Name: 141626-36-0|N-(2-Butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl)methanesulfonamide|98%
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1
[ 141626-36-0 ]
dronedarone hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydrogenchloride In diethyl ether; ethyl acetate at 0 - 20℃; for 2.08333h;	3 5.3. dronedarone hydrochloride (1HCl) The base 1 (0.76 g, 1.365 mmol) was converted to hydrochloride by dissolution in EtOAc (10 mL) followed by dropwise addition of a 2.25 M solution of HCl in Et2O (0.604 mL, 1.36 mmol) over 5 min. A suspension formed was stirred for 1 h at RT, 1 h at 0 °C. The solid was filtered off and dried to provide 1HCl (0.79 g, 98%) as off whitesolid, m.p. 142 °C. 1H NMR (CD3OD, ppm): 7.81 (d, 2H),7.52 (d, 1H), 7.32 (s, 1H), 7.23 (dd, 1H), 7.10 (d, 2H), 4.26 (t, 2H),3.43 (m, 2H), 3.23 (m, 4H), 2.90 (m, 5H), 2,30 (m, 2H), 1,79 -1,71 (m, 6H), 1.50 - 1.42 (m, 4H), 1.37 - 1.30 (m, 2H), 1.03 (t,6H), 0.89 (t, 3H)
97.6%	With hydrogenchloride In water; isopropyl alcohol at 0℃; for 5h;	20 Example 20.N-r2-¾-butyl-3-{4-f(3-dibutylamino)propoxylberi2oyl)-l-benzoruran-5-yl]- methanesulfonamide hydrogen chloride salt,the compound of the general formula (la)5 g dronedarone base was dissolved in 24 ml isopropanol and 0.98 g 37% hydrochloric acid was added to it. The mixture was cooled to 0°C and kept at that temperature for 5 hours. The precipitated white crystals were collected, washed with 3.5 ml isopropanol. The product was dried at 50°C under vacuum.Mass of the product: 5.2 g (97.6%)Purity (HPLC): 100%
97.56%	Stage #1: dronedarone With chloro-trimethyl-silane In ethyl acetate at 30℃; for 0.166667h; Stage #2: With water In ethyl acetate	5.3 Example 5.3. Dronedarone Hydrochloride Crude (Using TMSCl/Water)In a 250.0 ml round bottom flask was charged 2-n-butyl-3-[4-(3-di-n-butyl amino propoxy) benzoyl]-5-methyl sulfonamido benzofuran (5.0g) (8.99 mmols), ethyl acetate (180.0ml), Trimethyl silyl chloride (1.33 ml) (10.40 mmols) and stirred at 30.0°C for 10 minutes. To this solution water (0.10 ml) (5.55 mmols) was added dropwise pH of the reaction mass was observed to be 2-3.The reaction mass was stirred for 3 hours and the solid obtained was filtered and dried at 50.0°C under vacuum for 2 hours (Dry weight: 5.2 g).Molar yield: 97.56%HPLC purity: 98.34%

97.56%	With chloro-trimethyl-silane In water; ethyl acetate at 30℃; for 3.16667h;	5.5.3 In a 250.0 ml round bottom flask was charged 2-n-butyl-3-[4-(3-di-n-butyl amino propoxy) benzoyl]-5-methyl sulfonamido benzofuran (5.0g) (8.99 mmols), ethyl acetate (180.0ml), Trimethyl silyl chloride (1.33 ml) (10.40 mmols) and stirred at 30.0°C for 10 minutes. To this solution water (0.10 ml) (5.55 mmols) was added dropwise pH of the reaction mass was observed to be 2-3. The reaction mass was stirred for 3 hours and the solid obtained was filtered and dried at 50.0°C under vacuum for 2 hours (Dry weight: 5.2 g). Molar yield: 97.56% HPLC purity: 98.34% DSC: 140.67°C
91%	With hydrogenchloride In diethyl ether; butanone at -20℃; for 1h;	5 Dronedarone base (128.9 g; 0.23 mol) was dissolved in 2-butanone (1280 mL) and the solution was cooled down to -20°C. Hydrochloric acid (0.25 mol; 50 mL of 5M HCl in ether) was added dropwise. Precipitated white suspension was stirred for one hour at -20°C and then filtered off through sintered glass under nitrogen. Obtained crystal was washed with 2-butanone, cooled down to 0°C (200 mL) and then washed twice with ether cooled down to 0°C (500 mL). Yield was 124.2 g (91 %), HPLC purity was 99.3 %.
91%	With hydrogenchloride In diethyl ether; butanone at -20℃; for 1h;	5 Example 5 - Dronedarone hydrochloride Dronedarone base (128.9 g; 0.23 mol) was dissolved in 2-butanone (1280 mL) and the solution was cooled down to 20°C. Hydrochloric acid (0.25 mol; 50 mL of 5M HCl in ether) was added dropwise. Precipitated white suspension was stirred for one hour at 20°C and then filtered off through sintered glass under nitrogen. Obtained crystal was washed with 2-butanone, cooled down to 0°C (200 mL) and then washed twice with ether cooled down to 0°C (500 mL). Yield was 124.2 g (91 %), HPLC purity was 99.3 %.
90%	With hydrogenchloride In dichloromethane; water; isopropyl alcohol at -5℃;	5.2 5.2. Dronedarone and then dronedarone hydrochloride 5.2. Dronedarone and then dronedarone hydrochloride The dronedarone hydrochloride obtained in the preceding step is washed 5 times with 60 l of water. The dronedarone is concentrated and taken up in 94 l of isopropanol. 1.8 kg of water and 0.38 kg of hydrochloric acid are added. The medium is cooled to -5° C. The medium is filtered, and washed with 22 l of isopropanol. In this manner, dronedarone hydrochloride is obtained. Chemical yield =90%.
89%	With hydrochloric acid diethyl ether In acetone at -20℃; for 1h;
	With hydrogenchloride In water; isopropyl alcohol at 0℃;	4.B The dronedarone in crude form obtained in the preceding paragraph A. is concentrated and taken up in 24 ml of isopropanol. 3.24 g of 37% hydrochloric acid are added and then the medium is cooled to 0 C. The medium is filtered and washed with 8 ml of isopropanol.
	With hydrogenchloride In diethyl ether; ethyl acetate	6.C C. Dronedarone Hydrochloride 2 g of dronedarone are dissolved in 40 ml of anhydrous ethyl acetate. A solution of hydrochloric acid in ether is added with stirring until a pH of 3 is reached. After a few minutes, the hydrochloride begins to precipitate. It is filtered off after 0.75 hour, which gives 2.03 g of a white product. In this way, drondedarone hydrochloride is collected. M.p.: 143° C. (acetone)
	With hydrogenchloride In water; acetone at 5 - 10℃; for 3.5h;	4 EXAMPLE 4[0102] Preparation of dronedarone hydrochloridelOg of dronedarone (prepared as in Example 3) in 30mL of acetone was stirred at about 25°C to about 30°C for about 10-15min to get a clear solution. The solution was cooled to about 5°C to about 10°C. A solution of aqueous hydrogen chloride in 5mL of acetone was added dropwise to adjust the pH to about 2.5-3. The reaction mixture was stirred at about 5°C to about 10°C for about 3.5h. The solid obtained was filtered, washed with 5mL of cold acetone and dried under vacuum at about 40°C to about 45°C till constant weight. Yield: 7g
	With hydrogenchloride In ethyl acetate; isopropyl alcohol at 0 - 70℃; for 0.5h;	6 Example-6:Preparation of Dronedarone Hydrochloride100 g dronedarone free base as oil and 175 mL ethyl acetate was taken in round bottom flask at 25°C and stirred for 15 min. 2.5 g activated carbon was added and stirred for 30 min. The reaction mixture was filtered through hyflow bed and washed with 100 mL ethyl acetate. The organic layer was cooled to 0°C and 52.50 g isopronolic hydrochloride solution was added at 0°C. The reaction mixture was stirred at 0°C and heated to 70°C for 30 min. The reaction mixture was gradually cooled to 0°C and stirred for 1 hour. The precipitated product was filtered and washed with 100 mL chilled ethyl acetate and further dried to obtain dronedarone hydrochloride.
1.62 kg	With hydrogenchloride In dichloromethane; water for 0.5h; Large scale reaction;
	With hydrogenchloride In ethyl acetate for 1h;	10.c c). To solution from experiment (b), containing 1 g of 2-n-butyl 3-[4-(3-di-n- butylamino-propoxy)benzoyl] 5-methyl sulfonamido benzofuran in 20 ml of ethyl acetate, hydrogen chloride in ethyl acetate is added with stirring to pH=3. After a few minutes, the hydrochloride begins to precipitate. It is filtered off after 1 hour to give 1.03 g of a colorless product. In was filtered, washed with cold ethyl acetate and dried in vacuum, m.p.: 142-143° C.
	With hydrogenchloride In water; ethyl acetate at 20 - 30℃;	2 Preparation of Crude Dronedarone hydrochloride100 gm of 2-n-Butyl-3-(4-(3-dibutylaminopropoxy benzoyl-5-aminobenzofuran dioxalate, 500 ml Ethyl acetate & Aq. ammonia soln. (Aq. ammonia soln. (-25%) (70 ml) in water (700 ml) was charged in RBF. Stirred the reaction mass at 30+/-5°C for 20 to 30 minutes & settled the layers for 15-20 min. The organic layer was separated and aqueous layer was discarded. Charged organic layer followed by distil the solvent under vacuum 25- 45°C to obtained 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- amino benzofuran (oil). Charged dichloromethane (180 ml) & Pyridine (11.86 g) in to obtained oil. The reaction mixture was cooled at 0+/-5°C. Add Methanesulfonylchloride solution (Methanesulfonyl chloride (21.42g) in dichloromethane (36 ml) ) drop wise in 45-60 min. at 0+/-5°C. Stirred the reaction mixture at 0+/-5°C for 30 minutes. Settled the layers 10-15 min. The organic layer was separated and aqueous layer was discarded. Distiled out organic layer completely under vacuum at 25- 40°C to obtain Dronedarone base (Oil). Charged ethyl acetate in the obtained product. Add Ethyl acetate .HC1 drop wise (-93.6 ml) in 45-60 min at 25+/-5°C to adjust pH: 2-3. Stirred the reaction mixture for 60-90 min at 25+/-5°C. Filter the solid & washed the solid with ethyl acetate followed by drying the solid under vacuum at 45+/-5°C to obtain Crude Dronedarone HC1.

Reference： [1]Piotrkowska, Barbara; Nerdinger, Sven; Schreiner, Erwin; Selič, Lovro; Graczyk, Piotr P. [Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 14, p. 4330 - 4335]
[2]Current Patent Assignee: SANOFI - WO2011/70380, 2011, A1 Location in patent: Page/Page column 21
[3]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2012/52448, 2012, A1 Location in patent: Page/Page column 14
[4]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - EP2447256, 2012, A1 Location in patent: Page/Page column 9
[5]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - EP2371824, 2011, A1 Location in patent: Page/Page column 9
[6]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - EP2371808, 2011, A1 Location in patent: Page/Page column 9
[7]Current Patent Assignee: SANOFI - US2004/48921, 2004, A1 Location in patent: Page/Page column 5
[8]Li, Feng; Jin, Chunhua; Zou, Jianwei; Wu, Jun [Bulletin of the Korean Chemical Society, 2014, vol. 35, # 7, p. 1970 - 1972]
[9]Current Patent Assignee: SANOFI - US2004/48921, 2004, A1 Location in patent: Page/Page column 5
[10]Current Patent Assignee: SANOFI - US2004/10032, 2004, A1 Location in patent: Page/Page column 6
[11]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2012/7959, 2012, A1 Location in patent: Page/Page column 21-22
[12]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - WO2012/32545, 2012, A1 Location in patent: Page/Page column 36-37
[13]Location in patent: experimental part Hivarekar, Raghvendra R.; Deshmukh, Sanjay S.; Tripathy., Narendra K. [Organic Process Research and Development, 2012, vol. 16, # 4, p. 677 - 681]
[14]Current Patent Assignee: MAPI PHARMA LTD. - WO2011/99010, 2011, A1 Location in patent: Page/Page column 42
[15]Current Patent Assignee: ALEMBIC PHARMACEUTICALS LIMITED - WO2012/153225, 2012, A1 Location in patent: Page/Page column 3; 13

2
dronedarone hydrochloride [ No CAS ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
92.3%	With potassium carbonate In tert-butyl methyl ether; water at 50℃; Industry scale;	3.4 Example 3.4: 11,1 kg of dronedarone hydrochloride are dissolved in methyl t-butyl ether (MTBE) at 50°C. A aqueous solution of potassium carbonate is added to generate the base. The reaction mixture is stirred for 2 hours. The 2 phases are separated. The organic phase is washed 2 times with water and then concentrated up to 0.7 volume of MTBE. 4 volumes of n-heptane are added and the mixture is cooled down to 30°C. A seed is added at 30°C, followed by a isothermal period of 16 hours. The mixture is cooled down to 10°C at a rate of -5°C/h and remains at 10°C for 1 hour. The base is then filtered, washed and dried. The yield is 92,3 %.
86%	With sodium hydroxide In water	4.A The dronedarone hydrochloride obtained in Example 3 above is washed twice, this being with 24 ml of water, and then with 16 ml of a 10% aqueous sodium hydroxide solution and finally with 16 ml of water.
	With sodium hydroxide at 0 - 5℃; for 1h;	9 Preparation of Dronedarone base: Example 9 Preparation of Dronedarone base: 5 gm of Dronedarone hydrochloride was added to cold solution of sodium hydroxide (40ml,1M) to obtain a mixture. The mixture was stirred at 0-5°C for 1hr. 25ml of dichloromethane (MDC) was added to the mixture. The layers were separated and the organic layer was concentrated to obtain a residue. The obtained residue was treated with hexane to get 4.2 gm of Dronedarone base.

	With ammonia In dichloromethane	8 Example-8Preparation of N- 2-butyl-3 - 4-(3 -(di-n-butylamino)propoxy)benzoyll -5 - benzofuranyll methanesulfonamide (Dronedarone Base) N- [2-Butyl-3 [4-(3 -(dibuty lamino)propoxy)benzoy 1] -5 - benzofuran]methanesulfonamide hydrochloride (10 gm) was dissolved in dichloromethane (100 ml). The solution was neutralized by ammonia solution and the product was extracted in dichloromethane where the dichloromethane was removed under reduced pressure to get oily mass. The product was precipitated out from oily mass by adding hexane (100 ml) with continuous stirring. The product was filtered; wet cake was washed with hexane and dried to get N-[2-butyl-3-[4-(3-(di-n-butylamino)propoxy)benzoyl]-5- benzofuranyl]methanesulfon amide with purity of > 99.5 % measured by HPLC
	With potassium carbonate In water; toluene at 25℃; for 0.5h;	16 Example-16:Preparation of crystalline dronedarone free base185 g dronedarone hydrochloride Form-A and 925 mL toluene was taken in round bottom flask at 25°C and stirred for 15 minutes. 52 g potassium carbonate aqueous solution was added to the reaction mixture and stirred for 30 mins. The aqueous layer was separated and extracted with 185 mL toluene. The combined toluene layer was washed with water and distilled under vacuum to remove toluene. The residue was treated with 925 mL hexane and cooled to 0°C. The reaction mixture was cooled overnight and precipitated solid was filtered and washed with chilled hexane. The product was dried to obtain 145 g of dronedarone free base solid. The crystalline form is characterized by XRD substantially as depicted in FIG.12, Infrared spectrum substantially as depicted in FIG.13 and DSC substantially as depicted in FIG.14.
	With sodium hydroxide at 0 - 5℃; for 1h;	9 5 gm of Dronedarone hydrochloride was added to cold solution of sodium hydroxide (40 ml, 1M) to obtain a mixture. The mixture was stirred at 0-5° C. for 1 hr. 25 ml of dichloromethane (MDC) was added to the mixture. The layers were separated and the organic layer was concentrated to obtain a residue. The obtained residue was treated with hexane to get 4.2 gm of Dronedarone base.
5.61 g	With sodium hydrogencarbonate In dichloromethane Neutral conditions;	10.1 Preparation of Dronedarone 5.93 g dronedarone hydrochloride (0.01 mol) obtained in example 1 was dissolved in 40 mL methylene chloride to obtain a mixture. Then, the mixture was adjusted to neutral pH by adding saturated sodium bicarbonate solution. The organic layer was separated and washed with saturated sodium bicarbonate solution (10 mL×2), dried over sodium sulfate and evaporated under reduced pressure to get 5.61 g of oily product.

Reference： [1]Current Patent Assignee: SANOFI - EP2354132, 2011, A2 Location in patent: Page/Page column 7
[2]Current Patent Assignee: SANOFI - US2004/48921, 2004, A1 Location in patent: Page/Page column 5
[3]Current Patent Assignee: U S V LTD. - EP2428511, 2012, A1 Location in patent: Page/Page column 11-12
[4]Current Patent Assignee: FRICHEM PRIVATE - WO2012/4658, 2012, A2 Location in patent: Page/Page column 20-21
[5]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - WO2012/32545, 2012, A1 Location in patent: Page/Page column 41
[6]Current Patent Assignee: U S V LTD. - US2012/108828, 2012, A1 Location in patent: Page/Page column 8
[7]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - US2013/72697, 2013, A1 Location in patent: Paragraph 0058

3
[ 141644-91-9 ]
[ 124-63-0 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: (5-amino-2-butyl-benzofuran-3-yl)-[4-(3-dibutylamino-propoxy)-phenyl]-methanone; methanesulfonyl chloride In toluene at 108℃; for 3.5h; Stage #2: With sodium hydrogencarbonate In toluene at 60℃; for 0.5h;	5 Exam Ie-5:Preparation of 2-n-butyl3-i4-(3-di-n-buty amino-propoxy)benzoyll5-methyIsulfon- amido benzofuran (Dronedarone)100 g of 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2-n-butyl benzofuran and 1 L toluene are heated to 105°C for 30 min. 100 mL solution of methane sulfonyl chloride in toluene was added within 30 min at 108°C and stirred for 3 hours. After the completion of the reaction as monitored by TLC, the reaction mixture was cooled to 25°C. The reaction mixture was quenched with 5% sodium bicarbonate solution 400 mL and heated to 60°C for 30 min. The organic layer was separated and washed with 250 mL of water at 60°C. The separated organic layer was charcoalized with 2.5 g activated charcoal at 60°C and filtered through hyflow bed and washed with 100 mL toluene at 60°C. The organic layer was distilled under vacuum to obtain 95% 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy)benzoyl]5-methyl-sulfonamido benzofuran (dronedarone) as an oil. Purity > 99.5% (HPLC).
94.82%	In toluene for 3h; Reflux;	4.2 Example 4.2:In a 2.0 liter round bottom flask was charged 5-amino-3-[4-(3-di-n- butylamino-propoxy)benzoyl]-2-n-butylbenzofuran (100. Og) (209.20 mmols), toluene (1000.0 ml) and heated at 110.0°C. Added dropwise the solution of methane sulfonylchloride (21.10 ml in 100.0 ml of toluene) (271.44 mmols) and heated to reflux for 3.0 hours.At the end of reaction, the reaction mass was cooled to 30.0°C and charged saturated sodium bicarbonate solution (500.0 ml). The reaction mass was stirred for 10 minutes and toluene layer separated. Toluene layer was washed with water (500.0 mlx2) and dried over sodium sulphate (50.0 g). Toluene layer was concentrated to get dronedarone base as thick oil (110.0 g).Molar yield: 94.82 %HPLC purity: 97.30%
94.82%	Stage #1: (5-amino-2-butyl-benzofuran-3-yl)-[4-(3-dibutylamino-propoxy)-phenyl]-methanone; methanesulfonyl chloride In toluene for 3h; Reflux; Stage #2: With sodium hydrogencarbonate In toluene at 30℃; for 0.166667h;	4.4.2 In a 2.0 liter round bottom flask was charged 5-amino-3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2-n-butylbenzofuran (100.0g) (209.20 mmols), toluene (1000.0 ml) and heated at 110.0°C.Added dropwise the solution of methane sulfonylchloride (21.10 ml in 100.0 ml of toluene) (271.44 mmols) and heated to reflux for 3.0 hours. At the end of reaction, the reaction mass was cooled to 30.0°C and charged saturated sodium bicarbonate solution (500.0 ml). The reaction mass was stirred for 10 minutes and toluene layer separated. Toluene layer was washed with water (500.0 mlx2) and dried over sodium sulphate (50.0 g). Toluene layer was concentrated to get dronedarone base as thick oil (110.0 g). Molar yield: 94.82 % HPLC purity: 97.30%

92%	With sodium hydrogencarbonate In dichloromethane at 35℃; for 6h; Reflux;
	With triethylamine In 1,1-dichloroethane; hexane for 20h;	6.B B. Dronedarone A solution of 17.6 g (0.154 mol) of methanesulfonyl chloride in 375 ml of dichloroethane is added dropwise to a solution of 68.3 g (0.15 mol) of the compound obtained in the preceding paragraph A. and of 23.6 g (0.23 mol) of triethylamine in 750 ml of dichloroethane. The mixture is stirred for 20 hours and is poured into 500 ml of water. The mixture is separated by settling and the organic phase is washed with water and evaporated to dryness. The crude product thus obtained (79.5 g; crude yield: 100%) is purified by elution chromatography on a silica column (eluent: ethyl acetate). In this way, 48 g of purified dronedarone are collected. Yield: 61.6%. Treatment with hexane of the product thus obtained gave a fraction of 44 g in the crystalline state (purity by HPLC: 96.1%) and a fraction of 4 g in the crystalline state (purity by HPLC: 99%). Yield: 65.3%.
	With triethylamine In dichloromethane at 25 - 30℃;	3 EXAMPLE 3[0101] Preparation of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5- methylsulfonamidobenzofuran (dronedarone)a) A solution of 8g of methanesulfonyl chloride in 150mL of dichloromethane was added dropwise to a stirred solution of 30g of 5-amino-2-n-butyl-3-[4-(3-di-n- butylaminopropoxy)benzoyl]benzofuran and 10.6mL of triethylamine in 150mL of dichloromethane at about 25°C to about 30°C over about lh. The reaction mixture was stirred at about 25°C to about 30°C. After completion of reaction, as monitored by HPLC, the reaction mixture was cooled to about 10°C to about 15°C followed by addition of 150mL of water. The reaction mixture was stirred for about 15min and the two layers were separated. The organic layer was washed twice with 150mL of water, dried over sodium sulphate and concentrated under vacuum to give 35g of pale brown thick oil.Purity (HPLC): 93.39%Impurity compound of formula V: 4.57%b) To a stirred solution of 35g of crude product obtained in (a) in 90mL of ethanol was added dropwise a solution of 2.5g of sodium hydroxide in 150mL of ethanol at about 20°C to about 25°C over about lh. The reaction mixture was stirred at about 25°C to about 30°C for about 30minutes. 300mL of ethyl acetate and 750mL of water were then slowly added to the reaction mixture at about 10°C to about 25°C and stirred for about 15min. The two layers were separated and the aqueous layer was extracted twice with 300mL of ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to give 34g of pale brown thick oil.Purity (HPLC): 97.67%Impurity compound of formula V: below detection limitc) 34g of oil obtained in (b) in 60mL of hexane was stirred at about 40°C to about 45°C to get a clear solution. The solution was further stirred for about 2h at about 25°C to about 30°C. The solution was then cooled to about 15°C to about 20°C and 30mL of hexane was added to it and further stirred for about 30minutes. The solid obtained was filtered, washed with 50mL of hexane and dried under vacuum at about 30°C to about 35°C till constant weight. Yield: 25gPurity (HPLC): 98.15%
	Stage #1: (5-amino-2-butyl-benzofuran-3-yl)-[4-(3-dibutylamino-propoxy)-phenyl]-methanone; methanesulfonyl chloride With triethylamine In dichloromethane at 20℃; for 0.5h; Stage #2: With sodium hydroxide In ethanol at 20℃; for 1.5h;	6 EXAMPLE 6[0104] Preparation of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5- methylsulfonamidobenzofuran (dronedarone)a) A solution of 13.75g of methanesulfonyl chloride in 250mL of dichloromethane was added dropwise to a stirred solution of 50g of 5-amino-2-n-butyl-3-[4-(3-di-n- butylaminopropoxy)benzoyl]benzofuran and 17.6mL of triethylamine in dichloromethane at about room temperature. The reaction mass was stirred at about room temperature for about 30min. After completion of reaction, as monitored by HPLC, the reaction mass was cooled to about 15°C to about 20°C followed by slow addition of 250mL of water. The reaction mass was stirred for about 15min and the two layers were separated. To the organic layer at about 15°C to about 20°C, was added 150mL of water and the pH was adjusted with sodium hydroxide solution to about above 8. The organic layer was washed with water and sodium chloride solution and concentrated under vacuum to give pale brown thick oil which was degassed under vacuum at about temperature below 40°C for about 30min. Yield: 60gPurity (HPLC): 91.04%Impurity compound of formula V: 6.3%b) To a stirred solution of 60g of crude product obtained in (a) in 240mL of ethanol (industrial solvent) was added drop wise a solution of 7.6g of sodium hydroxide in 240mL of ethanol (industrial solvent) at about room temperature over about lh. The reaction mass was stirred at the same temperature for about 30min. The reaction mass was then cooled to about 15°C to about 20°C. 600mL of ethyl acetate and 2400mL of water were then slowly added to the reaction mass at about 15°C to about 25°C over about 30min. The reaction mass was stirred at about room temperature for about 15min. The two layers were separated and the aqueous layer was extracted twice, each with 300mL of ethyl acetate. The combined organic layer was washed with 300mL of 10% sodium chloride solution. The organic layer was treated with 3g of Norit charcoal and stirred for about 30min at about room temperature. The reaction mass was filtered over hyflo bed and washed with 60mL of ethyl acetate. The filtrate and the washings were collected together and concentrated under vacuum to give pale brown thick oil which was degassed under vacuum at about temperature below 40°C for about 30min. Yield: 57g Purity (HPLC): 96.64%Impurity compound of formula V: 0.04%
	With triethylamine In toluene at -5 - 5℃; for 0.5h;
	Stage #1: (5-amino-2-butyl-benzofuran-3-yl)-[4-(3-dibutylamino-propoxy)-phenyl]-methanone With hydrogenchloride In ethanol; water at 50℃; for 0.666667h; Stage #2: methanesulfonyl chloride With tetrabutyl-ammonium chloride In toluene at 80 - 90℃; for 5.5h;	5 4.8 g of (5-amino-2-butyl)-l-benzofuran-3-yl)[4-[3-(di-n-butylamino)propoxy]- phenyl] methanone is dissolved in 15 ml of abs. ethanol and 0.9 ml of hydrochloric acid of 37% is added in 10 minutes. The solution is stirred at 50 °C for 30 minutes and completely evaporated in reduced pressure. The residual material: 5.1 g (99 %) (5-amino-2-butyl)-l-benzofuran-3-yl)[4-[3 -(di-n-butylamino)propoxy]phenyl] -methanone monohydrochloride salt.To this salt 0.5 g of tetrabutylammonium chloride and 50 ml of toluene are added and heated to 80-90 °C. At this temperature 1.9 g of methanesulfonyl chloride is added in 30 minutes.This mixture is stirred at 80-90 °C for 5 hours and cooled to room temperature. 50 ml of ethylacetate and 50 ml of water are added and the phases are separated. The aqueous layer is washed with 25 ml of ethyl acetate. The combined organic layer is dried with Na2S04 and evaporated.Yield: 5.4 g (99 %). This product is purified through its oxalate salt according to example 1 (yield: 87 %). Purity of the obtained title product (HPLC): 99.7%.The product is identical with the compound prepared in Example 1.
	With pyridine In dichloromethane at -5 - 5℃;	2 Preparation of Crude Dronedarone hydrochloride100 gm of 2-n-Butyl-3-(4-(3-dibutylaminopropoxy benzoyl-5-aminobenzofuran dioxalate, 500 ml Ethyl acetate & Aq. ammonia soln. (Aq. ammonia soln. (-25%) (70 ml) in water (700 ml) was charged in RBF. Stirred the reaction mass at 30+/-5°C for 20 to 30 minutes & settled the layers for 15-20 min. The organic layer was separated and aqueous layer was discarded. Charged organic layer followed by distil the solvent under vacuum 25- 45°C to obtained 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- amino benzofuran (oil). Charged dichloromethane (180 ml) & Pyridine (11.86 g) in to obtained oil. The reaction mixture was cooled at 0+/-5°C. Add Methanesulfonylchloride solution (Methanesulfonyl chloride (21.42g) in dichloromethane (36 ml) ) drop wise in 45-60 min. at 0+/-5°C. Stirred the reaction mixture at 0+/-5°C for 30 minutes. Settled the layers 10-15 min. The organic layer was separated and aqueous layer was discarded. Distiled out organic layer completely under vacuum at 25- 40°C to obtain Dronedarone base (Oil). Charged ethyl acetate in the obtained product. Add Ethyl acetate .HC1 drop wise (-93.6 ml) in 45-60 min at 25+/-5°C to adjust pH: 2-3. Stirred the reaction mixture for 60-90 min at 25+/-5°C. Filter the solid & washed the solid with ethyl acetate followed by drying the solid under vacuum at 45+/-5°C to obtain Crude Dronedarone HC1.
0.094 g	With pyridine In dichloromethane at 20℃; for 1.5h;	N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5yl)methanesulfonamide (51): Crude 50 (0.112 g) was dissolved in DCM (3 mL), then Py (0.351 mmol, 0.025 mL) and MsCl (0.234mmol, 0.018 mL) were added dropwise. The reaction mixture was stirred at room temperature for 1.5hrs. After completion of the reaction, the reaction mixture was diluted with water and DCM. Theaqueous layer was extracted with DCM three times and the combined organic layers were dried over anhydrous MgSO4 and filtered. The solvents were removed in vacuo and the residue was then purifiedby flash column chromatography (CHCl3:MeOH, 40:1) to yield 51 as a yellow oil (0.094 g, 73% overtwo steps).1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.6 Hz, 1H), 7.32 - 7.26 (m, 2H),6.98 (d, J = 8.8 Hz, 2H), 4.14 (t, J = 6.3 Hz, 2H), 2.95 (s, 3H), 2.89 (t, 2H), 2.65 (t, J = 6.8 Hz, 2H),2.47 (t, 4H), 2.02 - 1.93 (m, 2H), 1.76 (qi, J = 7.6 Hz, 2H), 1.50 - 1.40 (m, 4H), 1.39 - 1.28 (m, 8H),0.95 - 0.86 (m, 9H).13C NMR (101 MHz, CDCl3) δ 190.20, 165.79, 163.25, 151.84, 132.38, 131.65, 131.30, 128.26,120.14, 116.77, 115.55, 114.29, 111.78, 66.54, 53.88, 50.35, 39.05, 30.02, 29.69, 29.13, 28.00,26.93, 22.31, 20.68, 14.05, 13.65.HRMS (ESI+): m/z [M+H+] calcd for C31H45N2O5S: 557.3049 , found: 557.3048.

Reference： [1]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - WO2012/32545, 2012, A1 Location in patent: Page/Page column 36
[2]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2012/52448, 2012, A1 Location in patent: Page/Page column 13
[3]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - EP2447256, 2012, A1 Location in patent: Page/Page column 9
[4]Madhasu, Madhu; Doda, Sai Reddy; Begari, Prem Kumar; Dasari, Krishna Rao; Thalari, Gangadhar; Kadari, Sudhakar; Yadav, Jhillu Singh [Journal of Heterocyclic Chemistry, 2021, vol. 58, # 9, p. 1861 - 1866]
[5]Current Patent Assignee: SANOFI - US2004/10032, 2004, A1 Location in patent: Page/Page column 6
[6]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2012/7959, 2012, A1 Location in patent: Page/Page column 20-21
[7]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2012/7959, 2012, A1 Location in patent: Page/Page column 23-24
[8]Location in patent: experimental part Hivarekar, Raghvendra R.; Deshmukh, Sanjay S.; Tripathy., Narendra K. [Organic Process Research and Development, 2012, vol. 16, # 4, p. 677 - 681]
[9]Current Patent Assignee: SANOFI - WO2012/131408, 2012, A1 Location in patent: Page/Page column 13
[10]Current Patent Assignee: ALEMBIC PHARMACEUTICALS LIMITED - WO2012/153225, 2012, A1 Location in patent: Page/Page column 3; 13
[11]Klucznik, Tomasz; Mikulak-Klucznik, Barbara; McCormack, Michael P.; Lima, Heather; Szymkuć, Sara; Bhowmick, Manishabrata; Molga, Karol; Zhou, Yubai; Rickershauser, Lindsey; Gajewska, Ewa P.; Toutchkine, Alexei; Dittwald, Piotr; Startek, Michał P.; Kirkovits, Gregory J.; Roszak, Rafał; Adamski, Ariel; Sieredzińska, Bianka; Mrksich, Milan; Trice, Sarah L.J.; Grzybowski, Bartosz A. [Chem, 2018, vol. 4, # 3, p. 522 - 532]

4
[ 141626-26-8 ]
[ 124-63-0 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In 1,1-dichloroethane; water	3.a a) a) 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 5-methylsulfonamido benzofuran A solution of 17.6 g (0.154 mole) of methanesulfonyl chloride in 375 ml of dichloroethane is added dropwise to a solution of 68.3 g (0.15 mole) of 5-amino 3-[4-(3-di-n-butylamino-propoxy) benzoyl] 2-n-butyl benzofuran and 23.6 g (0.23 mole) of triethylamine in 750 ml of dichloroethane. The mixture is stirred for 20 h and poured into 500 ml of water. The phases are separated, the organic phases washed with water and evaporated to dryness. The crude product thus obtained (79.5 g; crude yield: 100%) is then purified by elution chromatography on a column of silica (eluant: ethyl acetate). In this manner, 48 g of purified 2-n-butyl 3-[4-(3-di-n-butylamino-propoxy)benzoyl] 5-methylsulfonamido benzofuran are recovered. Yield: 61.6%. Treatment of the product thus obtained with hexane gave 44 g of a crystalline fraction (purity by HPLC: 96.1%) and 4 g of a crystalline fraction (purity by HPLC: 99%) M.p.: 65.3%

Reference： [1]Current Patent Assignee: SANOFI - US5223510, 1993, A

5
[ 1310430-05-7 ]
[ 111-92-2 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium iodide In butanone for 16h;	12 Example 12.N- [2- -buty 1-3 - { 4- [(3 -dibuty lamino)propoxy ]benzoy 11-1 -benzofuran-5 -y Π- methanesulfonamide, the compound of the general formula (I)5 g N-(2-«-butyl-3-[4-(3-chloropropoxy)benzoyl]benzofuran-5-yl)- methanesulfonamide -the compound of the general formula (II), where X is chloro atom- was dissolved in 90 ml methyl ethyl ketone, then 16.7 g dibutylamine and 6.46 g sodium iodide were added and the mixture was stirred for 16 hours. The reaction mixture was evaporated, 100 ml dichloromethane and 100 ml water were added. The phases were separated. The organic phase was washed by stirring with 50 ml 5% hydrochloric acid, then with 50 ml water. The solvent was distilled off. The dibutylamine recovered from the solvent was used in a next reaction.Mass of the product: 5.9 g (100.0%)Purity (HPLC): 98.7%The product is purified through its oxalate salt (90%).Purity of the oxalate salt (HPLC): 100%1H NMR (DMSO): 0.8-0.9ppm (m, 9H); 1.2-1.5ppm (m, lOH); 1.67ppm (5 2H); 1.87ppm (5', 2H); 2.38ppm (t, J=7.2Hz, 4H); 2.57ppm (m, 2H); 2.81ppm (t, J=7.5Hz, 2H); 2.91ppm (s, 3.H); 9.51ppm (t, J=6.2Hz, 2H); 7.09ppm (d, J=8.8Hz, 2H); 7.24ppm (dd, J=8.9; 2.2Hz, IH); 7.38ppm (d, J=2.1Hz, IH); 7.65ppm (d, J=8.8Hz, lH); 7.81ppm (d, J=8.8Hz, 2H)

Reference： [1]Current Patent Assignee: SANOFI - WO2011/70380, 2011, A1 Location in patent: Page/Page column 17-18

6
[ 1310430-06-8 ]
[ 111-92-2 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
98.7%	With sodium iodide In butanone for 16h;	16 Example 16.N-[2-^-butyl-3-(4-r(3-dibutylamino)propoxy1benzoy -l-benzofuran-5-yll- methanesulfonamide, the compound of the general formula (I)The reaction was performed as described in Example 12., using N-(2-«- butyl-3-[4-(3-bromopropoxy)benzoyl]benzofuran-5-yl)methanesulfonamide -the compound of the general formula (II), where X is bromo atom- for starting material.Yield of the product: 98.7%Purity (HPLC): 97.7%The product is identical with the product prepared in Example 12

Reference： [1]Current Patent Assignee: SANOFI - WO2011/70380, 2011, A1 Location in patent: Page/Page column 19

7
[ 1310430-09-1 ]
[ 111-92-2 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
89.1%	In butanone for 16h;	17 Example 17.N- [2-w-buty 1-3 - { 4- [(3 -dibuty lamino)propoxyl benzoyl } - 1 -benzofuran-5 - yll- methanesulfonamide, the compound of the general formula (I)The reaction was performed as described in Example 12., with the difference that the starting material was N-(2-n-butyl-3-[4-(3-methanesulfonyloxy- propoxy)benzoyl]benzofuran-5-yl)methanesulfonamide -the compound of the general formula (II), where X is methanesulfonyloxy group- and sodium iodide was not used. ,Yield of the product: 89.1% Purity (HPLC): 98.1%

Reference： [1]Current Patent Assignee: SANOFI - WO2011/70380, 2011, A1 Location in patent: Page/Page column 19-20

8
[ 1312300-15-4 ]
[ 111-92-2 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
97.81%	In butanone for 16h;	18 Example 18. N-[2-w-butyl-3- (4-f (3-dibutylamino)propoxyJbenzoyl }- 1 -benzofuran-5-νΠ- methanesulfonamide, the compound of the general formula (I)The reaction was performed as described in Example 12., with the difference that the starting material was N-(2-«-butyl-3-[4-(3-tosyloxy- propoxy)benzoyl]benzofuran-5-yl)-methanesUlforiamide -the compound of the general formula (II), where X is tosyloxy group- and sodium iodide was not used.Yield of the product: 97.81%Purity (HPLC): 97.6%

Reference： [1]Current Patent Assignee: SANOFI - WO2011/70380, 2011, A1 Location in patent: Page/Page column 20

9
[ 1310430-08-0 ]
[ 111-92-2 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene for 24h; Reflux;	19 Example 19.N-[2-«-butyl-3-(4- (3-dibutylamino)propoxylbenzoyl -l-benzofuran-5-yl1- methanesulfonamide, the compound of the general formula (I) - . , · 0.5 g N-(2-«-butyl-3-[4-(3-hydroxy-propoxy)-benzoyl]-benzofuran-5-yl)- methanesulfonamide -the compound of the general formula (II), where X is hydroxyl group- was dissolved in, 8 ml toluene. To the solution 1.5 g dibutylamine and 1.2 mol% [Ru(/?-cymene)Cl2]2 and 2.5 mol% l, l '-bis-(diphenylphosphino)- ferrocene catalysts were added and the reaction mixture was kept under reflux for 24 hours. The solvent was removed by evaporation, the residue was taken up in 10 ml dichloromethane and washed by stirring with 5 ml 1% hydrochloric acid, then with 10 ml water. The solvent was removed by evaporation.Mass of the product: 0,51 g (82.5%)Purity (HPLC): 92.4%The product is identical with the product prepared according to Example 12.

Reference： [1]Current Patent Assignee: SANOFI - WO2011/70380, 2011, A1 Location in patent: Page/Page column 20

10
[ 141645-16-1 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: potassium carbonate / butanone / 4 h / 81 - 82 °C 2: hydrogen / palladium 10% on activated carbon / ethanol / 2 h / 50 °C / 3750.38 Torr 3: pyridine / dichloromethane / 15 °C 4: sodium iodide / butanone / 16 h
	Multi-step reaction with 3 steps 1.1: potassium carbonate / butanone / 0.5 h / 20 °C 1.2: 12 h / 78 - 82 °C 2.1: hydrogen / palladium 10% on activated carbon / ethyl acetate / 25 - 35 °C 3.1: triethylamine / dichloromethane / 0.5 h / 20 °C 3.2: 1.5 h / 20 °C
	Multi-step reaction with 4 steps 1.1: potassium carbonate / acetonitrile / 0.5 h 1.2: Reflux 2.1: hydrogen / Raney nickel / methanol / 45 - 50 °C / 3677.86 Torr 3.1: tetramethlyammonium chloride / toluene / Reflux 4.1: sodium hydroxide / 1 h / 0 - 5 °C

	Multi-step reaction with 5 steps 1.1: potassium carbonate / butanone / 20 h / 85 °C 1.3: 0.5 h / 25 - 65 °C 2.1: potassium carbonate / toluene; water 3.1: hydrogen / Raney Nickel / methanol / 8 h / 55 °C / 3677.86 Torr 3.2: 0.5 h / 25 - 65 °C 4.1: potassium carbonate / toluene; water / 1 h / 35 °C 5.1: toluene / 3.5 h / 108 °C 5.2: 0.5 h / 60 °C
	Multi-step reaction with 3 steps 1.1: sodium hydroxide / water / 0.25 h 1.2: 5.25 h / 80 °C 2.1: hydrogen / 5%-palladium/activated carbon / ethanol / 6 h / 30 °C / 3677.86 Torr / Autoclave 3.1: toluene / 3 h / Reflux
	Multi-step reaction with 3 steps 1.1: sodium hydroxide / water / 0.25 h 1.2: 5.25 h / 90 °C 2.1: hydrogen / 5%-palladium/activated carbon / ethanol / 6 h / 30 °C / 3677.86 Torr / Autoclave 3.1: toluene / 3 h / Reflux 3.2: 0.17 h / 30 °C
	Multi-step reaction with 4 steps 1.1: sodium hydroxide / water / 0.25 h 1.2: 5.25 h / 90 °C 2.1: hydrogen / 5%-palladium/activated carbon / methanol / 6 h / 30 °C / 3677.86 Torr / Autoclave 2.2: 2 h / 0 °C / Reflux 3.1: sodium hydroxide / toluene; water / 0.5 h / pH 10 - 12 4.1: toluene / 3 h / Reflux 4.2: 0.17 h / 30 °C
	Multi-step reaction with 4 steps 1.1: potassium carbonate / acetonitrile / 0.5 h / Reflux 1.2: Reflux 2.1: hydrogen / Raney nickel / methanol / 20 °C / 3677.86 Torr 3.1: tetramethlyammonium chloride / toluene / Reflux 4.1: sodium hydroxide / 1 h / 0 - 5 °C
	Multi-step reaction with 5 steps 1: N-benzyl-trimethylammonium hydroxide / 48 h / 80 - 85 °C 2: hydrogen / palladium 10% on activated carbon / methanol / 50 °C / 3750.38 Torr 3: pyridine / dichloromethane / 3.17 h / 30 - 35 °C 4: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 5: pyridine / butan-1-ol / 14 h / 70 °C
	Multi-step reaction with 5 steps 1: N-benzyl-trimethylammonium hydroxide / 48 h / 80 - 85 °C 2: hydrogen / palladium 10% on activated carbon / methanol / 50 °C / 3750.38 Torr 3: pyridine / dichloromethane / 3.17 h / 30 - 35 °C 4: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 5: pyridine / butan-1-ol / 14 h / 70 °C
	Multi-step reaction with 5 steps 1: N-benzyl-trimethylammonium hydroxide / 48 h / 80 - 85 °C 2: hydrogen / palladium 10% on activated carbon / methanol / 50 °C / 3750.38 Torr 3: pyridine / dichloromethane / 3.17 h / 30 - 35 °C 4: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 5: sodium iodide; pyridine / butanone / 16.25 h / Reflux
	Multi-step reaction with 5 steps 1.1: N-benzyl-trimethylammonium hydroxide / 48 h / 80 - 85 °C 2.1: hydrogen / palladium 10% on activated carbon / 2 h / 50 °C / 3750.38 Torr 3.1: pyridine / dichloromethane / 3 h / 30 - 35 °C 4.1: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 5.1: sodium tetrahydroborate / 8 h / 55 °C 5.2: 0 °C
	Multi-step reaction with 5 steps 1: N-benzyl-trimethylammonium hydroxide / 48 h / 80 - 85 °C 2: hydrogen / palladium 10% on activated carbon / 2 h / 50 °C / 3750.38 Torr 3: pyridine / dichloromethane / 3 h / 30 - 35 °C 4: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 5: triacetoxyborohydride / dichloromethane / 12 h / 20 °C
	Multi-step reaction with 5 steps 1: N-benzyl-trimethylammonium hydroxide / 48 h / 80 - 85 °C 2: hydrogen / palladium 10% on activated carbon / 2 h / 50 °C / 3750.38 Torr 3: pyridine / dichloromethane / 3 h / 30 - 35 °C 4: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 5: sodium tetrahydroborate / 8 h / 55 °C
	Multi-step reaction with 4 steps 1.1: potassium carbonate / butanone / 20 - 81 °C / Reflux 2.1: hydrogen; acetic acid / palladium on activated charcoal / ethyl acetate / 15 - 21 °C / pH 4.5 - 4.8 / Inert atmosphere; Autoclave 2.2: 25 - 35 °C 2.3: 45 - 55 °C 3.1: ammonia / ethyl acetate; water / 25 - 35 °C 4.1: pyridine / dichloromethane / -5 - 5 °C
	Multi-step reaction with 5 steps 1: potassium carbonate; sodium iodide / 6 h / Reflux 2: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 50 °C / 7500.75 Torr 3: pyridine / dichloromethane / 2.5 h / 30 - 35 °C 4: sulfuric acid / tetrahydrofuran; water / 2 h / 50 °C 5: hydrogen / methanol / 4 h / 50 °C / 7500.75 Torr
	Multi-step reaction with 5 steps 1: N-benzyl-trimethylammonium hydroxide / 48 h / 80 - 85 °C 2: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 50 °C / 3750.38 Torr 3: pyridine / dichloromethane / 3.08 h / 30 - 35 °C 4: N-benzyl-N,N,N-triethylammonium chloride; hydrogenchloride; water / 6 h / 80 - 90 °C 5: sodium tetrahydroborate; boric acid / tetrahydrofuran / 9.25 h / 50 - 55 °C
	Multi-step reaction with 6 steps 1.1: palladium 10% on activated carbon; hydrogen / ethanol / 6 h / 50 °C / 3750.38 Torr 2.1: pyridine / dichloromethane / 0.5 h / 30 - 35 °C 3.1: pyridine / dichloromethane / 2 h / 10 - 12 °C 4.1: potassium carbonate; sodium iodide / butanone / 0.17 h / 20 °C 4.2: 5 h / 80 - 90 °C 5.1: sodium hydroxide / methanol / 1 h / Reflux 6.1: borane-THF / tetrahydrofuran / 1.25 h / 0 °C / Reflux
	Multi-step reaction with 7 steps 1: N-benzyl-trimethylammonium hydroxide / 48 h / 80 - 85 °C 2: palladium 10% on activated carbon; hydrogen / methanol / 2 h / 50 °C / 3750.38 Torr 3: pyridine / dichloromethane / 3.08 h / 30 - 35 °C 4: N-benzyl-N,N,N-triethylammonium chloride; hydrogenchloride; water / 6 h / 80 - 90 °C 5: thionyl chloride / dichloromethane / 1.5 h / Reflux 6: dichloromethane / 2 h / 20 °C 7: borane-THF / tetrahydrofuran / 1.25 h / 0 °C / Reflux
	Multi-step reaction with 5 steps 1.1: sodium hydroxide / isopropyl alcohol / 0.17 h / 20 °C 1.2: 1.5 h / Reflux 2.1: isopropyl alcohol / 4 h / Reflux 3.1: hydrogen; 5%-palladium/activated carbon / methanol / 1.5 h / 25 °C / 7500.75 Torr 4.1: pyridine / dichloromethane / 2 h / 30 - 35 °C 5.1: sodium iodide; dimethylsilicon dichloride / acetonitrile / 0.25 h / 25 °C
	Multi-step reaction with 5 steps 1: potassium carbonate; sodium iodide / acetonitrile / 6 h / Reflux 2: isopropyl alcohol / 4 h / Reflux 3: hydrogen; 5%-palladium/activated carbon / methanol / 1.5 h / 25 °C / 7500.75 Torr 4: pyridine / dichloromethane / 2 h / 30 - 35 °C 5: sodium iodide; dimethylsilicon dichloride / acetonitrile / 0.25 h / 25 °C
	Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 12.5 h / 20 °C / Reflux 2: palladium 10% on activated carbon; hydrogen / ethanol / 31 h / 55 °C / 7500.75 Torr 3: pyridine / dichloromethane / 1.5 h / 30 - 35 °C 4: sodium hydride / N,N-dimethyl-formamide / 10 h / 25 °C
	Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 5.5 h / 20 °C / Reflux 2: palladium 10% on activated carbon; hydrogen / ethanol / 3 h / 75 °C / 7500.75 Torr 3: pyridine / dichloromethane / 2.5 h / 30 - 35 °C 4: sodium hydride / N,N-dimethyl-formamide / 10 h / 25 °C
	Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 5.5 h / 20 °C / Reflux 2: palladium 10% on activated carbon; hydrogen / ethanol / 5 h / 75 °C / 7500.75 Torr 3: pyridine / dichloromethane / 3 h / 30 - 35 °C 4: sodium hydride / N,N-dimethyl-formamide / 10 h / 25 °C
	Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 5.5 h / 20 °C / Reflux 2: palladium 10% on activated carbon; hydrogen / ethanol / 6.5 h / 75 °C / 7500.75 Torr 3: pyridine / dichloromethane / 4.5 h / 30 - 35 °C 4: potassium hydroxide / N,N-dimethyl-formamide / 9 h / 40 °C
	Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 5.5 h / 20 °C / Reflux 2: palladium 10% on activated carbon; hydrogen / ethanol / 7 h / 75 °C / 7500.75 Torr 3: pyridine / dichloromethane / 5 h / 30 - 35 °C 4: potassium hydroxide / N,N-dimethyl-formamide / 9 h / 40 °C
	Multi-step reaction with 5 steps 1: N-benzyl-trimethylammonium hydroxide / 48 h / 80 - 85 °C 2: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 50 °C / 3750.38 Torr 3: pyridine / dichloromethane / 3.17 h / 30 - 35 °C 4: hydrogen / methanol / 24 h / 25 °C / 7500.75 Torr 5: triacetoxyborohydride / dichloromethane / 12 h / 20 °C
	Multi-step reaction with 5 steps 1.1: N-benzyl-trimethylammonium hydroxide / 48 h / 80 - 85 °C 2.1: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 50 °C / 3750.38 Torr 3.1: pyridine / dichloromethane / 0.08 h / 30 - 35 °C 3.2: 3.08 h / 30 - 35 °C 4.1: hydrogen / methanol / 24 h / 25 °C / 7500.75 Torr 5.1: pyridine / butan-1-ol
	Multi-step reaction with 5 steps 1.1: N-benzyl-trimethylammonium hydroxide / 48 h / 80 - 85 °C 2.1: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 50 °C / 3750.38 Torr 3.1: pyridine / dichloromethane / 0.08 h / 30 - 35 °C 3.2: 3.08 h / 30 - 35 °C 4.1: hydrogen / methanol / 24 h / 25 °C / 7500.75 Torr 5.1: pyridine; sodium iodide / butanone / 16.25 h / Reflux
	Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 85 °C 2: hydrogen; palladium 10% on activated carbon / tetrahydrofuran / 20 °C 3: pyridine / dichloromethane / 1.5 h / 20 °C

Reference： [1]Current Patent Assignee: SANOFI - WO2011/70380, 2011, A1
[2]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2012/7959, 2012, A1
[3]Current Patent Assignee: U S V LTD. - EP2428511, 2012, A1
[4]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - WO2012/32545, 2012, A1
[5]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2012/52448, 2012, A1
[6]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - EP2447256, 2012, A1
[7]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - EP2447256, 2012, A1
[8]Current Patent Assignee: U S V LTD. - US2012/108828, 2012, A1
[9]Current Patent Assignee: SANOFI - WO2012/131409, 2012, A1
[10]Current Patent Assignee: SANOFI - WO2012/131409, 2012, A1
[11]Current Patent Assignee: SANOFI - WO2012/131409, 2012, A1
[12]Current Patent Assignee: SANOFI - WO2012/131410, 2012, A1
[13]Current Patent Assignee: SANOFI - WO2012/131410, 2012, A1
[14]Current Patent Assignee: SANOFI - WO2012/131410, 2012, A1
[15]Current Patent Assignee: ALEMBIC PHARMACEUTICALS LIMITED - WO2012/153225, 2012, A1
[16]Current Patent Assignee: SANOFI - WO2013/14479, 2013, A1
[17]Current Patent Assignee: SANOFI - WO2013/14478, 2013, A1
[18]Current Patent Assignee: SANOFI - WO2013/14480, 2013, A1
[19]Current Patent Assignee: SANOFI - WO2013/14480, 2013, A1
[20]Current Patent Assignee: SANOFI - WO2013/121235, 2013, A2
[21]Current Patent Assignee: SANOFI - WO2013/121235, 2013, A2
[22]Current Patent Assignee: SANOFI - EP2617718, 2013, A1
[23]Current Patent Assignee: SANOFI - EP2617718, 2013, A1
[24]Current Patent Assignee: SANOFI - EP2617718, 2013, A1
[25]Current Patent Assignee: SANOFI - EP2617718, 2013, A1
[26]Current Patent Assignee: SANOFI - EP2617718, 2013, A1
[27]Current Patent Assignee: SANOFI - US2014/18554, 2014, A1
[28]Current Patent Assignee: SANOFI - US2014/114081, 2014, A1
[29]Current Patent Assignee: SANOFI - US2014/114081, 2014, A1
[30]Klucznik, Tomasz; Mikulak-Klucznik, Barbara; McCormack, Michael P.; Lima, Heather; Szymkuć, Sara; Bhowmick, Manishabrata; Molga, Karol; Zhou, Yubai; Rickershauser, Lindsey; Gajewska, Ewa P.; Toutchkine, Alexei; Dittwald, Piotr; Startek, Michał P.; Kirkovits, Gregory J.; Roszak, Rafał; Adamski, Ariel; Sieredzińska, Bianka; Mrksich, Milan; Trice, Sarah L.J.; Grzybowski, Bartosz A. [Chem, 2018, vol. 4, # 3, p. 522 - 532]

11
[ 65136-48-3 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: iron(III) chloride / dichloromethane / 5 - 45 °C 1.2: 1 h / 40 - 45 °C 2.1: sodium iodide / butanone / 16 h
	Multi-step reaction with 6 steps 1: tin(IV) chloride / dichloromethane / 1 h / 0 - 25 °C 2: tetrabutylammomium bromide; potassium iodide / N,N-dimethyl-formamide / 14 h / 85 °C 3: methylamine / water; isopropyl alcohol / 1 h / 75 °C 4: isopropyl alcohol / 1.5 h / 5 - 65 °C / Large scale reaction 5: sodium hydrogencarbonate / dichloromethane; water / 0.5 h 6: triethylamine / toluene / 0.5 h / -5 - 5 °C

Reference： [1]Current Patent Assignee: SANOFI - WO2011/70380, 2011, A1
[2]Hivarekar, Raghvendra R.; Deshmukh, Sanjay S.; Tripathy., Narendra K. [Organic Process Research and Development, 2012, vol. 16, # 4, p. 677 - 681]

12
[ 401840-61-7 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: iron(III) chloride / dichloromethane / 5 - 45 °C 1.2: 1.17 h / 40 - 45 °C 2.1: sodium iodide / butanone / 16 h

Reference： [1]Current Patent Assignee: SANOFI - WO2011/70380, 2011, A1

13
[ 437652-07-8 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: iron(III) chloride / dichloromethane / 5 - 45 °C 1.2: 1 h / 40 - 45 °C 2.1: sodium iodide / butanone / 16 h
	Multi-step reaction with 2 steps 1.1: iron(III) chloride / dichloromethane / 5 - 45 °C 1.2: 1.17 h / 40 - 45 °C 2.1: sodium iodide / butanone / 16 h
	Multi-step reaction with 3 steps 1: pyridine / dichloromethane / 5.5 h / 10 - 20 °C 2: iron(III) chloride / dichloromethane / 5 - 40 °C 3: potassium methylate / methanol / 2 h / 60 °C

	Multi-step reaction with 3 steps 1: pyridine / dichloromethane / 3.5 h / 10 - 20 °C 2: iron(III) chloride / dichloromethane / 5 - 40 °C 3: sodium hydroxide / methanol / 2 h / 65 °C
	Multi-step reaction with 3 steps 1: pyridine / dichloromethane / 6 h / 10 - 20 °C 2: aluminum (III) chloride / dichloromethane / 5 - 40 °C 3: hydrogenchloride; water / methanol / 3 h / 55 - 60 °C
	Multi-step reaction with 3 steps 1.1: iron(III) chloride / dichloromethane / 3.33 h / 5 - 20 °C 1.2: 0.83 h / 40 - 45 °C 2.1: sodium hydroxide / methanol / 3 h / Reflux 2.2: pH 6 3.1: pyridine / butan-1-ol / 14 h / 70 °C
	Multi-step reaction with 3 steps 1.1: iron(III) chloride / dichloromethane / 3.33 h / 5 - 20 °C 1.2: 0.83 h / 40 - 45 °C 2.1: sodium hydroxide / methanol / 3 h / Reflux 2.2: pH 6 3.1: pyridine / butan-1-ol / 14 h / 70 °C
	Multi-step reaction with 3 steps 1.1: iron(III) chloride / dichloromethane / 3.33 h / 5 - 20 °C 1.2: 0.83 h / 40 - 45 °C 2.1: sodium hydroxide / methanol / 3 h / Reflux 2.2: pH 6 3.1: sodium iodide; pyridine / butanone / 16.25 h / Reflux
	Multi-step reaction with 3 steps 1.1: iron(III) chloride / dichloromethane / 3.33 h / 5 - 20 °C 1.2: 0.83 h / 40 - 45 °C 2.1: sodium hydroxide; water / methanol / 3 h / pH 6 / Reflux 3.1: triacetoxyborohydride / dichloromethane / 12 h / 20 °C
	Multi-step reaction with 3 steps 1.1: iron(III) chloride / dichloromethane / 3.33 h / 5 - 20 °C 1.2: 0.83 h / 40 - 45 °C 2.1: sodium hydroxide; water / methanol / 3 h / pH 6 / Reflux 3.1: sodium tetrahydroborate / 8 h / 55 °C
	Multi-step reaction with 3 steps 1.1: iron(III) chloride / dichloromethane / 3.33 h / 5 - 20 °C 1.2: 0.83 h / 40 - 45 °C 2.1: sodium hydroxide; water / methanol / 3 h / pH 6 / Reflux 3.1: sodium tetrahydroborate / 8 h / 55 °C 3.2: 0 °C
	Multi-step reaction with 3 steps 1.1: pyridine / dichloromethane / 0.5 h / 10 °C 1.2: 5.5 h / 10 °C 2.1: dichloromethane / 0.25 h / 5 °C 2.2: 0.5 h / 35 - 40 °C 3.1: hydrogenchloride / methanol / 3 h / 55 - 60 °C
	Multi-step reaction with 3 steps 1.1: pyridine / dichloromethane / 3.5 h / 10 - 20 °C 2.1: dichloromethane / 0.25 h / 5 °C 2.2: 1 h / 20 °C 3.1: sodium hydroxide / methanol / 2 h / 65 °C
	Multi-step reaction with 3 steps 1.1: pyridine / dichloromethane / 5.5 h / 10 - 20 °C 2.1: dichloromethane / 0.25 h / 5 °C 2.2: 1 h / 20 °C 3.1: sodium methylate / methanol / 2 h / 60 °C
	Multi-step reaction with 3 steps 1: N-chloro-succinimide / dichloromethane; acetonitrile / 2.33 h / -8 °C 2: magnesium / tetrahydrofuran / 2.67 h / 35 - 60 °C 3: iron(III) chloride / tetrahydrofuran / 1 h / 35 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: N-chloro-succinimide / dichloromethane; acetonitrile / 2.33 h / -8 °C 2: magnesium / tetrahydrofuran / 2.67 h / 35 - 60 °C 3: iron(III) chloride / tetrahydrofuran / 3 h / 35 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: N-Bromosuccinimide / dichloromethane; acetonitrile / 3.5 h / -8 °C 2: magnesium / tetrahydrofuran / 2.75 h / 32 - 62 °C 3: iron(III) chloride / tetrahydrofuran / 3 h / 35 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: iron(III) chloride / dichloromethane / 3.33 h / 5 - 20 °C 2: sodium hydroxide / methanol / 3 h / Reflux 3: triacetoxyborohydride / dichloromethane / 12 h / 20 °C
	Multi-step reaction with 3 steps 1: iron(III) chloride / dichloromethane / 5 - 45 °C 2: sodium hydroxide / methanol / 3 h / Reflux 3: pyridine / butan-1-ol
	Multi-step reaction with 3 steps 1: iron(III) chloride / dichloromethane / 5 - 45 °C 2: sodium hydroxide / methanol / 3 h / Reflux 3: pyridine; sodium iodide / butanone / 16.25 h / Reflux

Reference： [1]Current Patent Assignee: SANOFI - WO2011/70380, 2011, A1
[2]Current Patent Assignee: SANOFI - WO2011/70380, 2011, A1
[3]Current Patent Assignee: SANOFI - WO2012/10913, 2012, A1
[4]Current Patent Assignee: SANOFI - WO2012/10913, 2012, A1
[5]Current Patent Assignee: SANOFI - WO2012/10913, 2012, A1
[6]Current Patent Assignee: SANOFI - WO2012/131409, 2012, A1
[7]Current Patent Assignee: SANOFI - WO2012/131409, 2012, A1
[8]Current Patent Assignee: SANOFI - WO2012/131409, 2012, A1
[9]Current Patent Assignee: SANOFI - WO2012/131410, 2012, A1
[10]Current Patent Assignee: SANOFI - WO2012/131410, 2012, A1
[11]Current Patent Assignee: SANOFI - WO2012/131410, 2012, A1
[12]Current Patent Assignee: SANOFI - US2013/131358, 2013, A1
[13]Current Patent Assignee: SANOFI - US2013/131358, 2013, A1
[14]Current Patent Assignee: SANOFI - US2013/131358, 2013, A1
[15]Current Patent Assignee: SANOFI - WO2013/178337, 2013, A1
[16]Current Patent Assignee: SANOFI - WO2013/178337, 2013, A1
[17]Current Patent Assignee: SANOFI - WO2013/178337, 2013, A1
[18]Current Patent Assignee: SANOFI - US2014/18554, 2014, A1
[19]Current Patent Assignee: SANOFI - US2014/114081, 2014, A1
[20]Current Patent Assignee: SANOFI - US2014/114081, 2014, A1

14
[ 1310430-03-5 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: hydrogen / palladium 10% on activated carbon / ethanol / 2 h / 50 °C / 3750.38 Torr 2: pyridine / dichloromethane / 15 °C 3: sodium iodide / butanone / 16 h

Reference： [1]Current Patent Assignee: SANOFI - WO2011/70380, 2011, A1

15
4-[3-(di-n-butylamino)-propoxy]-benzoic acid chloride hydrochloride [ No CAS ]
2-butyl-5-methanesulfonamido-benzofuran potassium salt [ No CAS ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
99.1%	Stage #1: 4-[3-(di-n-butylamino)-propoxy]-benzoic acid chloride hydrochloride; 2-butyl-5-methanesulfonamido-benzofuran potassium salt In dichloromethane for 0.5h; Stage #2: In dichloromethane at 5 - 25℃; for 2.25h;	3 Example 3.N- 2-butyl-3-{4- (3-dibutylamino)propoxy1benzoy -l-benzofuran-5-yn- methanesulfonamide IThe procedure as described in Example 1. was followed, with the difference that instead of 2-butyl-5-methanesulfonamido-benzofuran sodium salt lib, equivalent amount of 2-butyl-5-methanesulfonamido-benzofuran potassium salt lie was used. The resulting material is identical with the product of Example 1.Yield: 99.1%.Purity by HPLC: 98.4%

Reference： [1]Current Patent Assignee: SANOFI - WO2011/83346, 2011, A1 Location in patent: Page/Page column 8

16
[ 110-17-8 ]
[ 141626-36-0 ]
[ 1337978-10-5 ]

Yield	Reaction Conditions	Operation in experiment
77%	In acetone at -10℃; for 1.16667h; Sonographic reaction;	9 Dronedarone base (3.1 g; 2.6 mmol) was dissolved in acetone and the solution was cooled down to -10°C. Fumaric acid (5.6 mmol; 0.65 g in 10 mL of acetone) was added dropwise. Precipitated white suspension was ultrasonicated in ultrasonic cleaner for 10 minutes and then stirred for additional one hour at -10°C. Precipitate was filtered off through sintered glass under nitrogen and washed with acetone cooled to 0°C (10 mL) and twice with ether cooled down to 0°C (20 mL). Yield was 2.9 g (77 %). The product contained approximately 7 % of free fumaric acid and was taken for recrystallization.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - EP2371824, 2011, A1 Location in patent: Page/Page column 9

17
[ 75-75-2 ]
[ 141626-36-0 ]
[ 1337955-85-7 ]

Yield	Reaction Conditions	Operation in experiment
85%	In acetone at -20 - -10℃; for 1h;	3 Dronedarone base purified according to Example 1 and Example 2 (117.0 g; 0.21 mol) was dissolved in acetone and the solution was then cooled down to -20°C. Solution of methanesulphonic aicd (20.2 g; 13.6 mL; 0.21 mol) in acetone (211 mL) was added dropwise. Precipitated white suspension was stirred for one hour while the temperature was maintained bewenn -20 and -10°C. Precipitate was filtered off through sintered glass under nitrogen and washed twice with ether cooled to 0°C (500 mL). Product was dried at 40°C and 133 Pa. Yield was 99.6 g (85 %), HPLC purity was 98 %.
85%	In acetone at -20 - -10℃;	3 Example 3 - Precipitation of mesylate Dronedarone base purified according to Example 1 and Example 2 (117.0 g; 0.21 mol) was dissolved in acetone and the solution was then cooled down to 20°C. Solution of methanesulphonic aicd (20.2 g; 13.6 mL; 0.21 mol) in acetone (211 mL) was added dropwise. Precipitated white suspension was stirred for one hour while the temperature was maintained bewenn 20 and 10°C. Precipitate was filtered off through sintered glass under nitrogen and washed twice with ether cooled to 0°C (500 mL). Product was dried at 40°C and 133 Pa. Yield was 99.6 g (85 %), HPLC purity was 98 %.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - EP2371824, 2011, A1 Location in patent: Page/Page column 8
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - EP2371808, 2011, A1 Location in patent: Page/Page column 9

18
[ 141626-36-0 ]
dronedarone hemisulfate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With sulfuric acid In diethyl ether at -20 - -10℃; for 1h;	7 Dronedarone base (34.0 g; 0.06 mol) was dissolved in ether and the solution was cooled down to -20°C. Sulphuric acid (6.2 g; 0.06 mol; 3.4 mL 96-% H2SO4) was added dropwise. Precipitated white suspension was stirred for one hour while the temperature was maintained between -20 and -10°C. Precipitate was filtered off through sintered glass under nitrogen and washed twice with ether cooled down to 0°C (500 mL). Yield was 21.8 g (55 %), HPLC purity was 98.5 %.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - EP2371824, 2011, A1 Location in patent: Page/Page column 9

19
[ 1337955-85-7 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In dichloromethane; water	4 Dronedarone mesylate (150 g; 0.23 mol) was dissolved in dichloromethane and the solution was neutralized with saturated solution of NaHCO3 (approx. 100 mL). Organic layer was separated and water phase was washed with dichloromethane (150 mL). Combined organic layers were dried over anhydrous sodium sulfate and then evaporated on RVE. Yield was 128 g (almost theoretical), HPLC purity was 97.4 %.
	With sodium hydrogencarbonate In dichloromethane	4 Example 4 - Preparation of dronedarone base from mesylate Dronedarone mesylate (150 g; 0.23 mol) was dissolved in dichloromethane and the solution was neutralized with saturated solution of NaHCO3 (approx. 100 mL). Organic layer was separated and water phase was washed with dichloromethane (150 mL). Combined organic layers were dried over anhydrous sodium sulfate and then evaporated on RVE. Yield was 128 g (almost theoretical), HPLC purity was 97.4 %.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - EP2371824, 2011, A1 Location in patent: Page/Page column 9
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - EP2371808, 2011, A1 Location in patent: Page/Page column 9

20
4-[3-(di-n-butylamino)-propoxy]-benzoic acid chloride hydrochloride [ No CAS ]
[ 437652-07-8 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
	With aluminum (III) chloride In dichloromethane at 0 - 10℃; for 20h;	14 Example 14 4-(3-Dibutylaminopropoxy)benzoyl chloride (71.8 g; 0.198 mol; 1.06 eq.) and N-(2-butylbenzofuran-5-yl)methanesulfonamide (50.0 g; 0.187 mol) were mixed in CH2Cl2 (350 mL) and cooled down to 0 °C. AlCl3 (99.7 g; 0.748 mol; 4.0 eq) was added, during addition (two hours) the temperature was kept between 0 - 5 °C. Reaction mixture was kept between 0 - 10 °C for twenty hours. Workup: Reaction mixture was poured on the mixture ice/HCl 1:1. Water was extracted once with 1000 mL and twice with 500 mL CH2Cl2. Organic layer was washed once with 1000 mL water and dried with Na2SO4. Solvent was evaporated on RVE. Product was transferred to the base: dissolved in CH2Cl2 and extracted with saturated solution of NaHCO3 and dried with Na2SO4. Yield was nearly quantitative as light brown foam. Confirmation: HR-MS, (M+H)+ = 557.3043

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - EP2371808, 2011, A1 Location in patent: Page/Page column 11

21
[ 141644-91-9 ]
[ 124-63-0 ]
[ 141626-57-5 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃; for 0.5h;	6 EXAMPLE 6[0104] Preparation of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5- methylsulfonamidobenzofuran (dronedarone)a) A solution of 13.75g of methanesulfonyl chloride in 250mL of dichloromethane was added dropwise to a stirred solution of 50g of 5-amino-2-n-butyl-3-[4-(3-di-n- butylaminopropoxy)benzoyl]benzofuran and 17.6mL of triethylamine in dichloromethane at about room temperature. The reaction mass was stirred at about room temperature for about 30min. After completion of reaction, as monitored by HPLC, the reaction mass was cooled to about 15°C to about 20°C followed by slow addition of 250mL of water. The reaction mass was stirred for about 15min and the two layers were separated. To the organic layer at about 15°C to about 20°C, was added 150mL of water and the pH was adjusted with sodium hydroxide solution to about above 8. The organic layer was washed with water and sodium chloride solution and concentrated under vacuum to give pale brown thick oil which was degassed under vacuum at about temperature below 40°C for about 30min. Yield: 60gPurity (HPLC): 91.04%Impurity compound of formula V: 6.3%b) To a stirred solution of 60g of crude product obtained in (a) in 240mL of ethanol (industrial solvent) was added drop wise a solution of 7.6g of sodium hydroxide in 240mL of ethanol (industrial solvent) at about room temperature over about lh. The reaction mass was stirred at the same temperature for about 30min. The reaction mass was then cooled to about 15°C to about 20°C. 600mL of ethyl acetate and 2400mL of water were then slowly added to the reaction mass at about 15°C to about 25°C over about 30min. The reaction mass was stirred at about room temperature for about 15min. The two layers were separated and the aqueous layer was extracted twice, each with 300mL of ethyl acetate. The combined organic layer was washed with 300mL of 10% sodium chloride solution. The organic layer was treated with 3g of Norit charcoal and stirred for about 30min at about room temperature. The reaction mass was filtered over hyflo bed and washed with 60mL of ethyl acetate. The filtrate and the washings were collected together and concentrated under vacuum to give pale brown thick oil which was degassed under vacuum at about temperature below 40°C for about 30min. Yield: 57g Purity (HPLC): 96.64%Impurity compound of formula V: 0.04%

Reference： [1]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2012/7959, 2012, A1 Location in patent: Page/Page column 23-24

22
[ 141645-16-1 ]
[ 141626-57-5 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium carbonate / butanone / 0.5 h / 20 °C 1.2: 12 h / 78 - 82 °C 2.1: hydrogen / palladium 10% on activated carbon / ethyl acetate / 25 - 35 °C 3.1: triethylamine / dichloromethane / 0.5 h / 20 °C
	Multi-step reaction with 3 steps 1: sodium carbonate / toluene; isopropyl alcohol 2: palladium on activated charcoal; ammonium formate / 55 °C 3: organic base / dichloromethane

Reference： [1]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2012/7959, 2012, A1
[2]Mahender; Saravanan; Sridhar; Chandrashekar; Kumar, L. Jaydeep; Jayashree; Bandichhor, Rakeshwar [Organic Process Research and Development, 2014, vol. 18, # 1, p. 157 - 162]

23
[ 141645-23-0 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: hydrogen / palladium 10% on activated carbon / ethyl acetate / 25 - 35 °C 2.1: triethylamine / dichloromethane / 0.5 h / 20 °C 2.2: 1.5 h / 20 °C
	Multi-step reaction with 3 steps 1: hydrogen / Raney nickel / methanol / 45 - 50 °C / 3677.86 Torr 2: tetramethlyammonium chloride / toluene / Reflux 3: sodium hydroxide / 1 h / 0 - 5 °C
	Multi-step reaction with 3 steps 1: ammonium formate / palladium 10% on activated carbon / methanol 2: water / 2 h 3: ammonia / dichloromethane

	Multi-step reaction with 3 steps 1.1: hydrogen / Raney Nickel / methanol / 8 h / 55 °C / 3677.86 Torr 1.2: 0.5 h / 25 - 65 °C 2.1: potassium carbonate / toluene; water / 1 h / 35 °C 3.1: toluene / 3.5 h / 108 °C 3.2: 0.5 h / 60 °C
	Multi-step reaction with 2 steps 1: hydrogen / 5%-palladium/activated carbon / ethanol / 6 h / 30 °C / 3677.86 Torr / Autoclave 2: toluene / 3 h / Reflux
	Multi-step reaction with 2 steps 1.1: hydrogen / 5%-palladium/activated carbon / ethanol / 6 h / 30 °C / 3677.86 Torr / Autoclave 2.1: toluene / 3 h / Reflux 2.2: 0.17 h / 30 °C
	Multi-step reaction with 3 steps 1.1: hydrogen / 5%-palladium/activated carbon / methanol / 6 h / 30 °C / 3677.86 Torr / Autoclave 1.2: 2 h / 0 °C / Reflux 2.1: sodium hydroxide / toluene; water / 0.5 h / pH 10 - 12 3.1: toluene / 3 h / Reflux 3.2: 0.17 h / 30 °C
	Multi-step reaction with 3 steps 1: hydrogen / Raney nickel / methanol / 20 °C / 3677.86 Torr 2: tetramethlyammonium chloride / toluene / Reflux 3: sodium hydroxide / 1 h / 0 - 5 °C
	Multi-step reaction with 3 steps 1.1: hydrogen; acetic acid / palladium on activated charcoal / ethyl acetate / 15 - 21 °C / pH 4.5 - 4.8 / Inert atmosphere; Autoclave 1.2: 25 - 35 °C 1.3: 45 - 55 °C 2.1: ammonia / ethyl acetate; water / 25 - 35 °C 3.1: pyridine / dichloromethane / -5 - 5 °C
	Multi-step reaction with 2 steps 1: hydrogen; palladium 10% on activated carbon / tetrahydrofuran / 20 °C 2: pyridine / dichloromethane / 1.5 h / 20 °C
	Multi-step reaction with 2 steps 1: ammonium chloride; zinc / methanol / 0.5 h / 20 °C 2: sodium hydrogencarbonate / dichloromethane / 6 h / 35 °C / Reflux

Reference： [1]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2012/7959, 2012, A1
[2]Current Patent Assignee: U S V LTD. - EP2428511, 2012, A1
[3]Current Patent Assignee: FRICHEM PRIVATE - WO2012/4658, 2012, A2
[4]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - WO2012/32545, 2012, A1
[5]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2012/52448, 2012, A1
[6]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - EP2447256, 2012, A1
[7]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - EP2447256, 2012, A1
[8]Current Patent Assignee: U S V LTD. - US2012/108828, 2012, A1
[9]Current Patent Assignee: ALEMBIC PHARMACEUTICALS LIMITED - WO2012/153225, 2012, A1
[10]Klucznik, Tomasz; Mikulak-Klucznik, Barbara; McCormack, Michael P.; Lima, Heather; Szymkuć, Sara; Bhowmick, Manishabrata; Molga, Karol; Zhou, Yubai; Rickershauser, Lindsey; Gajewska, Ewa P.; Toutchkine, Alexei; Dittwald, Piotr; Startek, Michał P.; Kirkovits, Gregory J.; Roszak, Rafał; Adamski, Ariel; Sieredzińska, Bianka; Mrksich, Milan; Trice, Sarah L.J.; Grzybowski, Bartosz A. [Chem, 2018, vol. 4, # 3, p. 522 - 532]
[11]Madhasu, Madhu; Doda, Sai Reddy; Begari, Prem Kumar; Dasari, Krishna Rao; Thalari, Gangadhar; Kadari, Sudhakar; Yadav, Jhillu Singh [Journal of Heterocyclic Chemistry, 2021, vol. 58, # 9, p. 1861 - 1866]

24
[ 141645-23-0 ]
[ 141626-57-5 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: hydrogen / palladium 10% on activated carbon / ethyl acetate / 25 - 35 °C 2: triethylamine / dichloromethane / 0.5 h / 20 °C
	Multi-step reaction with 2 steps 1: palladium on activated charcoal; ammonium formate / 55 °C 2: organic base / dichloromethane

Reference： [1]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2012/7959, 2012, A1
[2]Mahender; Saravanan; Sridhar; Chandrashekar; Kumar, L. Jaydeep; Jayashree; Bandichhor, Rakeshwar [Organic Process Research and Development, 2014, vol. 18, # 1, p. 157 - 162]

25
[ 36421-15-5 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium carbonate / butanone / 0.5 h / 20 °C 1.2: 12 h / 78 - 82 °C 2.1: hydrogen / palladium 10% on activated carbon / ethyl acetate / 25 - 35 °C 3.1: triethylamine / dichloromethane / 0.5 h / 20 °C 3.2: 1.5 h / 20 °C
	Multi-step reaction with 4 steps 1.1: potassium carbonate / acetonitrile / 0.5 h 1.2: Reflux 2.1: hydrogen / Raney nickel / methanol / 45 - 50 °C / 3677.86 Torr 3.1: tetramethlyammonium chloride / toluene / Reflux 4.1: sodium hydroxide / 1 h / 0 - 5 °C
	Multi-step reaction with 3 steps 1.1: sodium hydroxide / water / 0.25 h 1.2: 5.25 h / 80 °C 2.1: hydrogen / 5%-palladium/activated carbon / ethanol / 6 h / 30 °C / 3677.86 Torr / Autoclave 3.1: toluene / 3 h / Reflux

	Multi-step reaction with 3 steps 1.1: sodium hydroxide / water / 0.25 h 1.2: 5.25 h / 90 °C 2.1: hydrogen / 5%-palladium/activated carbon / ethanol / 6 h / 30 °C / 3677.86 Torr / Autoclave 3.1: toluene / 3 h / Reflux 3.2: 0.17 h / 30 °C
	Multi-step reaction with 4 steps 1.1: sodium hydroxide / water / 0.25 h 1.2: 5.25 h / 90 °C 2.1: hydrogen / 5%-palladium/activated carbon / methanol / 6 h / 30 °C / 3677.86 Torr / Autoclave 2.2: 2 h / 0 °C / Reflux 3.1: sodium hydroxide / toluene; water / 0.5 h / pH 10 - 12 4.1: toluene / 3 h / Reflux 4.2: 0.17 h / 30 °C
	Multi-step reaction with 2 steps 1.1: potassium carbonate / N,N-dimethyl-formamide 2.1: diisobutylaluminium hydride; magnesium; lithium chloride; diisobutylaluminum chloride / n-heptane; tetrahydrofuran / -10 - 25 °C 2.2: 25 °C
	Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide 2.1: magnesium / tetrahydrofuran / 1 h / Reflux 2.2: 2 h / -78 °C 3.1: sodium carbonate; sodium dodecyl-sulfate / palladium dichloride / water; acetone / 60 °C
	Multi-step reaction with 2 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 1.33 h / 100 °C 2.1: diisobutylaluminium hydride; magnesium; lithium chloride; diisobutylaluminum chloride / n-heptane; tetrahydrofuran / 25 °C / Inert atmosphere 2.2: 0.08 h / -10 - 25 °C 2.3: -30 - 25 °C
	Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 1.33 h / 100 °C 2.1: magnesium / tetrahydrofuran / 1 h / Reflux 2.2: 2 h / -78 °C 2.3: 20 °C 3.1: sodium carbonate; sodium dodecyl-sulfate / palladium dichloride / water; acetone / 60 °C
	Multi-step reaction with 4 steps 1.1: potassium carbonate / acetonitrile / 0.5 h / Reflux 1.2: Reflux 2.1: hydrogen / Raney nickel / methanol / 20 °C / 3677.86 Torr 3.1: tetramethlyammonium chloride / toluene / Reflux 4.1: sodium hydroxide / 1 h / 0 - 5 °C
	Multi-step reaction with 4 steps 1.1: potassium carbonate / butanone / 20 - 81 °C / Reflux 2.1: hydrogen; acetic acid / palladium on activated charcoal / ethyl acetate / 15 - 21 °C / pH 4.5 - 4.8 / Inert atmosphere; Autoclave 2.2: 25 - 35 °C 2.3: 45 - 55 °C 3.1: ammonia / ethyl acetate; water / 25 - 35 °C 4.1: pyridine / dichloromethane / -5 - 5 °C
	Multi-step reaction with 3 steps 1.1: caesium carbonate; sodium iodide / acetonitrile / 23 h / 20 - 60 °C / Inert atmosphere 2.1: n-butyllithium / hexane; tetrahydrofuran / 0.75 h / -78 °C / Inert atmosphere 2.2: 23 h / 20 °C / Inert atmosphere 3.1: bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; methoxybenzene / 23 h / 80 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 85 °C 2: hydrogen; palladium 10% on activated carbon / tetrahydrofuran / 20 °C 3: pyridine / dichloromethane / 1.5 h / 20 °C
	Multi-step reaction with 7 steps 1.1: potassium carbonate / acetone / 4 h / 20 °C / Reflux 2.1: n-butyllithium / tetrahydrofuran / 1.33 h / -78 - 20 °C 2.2: 1.5 h / -78 - 20 °C 3.1: manganese(IV) oxide / dichloromethane / 2 h / 20 °C 4.1: potassium phosphate tribasic / acetonitrile / 75 °C 5.1: triphenylphosphine; palladium diacetate; silver carbonate / acetonitrile / 15 h / 115 °C / Inert atmosphere 6.1: ammonium chloride; zinc / methanol / 0.5 h / 20 °C 7.1: sodium hydrogencarbonate / dichloromethane / 6 h / 35 °C / Reflux

Reference： [1]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2012/7959, 2012, A1
[2]Current Patent Assignee: U S V LTD. - EP2428511, 2012, A1
[3]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2012/52448, 2012, A1
[4]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - EP2447256, 2012, A1
[5]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - EP2447256, 2012, A1
[6]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2452938, 2012, A1
[7]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2452938, 2012, A1
[8]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2012/62918, 2012, A1
[9]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - WO2012/62918, 2012, A1
[10]Current Patent Assignee: U S V LTD. - US2012/108828, 2012, A1
[11]Current Patent Assignee: ALEMBIC PHARMACEUTICALS LIMITED - WO2012/153225, 2012, A1
[12]Okitsu, Takashi; Ogasahara, Mizuki; Wada, Akimori [Chemical and Pharmaceutical Bulletin, 2016, vol. 64, # 8, p. 1149 - 1153]
[13]Klucznik, Tomasz; Mikulak-Klucznik, Barbara; McCormack, Michael P.; Lima, Heather; Szymkuć, Sara; Bhowmick, Manishabrata; Molga, Karol; Zhou, Yubai; Rickershauser, Lindsey; Gajewska, Ewa P.; Toutchkine, Alexei; Dittwald, Piotr; Startek, Michał P.; Kirkovits, Gregory J.; Roszak, Rafał; Adamski, Ariel; Sieredzińska, Bianka; Mrksich, Milan; Trice, Sarah L.J.; Grzybowski, Bartosz A. [Chem, 2018, vol. 4, # 3, p. 522 - 532]
[14]Madhasu, Madhu; Doda, Sai Reddy; Begari, Prem Kumar; Dasari, Krishna Rao; Thalari, Gangadhar; Kadari, Sudhakar; Yadav, Jhillu Singh [Journal of Heterocyclic Chemistry, 2021, vol. 58, # 9, p. 1861 - 1866]

26
[ 141645-51-4 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: pyridine / dichloromethane / 0.08 h / 20 °C 1.2: 0.5 h / 20 °C 2.1: pyridine / dichloromethane / 0.25 h / 30 - 35 °C 2.2: 5 h / 30 - 35 °C 3.1: iron(III) chloride / dichloromethane / 5 - 40 °C 4.1: sodium hydroxide / methanol / 2 h / 65 °C
	Multi-step reaction with 4 steps 1.1: pyridine / dichloromethane / 0.08 h / 20 °C 1.2: 0.5 h / 20 °C 2.1: triethylamine / dichloromethane / 0.25 h / 30 - 35 °C 2.2: 6.5 h / 30 - 35 °C 3.1: aluminum (III) chloride / dichloromethane / 5 - 40 °C 4.1: hydrogenchloride; water / methanol / 3 h / 55 - 60 °C
	Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 0.5 h / 10 °C / Inert atmosphere 2: aluminum (III) chloride / dichloromethane / 0 - 10 °C 3: sodium hydroxide / tetrahydrofuran / 3 h / 20 °C

	Multi-step reaction with 4 steps 1.1: pyridine / dichloromethane / 0.08 h / 20 °C 1.2: 0.5 h / 20 °C 2.1: dichloromethane / 0.25 h / 30 - 35 °C 2.2: 0.5 h 2.3: 4.5 h 3.1: dichloromethane / 0.25 h / 5 °C 3.2: 1 h / 20 °C 4.1: sodium hydroxide / methanol / 2 h / 65 °C
	Multi-step reaction with 4 steps 1.1: pyridine / dichloromethane / 0.08 h 1.2: 0.5 h / 20 °C 2.1: pyridine / dichloromethane / 0.25 h / 30 - 35 °C 2.2: 0.5 h 2.3: 6 h / 30 - 35 °C 3.1: dichloromethane / 0.25 h / 5 °C 3.2: 0.5 h / 35 - 40 °C 4.1: hydrogenchloride / methanol / 3 h / 55 - 60 °C

Reference： [1]Current Patent Assignee: SANOFI - WO2012/10913, 2012, A1
[2]Current Patent Assignee: SANOFI - WO2012/10913, 2012, A1
[3]Current Patent Assignee: MAPI PHARMA LTD. - WO2011/99010, 2011, A1
[4]Current Patent Assignee: SANOFI - US2013/131358, 2013, A1
[5]Current Patent Assignee: SANOFI - US2013/131358, 2013, A1

27
[ 1356536-09-8 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
95.8%	With hydrogenchloride; water In methanol at 55 - 60℃; for 3h;	3 2.5 g of N-[2-n-butyl-3-[4-[3(-di-n-butylamino)propoxy]benzoyl]-l-benzofuran-5-yl]-N'- benzoyl-methanesulfonamide (the compound of the general formula II where R represents phenyl group) is dissolved in the mixture of 20 ml of methanol and 1.15 ml of hydrochloric acid (37%). The reaction mixture is heated to 55-60 °C, stirred at that temperature for 3 hours, then cooled to room temperature and the solvent is removed by evaporation. The residue is dissolved in 25 ml of dichloromethane, and then 20 ml of water is added to it. The pH of the mixture is adjusted to 7 and the phases are separated. The dichloromethane phase is washed with 2 x 20 ml of 5 % sodium carbonate solution, then with 2 x 20 ml of water. The solvent is removed by evaporation.Mass of the raw product: 2.02 g (95.8 %).The raw product is purified through its oxalate salt. Purity of the oxalate salt: 100%.The product is identical with that obtained in Example 1.

Reference： [1]Current Patent Assignee: SANOFI - WO2012/10913, 2012, A1 Location in patent: Page/Page column 12-13

28
[ 1356536-07-6 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
96.4%	With potassium methylate In methanol at 60℃; for 2h;	4 2 g of N-[2-n-butyl-3-[4-[3(-di-n-butylamino)propoxy]benzoyl]-l-benzofuran-5-yl]-N'- acetyl-methanesulfonamide (the compound of the general formula II, where R represents methyl group) is dissolved in 20 ml of methanol. After complete dissolution, 1.05 g of sodium methylate is added, the reaction mixture is heated to 60 °C and stirred at that temperature for 2 hours. The mixture is cooled to room temperature and the solvent is removed by evaporation. The residue is dissolved in 95 ml of dichloromethane and washed with 2 x 30 ml of water.After evaporation 1.74 g (94%) raw product is obtained.Purity (HPLC): 95.7%.The raw product is purified through its oxalate salt.Purity of the liberated dronedarone base: 100%.'H NMR (DMSO): 0.8-0.9 (m, 9H); 1.2-1.5 (m, 10H); 1.67 (5", 2H); 1.87 (5 2H); 2.38 (t, J = 7.2 Hz, 4H); 2.57 (m, 2H); 2.81 (t, J = 7.5 Hz, 2H); 2.91 (s, 3H); 4.15 (t, J = 6.2 Hz, 2H); 7.09 (d, J = 8.8 Hz, 2H); 7.24 (dd, J = 8.9, 2.2 Hz, 1 H); 7.34 (d, J = 2.1 Hz, 1H); 7.65 (d, J = 8.8 Hz, 1 H); 7.81 (d, J = 8.8 Hz, 2H)._Example 4.N-[2-n-butyl-3-[4-[-3(-di-n-butylamino)propoxy]benzoyl]-l-benzofuran-5-yl]- methanesulfonamide (I)The procedure as described in Example 1. is followed, with the difference that potassium methylate is used, instead of sodium methylate.Yield: 94.5 %.Purity (HPLC): 96.4 %.
	With sodium methylate In methanol at 60℃; for 2h;	1 N-[2-n-butyl-3-[4-[-3(-di-n-butylamino)propoxy]benzoyl]-1-benzofuran-5-yl]-methanesulfonamide (I) EXAMPLE 1 N-[2-n-butyl-3-[4-[-3(-di-n-butylamino)propoxy]benzoyl]-1-benzofuran-5-yl]-methanesulfonamide (I) [0040] 2 g of N-[2-n-butyl-3-[4-[3 (-di-n-butylamino)propoxy]benzoyl]-1-benzofuran-5-yl]-N′-acetyl-methanesulfonamide (the compound of the general formula II, where R represents methyl group) is dissolved in 20 ml of methanol. After complete dissolution, 1.05 g of sodium methylate is added, the reaction mixture is heated to 60° C. and stirred at that temperature for 2 hours. The mixture is cooled to room temperature and the solvent is removed by evaporation. The residue is dissolved in 95 ml of dichloromethane and washed with 2×30 ml of water. [0041] After evaporation 1.74 g (94%) raw product is obtained. [0042] Purity (HPLC): 95.7%. [0043] The raw product is purified through its oxalate salt. [0044] Purity of the liberated dronedarone base: 100%. [0045] 1H NMR (DMSO): 0.8-0.9 (m, 9H); 1.2-1.5 (m, 10H); 1.67 (5′, 2H); 1.87 (5′, 2H); 2.38 (t, J=7.2 Hz, 4H); 2.57 (m, 2H); 2.81 (t, J=7.5 Hz, 2H); 2.91 (s, 3H); 4.15 (t, J=6.2 Hz, 2H); 7.09 (d, J=8.8 Hz, 2H); 7.24 (dd, J=8.9, 2.2 Hz, 1H); 7.34 (d, J=2.1 Hz, 1H); 7.65 (d, J=8.8 Hz, 1H); 7.81 (d, J=8.8 Hz, 2H).

Reference： [1]Current Patent Assignee: SANOFI - WO2012/10913, 2012, A1 Location in patent: Page/Page column 11; 13
[2]Current Patent Assignee: SANOFI - US2013/131358, 2013, A1 Location in patent: Paragraph 0040; 0041; 0042; 0043; 0044; 0045

29
N-[2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]-1-benzofuran-5-yl]-N'-ethoxycarbonyl-methanesulfonamide [ No CAS ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
94.8%	With sodium hydroxide In methanol at 65℃; for 2h;	2 2 g of N-[2-n-butyl-3-[4-[3(-di-n-butylamino)propoxy]benzoyl]-l-benzofuran-5-yl]- N'- ethoxycarbonyl-methanesulfonamide (the compound of the general formula II, where R represents ethoxy group) is dissolved in 20 ml of methanol. After complete dissolution0.89 g of sodium hydroxide is added, the reaction mixture is heated to 65 °C, stirred at that temperature for 2 hours, then cooled to room temperature and the solvent is removed by evaporation. The residue is dissolved in 30 ml of dichloromethane and washed with 2 x 25 ml of water. The solvent is removed by evaporation.Mass of the raw product: 1.68 g (94.8 %).Purity (HPLC): 96.7%.The raw product is purified through its oxalate salt.Purity of the liberated dronedarone base: 100%.The product is identical with that obtained in Example 1.

Reference： [1]Current Patent Assignee: SANOFI - WO2012/10913, 2012, A1 Location in patent: Page/Page column 12

30
[ 141644-91-9 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: tetramethlyammonium chloride / toluene / Reflux 2: sodium hydroxide / 1 h / 0 - 5 °C
	Multi-step reaction with 2 steps 1: water / 2 h 2: ammonia / dichloromethane
	Multi-step reaction with 2 steps 1: hydrogenchloride / ethanol; water / 50 °C 2: tetrabutyl-ammonium chloride / toluene / 5.5 h / 80 - 90 °C

Multi-step reaction with 2 steps 1: acetone; acetonitrile / 16 h / Reflux 2: sodium hydrogencarbonate / dichloromethane / Neutral conditions

Reference： [1]Current Patent Assignee: U S V LTD. - EP2428511, 2012, A1 Current Patent Assignee: U S V LTD. - US2012/108828, 2012, A1
[2]Current Patent Assignee: FRICHEM PRIVATE - WO2012/4658, 2012, A2
[3]Current Patent Assignee: SANOFI - WO2012/131408, 2012, A1
[4]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - US2013/72697, 2013, A1

31
[ 141626-36-0 ]
[ 1354567-97-7 ]

Yield	Reaction Conditions	Operation in experiment
87%	With hydrogen bromide In hexane; ethyl acetate at 25 - 65℃; for 1h;	12 Example-12:Preparation of crystalline dronedarone hvdrobromide15 g dronedarone freebase as solid and 30 mL ethyl acetate was taken in round bottom flask at 25°C and heated to 65°C for 1 hour. 7.4 g of cone. Hydrobromic acid (48%) solution was added and stirred for 30 min. 90 mL hexane was added to the reaction mixture and cooled to 25°C.The reaction mixture was stirred for 30 mins and filtered. The wet-cake was washed with hexane and dried to obtain 15 g (87%) of crystalline dronedarone hydrobromide. The crystalline form is characterized by XRD substantially as depicted in FIG.4, Infrared spectrum substantially as depicted in FIG.5 and DSC substantially as depicted in FIG.6.
	With hydrogen bromide In ethyl acetate	5 Example-5Preparation of N-r2-butyl-3-[4-(3-(di-n-butylamino)propoxy)benzoyl]-5- benzofuranyll methanesulfonamide hydrobromide (Dronedarone Hydrobromide) Hydrogen bromide in ether was added to the solution of N-[2-butyl-3[4-(3- dibutylamino)propoxy)benzoyl]-5-benzofuran] methanesulfonamide (10 gm) in anhydrous ethyl acetate (100 ml). The mixture was stirred continuously till the precipitation of the product. The product thus obtained was filtered; wet cake was washed with ethyl acetate and dried to get N-[2-butyl-3-[4-(3-(di-n- butylamino)propoxy)benzoyl]-5-benzofuranyl] methanesulfonamide hydrobromide having purity of > 99.5 % measured by HPLC.

Reference： [1]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - WO2012/32545, 2012, A1 Location in patent: Page/Page column 39
[2]Current Patent Assignee: FRICHEM PRIVATE - WO2012/4658, 2012, A2 Location in patent: Page/Page column 19

32
[ 100-07-2 ]
[ 141626-36-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: aluminum (III) chloride / chlorobenzene / 2 h / 25 °C / Reflux 2.1: aluminum (III) chloride / chlorobenzene / 2 h / 75 °C 2.2: 0.5 h / 5 - 65 °C 3.1: potassium carbonate / butanone / 20 h / 85 °C 3.3: 0.5 h / 25 - 65 °C 4.1: potassium carbonate / toluene; water 5.1: hydrogen / Raney Nickel / methanol / 8 h / 55 °C / 3677.86 Torr 5.2: 0.5 h / 25 - 65 °C 6.1: potassium carbonate / toluene; water / 1 h / 35 °C 7.1: toluene / 3.5 h / 108 °C 7.2: 0.5 h / 60 °C
	Multi-step reaction with 4 steps 1: iron(III) chloride / dichloromethane / 1.25 h / 5 - 40 °C 2: water; aluminum (III) chloride / 1,2-dichloro-ethane / 7.5 h / 64 - 66 °C 3: potassium carbonate / butanone / 8 h 4: ethanol; sodium / 0.5 h

Reference： [1]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - WO2012/32545, 2012, A1
[2]Current Patent Assignee: SANOFI - WO2011/158050, 2011, A1

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	{[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

CAS No. :	141626-36-0	MDL No. :	MFCD00910331
Formula :	C₃₁H₄₄N₂O₅S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	556.76 g/mol	Pubchem ID :	208898
Synonyms :	1. Dronedarone

Num. heavy atoms :	39
Num. arom. heavy atoms :	15
Fraction Csp3 :	0.52
Num. rotatable bonds :	18
Num. H-bond acceptors :	6.0
Num. H-bond donors :	1.0
Molar Refractivity :	161.2
TPSA :	97.23 Å²

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-4.56 cm/s

Log Po/w (iLOGP) :	5.26
Log Po/w (XLOGP3) :	7.23
Log Po/w (WLOGP) :	7.94
Log Po/w (MLOGP) :	2.79
Log Po/w (SILICOS-IT) :	7.03
Consensus Log Po/w :	6.05

[ CAS No. 141626-36-0 ]

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Physicochemical Properties

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Lipophilicity

Druglikeness

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Application In Synthesis of [ 141626-36-0 ]

[ 141626-36-0 ] Synthesis Path-Downstream 1~32

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[ 141626-36-0 ]

Precautionary Statements-General

Prevention

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Inquiry

Lipinski :	1.0
Ghose :	None
Veber :	1.0
Egan :	1.0
Muegge :	2.0
Bioavailability Score :	0.55

Log S (ESOL) :	-6.94
Solubility :	0.0000634 mg/ml ; 0.000000114 mol/l
Class :	Poorly soluble
Log S (Ali) :	-9.1
Solubility :	0.000000447 mg/ml ; 0.0000000008 mol/l
Class :	Poorly soluble
Log S (SILICOS-IT) :	-10.97
Solubility :	0.000000006 mg/ml ; 0.0 mol/l
Class :	Insoluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	3.0
Synthetic accessibility :	4.7

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P260-P264-P270-P301+P312+P330-P314-P501	UN#:	N/A
Hazard Statements:	H302-H373	Packing Group:	N/A
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
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P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
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P335	Brush off loose particles from skin.
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P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling