| 92% |
With sodium acetate; In ethanol; for 0.666667h;Reflux; |
Example 3: Preparing Form II Sodium acetate (purity 98.5percent, 35.32 g, 0.424 mol) and 2-(7-methoxy-l-naphthyl)- ethylamine hydrochloride (91.64 g, 0.385 mol) were suspended in ethanol (175 mL) at reflux temperature. Acetic acid anhydride (purity 98.5percent, 39.21 mL, 0.409 mol) was added dropwise with stirring. The mixture was then refiuxed for 40 minutes. After addition of water (326 mL), the mixture was cooled to room temperature and stirred for 14 hours. Agomelatine precipitated as polymorph II (86.16 g, 92percent). |
| 90% |
|
A mixture of 2-(7-methoxynanphthyl)ethanamine hydrochloride (10 g), toluene (50 ml), water (50 ml), aq. sodium hydroxide (2 gm sodium hydroxide in 10 ml water) stirred 15 minutes at 20 -25 °C. The mixture was partitioned between water and toluene. Organic phase was washed with brine solution and solvent was distilled out completely under vacuum, acetic acid (30 ml) is added to the residue and heated at 35 to 40 °C. Acetic anhydride (5. 14g) is added drop wise at 35-40 °C and stirred for 1 hour. Water (30 ml) was added 35-40 °C and stirred for 1 hour, cooled the reaction mixture at 10-15 °C and stirred for 1 hour. The solid was filtered. There was thus obtained N-[2-(7- methoxynaphthalene-1 -yl)ethyl]acetamide (Yield 90percent, HPLC purity 99.5 to 99.9 percent) (XPRD: form 1 , equivalent to figure 1 ) |
| 90% |
|
Example 3: Preparation of agomelatine of formula (I) 2-(7-methoxy- l -naphthyl)ethanamine hydrochloride of formula (D) (25 g) and methylene dichloride (120 ml) was added at 25°C to 35°C and stirred for 15 minutes followed by addition of triethyl amine (25 g). The reaction mass was stirred for 30 minutes and cooled to 10°C to 20°C. Acetic anhydride (12 g) was added and stirred for 1 hour. The reaction mass was treated with water (200 ml) followed by treatment of sodium bicarbonate solution (125 ml) and hydrochloric acid solution ( 125. ml). Organic layer was treated with ethyl acetate (50 ml) and heated at 45°C to 50°C followed by treatment of charcoal (2 g). The reaction mass was filtered and washed with chilled ethyl acetate ( 10 ml) afforded agomelatine of formula (I). Yield - 90percent |
| 86.7% |
With sodium acetate; In ethanol; for 1h;Reflux;Product distribution / selectivity; |
2) Synthesis of N-[2-(7-methoxy-1-naphthyl)ethyl] acetamide (I) (agomelatine) The compound V (6.0g, 0.03mol) produced as described above and sodium acetate (3.4g) were dissolved in 70ml of ethanol, and acetic anhydride (3.4g, 0.033mol) was added. The reaction solution was heated and refluxed for one hour. After cooling, about 100ml of water was added, and the mixture was extracted with ethyl acetate (50ml*3). The organic phases were combined, dried with anhydrous magnesium sulfate, and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure, to give a solid. The solid was recrystallized in a 2:1 toluene/n-hexane mixture, to produce 5.3g of agomelatine. The yield was 86.7percent. The melting point was 107-109°C (in Literature [2], 109°C). IRvcm-1: 3249.97, 1552.65, 1640.57 1HNMR (CDCl3) delta: 7.77 (d, 1H, J=8.8Hz), 7.16 (dd, 1H, J=8.8, 2.4Hz), 7.47 (d, 1H, J=2.4Hz), 5.55 (s, 1H), 3.99 (s, 3H), 3.65 (q, 2H, J=6.8Hz), 3.25 (t, 2H, CH2) MS: m/z 243 (M+1) |
| 52% |
With sodium acetate; In methanol;Reflux; |
To a mixture of 2-(7-methoxynaphthalen-l-yl)ethanamine hydrochloride (Formula Via, obtained in Example 4a, 1.5 g) and sodium acetate (0.57 g) in methanol (9 mL); acetic anhydride (0.68 g) was added drop-wise. The reaction mixture was heated to reflux and stirred for 3 to 4 hours. After completion of the reaction, the reaction mixture was cooled to 30°C to 35°C. The salt separated was filtered and the mother liquor was concentrated under vacuum (200-220 mbar) at 45°C to 50°C. The residue so obtained was extracted in dichloromethane/water (20/10 mL). The organic layer was concentrated under vacuum (400-420 mbar) at 40°C and crystallized in diisopropyl ether (15 mL). The solid obtained was dried under vacuum (5-10 mbar) at 45°C to 50°C over 10 to 15 hours to obtain the title product.Yield (w/w): 52percent |
| 52% |
With sodium acetate; In methanol;Reflux; |
To a mixture of <strong>[139525-77-2]2-(7-methoxynaphthalen-1-yl)ethanamine hydrochloride</strong> (Formula VIa, obtained in Example 4a, 1.5 g) and sodium acetate (0.57 g) in methanol (9 mL); acetic anhydride (0.68 g) was added drop-wise. The reaction mixture was heated to reflux and stirred for 3 to 4 hours. After completion of the reaction, the reaction mixture was cooled to 30° C. to 35° C. The salt separated was filtered and the mother liquor was concentrated under vacuum (200-220 mbar) at 45° C. to 50° C. The residue so obtained was extracted in dichloromethane/water (20/10 mL). The organic layer was concentrated under vacuum (400-420 mbar) at 40° C. and crystallized in diisopropyl ether (15 mL). The solid obtained was dried under vacuum (5-10 mbar) at 45° C. to 50° C. over 10 to 15 hours to obtain the title product. Yield (w/w): 52percent |
|
With sodium acetate; In ethanol;Reflux; |
In a reactor, 5 g of the compound obtained in Step C and 2 g of sodium acetate are introduced into ethanol. The mixture is stirred, 2.3 g of acetic anhydride are then added, the reaction mixture is heated to reflux and 20 ml of water are added. The reaction mixture is allowed to return to ambient temperature and the precipitate obtained is filtered off and washed with an ethanol/water 35/65 mixture to yield the title product.Melting point: 108° C. |
|
|
Load 2000 ml of water, 250g of 2-(7-methoxy-l-naphthyl)methylamine HC1 and 2500 ml of toluene in a 5 litre reactor. Stir and load 80g of ammonia at 30percent in water, thus obtaining pH > 9. Stir for 1 hour, decant for 20 minutes and separate the phases. Counter-extract the aqueous phase with 250 ml of fresh toluene. Re-combine the two toluene-rich phases and wash with 500 ml of water. Discard the aqueous phases. Anhydrify the toluene phase distilling approximately 250 ml of solvent. Heat the anhydrified toluene-rich phase to 35°C and load 120 g of triethyl amine. Load 120 g of acetic anhydride in 10 minutes; the temperature will increase to 47°C. Bring to 65°C and maintain for 1 hour. Stop the heating_and load 1000 ml of water, stir for 20 minutes at 50°C, decant for 20 minutes and discard the aqueous phase. Wash the toluene phase at 50°C with 1000 ml of NaHC03 2percent in water and then with 1000 ml of water. Maintain the toluene phase at 50-60°C and load it slowly in a reactor pre- cooled to at least -20°C and containing 400 ml of toluene pre-cooled to -20°C saturated with agomelatine. Adjust the addition speed so as to always maintain an internal temperature of at least -20°C. At the end of the addition, leave under stirring for 10-20 minutes and then filter, washing the panel with 400 ml of cold toluene. 220 g wet of polymorphous agomelatine VII are obtained. |
| 220 g |
|
Example 1 Preparation of the crystalline form VII of agomelatine starting from 2-(7-methoxy-1-naphthyl)methylamine HCl Load 2000 ml of water, 250g of 2-(7-methoxy-1-naphthyl)methylamine HCl and 2500 ml of toluene in a 5 litre reactor. Stir and load 80g of ammonia at 30percent in water, thus obtaining pH?9. Stir for 1 hour, decant for 20 minutes and separate the phases. Counter-extract the aqueous phase with 250 ml of fresh toluene. Re-combine the two toluene-rich phases and wash with 500 ml of water. Discard the aqueous phases. Anhydrify the toluene phase distilling approximately 250 ml of solvent. Heat the anhydrified toluene-rich phase to 35° C. and load 120 g of triethyl amine. Load 120 g of acetic anhydride in 10 minutes; the temperature will increase to 47° C. Bring to 65° C. and maintain for 1 hour. Stop the heating_and load 1000 ml of water, stir for 20 minutes at 50° C., decant for 20 minutes and discard the aqueous phase. Wash the toluene phase at 50° C. with 1000 ml of NaHCO3 2percent in water and then with 1000 ml of water. Maintain the toluene phase at 50-60° C. and load it slowly in a reactor pre-cooled to at least ?20° C. and containing 400 ml of toluene pre-cooled to ?20° C. saturated with agomelatine. Adjust the addition speed so as to always maintain an internal temperature of at least ?20° C. At the end of the addition, leave under stirring for 10-20 minutes and then filter, washing the panel with 400 ml of cold toluene. 220 g wet of polymorphous agomelatine VII are obtained. |
|
With sodium acetate; In ethanol;Reflux; |
To a solution of compound Va (2.0 g) in ethanol, sodium acetate (2.9 g) and acetic anhydride (2.3 g) are added successively. The resulting mixture is heated to reflux until full consumption of the starting material. Water (20.0 ml) is added and mixture is stirred for 10 min and then extracted with ethyl acetate (2 x 20.0 ml). The combined organic phases are dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to deliver compound of Formula VI (Agomelatine). HRMS (ESI): calcd for C15Hi8N02 [M+H]+ 244.13335; found: 244.13321. 1H NMR (500 MHz, CDC13): delta 7.76 (d, J= 8.9 Hz, 1H), 7.69 (d, J= 7.0 Hz, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.19 (dd, J = 8.9, 2.4 Hz, 1H), 5.63 (brs, 1H), 3.99 (s, 3H), 3.62 (q, J= 7.0 Hz, 2H), 3.25 (t, J= 7.0 Hz, 2H), 1.96 (s, 3H). 13C NMR (126 MHz, CDC13) delta 170.3, 157.9, 133.6, 133.2, 130.2, 129.3, 127.1, 127.0, 123.1, 118.3, 102.4, 55.5, 40.1, 33.2, 23.3. |
| 42.5 g |
With potassium carbonate; In water; ethyl acetate; at 10℃; for 0.5h; |
A mixture of N-[2-(7-methoxy-1-naphthyl)ethyl]formamide) 10a, N-formyl-N-[2-(7-methoxy-1-naphthyl)ethyl]formamide 10b) (50 g, 0.21 mol), and HCl (42 g, 0.41 mol) was added to a solution of methanol (250 mL) and intermediate 9. Then the reaction mixture was heated to 60 °C and stirred for 4 h. The reaction mixture was concentrated under reduced pressure followed by co-distillation with toluene (100 L) to obtain a suspension, which was dissolved in water (600 mL) and washed with toluene (2×100 mL). The aqueous layer was treated with carbon (5 g) and filtered through hyflow. Ethyl acetate (375 mL) was added to the filtrate and then K2CO3 solution (71 g, 0.51 mol of K2CO3 in 36 L water) was added slowly. Then acetic anhydride (23 mL, 0.25 mol) was added slowly below 30 °C, and stirring continued for 30 min. The reaction was monitored by TLC; organic layer was separated, washed with 2percent NaCl solution (250 mL), and concentrated under reduced pressure to obtain the crude product. Toluene (150 mL) was added and codistilled. Toluene (150 mL) was added again and heated to 65 °C. The reaction mixture was cooled to 10 °C and stirred for 2 h. The solid product was filtered, washed with toluene (50 mL), and then dried at 60 °C under vacuum to give 1 (42.5 g, 85percent) with HPLC purity of 99.9percent. ESI-MS: m/z 244.2 (M+H); calcd. for C15H17NO2: 243.0; 1H NMR (400 MHz, DMSO-d6) delta 1.84 (s, 3H, OCH3), 3.13 (t, J = 7.2 Hz, 2H, CH2CH2NHAc), 3.34 (m, 2H, CH2CH2NHAc), 3.95 (s, 3H, OCH3), 7.17 (dd, J = 2.5, 8.9 Hz, 1H, Ar-H), 7.25?7.29 (m, 1H, Ar-H), 7.32-7.34 (dd, J = 1.23, 6.96 Hz, 1H, Ar-H), 7.62 (s, 1H, Ar-H), 7.71 (d, J = 7.8 Hz, 1H, Ar-H), 7.83 (d, J = 8.9 Hz, 1H, Ar-H), 8.13 (brs, 1H, NHCO); 13C NMR (400 MHz, DMSO-d6) delta 23.1, 33.5, 40.6, 55.7, 103.1, 118.5, 123.6, 127.0, 127.4, 129.3, 130.5, 133.4, 134.6, 157.9, 170.0; IR numax cm-1 1639, 1626, 1509, 1251, 1031. |
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