for 10 min. To the reaction mixture 50ml of acetone was added and stirred at 50-60 °C for 15 minutes. The reaction mass was cooled to 20-25 °C and stirred for 30 minutes. After completion of the reaction, the reaction mass was filtered and washed with 20 ml of methanol. To the filtrate, 30 ml of methanol was added and heated to 50-60 °C and stirred for 30 minutes. 1.0 g of activated carbon was added to the reaction mass and then stirred for 10 minutes. Then the reaction mass was filtered and washed with 10 ml of hot methanol. The filtrate was cooled to 20-22 °C and stirred for 40 minutes at 20-22 °C. The solid was filtered and washed with 10ml of cold methanol and dried at below 60-70 °C to obtain pure Bilastine (I). Yield: 7.0 g; Purity: 99.9%. Example 11: Purification of Bilastine (I) A mixture of 10 g of Bilastine(I) and 75 ml of isopropyl alcohol was heated to SO- 85 °C and stirred for 30 min at 80-85 °C. The reaction mixture was cooled to 5-10 °C and stirred for 30 min. The obtained solid was filtered, washed with 25 mL isopropyl alcohol, and dried the material to get pure Bilastine (I). Yield: 7.0 g; Purity: 99.89%. |
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