Name: 138112-76-2|N-(2-(7-Methoxynaphthalen-1-yl)ethyl)acetamide|98%
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1
[ 139525-77-2 ]
[ 75-36-5 ]
[ 138112-76-2 ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium carbonate; In dichloromethane; water; at 0 - 20℃; for 2h;	400 ml of purified water and 600 ml of methylene chloride were added to 23 g of 2-(7-methoxynaphthalen-1-yl) ethaneamine of the formula VII obtained in Example 2, and 138 g of potassium carbonate was added. After cooling to 0 to 5 ° C, 10 g of acetyl chloride was slowly added dropwise. After stirring at room temperature for 2 hours, the organic layer was separated, dried over anhydrous sodium sulfate, and distilled to obtain coagomeramine, which was recrystallized from toluene/heptane to obtain 21.5 g (91percent) of the title compound.
90%		Example 4: 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. Acetyl chloride (9 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
		General procedure: To a suspension of 2-(7-methoxy-naphthalen-1-yl)ethylamine hydrochloride (compound A) (5.0 g, 21.0 mmol) in 100 mL of a mixture of water-ethyl acetate (1/1), potassium carbonate (8.7 g, 63.0 mmol) was added and the reaction mixture was cooled at 0 °C in an ice-bath. Ethyl malonyl chloride (3.58 mL, 27.8 mmol) was added and the mixture stirred for 1 h at room temperature. The organic phase was then washed respectively with an aqueous solution of HCl (1 M) and water, dried over MgSO4, filtered and evaporated under reduced pressure to give 6.09 g (92percent yield) of the desired product after recrystallization from isopropyl ether as a white solid.

Reference： [1]Patent: KR101606395,2016,B1 .Location in patent: Paragraph 0080-0081
[2]Patent: WO2014/72998,2014,A1 .Location in patent: Page/Page column 15; 16
[3]Journal of Medicinal Chemistry,1994,vol. 37,p. 3231 - 3239
[4]Journal of Medicinal Chemistry,1992,vol. 35,p. 1484 - 1486
[5]European Journal of Medicinal Chemistry,2012,vol. 49,p. 310 - 323

2
[ 138113-09-4 ]
[ 138112-76-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sheep pineal supernatant (serotonin-N-acetyl transferase); Pargyline In phosphate buffer at 37℃; for 0.166667h;

Reference： [1]Shen, Shuren; Bremont, Beatrice; Serraz, Isabelle; Andrieux, Jean; Poncet, Annie; Mathe-Allainmat, Monique; Chanut, Evelyne; Trouvin, Jean-Hugues; Langlois, Michel [European Journal of Pharmacology, 1996, vol. 307, # 2, p. 133 - 140]

3
[ 6836-22-2 ]
[ 138112-76-2 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 1484 - 1486
[2]Journal of Medicinal Chemistry,1992,vol. 35,p. 1484 - 1486
[3]Patent: EP2474522,2012,A1
[4]Patent: WO2014/1939,2014,A1
[5]Tetrahedron Letters,2014,vol. 55,p. 3885 - 3887
[6]Tetrahedron Letters,2014,vol. 55,p. 3885 - 3887
[7]Tetrahedron Letters,2014,vol. 55,p. 3885 - 3887

4
[ 138113-08-3 ]
[ 138112-76-2 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 1484 - 1486
[2]Patent: EP2474522,2012,A1
[3]Patent: WO2014/1939,2014,A1
[4]Patent: WO2014/72998,2014,A1
[5]Patent: CN104803882,2017,B

5
[ 138112-76-2 ]
[ 152302-45-9 ]

Yield	Reaction Conditions	Operation in experiment
80%		Compound 1 (8.5 g, 35.0 mmol) was dissolved in dichloromethane (250 mL) at 0 C and boron tribromide (6.7 mL, 70.0 mmol) was added dropwise cautiously. The reaction mixture was allowed to stir at 0 C for 2 h then hydrolyzed and the two phases were separated. The organic layer was washed, dried and evaporated under reduced pressure to give the desired product after recrystallization from toluene as a white solid (6.42 g, 80% yield); m.p. 123-125 C; 1H NMR (300 MHz, DMSO-d6): deltaH 1.80 (s, 3H, CH3), 3.04 (t, J = 7.4, 2H, CH2-a), 3.33 (m, 2H, CH2-b), 7.10 (dd, J = 9.0, J = 2.1, 1H, H-6), 7.15-7.25 (m, 2H, H-2 and 3), 7.32 (d, J = 2.1, 1H, H-8), 7.65 (d, J = 7.4, 1H, H-4), 7.76 (d, J = 9.0, 1H, H-5), 8.02 (br s, 1H, NH), 9.75 (br s, 1H, OH); IR (neat, cm-1): 3345, 3102, 1639; LC/MS m/z 230.3 (M + 1).
74.8%	With hydrogenchloride; In water; at 80℃;	Add 100 g of olgelacine to 100 ml three-necked flask, 15 ml of concentrated HCl, stir, raise, t = 80 CSolution, insulation reaction 2-3h, the reaction is complete, stop heating, natural cooling, room temperature by adding 20 mL of water, a large number of white solid precipitation,Mix for 1h, filter, 10 mL * 2 water to wash the filter cake, filter cake set 40 blast drying oven to constant weight (about 10-14h), weighing: 2.2 g, yield: 74.8%.
	With boron tribromide; In dichloromethane;	PREPARATION 1 N-[2-(7-Hydroxy-1-naphthyl)ethyl]-acetamide Under an inert atmosphere, 27.5 mmol of the boron tribromide/dimethyl sulphide complex are dissolved in 100 ml of dichloromethane and stirred for 15 minutes at room temperature. A solution of 13.7 mmol of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide in 50 ml of dichloromethane is added, and the reaction mixture is refluxed for 30 hours. After cooling, the reaction mixture is hydrolyzed cautiously and the dichloromethane is removed by evaporation. The mixture is then extracted with ethyl acetate, and the combined organic phases are washed with an aqueous 1M potassium hydrogen carbonate solution. The organic phase is dried over magnesium sulphate and concentrated to yield the title compound. White solid. Melting point: 125-126 C. Preparations 2 to 35 are obtained by proceeding as for Preparation 1 starting from the appropriate substrate:

		Step a N-[2-(7-Hydroxy-1-naphthyl)ethyl]acetamide The expected product is obtained according to the process described in Example 44, using N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide (described in Patent EP 447 285) as starting material.
	With boron tribromide-dimethyl sulfide complex; In dichloromethane; for 30h;Heating / reflux;	Under an inert atmosphere, 27.5 mmol of boron tribromide/dimethyl sulphide complex are dissolved in 100 ml of dichloromethane and stirred for 15 minutes at ambient temperature. A solution of 13.7 mmol of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide in 50 ml of dichloromethane is added, and the reaction mixture is heated at reflux for 30 hours. After cooling, the reaction mixture is cautiously hydrolysed and the dichloromethane is evaporated off. The mixture is then extracted with ethyl acetate and the combined organic phases are washed with an aqueous 1M potassium hydrogen carbonate solution. The organic phase is dried over magnesium sulphate and concentrated to yield the title compound. White solid. [0077] Melting Point: 125-126 C.

Reference： [1]Organic Letters,2019,vol. 21,p. 448 - 452
[2]European Journal of Medicinal Chemistry,2012,vol. 49,p. 310 - 323
[3]Patent: CN106565526,2017,A .Location in patent: Paragraph 0008
[4]Patent: US6310074,2001,B1
[5]Patent: US6143789,2000,A
[6]Patent: US2004/14969,2004,A1 .Location in patent: Page 4
[7]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 3426 - 3436
[8]MedChemComm,2015,vol. 6,p. 1340 - 1344
[9]Bioorganic Chemistry,2019,vol. 85,p. 349 - 356

6
[ 138112-76-2 ]
[ 686319-38-0 ]

Yield	Reaction Conditions	Operation in experiment
73%	With bromine; acetic acid; at 20℃; for 6h;	To a solution of compound 1 (7.0 g, 28.8 mmol) in 150 mL of acetic acid at 70 C, was added dropwise cautiously a solution of bromine (1.8 mL, 34.8 mmol) in 20 mL of acetic acid. The reaction mixture was allowed to stir for 6 h. After cooling, the reaction mixture was poured into an ice-water mixture and allowed to stir for 30 min. The solid formed was filtered, washed with ethyl ether and recrystallized from toluene to lead to the desired product (6.77 g, 73% yield); White solid, m.p. 106-108 C; 1H NMR (300 MHz, DMSO-d6): deltaH 1.80 (s, 3H, CH3), 3.12 (t, J = 8.3, 2H, CH2-a), 3.32 (m, 2H, CH2-b), 3.96 (s, 3H, OCH3), 7.18 (dd, J = 9.0, J = 2.4, 1H, H-6), 7.46 (d, J = 2.0, 1H, H-2), 7.63 (d, J = 2.4, 1H, H-8), 7.83 (d, J = 9.0, 1H, H-5), 8.00 (d, J = 2.0, 1H, H-4), 8.14 (br s, 1H, NH); IR (neat, cm-1): 3300 (NH), 1633 (CO); LC/MS m/z 323.2 (M + 1).
	With bromine; In acetic acid; at 70℃; for 6h;	N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide (29 mmol) is dissolved in 160 ml of acetic acid. The mixture is heated to 70 C. and bromine (35 mmol) is added dropwise in solution in 20 ml of acetic acid. After stirring for 6 hours at that temperature, the reaction mixture is cooled and then poured into iced water. After stirring vigorously for 30 minutes, the mixture is extracted with ethyl acetate. The ethyl acetate phase is dried over magnesium sulphate and then evaporated under reduced pressure. The residue obtained is recrystallised from toluene to yield the title product in the form of a beige solid. Melting point: 103-105 C.

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 8339 - 8348
[2]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 2963 - 2974
[3]European Journal of Medicinal Chemistry,2012,vol. 49,p. 310 - 323
[4]Patent: US2006/106111,2006,A1 .Location in patent: Page/Page column 4
[5]European Journal of Medicinal Chemistry,2012,vol. 49,p. 310 - 323

7
[ 139525-77-2 ]
[ 108-24-7 ]
[ 138112-76-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium acetate; In Isopropyl acetate;	2-(7-methoxynaphthalen-1 -yl)ethan-1 -amine hydrochloride (245 g), isopropyl acetate (2,45 L) and sodium acetate trihydrate (140,3 g) is charged in 5 L reactor. To white suspension acetic anhydride (107 mL) is added dropwise. Reaction is monitored with TLC and aftercompletition is extracted with NaHCOs solution and water. Solvent is evaporated. (250g, yield 99percent).
95%	With sodium acetate; In ethanol; for 1h;Reflux;	2.377 g of <strong>[139525-77-2]2-(7-methoxy-1-naphthyl)ethanamine hydrochloride</strong> as obtained in Example 5,20 mmol of sodium acetate was dissolved in 50 mL of ethanol.Add 11mmol acetic anhydride, reflux 1h,Cool the reaction solutionAdd 100mL water,Ethyl acetate extraction (50 mL * 3), the organic phase was combined, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a solid, which was recrystallized by adding a mixed solvent having a toluene:n-hexane volume ratio of 2:1.2.42 g of agomelatine crystals with a purity of 99.6percent and a molar yield of 95percent.
92.5%	With sodium acetate; In ethanol;Heating / reflux;	173 kg of the compound obtained in Step C and 66 kg of sodium acetate in ethanol are introduced into a 1600 litre reactor. The mixture is stirred and then 79 kg of acetic anhydride are added; the reaction mixture is heated at reflux and 600 l of water are added. The reaction mixture is allowed to return to ambient temperature and the precipitate obtained is filtered off and washed with a 35/65 ethanol/water mixture to give the title product in a yield of 92.5percent and with a chemical purity exceeding 99percent. Melting Point: 108° C.

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.

Reference： [1]European Journal of Organic Chemistry,2014,vol. 2014,p. 6376 - 6379
[2]Patent: WO2019/72864,2019,A1 .Location in patent: Page/Page column 41
[3]Patent: CN106831467,2017,A .Location in patent: Paragraph 0034; 0035
[4]Patent: US2005/182276,2005,A1 .Location in patent: Page/Page column 6
[5]Patent: WO2013/82302,2013,A1 .Location in patent: Page/Page column 10
[6]Patent: WO2014/1939,2014,A1 .Location in patent: Page/Page column 17
[7]Patent: WO2014/72998,2014,A1 .Location in patent: Page/Page column 14; 15
[8]Patent: EP2322508,2011,A1 .Location in patent: Page/Page column 8
[9]Patent: WO2013/80095,2013,A1 .Location in patent: Page/Page column 12
[10]Patent: US2014/336380,2014,A1 .Location in patent: Paragraph 0055; 0056
[11]Patent: US2010/36162,2010,A1 .Location in patent: Page/Page column 3
[12]Patent: WO2012/172387,2012,A1 .Location in patent: Page/Page column 6; 7
[13]Patent: US2014/221690,2014,A1 .Location in patent: Paragraph 0050
[14]Patent: WO2015/555,2015,A2 .Location in patent: Page/Page column 23
[15]Synthetic Communications,2015,vol. 45,p. 1864 - 1870

8
[ 138113-09-4 ]
[ 75-36-5 ]
[ 138112-76-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine; In dichloromethane; at 0 - 5℃;	N-(2-(7-methoxynaphthalen-1-yl)ethyl)acetamide (Agomelatine) 1: A stirred solution of compound 9 (6.5 g, 3.2 mmoles) in dichloromethane (25 mL) was cooled to 0 oC. TEA (5.82 mL, 0.4 mmol) was added to the reaction mixture and followed by addition of acetyl chloride (2.51 mL, 3.5 moles). The resulting reaction mixture was stirred at 0 oC - 5 oC for 30 min. The progress of the reaction was monitored by TLC, after completion of the reaction, the reaction mass was diluted with water (25 mL). Separated the layers and aqueous solution was extracted with dichloromethane (2 x 25 mL) and the combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The obtained crude compound was triturated with n-Hexane to furnish the 1 (7.37 g, 95%) as an off white solid. (Hexane-EtOAc, 1:1; Rf = 0.7); IR (Neat) cm-1 3252, 2937, 1621, 1509, 1031, 755; mp: 107-108 C (Lit: 107-109 C)4; 1H NMR (400 MHz, DMSO-d6): delta 7.72 (d, J = 8.9 Hz, 1H), 7.64 (dd, J = 6.5, 2.8 Hz, 2H), 7.44 (d, J = 2.4 Hz, 1H), 7.20-7.27 (m, 2 H), 7.13 (dd, J = 2.4, 8.8 Hz, 2H), 5.70 (br s, 1H), 3.95 (s, 3H), 3.58 (q, J = 6.8 Hz, 2H), 3.21 (t, 2H), 1.89 (s, 3 H); 13C NMR (100 MHz, CDCl3): delta 171.30, 158.02, 133.24, 133.12, 130.28, 129.29, 127.15, 123.13, 118.30, 102.35, 55.56, 40.48, 32.96, 22.73. ESI-MS: m/z = 244.1 (M+H, 100%); calcd. for C15H17NO2: 243.0.
92%	In pyridine;	EXAMPLE 1 N-[2-(7-methoxynaphth-1-yl)ethyl]acetamide 0.01 ml of 2-(7-methoxynaphth-1-yl)ethylamine is dissolved in 6 ml of pyridine. The mixture is cooled in an ice bath with agitation, and 0.012 mol of acetyl chloride is added dropwise. The agitation is maintained for 30 minutes, and then the reaction medium is poured onto ice. The precipitate formed is spun down, washed, dried and recrystallized in isopropyl ether. Yield: 92% Melting point: 109-110 C. Spectral characteristics: Infrared: 3240 cm-1 vNH 1640 cm-1 vCO 1H Nuclear maonetic resonance, solvent CDCl3 delta: 1.93 ppm, singlet, 3H, COCH3 delta: 3.96 ppm, singlet, 3H, OCH3
92%	With pyridine; for 0.5h;Cooling with ice;Product distribution / selectivity;	0.01ml of 2-(7-methoxynaphth-l-yl)etylamine is added to 6ml of pyridine. The mixture was cooled in an ice bath with stirring, and 0.012 mol of acetylchloride was added drop wise. The stirring was continued for 30minutes, and then the reaction mass was poured onto ice. The formed precipitate was washed and dried and recrystallized from Isopropyl ether. Yield: 92%

19%	With pyridine; In chloroform; at 0 - 20℃;	Step 8 N-[2-(7-Methoxy-naphthalen-1-yl)-ethyl]-acetamide: At about 0 C., acetyl chloride (187 mg; 2.4 mmol) was added dropwise to a solution of 2-(7-methoxy-naphthalen-1-yl)-ethylamine (400 mg; 2.0 mmol) in chloroform (15 mL), and pyridine (471 mg; 6.0 mmol). Under continuous stirring, the mixture was maintained at about 0 C. until 2-(7-methoxy-naphthalen-1-yl)-ethylamine was no longer detected by TLC. The mixture was allowed to warm to ambient temperature. The crude product was isolated by standard extractive work up, and purified by flash column chromatography on silica gel (1*16 cm, ethyl acetate/petroleum ether=1:1 elution). Recrystallization from toluene and hexane gave the title product as a white solid (90 mg, 19%). 1H NMR (300 MHz, CDCl3): delta 1.97 (s, 3H), 3.27 (t, J=7.2 Hz, 2H), 3.63 (t, J=6.9 Hz, 2H), 4.04 (s, 3H), 5.59 (br. s, 1H), 7.15 (d, J=8.7 Hz, 1H), 7.27 (s, 2H), 7.47 (s, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H). LC-MS: 244 (M+H)+.
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 2h;	Example 9: Preparation of AgomelatineSolution of acetyl chloride (40 gm) in methylene dichloride (MDC) was added dropwise to a stirred solution of 2-(7-methoxynaphthalen-1 -yl) ethanamine (80 gm), DIPEA (1 08.7 gm) and MDC (400 ml). The reaction mass was stirred for 2 hr at below 0C and quenched with water. The organic layer was separated and washed with water and dried over anhydrous sodium sulphate. The organic layer was dried under reduced pressure. DIPE (240 ml) was added to the reaction mass and stirred for 4 hr at room temperature. The reaction mass was filtered and dried to obtain Agomelatine (68 gm, 82.92% yield).
		Reference example 7: The preparation of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide (agomelatine) 40g 2-(7-methoxy-1-naphthyl)ethylamine was dissolved in 250ml pyridine and heated to 40C for complete dissolution. 21.9g acetyl chloride was slowly added in drops with stirring in ice bath. After completion of addition, the ice bath was removed and the solution was stirred at room temperature for 30min. Subsequently, the reaction solution was poured into 300ml ice water together with vigorous stirring, resulting in a large amount of white precipitate being precipitated. The stirring was carried out for another 1 hour. Then, the solution was filtered and the filter cake was washed by 200ml*2 water to obtain 48g crude product (which was used in the following preparation examples). 1H NMR (400 MHZ, CDCl3): delta 7.77-7.15 (m, 6H, ); delta 5.61 (s, 1H, ); delta 3.99 (s, 3H, ); delta 3.62 (m, 2H, ); delta 3.25 (t, 2H, ); delta 1.95 (s, 3H, ), which is consistent with that in the literature ().

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 7125 - 7127
[2]Patent: US5194614,1993,A
[3]Patent: WO2012/46253,2012,A2 .Location in patent: Page/Page column 36
[4]Patent: US2008/280991,2008,A1 .Location in patent: Page/Page column 36
[5]Patent: WO2012/70025,2012,A1 .Location in patent: Page/Page column 11
[6]Patent: EP2474522,2012,A1 .Location in patent: Page/Page column 9

9
[ 138112-76-2 ]
[ 75-36-5 ]
[ 166526-96-1 ]

Yield	Reaction Conditions	Operation in experiment
80%	With aluminum (III) chloride; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 1h;	General procedure: To a solution of compound 1 (20.5 mmol) in 60 mL of a mixture of dichloromethane-DMF at 0 C, was added the aluminum chloride (61.6 mmol) and the mixture was allowed to stir for 5 min while keeping the temperature at 0 C. The desired acyl chloride (26.7 mmol) was added dropwise cautiously and the mixture stirred for 1 h at room temperature. The reaction mixture was then hydrolyzed with ice-water (100 mL) and the two phases were separated. The organic phase was washed with water, dried (MgSO4), filtered and evaporated under reduced pressure to give the desired product.
	aluminium chloride; In dichloromethane;	Step a N-[2-(3-Acetyl-7-methoxy-1-naphthyl)ethyl]acetamide 0.45 mol (60 g) of aluminium chloride are added at 0 C. to a solution of 0.16 mol (40 g) of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide (described in Patent EP 447 285) in 350 ml of dichloromethane. 0.21 mol (15.3 ml) of acetyl chloride is then added dropwise at 0 C. The reaction medium is stirred at room temperature for 1 hour and then poured onto ice. The organic phase is decanted and concentrated to yield the expected compound.

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 49,p. 310 - 323
[2]Patent: US6143789,2000,A

10
[ 108-24-7 ]
[ 138113-08-3 ]
[ 138112-76-2 ]

Yield	Reaction Conditions	Operation in experiment
89%	With hydrogen;Raney nickel; In ethanol; water; at 70℃; under 22502.3 Torr;	Step C: N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide There are introduced into an 8 litre reactor 136 g of Raney nickel, 2.06 litres of ethanol and 0.23 litre of water. Whilst stirring at 70 C. and under 30 bars of hydrogen, the compound obtained in Step B (0.8 kg), dissolved in acetic anhydride (2.4 litres), is added slowly. At the end of the addition, the reaction mixture is stirred for 1 hour under hydrogen at 30 bars; the reactor is then subjected to decompression and the liquors are filtered. After concentrating the mixture, the residue is crystallized from an ethanol/water 35/65 mixture to yield the title product in a yield of 89% and with a chemical purity of more than 99%. Melting point: 108 C.
89%	With hydrogen; In ethanol; water; at 70℃; under 22502.3 Torr;	The reaction was carried out on a larger batch in order to optimise the yield obtained: 136 g of Raney nickel, 2.06 L of ethanol and 0.23 L of water are introduced into an 8 L reactor. Whilst stirring at 70 C. and under 30 bars of hydrogen, the compound obtained in Step D (0.8 kg) dissolved in acetic anhydride (2.4 L) is slowly added. At the end of the addition, the reaction mixture is stirred for 1 hour under hydrogen at 30 bar, the reactor is then decompressed and the liquors are filtered. After concentration of the mixture, the residue is crystallised from a mixture of ethanol/water 35/65 to yield the title product in a yield of 89% and with a chemical purity greater than 99%. Melting point: 108 C.
89%	With hydrogen; In ethanol; water; at 70℃; under 22502.3 Torr; for 1h;	136 g of Raney nickel, 2.06 L of ethanol and 0.23 L of water are introduced into an 8-L reactot Whilst stirring at 70 C. and under 30 bars of hydrogen, the compound obtained in Step D above (0.8 kg) dissolved in acetic anhydride (2.4 L) is added slowly. When the addition is complete, the reaction mixture is stirred for 1 hour under hydrogen at 30 bars, and then the reactor is depressurised and the liquors are filtered. Afier concentration of the mixture, the residue is crystallised from a mixture of ethanol/water 35/65 to yield the title product in a yield of 89% and with a chemical purity greater than 99%.10075] Melting point: 108 C. ?H NMR spectroscopic analysis (CD3OD, 300.13MHz, oe in ppm): 8.21 (bs, 1H); 7.74 (d, J=8.9 Hz, 1H); 7.65 (d, J=8.0 Hz, 1H); 7.52 (d, J=2.5 Hz, 1H); 7.31-7.2 (m, 2H); 7.11 (dd, J=8.9 and 2.5 Hz, 1H); 3.96 (s, 3H); 3.52-3.44 (m, 2H); 3.23-3.18 (m, 2H); 1.94 (s, 3H). ?3C NMR spectroscopic analysis (CD3OD, 75.5 MHz, oe in ppm): 173.4 (s); 159.4 (s); 135.1 (s); 134.6 (s); 131.2 (d); 130.8 (s); 128.2 (d); 127.9 (d); 124.2 (d); 119.3 (d); 103.2 (d); 55.9 (q); 41.4 (0; 34.2 (0; 22.6 (q).

In 10L reactor 2-(7-methoxynaphthalen-1 -yl)acetonitrile (750g), methanol (6,3L), NaOH solution (228g NaOH is diluted in 750ml_ water) and 134g of Raney-Nickel is charged. Reaction mixture is stired at 30C and 4 bar H2 and monitored with HPLC. After reaction is done, it is cooled to 15C and acetic anhydride (750mL) is added and warmed to 25C. Reaction is monitored with HPLC. Once the reaction is finished it is filtered, solvent evaporated, than ethyl acetate (5L) is added and organic phase is extracted with water (5L). Solvent is evaporated to obtain agomelatine of 96,4% HPLC purity.

Reference： [1]Patent: US2010/36161,2010,A1 .Location in patent: Page/Page column 2
[2]Patent: US2013/289307,2013,A1 .Location in patent: Paragraph 0054; 0055
[3]Patent: US2016/368859,2016,A1 .Location in patent: Paragraph 0074; 0075; 0076; 0077
[4]Molecules,2013,vol. 18,p. 154 - 166
[5]Patent: WO2019/72864,2019,A1 .Location in patent: Page/Page column 41

11
[ 138113-09-4 ]
[ 108-24-7 ]
[ 138112-76-2 ]

Yield	Reaction Conditions	Operation in experiment
97.5%	In tetrahydrofuran; at 0 - 20℃; for 6h;	To 500 g of tetrahydrofuran was added 165.7 g (0.82 mol) of 2- (7-methoxy-1-naphthyl) ethylamine, the temperature was lowered to 0 C with stirring, 105.0 g (1.0 mol) of acetic anhydride was slowly added dropwise, After the incubation reaction 3h, the reaction was heated to 20 incubated 3h, the resulting agomelatine reaction solution was washed with water and dried separation, and then concentrated to make, to obtain agomelatine white powder 195.4g (0.80mol) The molar yield was 97.5%.
92%	With sodium acetate; In ethanol; at 65℃;Green chemistry;	Compound (II) (4.0 g, 16·8 mmol) and sodium acetate (3.0 g, 37.0 mmol) were added to a 100 mL single-mouth flask and dissolved in 40 mL of absolute ethanol to give a suspension liquid; Acetic anhydride (2.0 g, 20.2 mmol) was added with stirring; the reaction was stirred at 65 C., and the reaction was monitored by TLC until the reaction was complete; the reaction solution was poured into saturated aqueous sodium bicarbonate solution to precipitate a large amount of light yellow-brown precipitate; the suspension was filtered by suction. The filter cake was rinsed with water to obtain crude agomelatine crude; the crude agomelatine was dissolved in absolute ethanol/ethyl acetate (nu/nu 7/3), and crystallized after stirring at room temperature; The crystals produced by filtration were dried at 50 C. to give an off-white solid, ie, crystalline form of agomelatine II in an amount of 3.8 g. The yield was 92%. Product properties: white powder. Purity: 99.90 %
90%	With triethylamine; In toluene; at 20 - 30℃;	Example 8 Synthesis of agomelatine 23.26 g of 2-(7-methoxyl-1-naphthyl) ethylamine prepared in Example 3, 20 ml of triethylamine and 120 ml of toluene into a reaction flask, followed by stirring and then cooling to 20 C; 17 g of acetic anhydride was added dropwise slowly, and the temperature was controlled below 30 C until addition is completed; the reaction was conducted for 4-5 hours at the temperature of 20-30 C, when the reaction was detected to reach completion, 100 ml water was added followed by stirring for 10 minutes and then filtration; the filter cake was rinsed with 3100 ml of water for 3 times, and the filtrate was allowed for layering, where the toluene layer was extracted for 3 times by adding 3100 ml of water ; the toluene layer and the filter cake was pooled and concentrated under reduced pressure until dry; 100 ml of toluene was added to the residue, followed by heating to refluxing and maintaining the temperature for 30 minutes; the solution was cooled to 0-5 C to allow for crystallization while stirring for 2 hours, followed by filtration and drying to obtain 25.30 g of white crystalline agomelatine. The yield was 90% and the purity was 99.9%. The HPLC chromatogram was shown in Figure 1. .

83%	In toluene; at 40℃; for 3h;	1.6 g of acetic anhydride (15.6 mmols) is added to the toluene solution obtained from example 5 and loaded into a three-necked reaction flask, magnetically stirred and equipped with a temperature probe. The reaction mixture is heated to 40C and maintained at that temperature for about 3 hours. At the end of the reaction, 20 ml of water is added,the phases are separated, and the washing is repeated twice more. The organic phase is evaporated to obtain 2.15 gof Agomelatine. 83% yield from the intermediate 2-(7-methoxynaphthalen-1-yl)ethyl methanesulphonate 25. The productobtained was identified by NMR analysis: 1H NMR (400 MHz, CDCl3) delta 7.78 (m, 1H), 7.71 (m, 1H), 7.49 (m, 1H), 7.30(m, 2H), 7.19 (m, 1H), 5.66 (s, 1H), 4.02 (s, 3H), 3.65 (t, 2H), 3.28 (t, 2H), 1.98 (s, 3H).
83.8%	With triethylamine; In toluene; at 0 - 30℃; for 0.5h;	To the autoclave was charged 30 g of (7-methoxy-1-naphthyl) acetonitrile prepared in Example 19, 7.5 g of Raney nickel,95% ethanol 200ml, ammonia 60ml, autoclave sealed, nitrogen replacement, access to hydrogen,Control the pressure of 0.3-0.4Mpa, temperature 30-40 , holding pressure after 24 hours, cooling, remove the reaction solution, filter recovery Raney nickel, the filtrate evaporated under vacuum (7-methoxy-1-naphthyl) Ethylamine oil;To the oil was added 120 ml of toluene, 25 ml of triethylamine was stirred and dissolved,Control temperature below 30 add acetic anhydride 17ml, and 0-10 incubation reaction 30min,Then, 120 ml of water was added dropwise and cooled to 0-5 C for 2 h. The mixture was filtered and dried to give 31 g of aggamatine, the yield was 83.8% and the HPLC purity was 99.9%.
80%	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, washed with an ethanol/water 35/65 mixture to yield the title product in a yield of 80% with a chemical purity of 99%.Melting point: 108 C.
	With sodium acetate; In ethanol;Reflux;	In a reactor, 5 g of the compound obtained in Step D 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 in a yield of 80% for the two Steps D and E and with a chemical purity of more than 99%.Melting point: 108 C.
3 g	With sodium acetate; In ethanol; at 30 - 80℃; for 2.4h;	Example 11: Preparation of N-[2-(7-methoxy-1-naphthylen-1-yl)ethyl]acetamide (agomelatine):1-(2-aminoethyl)-7-methoxynaphthalene (5.1 g) and ethanol (40 mL) are charged into a round bottom flask at 30C. Sodium acetate (2.51 g) is added to the reaction mass at 30C. Acetic anhydride (3.25 mL) is added to the reaction mass dropwise in 15 minutes at 30C.The reaction mass is heated to 80C and stirred for 2 hours at the same temperature. The reaction mass is cooled to 30C after completion of the reaction and water (250 mL) is added. Dichloromethane (50 mL) is added to the reaction mass and stirred for 15 minutes at 30C. The layers are separated and the aqueous layer is extracted with dichloromethane (50 mL). The combined organic layer is washed with brine solution and dried over sodium sulphate. The solvent from the organic layer is evaporated to obtain a residue. The obtained residue is evaporated with hexane to obtain the product as crude (solid). The crude product is recrystallized in mixture of dichloromethane and hexane. Yield: 3 g.
220 g	With triethylamine; In toluene; at 35 - 65℃; for 1.16667h;	Example 4 Preparation of the crystalline form VII of agomelatine starting from 2-(7-methoxy-1-naphthyl)methylamine (base) Load 120 g of triethylamine under stirring in a 5 litre reactor containing 210 g of 2-(7-methoxy-1-naphthyl)methylamine (base) in 2500 ml of toluene heated to 35 C. Load 120 g of acetic anhydride in 10 minutes; the temperature will rise 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 2% 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 maintain the internal temperature always 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 agomelatine (polymorph VII) are obtained.

Reference： [1]Patent: CN107501113,2017,A .Location in patent: Paragraph 0018; 0022; 0026
[2]Patent: CN106928082,2017,A .Location in patent: Paragraph 0085; 0098; 0099
[3]Patent: EP2921473,2015,A1 .Location in patent: Paragraph 0036; 0037; 0038
[4]Patent: EP2703383,2014,A1 .Location in patent: Paragraph 0042; 0043
[5]Patent: CN104803882,2017,B .Location in patent: Paragraph 0046; 0047
[6]Patent: US2010/36163,2010,A1 .Location in patent: Page/Page column 2
[7]Patent: US2010/36162,2010,A1 .Location in patent: Page/Page column 2
[8]Patent: EP2562151,2013,A1 .Location in patent: Paragraph 0117
[9]Patent: US2014/221690,2014,A1 .Location in patent: Paragraph 0053

12
[ 138112-76-2 ]
[ 1176316-99-6 ]

Yield	Reaction Conditions	Operation in experiment
88.7%	With hydrogenchloride; In water; ethyl acetate; at 10℃;Product distribution / selectivity;	10 g of <strong>[138112-76-2]agomelatine</strong> was added to 100 ml of EtOAc, and 4.6 g of aqueous HC1 solution (36%) was added dropwise at 10 C. The mixture was stirred for lh, and then filtered, and the solid was rinsed twice with 10 ml of EtOAc and dried at 40 C to afford 10.2 g of white solid (purity: 99.8%; yield: 88.7%).Elemental analysis for CI:Calculated: Cl% (11.91 wt%)Found: Cl% (1 1.86 wt%)Mp: 88-90 C
88.7%	With hydrogenchloride; In water; ethyl acetate; at 10℃; for 1h;	10g of <strong>[138112-76-2]agomelatine</strong> is added to a 100ml solution of ethyl acetate. At a temperature of 10C, 4.6g of an aqueous solution of HCl (36%) is slowly added dropwise. Agitation is then carried out for 1 hour, followed by filtration and the resulting solid is washed twice in 10ml of ethyl acetate, then dried at a temperature of 40C to obtain 10.2g of form II white solid; purity: 99.8%, yield: 88.7%. Cl elemental analysis: Theoretically calculated value: Cl content 11.91 wt% Measured value: Cl content 11.86 wt% Determination of crystal water content of <strong>[138112-76-2]agomelatine</strong> compound of formula (II): The calculated theoretical crystal water content of C15H17NO2·HCl?H2O is 6.06 wt%. 5.1 The Fischer method (Chinese Pharmacopoeia 2010 edition, appendix VIII M) The product resulting from embodiment 5 was measured according to the Fischer method as mentioned above, and the crystal water content recorded was: 6.15 wt %.5.2 Thermogravimetric analysis (Chinese Pharmacopoeia 2010 edition, appendix VIII Q) The product resulting from embodiment 5 was measured according to thermogravimetric analysis as mentioned above, and the loss of crystal water recorded was: 6.67 wt %, i.e. the crystal water content of the original product was 6.67 wt %. For TGA curve, please refer to Figure 3.
88.7%	With hydrogenchloride; In water; ethyl acetate; at 10℃; for 1h;	10 g of <strong>[138112-76-2]agomelatine</strong> is added to a 100 ml solution of ethyl acetate. At a temperature of 10 C., 4.6 g of an aqueous solution of HCl (36%) is slowly added dropwise. Agitation is then carried out for 1 hour, followed by filtration and the resulting solid is washed twice in 10 ml of ethyl acetate, then dried at a temperature of 40 C. to obtain 10.2 g of form II white solid; purity: 99.8%, yield: 88.7%.

	With hydrogenchloride; In ethyl acetate; at 20℃; for 1h;Product distribution / selectivity;	10 g of <strong>[138112-76-2]agomelatine</strong> was added to 100 ml of EtOAc solution saturated with HCl gas. The mixture was stirred for 1 h at room temperature and then filtered, the solid washed twice with 10 ml of EtOAc and dried at 30 C. to yield 10.9 g of white solid (purity: 99.8%).Analytical results: (C15H17NO2.HCl)Calculated: Cl % (12.69%)Found: Cl % (12.39%)Melting point: 64-66 C.
	With hydrogenchloride; In ethyl acetate; at 20℃;Product distribution / selectivity;	Example 2: 3.0 g of <strong>[138112-76-2]agomelatine</strong> was dissolved in 30 ml of EtOAc with stirring, dry HCl gas was bubbled through the solution at room temperature until the solution stopped gaining weight. The mixture was then filtered, the solid washed twice with 5 ml of EtOAc and dried at 30C to yield 3.2 g of white solid (purity: 99.8%). Analytical results: (C15H17NO2?HCl)Calculated: Cl% (12.69%)Found: Cl% (12.60%)Melting point: 64-66C
	With hydrogenchloride; In ethyl acetate; at 0 - 5℃; for 1.5h;pH 2;	A mixture of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (25 g) and ethylacetate (50 ml) was cooled to 0-5C and slowly added ethylacetate-hydrochloride over a period of 30 minutes until pH equals to 2. The reaction mixture was stirred for 60 minutes. Filtered the solid, washed with ethyl acetate and then dried to get N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide hydrochloride. Yield: 16 gThe PXRD of obtained N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide hydrochloride compound of formula-2b of the present invention is depicted in figure-4.
	With hydrogenchloride; In water; ethyl acetate; at 10℃; for 1h;	Example 210 g of <strong>[138112-76-2]agomelatine</strong> was added to 100 ml of EtOAc, and 4.6 g of aqueous HCl solution (36%) was added dropwise at 10 C. The mixture was stirred for 1 h, and then filtered, and the solid was rinsed twice with 10 ml of EtOAc and dried at 40 C. to afford 10.2 g of white solid (purity: 99.8%; yield: 88.7%).Elemental analysis for Cl:Calculated: Cl % (11.91 wt)Found: Cl % (11.86 wt %)Mp: 88-90 C.
	With hydrogenchloride; In water; ethyl acetate; at 10℃; for 1h;	10g of <strong>[138112-76-2]agomelatine</strong> is added to a 100ml solution of ethyl acetate. At a temperature of 10C, 4.6g of an aqueous solution of HCl (36%) is slowly added dropwise. Agitation is then carried out for 1 hour, followed by filtration and the resulting solid is washed twice in 10ml of ethyl acetate, then dried at a temperature of 40C to obtain 10.2g of form II white solid; purity: 99.8%, yield: 88.7%. Cl elemental analysis: Theoretically calculated value: Cl content 11.91 wt % Measured value: Cl content 11.86 wt % Determination of crystal water content of <strong>[138112-76-2]agomelatine</strong> compound of formula (II): The calculated theoretical crystal water content of C15H17NO2?HCl?-H2O is 6.06 wt %. 5.1 The Fischer method (Chinese Pharmacopoeia 2010 edition, appendix VIII M) The product resulting from embodiment 5 was measured according to the Fischer method as mentioned above, and the crystal water content recorded was: 6.15 wt %.5.2 Thermogravimetric analysis (Chinese Pharmacopoeia 2010 edition, appendix VIII Q) The product resulting from embodiment 5 was measured according to thermogravimetric analysis as mentioned above, and the loss of crystal water recorded was: 6.67 wt %, i.e. the crystal water content of the original product was 6.67 wt %. For TGA curve, please refer to Figure 7.
11.2 g	With hydrogenchloride; In ethanol;	Take N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide 10g, was added to the ethanol dissolved in stirring. Hydrogen chloride gas is then slowly passed through, and when no solid is produced, the hydrogen chloride gas is stopped and filtered to give N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide hydrochloride 11.2 g<strong>[138112-76-2]Agomelatine</strong> hydrochloride.

Reference： [1]Patent: WO2011/113362,2011,A1 .Location in patent: Page/Page column 3
[2]Patent: EP2690087,2014,A1 .Location in patent: Paragraph 0043 - 0045
[3]Patent: US2014/11883,2014,A1 .Location in patent: Paragraph 0074
[4]Patent: US2011/313198,2011,A1 .Location in patent: Page/Page column 2
[5]Patent: EP2418195,2012,A1 .Location in patent: Page/Page column 3
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[7]Patent: US2013/5820,2013,A1 .Location in patent: Page/Page column 2
[8]Patent: EP2690088,2014,A1 .Location in patent: Paragraph 0045 - 0049
[9]Patent: CN107325011,2017,A .Location in patent: Paragraph 0017

13
[ 138112-76-2 ]
[ 1176317-02-4 ]

Yield	Reaction Conditions	Operation in experiment
85.3%	With hydrogen bromide; In water; ethyl acetate; at 20℃; for 1h;Product distribution / selectivity;	100 g of <strong>[138112-76-2]agomelatine</strong> was dissolved in 800 ml of EtOAc with stirring, and aqueous HBr solution (84g, 40%) was added dropwise at a temperature below the room temperature. The mixture was stirred for lh, and then filtered, and the solid was rinsed twice with 100 ml of EtOAc and dried at 40 C to afford 120g of white solid (purity: 99.9%; yield: 85.3%).Analytical results: (Ci5H17N02-HBrH20)Calculated: Br% (23.35%)Found: Br% (23.21 %)Mp: 88-90C
85.3%	With hydrogen bromide; In water; ethyl acetate; at 20℃; for 1h;	Example 7[0036]100 g of <strong>[138112-76-2]agomelatine</strong> was dissolved in 800 ml of EtOAc with stirring, and aqueous HBr solution (84 g, 40%) was added dropwise at a temperature below the room temperature. The mixture was stirred for 1 h, and then filtered, and the solid was rinsed twice with 100 ml of EtOAc and dried at 40 C. to afford 120 g of white solid (purity: 99.9%; yield: 85.3%).[0037]Analytical results: (C15H17NO2.HBr.H2O)[0038]Calculated: Br % (23.35%)[0039]Found: Br % (23.21%)[0040]Mp: 88-90 C.
85.3%	With hydrogen bromide; In water; ethyl acetate; for 1h;	100g of <strong>[138112-76-2]agomelatine</strong> is stirred and dissolved in 800ml of ethyl acetate. At a low temperature an aqueous solution of HBr (8.32 g, 40%) is added dropwise and then agitated for 1 hour before being filtered. The resulting solid is then washed twice in 100ml of ethyl acetate, then dried at a temperature of 40C to obtain 120g of white solid; purity 99.9%, yield: 85.3%. Analysis results (C15H17NO2?HBr?H2O) Calculated value: Br% (23.35%) Measured value: Br% (23.29%) Determination of crystal water content of agomclatine compound of formula (III): The calculated theoretical crystal water content of C15H17NO2·HBr?H2O is 5.26 wt%. 6.1 The Fischer method (Chinese Pharmacopoeia 2010 edition, appendix VIII M) The product resulting from embodiment 6 was measured according to the Fischer method as mentioned above, and the crystal water content recorded was: 5.10 wt %.6.2 Thermogravimetric analysis (Chinese Pharmacopoeia 2010 edition, appendix VIII Q) The product resulting from embodiment 6 was measured according to thermogravimetric analysis as mentioned above, and the loss of crystal water recorded was: 5.70 wt %, i.e. the crystal water content of the original product was 5.70 wt %. For TGA curve, please refer to Figure 4.

85.3%	With hydrogen bromide; In water; ethyl acetate; for 1h;	100g of <strong>[138112-76-2]agomelatine</strong> is stirred and dissolved in 800 ml of ethyl acetate. At a low temperature an aqueous solution of HBr (8.32 g, 40%) is added dropwise and then agitated for 1 hour before being filtered. The resulting solid is then washed twice in 100 ml of ethyl acetate, then dried at a temperature of 40 C. to obtain 120 g of white solid; purity 99.9%, yield: 85.3%.
	With hydrogen bromide; In ethyl acetate; at 20℃;	10 g of <strong>[138112-76-2]agomelatine</strong> was dissolved in 100 ml of EtOAc with stirring, and dry HBr gas was bubbled through the solution at room temperature until it stopped gaining weight. The mixture was then filtered, the solid washed twice with 10 ml of EtOAc and dried at 30 C. to yield 11.2 g of white solid (purity: 99.3%).Analytical results: (C15H17NO2.HCl)Calculated: Br % (24.6%)Found: Br % (23.8%)Melting point: 85-87 C.
	With hydrogen bromide; In ethyl acetate; at 20℃;	Example 7: 10 g of <strong>[138112-76-2]agomelatine</strong> was dissolved in 100 ml of EtOAc with stirring, and dry HBr gas was bubbled through the solution at room temperature until it stopped gaining weight. The mixture was then filtered, the solid washed twice with 10 ml of EtOAc and dried at 30C to yield 11.2 g of white solid (purity: 99.3%). Analytical results: (C15H17NO2?HCl)Calculated: Br% (24.6%)Found:Br%(23.8%)Melting point: 85-87C

Reference： [1]Patent: WO2011/113363,2011,A1 .Location in patent: Page/Page column 4
[2]Patent: US2013/12592,2013,A1 .Location in patent: Paragraph 0036-0040
[3]Patent: EP2690087,2014,A1 .Location in patent: Paragraph 0046 - 0048
[4]Patent: US2014/11883,2014,A1 .Location in patent: Paragraph 0080
[5]Patent: US2011/313198,2011,A1 .Location in patent: Page/Page column 2
[6]Patent: EP2418195,2012,A1 .Location in patent: Page/Page column 4

14
[ 1352139-51-5 ]
[ 138112-76-2 ]

Yield	Reaction Conditions	Operation in experiment
91.8%	With 2,3-dicyano-5,6-dichloro-p-benzoquinone; In dichloromethane; at 20℃;	4) Synthesis of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide (the compound I) The compound B (25.5 g) was dissolved in dichloromethane (250 ml), DDQ (26.1 g) was added portionwise, and the mixture was stirred overnight at RT. After the reaction was completed, the mixture was filtered, and the filtrate was washed with saturated aqueous NaHCO3 (150 ml*2), water (150 ml) and saturated aqueous NaCl (150 ml). The organic phase obtained was dried over anhydrous sodium sulfate, filtered and the solvent was evaporated off. The residue was recrystallized from ethanol-water (1:1), dried in an oven to obtain white powder (46.4 g). Yield: 91.8%. 1HNMR(CDCl3) delta: 1.922 (s, 3H), 3.21-3.24(t, 2H), 3.56-3.61(q, 2H), 3.96(s, 3H), 5.97 (s, 1H), 7.14-7.16 (q, 1H), 7.22-7.26 (m, 2H), 7.46-7.47 (m, 1H), 7.64-7.67 (m, 1H), 7.72-7.74 (d, 1H). ESI -MS(m/z): 244.14 (M+H).
90%	With 2,3-dicyano-5,6-dichloro-p-benzoquinone; for 4h;Reflux;Product distribution / selectivity;	Example-4: 5 g. (0.02 mol) of N-[2-(7-Methoxy-3,4-dihydro-l-naphthyl)ethyl]acetamide, 6 g. (0.03 mol.) of 2,3-Dichloro-5,6-dicyano-benzoquinone (DDQ) and 200 ml. O-xylene or toluene were charged in a clean and dry 4 neck R.B. Flask and heated to reflux temperature for about 4 hrs. The resultant reaction mixture was cooled to about 30C and filtered. The filtrate was washed with 3x30 ml. of 10% w/v of sodium hydroxide solution and 2x30 ml. of water. After removal of the solvent by evaporation, the resultant solid residue was recrystallized from an ethyl acetate and n-hexane mixture in a ratio of 1 :2 to provide 4.5 g. (90%) of the title compound with a chemical purity exceeding 99%.
80%	With 2,3-dicyano-5,6-dichloro-p-benzoquinone; In tetrahydrofuran; at 20℃;Product distribution / selectivity;	To a solution of N-[2-(7-methoxy-3,4-dihydro-naphthalene-l-yl)-ethyl]- acetamide, Compound (V) (250 g, 1.02 moles) in tetrahydrofuran (2 1), DDQ (255 g, 1.12 moles) is added.During the addition the internal temperature is kept around 20C.The reaction mixture is distilled at reduced pressure, replacing the solvent by toluene. The final suspension is filtered at room temperature, and the obtained solid is suspended again in toluene at 40-45C.The combined toluene solution is distilled at reduced pressure to a final volume of about 250 ml.The resulting suspension is cooled at 0-5C and then filtered and dried in an oven at 60C.The solid obtained, whose -NMR spectrum coincides with that of a purified sample, is dried at 60C.Yield: 198 g (80%). Titration (HPLC): > 98%.

	With 2,3-dicyano-5,6-dichloro-p-benzoquinone; In dichloromethane; at 20℃;	Example 7: 4) Synthesis of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (the compound I); The compound B (25.5 g) was dissolved in dichloromethane (250 ml), DDQ (26.1 g) was added portionwise, and the mixture was stirred overnight at RT. After the reaction was completed, the mixture was filtered, and the filtrate was washed with saturated aqueous NaHC03 (150 ml x 2), water (150 ml) and saturated aqueous NaCl (150 ml). The organic phase obtained was dried over anhydrous sodium sulfate, filtered and the solvent was evaporated off. The residue was recrystallized from ethanol-water (1 : 1), dried in an oven to obtain white powder (46.4 g). Yield: 91.8%.1HNMR(CDC13) delta : 1.922 (s, 3H), 3.21-3.24(t, 2H), 3.56-3.61(q, 2H) , 3.96(s, 3H), 5.97 (s, 1H),7.14-7.16 (q, 1H) , 7.22-7.26 (m, 2H) , 7.46-7.47 (m, 1H) , 7.64-7.67 (m, 1H) , 7.72-7.74 (d, 1H). ESI -MS(m/z): 244.14 (M+H).
	With 2,3-dicyano-5,6-dichloro-p-benzoquinone; In dichloromethane; at 0 - 30℃;Product distribution / selectivity;	A solution of N-(2-(7-methoxy-3,4-dihydronaphthalen-l-yl)ethyl)acetamide compound of formula-7 (100 g) in dichloromethane (800 ml) was cooled to 0-5C. A solution of DDQ (111.5 g) in dichloromethane (200 ml) was slowly added to the above reaction mixture at 0-5C and then stirred for 10-20 minutes. The temperature of the reaction mixture was raised to 25-30C and then stirred for 14 hours at same temperature. After completion of the reaction, filtered the reaction mixture and washed with dichloromethane. Filtrate was washed with 0.5% sodium hydroxide solution, followed by 1% hydrochloride solution and followed by water. Distilled off the solvent completely from the dichloromethane layer and co-distilled with acetone. The obtained residue was cooled to 25-30C. Acetone (200 ml) was added to the obtained residue and then carbon (10 g) was added to the reaction mixture. The reaction mixture was heated to reflux temperature and stirred for 20 minutes at the same temperature. Filtered the reaction mixture and washed with acetone. Filtrate was added to 2% sodium hydroxide solution at 10-15C and then stirred for 2 hours at 10-15C. Filtered the obtained solid, washed with 2% sodium hydroxide solution and then washed with 0.5 % hydrochloric acid and followed by water to get title compound. Acetone (140 ) was added to the obtained solid and then heated to 45-50C. The reaction mixture was stirred for 10 minutes at 45-50C. Filtered the reaction mixture, washed with acetone. Filtrate was added to the water and then stirred for 2 hours at 25- 30C. Filtered the reaction mixture, washed with water and then dried to get the pure title compound. Yield: 60 grams, MR: 97-103C; Purity (by HPLC): 99.86 %.
	With sulfur; at 180℃; for 0.5h;	Example-9: Preparation of N-[2-(7-methoxy-l-naphthyl) ethyl] acetamide (I)II I20gms of N-[2-(7-methoxy-3,4-dihydro-l-naphthyl)ethyl]acetamide (II) and 6.5gms of sulphur were charged into a clean and dry 500ml RB Flask followed by heating to about 180C and for about 30min. The resultant reaction mass was cooled to about 60-65C then 100ml of ethanol was charged and stirred for about 30min. The reaction solution was given carbon treatment with 2 gms of carbon. Then the reaction solution was distilled completely under vacuum followed by recrystallisation of the residue using from toluene and n-hexane mixture to afford 18gms of the title compound.Yield: 5gms.

Reference： [1]Patent: US2013/267738,2013,A1 .Location in patent: Paragraph 0053; 0054
[2]Patent: WO2012/127483,2012,A1 .Location in patent: Page/Page column 11
[3]Patent: WO2011/154140,2011,A2 .Location in patent: Page/Page column 14-15
[4]Patent: WO2011/153939,2011,A1 .Location in patent: Page/Page column 11
[5]Patent: WO2012/46253,2012,A2 .Location in patent: Page/Page column 26; 29; 30
[6]Patent: WO2012/93402,2012,A1 .Location in patent: Page/Page column 37-38

15
[ 1352139-49-1 ]
[ 138112-76-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	With acetic acid; 2,3-dicyano-5,6-dichloro-p-benzoquinone; In toluene; at 40℃; for 5h;	3) Synthesis of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide (the compound I) The compound A (56.0 g) was dissolved in toluene (500 ml) and acetic acid (50 ml), DDQ (53.2 g) was added, and the mixture was heated at 40 C. for about 5 h. After the reaction was completed, the mixture was filtered, and the filtrate was washed with saturated aqueous NaHCO3 (250 ml*2), water (250 ml) and saturated aqueous NaCl (250 ml). The resulting organic phase was dried over anhydrous sodium sulfate, filtered and the solvent was evaporated off. The residue was recrystallized from ethanol-water (1:1), dried in an oven to obtain the title product as white powder (43.8 g). Yield: 85%. 1HNMR(CDCl3) delta: 1.922 (s, 3H), 3.21-3.24(t, 2H), 3.56-3.61(q, 2H), 3.96(s, 3H), 5.97 (s, 1H), 7.14-7.16 (q, 1H), 7.22-7.26 (m, 2H), 7.46-7.47 (m, 1H), 7.64-7.67 (m, 1H), 7.72-7.74 (d, 1H). ESI -MS(m/z): 244.14 (M+H).
	With acetic acid; 2,3-dicyano-5,6-dichloro-p-benzoquinone; In toluene; at 40℃; for 5h;	Example 3: 3) Synthesis of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide (the compound I); The compound A (56.0 g) was dissolved in toluene (500 ml) and acetic acid (50 ml), DDQ (53.2g) was added, and the mixture was heated at 40C for about 5 h. After the reaction was completed, the mixture was filtered, and the filtrate was washed with saturated aqueous NaHC03 (250 ml x 2), water (250 ml) and saturated aqueous NaCl (250 ml). The resulting organic phase was dried over anhydrous sodium sulfate, filtered and the solvent was evaporated off. The residue was recrystallized from ethanol- water (1:1), dried in an oven to obtain the title product as white powder (43.8 g). Yield: 85%.1HNMR(CDC13) delta : 1.922 (s, 3H), 3.21-3.24(t, 2H), 3.56-3.61(q, 2H) , 3.96(s, 3H), 5.97 (s, 1H),7.14-7.16 (q, 1H) , 7.22-7.26 (m, 2H) , 7.46-7.47 (m, 1H) , 7.64-7.67 (m, 1H) , 7.72-7.74 (d, 1H). ESI -MS(m/z): 244.14 (M+H).

Reference： [1]Patent: US2013/267738,2013,A1 .Location in patent: Paragraph 0043; 0044
[2]Patent: WO2011/153939,2011,A1 .Location in patent: Page/Page column 9
[3]Patent: US2013/267738,2013,A1

16
[ 79-03-8 ]
[ 138112-76-2 ]
N-[2-(7-methoxy-3-propanoyl-naphthalen-1-yl)ethyl]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With aluminum (III) chloride; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 1h;	General procedure: To a solution of compound 1 (20.5 mmol) in 60 mL of a mixture of dichloromethane-DMF at 0 C, was added the aluminum chloride (61.6 mmol) and the mixture was allowed to stir for 5 min while keeping the temperature at 0 C. The desired acyl chloride (26.7 mmol) was added dropwise cautiously and the mixture stirred for 1 h at room temperature. The reaction mixture was then hydrolyzed with ice-water (100 mL) and the two phases were separated. The organic phase was washed with water, dried (MgSO4), filtered and evaporated under reduced pressure to give the desired product.