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Chemical Structure| 141626-36-0
Chemical Structure| 141626-36-0
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Product Details of [ 141626-36-0 ]

CAS No. :141626-36-0 MDL No. :MFCD00910331
Formula : C31H44N2O5S Boiling Point : -
Linear Structure Formula :- InChI Key :ZQTNQVWKHCQYLQ-UHFFFAOYSA-N
M.W : 556.76 Pubchem ID :208898
Synonyms :
SR 33589
Chemical Name :N-(2-Butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl)methanesulfonamide

Calculated chemistry of [ 141626-36-0 ]      Expand+

Physicochemical Properties

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 Ų

Pharmacokinetics

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

Lipophilicity

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

Druglikeness

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

Water Solubility

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

Medicinal Chemistry

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

Safety of [ 141626-36-0 ]

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:

Application In Synthesis of [ 141626-36-0 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 141626-36-0 ]

[ 141626-36-0 ] Synthesis Path-Downstream   1~96

  • 1
  • [ 141626-36-0 ]
  • dronedarone hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
98% With hydrogenchloride In diethyl ether; ethyl acetate at 0 - 20℃; for 2.08333h; 3 5.3. dronedarone hydrochloride (1*HCl) 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 1*HCl (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 ]
YieldReaction ConditionsOperation 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.

  • 3
  • [ 141644-91-9 ]
  • [ 124-63-0 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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%
  • 5
  • [ 1310430-05-7 ]
  • [ 111-92-2 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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)
  • 6
  • [ 1310430-06-8 ]
  • [ 111-92-2 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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
  • 7
  • [ 1310430-09-1 ]
  • [ 111-92-2 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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%
  • 8
  • [ 1312300-15-4 ]
  • [ 111-92-2 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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%
  • 9
  • [ 1310430-08-0 ]
  • [ 111-92-2 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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.
  • 10
  • [ 141645-16-1 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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
  • 12
  • [ 401840-61-7 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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
  • 13
  • [ 437652-07-8 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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

  • 14
  • [ 1310430-03-5 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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
  • 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 ]
YieldReaction ConditionsOperation 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%
  • 16
  • [ 110-17-8 ]
  • [ 141626-36-0 ]
  • [ 1337978-10-5 ]
YieldReaction ConditionsOperation 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.
  • 17
  • [ 75-75-2 ]
  • [ 141626-36-0 ]
  • [ 1337955-85-7 ]
YieldReaction ConditionsOperation 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 %.
  • 18
  • [ 141626-36-0 ]
  • dronedarone hemisulfate [ No CAS ]
YieldReaction ConditionsOperation 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 %.
  • 19
  • [ 1337955-85-7 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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 %.
  • 20
  • 4-[3-(di-n-butylamino)-propoxy]-benzoic acid chloride hydrochloride [ No CAS ]
  • [ 437652-07-8 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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
  • 21
  • [ 141644-91-9 ]
  • [ 124-63-0 ]
  • [ 141626-57-5 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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%
  • 22
  • [ 141645-16-1 ]
  • [ 141626-57-5 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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
  • 23
  • [ 141645-23-0 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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

  • 24
  • [ 141645-23-0 ]
  • [ 141626-57-5 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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
  • 25
  • [ 36421-15-5 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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

  • 27
  • [ 1356536-09-8 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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.
  • 28
  • [ 1356536-07-6 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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).
  • 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 ]
YieldReaction ConditionsOperation 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.
  • 30
  • [ 141644-91-9 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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

  • 31
  • [ 141626-36-0 ]
  • [ 1354567-97-7 ]
YieldReaction ConditionsOperation 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.
  • 32
  • [ 100-07-2 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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
  • 33
  • [ 133238-87-6 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation 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
  • 34
  • [ 141626-36-0 ]
  • 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-methansulfonylamino-benzofuran sulfate [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With sulfuric acid In ethyl acetate at 25 - 70℃; for 1h; 14 Example-14:Preparation of crystalline dronedarone hydrogensulfate10 g dronedarone freebase as solid and 50 mL ethyl acetate was taken in round bottom flask at 25°C and stirred to get clear solution. Cone. Sulfuric acid solution (1 gm in 10 ml ethyl acetate) was added and stirred for 30 min. The reaction mixture was heated to 65°C to 70°C and stirred for 30 tnins. The reaction mixture was cooled to 25°C and filtered. The wet-cake was washed with ethyl acetate and dried to obtain 9.6 g (75%) of crystalline dronedarone hydrogensulfate. The crystalline form is characterized by XRD substantially as depicted in FIG.8, Infrared spectrum substantially as depicted in FIG.9 and DSC substantially as depicted in FIG.10.
5.5 g With sulfuric acid In water; acetone at 10 - 52℃; for 1.33333h; 10.2 Preparation of Dronedarone Sulfate The obtained oily product was dissolved in 12 mL acetone to obtain a mixture, then 2 mL water were added to the mixture. Then, a solution of 1.1 mL concentrated sulfuric acid in 3 mL acetone was added dropwise under 10˜15° C. in about 20 min. Then, the mixture was heated to 52° C. and stirred for 1 h. The mixture was cooled by ice water bath under stirring for crystallization. After about 3.5 h later, lots of solid was precipitated. The solid obtained was filtered and dried at 50° C. under vacuum to obtain 5.5 g targeted compound. Yield: 84%, (Calculation by dronedarone hydrochloride), Purity of HPLC: 99.85%.
  • 35
  • [ 141627-42-1 ]
  • [ 141626-36-0 ]
  • 36
  • 5-amino-2-n-butyl-3-[4-(3-di-n-butylamino propoxy)benzoyl]benzofuran bisoxalate [ No CAS ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium carbonate / toluene; water / 1 h / 35 °C 2.1: toluene / 3.5 h / 108 °C 2.2: 0.5 h / 60 °C
Multi-step reaction with 2 steps 1: sodium hydroxide / toluene; water / 0.5 h / pH 10 - 12 2: toluene / 3 h / Reflux
Multi-step reaction with 2 steps 1.1: sodium hydroxide / toluene; water / 0.5 h / pH 10 - 12 2.1: toluene / 3 h / Reflux 2.2: 0.17 h / 30 °C
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / dichloromethane; water / 0.5 h 2: triethylamine / toluene / 0.5 h / -5 - 5 °C
Multi-step reaction with 2 steps 1: ammonia / ethyl acetate; water / 25 - 35 °C 2: pyridine / dichloromethane / -5 - 5 °C

  • 37
  • [ 141626-57-5 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
90.3% With ethanol; sodium for 0.5h; 1 Example 1.N-r2-n-butyl-3-{4-r(3-di-n-butylamino)-propoxy1-benzov -l-benzofuran-5- yll-methane-sulfonamide (I)To 7g of 2-n-butyl-3-[(di-n-butylamino)-3-propoxy)-4-benzoyl]-5-bis- (methylsulfonamido)-benzofuran (II) the solution prepared from 5 g sodium and 170 ml abs. ethanol is added. The reaction mixture is boiled for 30 minutes, then evaporated under reduced pressure. To the residue 30 ml of dichloromethane and 50 ml of water are added and the mixture is stirred for 20 minutes. The phases are separated. The organic phase is washed with 20 ml of water and evaporated.Product: oil (yield: 97.9%). Purity (HPLC): 93.1%.The product is purified through its oxalate salt (yield: 90.3%). Purity (HPLC): 99.5%.lH NMR(DMSO): 0.8-0.9 ppm (m, 9H); 1.2-1.5 ppm (m, 10H); 1.67 ppm (5 2H); 1.87 ppm (5 2H); 2.38 ppm (t, J=7.2Hz, 4H); 2.57 ppm (m, 2H); 2.81 ppm (t, J=7.5Hz, 2H); 2.91 ppm (s, 3H); 4.15 ppm (t, J=6.2Hz, 2H); 7.09 (d, J=8.8Hz, 2H); 7.24 ppm (dd, J=8.9; 2.2Hz, IH); 7.34 ppm (d, J=2.1Hz, IH); 7.65 ppm (d, J=8.8Hz, IH); 7.81 ppm (d, J=8.8Hz, 2H).
With sodium hydroxide In tetrahydrofuran at 20℃; for 3h; 10.b b). Preparation of N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]benzofuran-5- yl]methanesulfonamide-Dronedarone ( 1 )A crude mixture from experiment (a) (585.1 g, 0.871 mmol) was dissolved in tetrahydrofuran (6 ml) and 5N NaOH (0.5 ml) was added. The mixture was stirred at rt for 3h under HPLC monitoring. After completion reaction the solvent was concentrated, ethyl acetate and water were added. The organic layer was separate, and the aqueous one extracted two more times. The combined organic layers were dried over sodium sulfate, filtered and concentrated to half of volume. The analytical sample was prepared by evaporation of solvent, giving a yellow oil.
  • 38
  • [ 141645-85-4 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
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
Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 0 - 10 °C 2: sodium hydroxide / tetrahydrofuran / 3 h / 20 °C
  • 39
  • [ 111-92-2 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: tetrabutylammomium bromide; potassium iodide / N,N-dimethyl-formamide / 14 h / 85 °C 2: methylamine / water; isopropyl alcohol / 1 h / 75 °C 3: isopropyl alcohol / 1.5 h / 5 - 65 °C / Large scale reaction 4: sodium hydrogencarbonate / dichloromethane; water / 0.5 h 5: triethylamine / toluene / 0.5 h / -5 - 5 °C
Multi-step reaction with 4 steps 1: isopropyl alcohol / 4 h / Reflux 2: hydrogen; 5%-palladium/activated carbon / methanol / 1.5 h / 25 °C / 7500.75 Torr 3: pyridine / dichloromethane / 2 h / 30 - 35 °C 4: sodium iodide; dimethylsilicon dichloride / acetonitrile / 0.25 h / 25 °C
Multi-step reaction with 5 steps 1.1: lithium tetrafluoroborate / acetonitrile / 4 h / 20 °C / Inert atmosphere 2.1: thionyl chloride / chloroform / 1 h / 20 °C / Reflux; Inert atmosphere 3.1: caesium carbonate; sodium iodide / acetonitrile / 23 h / 20 - 60 °C / Inert atmosphere 4.1: n-butyllithium / hexane; tetrahydrofuran / 0.75 h / -78 °C / Inert atmosphere 4.2: 23 h / 20 °C / Inert atmosphere 5.1: bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; methoxybenzene / 23 h / 80 °C / Inert atmosphere
Multi-step reaction with 6 steps 1: methanol / 8 h / 20 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 8 h / 20 °C 3: thionyl chloride / chloroform / 7 h / Reflux 4: potassium carbonate / N,N-dimethyl-formamide / 4 h / 85 °C 5: hydrogen; palladium 10% on activated carbon / tetrahydrofuran / 20 °C 6: pyridine / dichloromethane / 1.5 h / 20 °C

  • 40
  • [ 51767-39-6 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: lead(IV) tetraacetate; acetic acid / ethylene glycol / 1.67 h / 20 °C 2: acetic acid / N,N-dimethyl-formamide / 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: lead(IV) tetraacetate; acetic acid / ethylene glycol / 1.67 h / 20 °C 2: trityl perchlorate / dichloromethane / 45 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: lead(IV) tetraacetate; acetic acid / ethylene glycol / 1.67 h / 20 °C 2: sodium methylate / 1,4-dioxane / 1 h / 20 °C
Multi-step reaction with 5 steps 1.1: lead(IV) tetraacetate; acetic acid / ethylene glycol / 1.67 h / 20 °C 2.1: sodium methylate / 1,4-dioxane / 1 h / 20 °C 2.2: Reflux 3.1: water; lithium hydroxide / 1,4-dioxane / 16 h 4.1: 0 °C / Inert atmosphere; Reflux 5.1: sodium carbonate; sodium dodecyl-sulfate / palladium dichloride / water; acetone / 60 °C
Multi-step reaction with 5 steps 1.1: lead(IV) tetraacetate; acetic acid / ethylene glycol / 1.67 h / 20 °C 2.1: sodium methylate / 1,4-dioxane / 1 h / 20 °C 2.2: Reflux 3.1: water; lithium hydroxide / 1,4-dioxane / 16 h 4.1: 0 °C / Inert atmosphere; Reflux 5.1: diisobutylaluminium hydride; magnesium; lithium chloride; diisobutylaluminum chloride / n-heptane; tetrahydrofuran / -10 - 25 °C 5.2: 25 °C
Multi-step reaction with 2 steps 1: lead(IV) tetraacetate; acetic acid / 0.67 h / 20 °C 2: acetic acid / N,N-dimethyl-formamide / 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: lead(IV) tetraacetate; acetic acid / 0.67 h / 20 °C 2: trityl perchlorate / dichloromethane / 45 °C / Inert atmosphere
Multi-step reaction with 3 steps 1.1: lead(IV) tetraacetate; acetic acid / 0.67 h / 20 °C 2.1: sodium methylate / 1,4-dioxane / 1 h / 20 °C 3.1: trifluoroacetic anhydride; phosphoric acid / 20 h / Reflux 3.2: pH 8 / Cooling
Multi-step reaction with 5 steps 1.1: lead(IV) tetraacetate; acetic acid / 0.67 h / 20 °C 2.1: sodium methylate / 1,4-dioxane / 1 h / 20 °C 3.1: water; lithium hydroxide / 1,4-dioxane / 16 h / 20 °C 4.1: thionyl chloride / 0 °C / Inert atmosphere; Reflux 5.1: aluminum (III) chloride / dichloromethane / Reflux 5.2: 25 °C
Multi-step reaction with 5 steps 1.1: lead(IV) tetraacetate; acetic acid / 0.67 h / 20 °C 2.1: sodium methylate / 1,4-dioxane / 1 h / 20 °C 3.1: water; lithium hydroxide / 1,4-dioxane / 16 h / 20 °C 4.1: thionyl chloride / 0 °C / Inert atmosphere; Reflux 5.1: diisobutylaluminium hydride; magnesium; lithium chloride; diisobutylaluminum chloride / n-heptane; tetrahydrofuran / 25 °C / Inert atmosphere 5.2: 0.08 h / -10 - 25 °C 5.3: -30 - 25 °C
Multi-step reaction with 5 steps 1: lead(IV) tetraacetate; acetic acid / 0.67 h / 20 °C 2: sodium methylate / 1,4-dioxane / 1 h / 20 °C 3: water; lithium hydroxide / 1,4-dioxane / 16 h / 20 °C 4: thionyl chloride / 0 °C / Inert atmosphere; Reflux 5: sodium carbonate; sodium dodecyl-sulfate / palladium dichloride / water; acetone / 60 °C
Multi-step reaction with 5 steps 1: manganese(IV) oxide; acetic acid / 1 h / 25 °C 2: sodium methylate / 1,4-dioxane / 0.5 h / 20 °C 3: hydrogenchloride / water; acetone / 5 h / Reflux 4: thionyl chloride / 3.5 h / 20 - 79 °C 5: aluminum (III) chloride / 1,2-dichloro-ethane / 4 h / 0 - 25 °C

  • 41
  • [ 1333493-68-7 ]
  • [ 73021-84-8 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
75% Stage #1: 1-{4-[3-(di-n-butylamino)propoxy]phenyl}-1,3-heptanedione; N-(4-oxocyclohexa-2,5-dien-1-ylidene)methanesulphonamide With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 20℃; for 3.28333h; Stage #2: With triethylamine; zinc(II) chloride In tetrahydrofuran; 1,4-dioxane for 45h; Reflux; 3 5.2. dronedarone base (1) The mixture of 24 and 25 (1.05 g, 1.83 mmol) was dissolved in anh. dioxane (15 mL). Triethylamine (0.382 mL, 2.74 mmol) was added followed by 0.5 M solution of ZnCl2 in THF (1.0 mL, 0.50mmol). The reaction mixture was then refluxed for 45 h, cooled to RT and filtered through a pad of Celite. The charcoal was addedto the filtrate and the mixture was stirred for 1 h at 50 C. Solids were filtered off on a pad of silica and Celite and the cake was washed with dioxane until all product was eluted. The filtrate was concentrated to provide 1 (0.76 g, 1.365 mmol, 75%, HPLC purity>95%) as a yellow oil. 1H NMR (ppm, CDCl3): 7.80 (d, 2H), 7.43(d, 1H), 7.36 (d, 1H), 7.28 (m, 1H), 6.95 (d, 2H), 4.10 (t, 2H), 2.91 (s,3H), 2.83 (t, 2H), 2.61 (t, 2H), 2.43 (t, 4H), 1.95 (m, 2H), 1.72 (m,2H), 1.42 (m, 4H), 1.30 (m, 6H), 0.89 (m, 9H)
Stage #1: 1-{4-[3-(di-n-butylamino)propoxy]phenyl}-1,3-heptanedione; N-(4-oxocyclohexa-2,5-dien-1-ylidene)methanesulphonamide With sodium methylate In 1,4-dioxane at 20℃; for 1h; Stage #2: With hydrogenchloride In water 15 Synthesis of N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl) methanesulfonamide (1) Example 15 Synthesis of N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl) methanesulfonamide (1) To a solution of N-(4-oxocyclohexa-2,5-dienylidene)methanesulfonamide (5, 1eq.) and 1-(4-(3-(dibutylamino)propoxy)phenyl)heptane-1,3-dione (17, 1,1eq.) in dioxane is added sodium methoxide (0.1eq.) and the mixture is allowed to stand at room temperature for 1h. The reaction mixture is filtered and the filtrate is concentrated under vacuo to a small volume. The crude product is solidified by cooling the solution and adding a small amount of heptane. A suspension of the obtained solid is heated in hydrochloric acid under reflux for several hours. After neutralizing by sodium hydroxide solution, the product was extracted by dichloromethane, concentrated and purified by column chromatography (SiO2) to give the title compound as a solid.
  • 42
  • [ 64010-38-4 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium carbonate; potassium iodide / butanone / 72 h / Reflux 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; potassium iodide / butanone / 72 h / Reflux 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; potassium iodide / butanone / 72 h / Reflux 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; potassium iodide / butanone / 72 h / Reflux 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

  • 43
  • [ 106-41-2 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
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 3 steps 1.1: potassium carbonate / butanone / Reflux 2.1: potassium carbonate; potassium iodide / butanone / 72 h / Reflux 3.1: diisobutylaluminium hydride; magnesium; lithium chloride; diisobutylaluminum chloride / n-heptane; tetrahydrofuran / -10 - 25 °C 3.2: 25 °C
Multi-step reaction with 4 steps 1.1: potassium carbonate / butanone / Reflux 2.1: potassium carbonate; potassium iodide / butanone / 72 h / Reflux 3.1: magnesium / tetrahydrofuran / 1 h / Reflux 3.2: 2 h / -78 °C 4.1: 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 3 steps 1.1: potassium carbonate / butanone / Reflux 2.1: potassium carbonate; potassium iodide / butanone / 72 h / Reflux 3.1: diisobutylaluminium hydride; magnesium; lithium chloride; diisobutylaluminum chloride / n-heptane; tetrahydrofuran / 25 °C / Inert atmosphere 3.2: 0.08 h / -10 - 25 °C 3.3: -30 - 25 °C
Multi-step reaction with 4 steps 1.1: potassium carbonate / butanone / Reflux 2.1: potassium carbonate; potassium iodide / butanone / 72 h / Reflux 3.1: magnesium / tetrahydrofuran / 1 h / Reflux 3.2: 2 h / -78 °C 3.3: 20 °C 4.1: sodium carbonate; sodium dodecyl-sulfate / palladium dichloride / water; acetone / 60 °C

  • 44
  • [ 73021-84-8 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: sodium methylate / 1,4-dioxane / 1 h / 20 °C 1.2: Reflux 2.1: water; lithium hydroxide / 1,4-dioxane / 16 h 3.1: 0 °C / Inert atmosphere; Reflux 4.1: sodium carbonate; sodium dodecyl-sulfate / palladium dichloride / water; acetone / 60 °C
Multi-step reaction with 4 steps 1.1: sodium methylate / 1,4-dioxane / 1 h / 20 °C 1.2: Reflux 2.1: water; lithium hydroxide / 1,4-dioxane / 16 h 3.1: 0 °C / Inert atmosphere; Reflux 4.1: diisobutylaluminium hydride; magnesium; lithium chloride; diisobutylaluminum chloride / n-heptane; tetrahydrofuran / -10 - 25 °C 4.2: 25 °C
Multi-step reaction with 2 steps 1.1: sodium methylate / 1,4-dioxane / 1 h / 20 °C 2.1: trifluoroacetic anhydride; phosphoric acid / 20 h / Reflux 2.2: pH 8 / Cooling
Multi-step reaction with 4 steps 1.1: sodium methylate / 1,4-dioxane / 1 h / 20 °C 2.1: water; lithium hydroxide / 1,4-dioxane / 16 h / 20 °C 3.1: thionyl chloride / 0 °C / Inert atmosphere; Reflux 4.1: aluminum (III) chloride / dichloromethane / Reflux 4.2: 25 °C
Multi-step reaction with 4 steps 1.1: sodium methylate / 1,4-dioxane / 1 h / 20 °C 2.1: water; lithium hydroxide / 1,4-dioxane / 16 h / 20 °C 3.1: thionyl chloride / 0 °C / Inert atmosphere; Reflux 4.1: diisobutylaluminium hydride; magnesium; lithium chloride; diisobutylaluminum chloride / n-heptane; tetrahydrofuran / 25 °C / Inert atmosphere 4.2: 0.08 h / -10 - 25 °C 4.3: -30 - 25 °C
Multi-step reaction with 4 steps 1: sodium methylate / 1,4-dioxane / 1 h / 20 °C 2: water; lithium hydroxide / 1,4-dioxane / 16 h / 20 °C 3: thionyl chloride / 0 °C / Inert atmosphere; Reflux 4: sodium carbonate; sodium dodecyl-sulfate / palladium dichloride / water; acetone / 60 °C
Multi-step reaction with 4 steps 1: sodium methylate / 1,4-dioxane / 0.5 h / 20 °C 2: hydrogenchloride / water; acetone / 5 h / Reflux 3: thionyl chloride / 3.5 h / 20 - 79 °C 4: aluminum (III) chloride / 1,2-dichloro-ethane / 4 h / 0 - 25 °C

  • 45
  • [ 1374967-92-6 ]
  • [ 73021-84-8 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
With trityl perchlorate In dichloromethane at 45℃; Inert atmosphere; 14 The compound of previous step (18, 1.1 eq.) is diluted by dichloromethane, followed by addition of N-(4-oxocyclohexa-2,5-dienylidene)methanesulfonamide (5, 1eq.) and trityl perchlorate (5-10 mol%). The mixture is then heated to 45°C under nitrogen for several hours. When the reaction is complete, the mixture is partitioned between dichloromethane and water, and the aqueous layer is extracted several times with dichloromethane. The organic layers are combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product. Purification of this material by column chromatography (SiO2) affords the title compound as a solid in 90% yield.
With trityl perchlorate In dichloromethane at 45℃; Inert atmosphere; 13 The compound of previous step (18, 1.1 eq.) is diluted by dichloromethane, followed by addition of N-(4-oxocyclohexa-2,5-dienylidene)methanesulfonamide (5, 1 eq.) and trityl perchlorate (5-10 mol%). The mixture is then heated to 45°C under nitrogen for several hours. When the reaction is complete, the mixture is partitioned between dichloromethane and water, and the aqueous layer is extracted several times with dichloromethane. The organic layers are combined, dried over anhydrous Na2S04, filtered and concentrated in vacuo to give the crude product. Purification of this material by column chromatography (Si02) affords the title compound as a solid.
  • 46
  • [ 1374967-93-7 ]
  • [ 73021-84-8 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
With acetic acid In N,N-dimethyl-formamide at 20℃; Inert atmosphere; 16 The compound 19 of previous step (1 eq.) in DMF is added a solution of N-(4-oxocyclohexa-2,5-dienylidene)methanesulfonamide (5, 1eq.) in DMF and acetic acid is added at room temperature under nitrogen. When the reaction is complete, the mixture is partitioned between diethyl ether and water, and the aqueous layer is extracted several times with diethyl ether. The organic layers are combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product. Purification of this material by column chromatography (SiO2) affords the title compound as a greasy solid.
With acetic acid In N,N-dimethyl-formamide at 20℃; Inert atmosphere; 15 The compound 19 of previous step (1 eq.) in DMF is added a solution of N-(4-oxocyclohexa- 2,5-dienylidene)methanesulfonamide (5, 1eq.) in DMF and acetic acid is added at room temperature under nitrogen. When the reaction is complete, the mixture is partitioned between diethyl ether and water, and the aqueous layer is extracted several times with diethyl ether. The organic layers are combined, dried over anhydrous Na2S04, filtered and concentrated in vacuo to give the crude product. Purification of this material by column chromatography (Si02) affords the title compound as a greasy solid.
  • 47
  • [ 627040-50-0 ]
  • [ 1329684-25-4 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
70% Stage #1: N-(3-(4-bromophenoxy)propyl)-N-butylbutan-1-amine With diisobutylaluminum chloride; diisobutylaluminium hydride; magnesium; lithium chloride In tetrahydrofuran; n-heptane at -10 - 25℃; Stage #2: 2-butyl-5-(methanesulfonamido)benzofuran-3-carbonyl chloride With copper(I) cyanide di(lithium chloride) In tetrahydrofuran; n-heptane at 25℃; 12 Synthesis of N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl) methanesulfonamide (1) Example 12 Synthesis of N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl) methanesulfonamide (1) To a stirred mixture of anhydrous LiCl (1,5 eq.), and magnesium turnings (3,0 eq.) in freshly distilled THF under argon, is added a DIBAL-H solution (0.1 M solution in THF, 0,01 eq.). After heating for about 1 min and then cooling to 25°C, an i-Bu2AlCl solution (1,4 eq. 0.8 M in heptane) is added. Finally, N-(3-(4-bromophenoxy)propyl)-N-butylbutan-1-amine (9, 1,25 eq.) is added in one portion at 25°C. After completion of the reaction at this temperature, the reaction mixture is transferred into a new flask and is cooled to -10°C. To the stirred mixture is added CuCN·2LiCl (1 M in THF, 0,10 eq.), and the reaction mixture is stirred for 5 min. After the addition of 2-butyl-5-(methylsulfonamido)benzofuran-3-carbonyl chloride (16, 1,0 eq.) the cooling bath is removed and the mixture is stirred for several hours at 25°C. The reaction is quenched with acetic acid at -30°C and then kept at 25°C for several minutes. The mixture is extracted several times with ethyl acetate, washed with aqueous saturated NaHCO3, water, and saturated NaCl solution. The combined organic layers are dried over Na2SO4 and the solvents are removed under reduced pressure to furnish the crude product, which is further purified by column chromatography (SiO2) to obtain the title compound in 70% yield.
Stage #1: N-(3-(4-bromophenoxy)propyl)-N-butylbutan-1-amine With diisobutylaluminum chloride; diisobutylaluminium hydride; magnesium; lithium chloride In tetrahydrofuran; n-heptane at 25℃; Inert atmosphere; Stage #2: 2-butyl-5-(methanesulfonamido)benzofuran-3-carbonyl chloride With copper(I) cyanide di(lithium chloride) In tetrahydrofuran; n-heptane at -10 - 25℃; for 0.0833333h; Stage #3: With water; sodium hydrogencarbonate; acetic acid In tetrahydrofuran; n-heptane; ethyl acetate at -30 - 25℃; 11 To a stirred mixture of anhydrous LiCI (1 ,5 eq.), and magnesium turnings (3,0 eq.) in freshly distilled THF under argon, is added a DIBAL-H solution (0.1 M solution in THF, 0,01 eq.). After heating for about 1 min and then cooling to 25°C, an /-Bu2AICI solution (1 ,4 eq. 0.8 M in heptane) is added. Finally, N-(3-(4-bromophenoxy)propyl)-N-butylbutan-1-amine (9, 1 ,25 eq.) is added in one portion at 25°C. After completion of the reaction at this temperature, the reaction mixture is transferred into a new flask and is cooled to -10°C. To the stirred mixture is added CuCN-2l_iCI (1 M in THF, 0, 10 eq.), and the reaction mixture is stirred for 5 min. After the addition of 2-butyl-5-(methylsulfonamido)benzofuran-3-carbonyl chloride (16, 1 ,0 eq.) the cooling bath is removed and the mixture is stirred for several hours at 25°C. The reaction is quenched with acetic acid at -30°C and then kept at 25°C for several minutes. The mixture is extracted several times with ethyl acetate, washed with aqueous saturated NaHC03, water, and saturated NaCI solution. The combined organic layers are dried over Na2S04 and the solvents are removed under reduced pressure to furnish the crude product, which is further purified by column chromatography (Si02) to obtain the title compound.
  • 48
  • [ 1329684-19-6 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: water; lithium hydroxide / 1,4-dioxane / 16 h 2.1: 0 °C / Inert atmosphere; Reflux 3.1: diisobutylaluminium hydride; magnesium; lithium chloride; diisobutylaluminum chloride / n-heptane; tetrahydrofuran / -10 - 25 °C 3.2: 25 °C
Multi-step reaction with 3 steps 1: water; lithium hydroxide / 1,4-dioxane / 16 h 2: 0 °C / Inert atmosphere; Reflux 3: sodium carbonate; sodium dodecyl-sulfate / palladium dichloride / water; acetone / 60 °C
Multi-step reaction with 3 steps 1.1: water; lithium hydroxide / 1,4-dioxane / 16 h / 20 °C 2.1: thionyl chloride / 0 °C / Inert atmosphere; Reflux 3.1: aluminum (III) chloride / dichloromethane / Reflux 3.2: 25 °C
Multi-step reaction with 3 steps 1.1: water; lithium hydroxide / 1,4-dioxane / 16 h / 20 °C 2.1: thionyl chloride / 0 °C / Inert atmosphere; Reflux 3.1: diisobutylaluminium hydride; magnesium; lithium chloride; diisobutylaluminum chloride / n-heptane; tetrahydrofuran / 25 °C / Inert atmosphere 3.2: 0.08 h / -10 - 25 °C 3.3: -30 - 25 °C
Multi-step reaction with 3 steps 1: water; lithium hydroxide / 1,4-dioxane / 16 h / 20 °C 2: thionyl chloride / 0 °C / Inert atmosphere; Reflux 3: sodium carbonate; sodium dodecyl-sulfate / palladium dichloride / water; acetone / 60 °C

  • 49
  • [ 1374967-90-4 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: 0 °C / Inert atmosphere; Reflux 2.1: diisobutylaluminium hydride; magnesium; lithium chloride; diisobutylaluminum chloride / n-heptane; tetrahydrofuran / -10 - 25 °C 2.2: 25 °C
Multi-step reaction with 2 steps 1: 0 °C / Inert atmosphere; Reflux 2: sodium carbonate; sodium dodecyl-sulfate / palladium dichloride / water; acetone / 60 °C
Multi-step reaction with 2 steps 1.1: thionyl chloride / 0 °C / Inert atmosphere; Reflux 2.1: aluminum (III) chloride / dichloromethane / Reflux 2.2: 25 °C
Multi-step reaction with 2 steps 1.1: thionyl chloride / 0 °C / Inert atmosphere; Reflux 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 2 steps 1: thionyl chloride / 0 °C / Inert atmosphere; Reflux 2: sodium carbonate; sodium dodecyl-sulfate / palladium dichloride / water; acetone / 60 °C

  • 50
  • [ 1329684-25-4 ]
  • [ 1374967-91-5 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
With sodium dodecyl-sulfate; sodium carbonate In water; acetone at 60℃; 11 To a stirred mixture of Na2CO3 (1.6 eq.) and PdCl2 (1.7 mol %) in acetone/water (1:1) is added sodium dodecyl sulfate (0.5 eq.) and the mixture is heated to 60°C with stirring. To this mixture 4-(3-(dibutylamino)propoxy) phenylboronic acid (1,2 eq.) from the previous step and 2-butyl-5-(methylsulfonamido)benzofuran-3-carbonyl chloride (1,0 eq.) are added and the mixture is held at 60°C for several hours. When the reaction is complete, the mixture is cooled to room temperature and the resulting suspension is extracted several times with diethyl ether. The combined organic layers are dried over Na2SO4 and evaporated under reduced pressure. Further purification of the product is achieved by flash column chromatography on silica gel to get a solid product in over 40 % yield of both steps.
With sodium dodecyl-sulfate; sodium carbonate In water; acetone at 60℃; 10 To a stirred mixture of Na2C03 (1.6 eq.) and PdCI2 (1.7 mol %) in acetone/water (1 : 1) is added sodium dodecyl sulfate (0.5 eq.) and the mixture is heated to 60°C with stirring. To this mixture 4-(3-(dibutylamino)propoxy) phenylboronic acid (1 ,2 eq.) from the previous step and 2-butyl-5-(methylsulfonamido)benzofuran-3-carbonyl chloride (1 ,0 eq.) are added and the mixture is held at 60°C for several hours. When the reaction is complete, the mixture is cooled to room temperature and the resulting suspension is extracted several times with diethyl ether. The combined organic layers are dried over Na2S04 and evaporated under reduced pressure. Further purification of the product is achieved by flash column chromatography on silica gel to get a solid product in over 40 % yield of both steps.
  • 51
  • [ 51767-39-6 ]
  • [ 1375149-24-8 ]
  • [ 1375149-23-7 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: lead(IV) tetraacetate; acetic acid / 0.67 h / 20 °C 2: sodium methylate / 1,4-dioxane / 1 h / 20 °C
  • 52
  • [ 1333493-68-7 ]
  • [ 73021-84-8 ]
  • [ 1375149-24-8 ]
  • [ 1375149-23-7 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
With sodium methylate In 1,4-dioxane at 20℃; for 1h; 14 To a solution of N-(4-oxocyclohexa-2,5-dienylidene)methanesulfonamide (5, 1eq.) and 1-(4- (3-(dibutylamino)propoxy)phenyl)heptane-1 ,3-dione (17, 1 , 1eq.) in dioxane is added sodium methoxide (0.1 eq.) and the mixture is allowed to stand at room temperature for 1 h. The reaction mixture is filtered and the filtrate is concentrated under vacuo to a small volume. The crude product is solidified by cooling the solution and adding a small amount of heptane. A suspension of the obtained solid is heated in hydrochloric acid under reflux for several hours. After neutralizing by sodium hydroxide solution, the product was extracted by dichloromethane, concentrated and purified by column chromatography (Si02) to give a mixture of retro-Claisen products 21 and 22 with minor amounts of N-(2-butyl-3-(4-(3- (dibutylamino)propoxy)benzoyl)benzofuran-5-yl) methanesulfonamide (1).
In 1,4-dioxane at 20℃; for 16.1667h; 2 5.1. mixture of 24 and 25 General procedure: To a solution of 1,3-diketone 14 (R = CH2CH2CH2NBu2) (1.0 g,2.57 mmol) in anh. dioxane (dried over molecular sieves), DIPEA(0.448 mL, 2.57 mmol) was added followed by dropwise addition of the solution of 20 (0.48 g, 2.57 mmol) in dioxane (5 mL) within 17 min. After addition was completed the brown reaction mixture was stirred for 3 h at RT. The solvent was evaporated (water bath 40 °C) to provide the crude mixture of 24 and 25 as a brown oil. It was purified by column chromatography using hexane: ethyl acetate: NEt3 (1:1:0.15; v/v/v) as eluent (product Rf = 0.5). Fractions containing the desired products were combined to provide a mixture of 24 and 25 as light yellow viscous oil (1.08 g, 73%; purity 97.3%). The mixture was used directly in the next step
  • 53
  • [ 627040-50-0 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: magnesium / tetrahydrofuran / 1 h / Reflux 1.2: 2 h / -78 °C 1.3: 20 °C 2.1: sodium carbonate; sodium dodecyl-sulfate / palladium dichloride / water; acetone / 60 °C
Multi-step reaction with 2 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / 0.75 h / -78 °C / Inert atmosphere 1.2: 23 h / 20 °C / Inert atmosphere 2.1: bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; methoxybenzene / 23 h / 80 °C / Inert atmosphere
  • 54
  • [ 1329684-22-1 ]
  • [ 116871-21-7 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
82% With trifluoroacetic anhydride for 15h; Reflux; Preparation of N-(2-Butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl)methanesulfonamide (10) To a solution of 9 (5.0 mmol, 1.55 g) in trifluoroacetic anhydride (100 mmol, 21.0 g) was added N-(3-phenoxypropyl)-N-butylbutan-1-amine (5.0 mmol, 1.32 g) and polyphosphoric acid (5.0 mmol, 1.69 g). The mixture was refluxed for 15 h and then the solvents were evaporated. The residue was dissolved in CH2Cl2 (20 mL), and then the mixture was adjusted pH to 5 with 2 M aqueous NaOH. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic phase was washed with brine, dried over Na2SO4 and evaporated in vacuo. The residue was purified by chromatography on a silica gel column (AcOEt/PE = 1/2) to afford 10 (2.27 g, 82%) as a white solid. mp 65.5-66 oC (lit.6 mp 65.3 oC); 1H NMR (400 MHz, CDCl3) δ 0.86-0.90 (m, 9H), 1.27-1.31 (m, 6H), 1.42-1.47 (m, 4H), 1.69-1.73 (m, 2H), 1.93-1.96 (m, 2H), 2.44 (t, J = 7.2 Hz,4H), 2.64 (t, J = 7.2 Hz, 2H), 2.81 (t, J = 7.2 Hz, 2H), 2.90 (s, 3H), 4.07 (t, J = 5.6 Hz, 2H), 7.05-7.78 (m, 7H).
70% Stage #1: 2-butyl-5-(methanesulfonamido)benzofuran-3-carboxylic acid; N-(3-phenoxypropyl)-N-butylbutan-1-amine With phosphoric acid; trifluoroacetic anhydride for 20h; Reflux; Stage #2: With sodium hydroxide In dichloromethane Cooling; 18 Trifluoroacetic anhydride (60 eq) and 85% phosphoric acid (7 eq) are added to 2-butyl-5- (methylsulfonamido)benzofuran-3-carboxylic acid (15, 1 eq) followed by the addition of N-(3- phenoxypropyl)-N-butylbutan-1-amine (11 , 1.2 eq). The mixture is refluxed for 20 hours and then the solvents are evaporated. The residue is dissolved in dichloromethane and added into a cold mixture of sodium hydroxide and dichloromethane. The pH is set to 8 and the phases are separated. The organic layer is washed with water dried over anhydrous Na2S04 and evaporated to give the title compound in 70 % yield.
  • 55
  • [ 1329684-25-4 ]
  • [ 116871-21-7 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
72% Stage #1: 2-butyl-5-(methanesulfonamido)benzofuran-3-carbonyl chloride; N-(3-phenoxypropyl)-N-butylbutan-1-amine With aluminum (III) chloride In dichloromethane Reflux; Stage #2: With water; sodium hydrogencarbonate In dichloromethane at 25℃; 17 2-Butyl-5-(methylsulfonamido)benzofuran-3-carbonyl chloride (16, 1 eq) is dissolved in dichloromethane. N-(3-phenoxypropyl)-N-butylbutan-1-amine (11 , 1 eq) and aluminum chloride (4.5 eq) are added. The mixture is refluxed overnight. The reaction mixture is then cooled to 25 °C and saturated aqueous solution of sodium bicarbonate is added slowly while stirring vigorously. Dichloromethane and potassium sodium tartrate solution are added and the phases are separated. The organic phase is washed with 1 M sodium hydroxide and water, dried over anhydrous Na2S04 and evaporated to give the title compound in 72 % yield.
  • 56
  • [ 106-48-9 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1.1: Tri-n-octylamine / tin(IV) chloride / toluene / 100 °C / Inert atmosphere 2.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere 3.1: sodium hydroxide / methanol / 0.5 h / Reflux 4.1: triethylamine; p-toluenesulfonyl chloride / benzene / Inert atmosphere; Reflux 5.1: bis(dibenzylideneacetone)-palladium(0); bis(tri-t-butylphosphine)palladium(0) / toluene / 2 h / 100 °C / Inert atmosphere 6.1: hydrogenchloride; water / toluene; diethyl ether 6.2: pH 10 7.1: triethylamine / dichloromethane / 0.5 h / 10 °C / Inert atmosphere 8.1: aluminum (III) chloride / dichloromethane / 0 - 10 °C 9.1: sodium hydroxide / tetrahydrofuran / 3 h / 20 °C
Multi-step reaction with 9 steps 1.1: trifluoroacetic acid / 20 h / 0 - 60 °C 1.2: 1 h / 20 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere 3.1: sodium hydroxide / methanol / 0.5 h / Reflux 4.1: triethylamine; p-toluenesulfonyl chloride / benzene / Inert atmosphere; Reflux 5.1: bis(dibenzylideneacetone)-palladium(0); bis(tri-t-butylphosphine)palladium(0) / toluene / 2 h / 100 °C / Inert atmosphere 6.1: hydrogenchloride; water / toluene; diethyl ether 6.2: pH 10 7.1: triethylamine / dichloromethane / 0.5 h / 10 °C / Inert atmosphere 8.1: aluminum (III) chloride / dichloromethane / 0 - 10 °C 9.1: sodium hydroxide / tetrahydrofuran / 3 h / 20 °C
  • 57
  • [ 497225-66-8 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: potassium phosphate / copper(l) iodide; dimethylaminoacetic acid / N,N-dimethyl-formamide / Reflux 2: aluminum (III) chloride / dichloromethane / 0 - 10 °C 3: sodium hydroxide / tetrahydrofuran / 3 h / 20 °C
Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 20 - 30 °C / Inert atmosphere 2: caesium carbonate; bis(dibenzylideneacetone)-palladium(0); tert-butyl XPhos / 1,4-dioxane / 24 h / Inert atmosphere; Sealed tube; Reflux
  • 58
  • (5-amino-2-butyl-1-benzofuran-3-yl)[4-[3-(di-n-butylamino)propoxy]phenyl]-methanone dihydrochloride [ No CAS ]
  • [ 124-63-0 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
With tetrabutyl-ammonium chloride In toluene at 80 - 90℃; for 5.5h; 1 1 g of (5-amino-2-butyl)-l -benzofuran-3-yl)[4-[3'-(di-n-butylamino)propoxy]-phenyl]- methanone dihydrochloride salt and 0,12 g of tetrabutylammonium chloride is added to 10 ml of toluene. It is heated under stirring to 80-90 °C and at this temperature 0.41 g of methanesulfonyl chloride is added in 30 minutes. The mixture is stirred at 80-90 °C for 5 hours. The mixture is cooled to room temperature and 10 ml of ethyl acetate and 10 ml of water are added. The organic layer is separated and the aqueous layer is extracted with 5 ml of ethyl acetate. The combined organic layers are dried on Na2S04 and evaporated.Yield: 1.07 g (99.5 %).This product is purified by forming its oxalate salt as follows: to the residue 4 ml of methylethyl ketone is added and the mixture heated to 70 °C . To this solution 0.22 g of oxalic acid dissolved in 2.5 ml of methylethyl ketone is added at 70° C. After cooling to 20 °C in 6 hours the mixture is stirred at 10 °C for 1 hour and filtered. To the obtained oxalate salt 3.5 ml of water and 5 ml of dichloromethane and 0.59 g of potassium carbonate are added. After stirring for 30 minutes the separated potassium oxalate is filtered and washed with 3 ml of; dichloromethane and the solvent is evaporated.Mass of purified product 0.98 g (92 %).Purity of the obtained title product: 99.8 % (HPLC).HNMR (DMSO): 0.8-0.9ppm (m,9H); 1.2-1.5pp (m, 10H); 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, 3H); 4.15ppm (t, J=6.2Hz, 2H); 7.09ppm (d, J=8.8Hz, 2H); 7.24ppm (dd, J=8.9, 2.2Hz, 1H); 7.34ppm (d, J=2.1Hz; 1H); 7.65ppm (d, J=8.8Hz, 1H); 7.81ppm (d, J=8.8Hz, 2H)
  • 59
  • [ 141644-91-9 ]
  • [ 75-75-2 ]
  • [ 7143-01-3 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
Stage #1: (5-amino-2-butyl-benzofuran-3-yl)-[4-(3-dibutylamino-propoxy)-phenyl]-methanone; methanesulfonic acid In dichloromethane Stage #2: Methanesulfonic anhydride With N-benzyl-N,N,N-triethylammonium chloride In n-heptane at 80 - 90℃; for 5.5h; Stage #3: With sodium hydrogencarbonate In n-heptane; ethyl acetate 4 0.9 g of (5-amino-2-butyl)-l-benzofuran-3-yl)[4-[3-(di-n-butylamino)propoxy]- phenyl] methanone is dissolved in 10 ml of dichloromethane. 0.37 g of methanesulfonic acid is added in 5 minutes and the, mixture is stirred for 5 minutes. The solvent is evaporated. To the residual salt mixed with 10 ml of heptane and 0.1 1 g of triethylbenzyl ammonium chloride is added and the mixture is heated to 80-90 °C. At this temperature 0.62 g of methansulfonic anhydride is added in 5 minutes and the mixture is stirred at this temperature for additional 5 hours. After cooling to room temperature 15 ml of ethyl acetate and 1 ml of sodium hydrocarbonate (5%) is added. The organic layer is washed with 5 ml of water and evaporated. Yield: 0.98 g (94.8 %). This product is purified through its oxalate salt according to example 1 (yield: 90.6%). Purity of the obtained title product (HPLC): 99.8 %.
  • 60
  • [ 778-28-9 ]
  • [ 1026754-33-5 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
81% With pyridine; In butan-1-ol; at 70℃; for 14h; The process is performed according to example 2 with the difference that instead of 0.68 g of butyl methanesulfonate 1.0 g of butyl-(4-toluene-sulfonate) (III) is added [prepared according to the method in Synthesis (1979), 11, 882]. Yield of purified product: 0.81 g (81 % ). Purity: 100 % (HPLC).
  • 61
  • [ 109-65-9 ]
  • [ 1026754-33-5 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
88% With pyridine; sodium iodide In butanone for 16.25h; Reflux; 1 lg of N-[2-butyl-3-{4-[(3-amino)propoxy]benzoyl}-l-benzofuran-5-yl]- methansulfonamide (II) is dissolved in 5 ml of methyl ethyl ketone. 0.18 g of pyridine and 0.34 g of sodium iodide are added and the mixture is heated to boiling point. 0.62 g of 1 -bromobutane (III) dissolved in 1 ml of methyl ethyl ketone is added at this temperature during 15 minutes and the mixture is boiled for 16 hours. The reaction mixture is evaporated, 20ml of water and 20 ml of dichloromethane are added. The organic phase is washed with 5 ml of 5 % NaHC03 solution, separated and evaporated. The product is purified by forming its oxalate salt as follows: to the residue 4 ml of methylethyl ketone is added and the mixture heated to70 °C . To this solution 0.24 g of oxalic acid dissolved inl .5 ml of methylethyl ketone is added at 70° C. After cooling to 20 °C in 6 hours the mixture is stirred at 10 °C for 1 hour and filtered. To the obtained oxalate salt 2.5 ml of water and 4 ml of dichloromethane and 0.63g of potassium carbonate are added. After stirring for 30 minutes the separated potassium oxalate is filtered and washed with 2 ml of dichloromethane and the solvent is evaporated.Yield: l . lg'(88 %). Purity of the oxalate salt: 99.8 % (HPLC).1H NMR(DMSO): 0.8-0.9 ppm (m, 9H); 1.2-1.5 ppm (m, 10H); 1.67 ppm (5', 2H); 1.87 ppm (5', 2H); 2.38 ppm (t, J=7.2,Hz, 4H); 2.57 ppm (m, 2H); 2.88 ppm (t, J=7.5Hz, 2H); 2.91 ppm (s, 3H); 9.51 ppm (t, J=6.2Hz, 2H); 7.09 ppm (d, J=8.8Hz, 2H); 7.24 ppm (dd, J=8.9, 2.2Hz, lH); 7.38 ppm (d, J=2.1Hz, 1H); 7.65 ppm (d, J=8.8Hz, 1H); 7.81 ppm (d, J=8.8Hz, 2H)
With pyridine; sodium iodide In butanone for 16.25h; Reflux; 1 Example 1 N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-1-benzofuran-5-yl]methanesulfonamide (I) 1 g of N-[2-butyl-3-{4-[(3-amino)propoxy]benzoyl}-1-benzofuran-5-yl]-methansulfonamide (II) is dissolved in 5 ml of methyl ethyl ketone. 0.18 g of pyridine and 0.34 g of sodium iodide are added and the mixture is heated to boiling point. 0.62 g of 1-bromobutane (III) dissolved in 1 ml of methyl ethyl ketone is added at this temperature during 15 minutes and the mixture is boiled for 16 hours. The reaction mixture is evaporated, 20 ml of water and 20 ml of dichloromethane are added. The organic phase is washed with 5 ml of 5% NaHCO3, solution, separated and evaporated. The product is purified by forming its oxalate salt as follows: to the residue 4 ml of methylethyl ketone is added and the mixture heated to 70. To this solution 0.24 g of oxalic acid dissolved in 1.5 ml of methylethyl ketone is added at 70° C. After cooling to 20° C. in 6 hours the mixture is stirred at 10° C. for 1 hour and filtered. To the obtained oxalate salt 2.5 ml of water and 4 ml of dichloromethane and 0.63 g of potassium carbonate are added. After stirring for 30 minutes the separated potassium oxalate is filtered and washed with 2 ml of dichloromethane and the solvent is evaporated. [0095] Yield: 1.1 g (88%). Purity of the oxalate salt: 99.8% (HPLC). [0096] 1H NMR (DMSO): 0.8-0.9 ppm (m, 9H); 1.2-1.5 ppm (m, 10H); 1.67 ppm (5′, 2H); 1.87 ppm (5′, 2H); 2.38 ppm (t, J=7.2 Hz, 4H); 2.57 ppm (m, 2H); 2.88 ppm (t, J=7.5 Hz, 2H); 2.91 ppm (s, 3H); 9.51 ppm (t, J=6.2 Hz, 2H); 7.09 ppm (d, J=8.8 Hz, 2H); 7.24 ppm (dd, J=8.9, 2.2 Hz, 1H); 7.38 ppm (d, J=2.1 Hz, 1H); 7.65 ppm (d, J=8.8 Hz, 1H); 7.81 ppm (d, J=8.8 Hz, 2H)
  • 62
  • [ 1912-32-9 ]
  • [ 1026754-33-5 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
79% With pyridine; In butan-1-ol; at 70℃; for 14h; 0.8 g of N- [2-butyl-3 - { 4- [(3 -amino)propoxy] benzoyl } - 1 -benzofuran-5- yl]methanesulfonamide (II) is dissolved in 5 ml of n-butanol. 0.15 g of pyridine is added and the mixture is heated to 70 C at this temperature 0.68 g of butyl-methanesulfohate (III) dissolved in 1 ml of n-butanol is added during 15 minutes and the mixture is kept at 70 C for 14 hours. [The methanesulfonate is prepared according to the procedure described in J. of Steroid Biochemistry and Molecular Biology 80 (2002) 429-440.] The reaction mixture is evaporated and 20 ml of dichloromethane and 10 ml of water is added. The phases are separated. The organic phase is washed with 10ml of NaHC03 of 5 %. The organic phase is evaporated. The product is purified by on silica gel (ethyl acetate/hexane; 1 :3 v/v ).Yield: 0.79 g (79 %). Purity: 100 % (HPLC).The product is identical with the compound prepared in example 1.
79% With pyridine; In butan-1-ol; 0.8 g of N-[2-butyl-3-{4-[(3-amino)propoxy]benzoyl}-1-benzofuran-5-yl]methanesulfonamide (II) is dissolved in 5 ml of n-butanol. 0.15 g of pyridine is added and the mixture is heated to 70 C. at this temperature 0.68 g of <strong>[1912-32-9]butyl-methanesulfonate</strong> (III) dissolved in 1 ml of n-butanol is added during 15 minutes and the mixture is kept at 70 C. for 14 hours. [The methanesulfonate is prepared according to the procedure described in J. of Steroid Biochemistry and Molecular Biology 80 (2002) 429-440.] The reaction mixture is evaporated and 20 ml of dichloromethane and 10 ml of water is added. The phases are separated. The organic phase is washed with 10 ml of NaHCO3 of 5%. The organic phase is evaporated. The product is purified by on silica gel (ethyl acetate/hexane; 1:3 v/v). [0098] Yield: 0.79 g (79%). Purity: 100% (HPLC).
  • 63
  • [ 1401355-74-5 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 2: sodium iodide; pyridine / butanone / 16.25 h / Reflux
Multi-step reaction with 2 steps 1: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 2: pyridine / butan-1-ol / 14 h / 70 °C
Multi-step reaction with 2 steps 1: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 2: pyridine / butan-1-ol / 14 h / 70 °C
Multi-step reaction with 2 steps 1.1: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 2.1: sodium tetrahydroborate / 8 h / 55 °C 2.2: 0 °C
Multi-step reaction with 2 steps 1: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 2: sodium tetrahydroborate / 8 h / 55 °C
Multi-step reaction with 2 steps 1: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 2: triacetoxyborohydride / dichloromethane / 12 h / 20 °C
Multi-step reaction with 2 steps 1: N-benzyl-N,N,N-triethylammonium chloride; hydrogenchloride; water / 6 h / 80 - 90 °C 2: sodium tetrahydroborate; boric acid / tetrahydrofuran / 9.25 h / 50 - 55 °C
Multi-step reaction with 4 steps 1: N-benzyl-N,N,N-triethylammonium chloride; hydrogenchloride; water / 6 h / 80 - 90 °C 2: thionyl chloride / dichloromethane / 1.5 h / Reflux 3: dichloromethane / 2 h / 20 °C 4: borane-THF / tetrahydrofuran / 1.25 h / 0 °C / Reflux
Multi-step reaction with 2 steps 1: hydrogen / methanol / 24 h / 25 °C / 7500.75 Torr 2: triacetoxyborohydride / dichloromethane / 12 h / 20 °C
Multi-step reaction with 2 steps 1: hydrogen / methanol / 24 h / 25 °C / 7500.75 Torr 2: pyridine / butan-1-ol
Multi-step reaction with 2 steps 1: hydrogen / methanol / 24 h / 25 °C / 7500.75 Torr 2: pyridine; sodium iodide / butanone / 16.25 h / Reflux

  • 64
  • [ 1401355-75-6 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: pyridine / dichloromethane / 3.17 h / 30 - 35 °C 2: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 3: pyridine / butan-1-ol / 14 h / 70 °C
Multi-step reaction with 3 steps 1: pyridine / dichloromethane / 3.17 h / 30 - 35 °C 2: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 3: pyridine / butan-1-ol / 14 h / 70 °C
Multi-step reaction with 3 steps 1: pyridine / dichloromethane / 3.17 h / 30 - 35 °C 2: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 3: sodium iodide; pyridine / butanone / 16.25 h / Reflux
Multi-step reaction with 3 steps 1.1: pyridine / dichloromethane / 3 h / 30 - 35 °C 2.1: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 3.1: sodium tetrahydroborate / 8 h / 55 °C 3.2: 0 °C
Multi-step reaction with 3 steps 1: pyridine / dichloromethane / 3 h / 30 - 35 °C 2: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 3: triacetoxyborohydride / dichloromethane / 12 h / 20 °C
Multi-step reaction with 3 steps 1: pyridine / dichloromethane / 3 h / 30 - 35 °C 2: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 3: sodium tetrahydroborate / 8 h / 55 °C
Multi-step reaction with 3 steps 1: pyridine / dichloromethane / 3.08 h / 30 - 35 °C 2: N-benzyl-N,N,N-triethylammonium chloride; hydrogenchloride; water / 6 h / 80 - 90 °C 3: sodium tetrahydroborate; boric acid / tetrahydrofuran / 9.25 h / 50 - 55 °C
Multi-step reaction with 5 steps 1: pyridine / dichloromethane / 3.08 h / 30 - 35 °C 2: N-benzyl-N,N,N-triethylammonium chloride; hydrogenchloride; water / 6 h / 80 - 90 °C 3: thionyl chloride / dichloromethane / 1.5 h / Reflux 4: dichloromethane / 2 h / 20 °C 5: borane-THF / tetrahydrofuran / 1.25 h / 0 °C / Reflux
Multi-step reaction with 3 steps 1: pyridine / dichloromethane / 3.17 h / 30 - 35 °C 2: hydrogen / methanol / 24 h / 25 °C / 7500.75 Torr 3: triacetoxyborohydride / dichloromethane / 12 h / 20 °C
Multi-step reaction with 3 steps 1.1: pyridine / dichloromethane / 0.08 h / 30 - 35 °C 1.2: 3.08 h / 30 - 35 °C 2.1: hydrogen / methanol / 24 h / 25 °C / 7500.75 Torr 3.1: pyridine / butan-1-ol
Multi-step reaction with 3 steps 1.1: pyridine / dichloromethane / 0.08 h / 30 - 35 °C 1.2: 3.08 h / 30 - 35 °C 2.1: hydrogen / methanol / 24 h / 25 °C / 7500.75 Torr 3.1: pyridine; sodium iodide / butanone / 16.25 h / Reflux

  • 65
  • [ 1401355-76-7 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: hydrogen / palladium 10% on activated carbon / methanol / 50 °C / 3750.38 Torr 2: pyridine / dichloromethane / 3.17 h / 30 - 35 °C 3: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 4: sodium iodide; pyridine / butanone / 16.25 h / Reflux
Multi-step reaction with 4 steps 1: hydrogen / palladium 10% on activated carbon / methanol / 50 °C / 3750.38 Torr 2: pyridine / dichloromethane / 3.17 h / 30 - 35 °C 3: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 4: pyridine / butan-1-ol / 14 h / 70 °C
Multi-step reaction with 4 steps 1: hydrogen / palladium 10% on activated carbon / methanol / 50 °C / 3750.38 Torr 2: pyridine / dichloromethane / 3.17 h / 30 - 35 °C 3: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 4: pyridine / butan-1-ol / 14 h / 70 °C
Multi-step reaction with 4 steps 1.1: hydrogen / palladium 10% on activated carbon / 2 h / 50 °C / 3750.38 Torr 2.1: pyridine / dichloromethane / 3 h / 30 - 35 °C 3.1: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 4.1: sodium tetrahydroborate / 8 h / 55 °C 4.2: 0 °C
Multi-step reaction with 4 steps 1: hydrogen / palladium 10% on activated carbon / 2 h / 50 °C / 3750.38 Torr 2: pyridine / dichloromethane / 3 h / 30 - 35 °C 3: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 4: triacetoxyborohydride / dichloromethane / 12 h / 20 °C
Multi-step reaction with 4 steps 1: hydrogen / palladium 10% on activated carbon / 2 h / 50 °C / 3750.38 Torr 2: pyridine / dichloromethane / 3 h / 30 - 35 °C 3: hydrogen / Raney-Ni / methanol / 24 h / 25 °C / 7500.75 Torr 4: sodium tetrahydroborate / 8 h / 55 °C
Multi-step reaction with 4 steps 1: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 50 °C / 3750.38 Torr 2: pyridine / dichloromethane / 3.08 h / 30 - 35 °C 3: N-benzyl-N,N,N-triethylammonium chloride; hydrogenchloride; water / 6 h / 80 - 90 °C 4: sodium tetrahydroborate; boric acid / tetrahydrofuran / 9.25 h / 50 - 55 °C
Multi-step reaction with 6 steps 1: palladium 10% on activated carbon; hydrogen / methanol / 2 h / 50 °C / 3750.38 Torr 2: pyridine / dichloromethane / 3.08 h / 30 - 35 °C 3: N-benzyl-N,N,N-triethylammonium chloride; hydrogenchloride; water / 6 h / 80 - 90 °C 4: thionyl chloride / dichloromethane / 1.5 h / Reflux 5: dichloromethane / 2 h / 20 °C 6: borane-THF / tetrahydrofuran / 1.25 h / 0 °C / Reflux
Multi-step reaction with 4 steps 1: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 50 °C / 3750.38 Torr 2: pyridine / dichloromethane / 3.17 h / 30 - 35 °C 3: hydrogen / methanol / 24 h / 25 °C / 7500.75 Torr 4: triacetoxyborohydride / dichloromethane / 12 h / 20 °C
Multi-step reaction with 4 steps 1.1: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 50 °C / 3750.38 Torr 2.1: pyridine / dichloromethane / 0.08 h / 30 - 35 °C 2.2: 3.08 h / 30 - 35 °C 3.1: hydrogen / methanol / 24 h / 25 °C / 7500.75 Torr 4.1: pyridine / butan-1-ol
Multi-step reaction with 4 steps 1.1: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 50 °C / 3750.38 Torr 2.1: pyridine / dichloromethane / 0.08 h / 30 - 35 °C 2.2: 3.08 h / 30 - 35 °C 3.1: hydrogen / methanol / 24 h / 25 °C / 7500.75 Torr 4.1: pyridine; sodium iodide / butanone / 16.25 h / Reflux

  • 66
  • [ 1401355-77-8 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: sodium hydroxide / methanol / 3 h / Reflux 1.2: pH 6 2.1: pyridine / butan-1-ol / 14 h / 70 °C
Multi-step reaction with 2 steps 1.1: sodium hydroxide / methanol / 3 h / Reflux 1.2: pH 6 2.1: pyridine / butan-1-ol / 14 h / 70 °C
Multi-step reaction with 2 steps 1.1: sodium hydroxide / methanol / 3 h / Reflux 1.2: pH 6 2.1: sodium iodide; pyridine / butanone / 16.25 h / Reflux
Multi-step reaction with 2 steps 1.1: sodium hydroxide; water / methanol / 3 h / pH 6 / Reflux 2.1: sodium tetrahydroborate / 8 h / 55 °C 2.2: 0 °C
Multi-step reaction with 2 steps 1: sodium hydroxide; water / methanol / 3 h / pH 6 / Reflux 2: sodium tetrahydroborate / 8 h / 55 °C
Multi-step reaction with 2 steps 1: sodium hydroxide; water / methanol / 3 h / pH 6 / Reflux 2: triacetoxyborohydride / dichloromethane / 12 h / 20 °C
Multi-step reaction with 2 steps 1: sodium hydroxide / methanol / 3 h / Reflux 2: triacetoxyborohydride / dichloromethane / 12 h / 20 °C
Multi-step reaction with 2 steps 1: sodium hydroxide / methanol / 3 h / Reflux 2: pyridine / butan-1-ol
Multi-step reaction with 2 steps 1: sodium hydroxide / methanol / 3 h / Reflux 2: pyridine; sodium iodide / butanone / 16.25 h / Reflux

  • 67
  • [ 1401355-78-9 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
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: 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

  • 68
  • [ 1026754-33-5 ]
  • [ 123-72-8 ]
  • [ 107-92-6 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
Stage #1: N-[2-butyl-3-{4-[(3-amino)propoxy]benzoyl}-1-benzofuran-5-yl]-methansulfonamide; butyraldehyde; butyric acid With sodium tetrahydroborate at 55℃; for 8h; Stage #2: With potassium hydroxide In water at 0℃; 2 1 g of N- [2-butyl-3 - {4- [(3 -amino)propoxy]benzoyl } - 1 -benzofuran-5 - yl]methanesulfonamide is dissolved in 12 ml of butanoic acid. 0.2 g of butyraldehyde and 0.26 g of sodium borohydride are added. The mixture is stirred at 55°C for 8 hours. Cooled down to 0°C and 20 ml of water is added. The mixture is made strongly basic with solid potassium hydroxide and extracted with 2 x 20 ml of dichloromethane. The solution is washed with 25 ml of water, with 15 ml of 5% NaHC03 and with 10 ml of water, and evaporated.Yield: 1.10 g (85.9%)The product is purified through its oxalate salt according to Example 1 (87%).Purity of product: 99.6% (HPLC). The product is identical with the compound prepared in example 1.
  • 69
  • [ 1026754-33-5 ]
  • [ 123-72-8 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
89% With triacetoxyborohydride In dichloromethane at 20℃; for 12h; 1 1 g of N- [2-buty 1-3 - { 4- [(3 -amino)propoxy]benzoyl } - 1 -benzofuran-5 -yl] - methansulfonamide is dissolved in 30 ml of dichloromethane. 0.5 g of butyraldehide and 1.8 g of triacetoxyborohydride is added, and the reaction mixture is stirred at 20°C for 12 hours. The reaction mixture is evaporated and the residue is dissolved in isopropyl acetate. The solution is washed with 20 ml of water, with 10 ml of 5% NaHC03 solution and with 10 ml of water. The solvent is evaporated.Yield: 1.21 g (94.5%).This product is purified by forming its oxalate salt as follows: to the residue 6 ml of methylethyl ketone is added and the mixture heated to 70 °C. To this solution 0.26 g of oxalic acid dissolved in 2.5 ml of methylethyl ketone is added at 70° C. After cooling to 20 °C in 6 hours the mixture, is stirred at 10 °C for 1 hour and filtered. To the obtained oxalate salt 4 ml of water and 6 ml of dichloromethane and 0.70 g of potassium carbonate are added. After stirring for 30 minutes the separated potassium oxalate is filtered and washed with 3 ml ofdichloromethane and the solvent is evaporated. 1 Mass of purified product 1.08 g (89 %).Purity of product: 99.7% (HPLC).1H NMR(DMSO): 0.8-0.9ppm (m, 9H); 1.2-1.5ppm (m, 10H); 1.67ppm (5 2H); 1.87ppm (5 2H); 2.38ppm (t, J=7.2 Hz, 4H); 2.57ppm (m, 2H); 2.88ppm (t, J=7.5Hz, 2H); 2.91ppm (s, 3H); 9.51ppm (t, J=6.2Hz, 2H); 7.09ppm (d, J=8.8Hz, 2H); 7.24ppm (dd, J=8.9, 2.2Hz, 1H); 7.38ppm (d, J=2.1Hz, 1H); 7.65ppm(d, J=8.8Hz, lH); 7.81ppm (d, J=8.8Hz,.2H)
1.08 g With triacetoxyborohydride In dichloromethane at 20℃; for 12h; 1 Example 1. N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-1-benzofuran-5-yl]methanesulfonamide (I) [0126] 1 g of N-[2-butyl-3-{4-[(3-amino)propoxy]benzoyl}-1-benzofuran-5-yl]-methansulfonamide is dissolved in 30 ml of dichloromethane. 0.5 g of butyraldehide and 1.8 g of triacetoxyborohydride is added, and the reaction mixture is stirred at 20° C. for 12 hours. The reaction mixture is evaporated and the residue is dissolved in isopropyl acetate. The solution is washed with 20 ml of water, with 10 ml of 5% NaHCO3 solution and with 10 ml of water. The solvent is evaporated. [0127] Yield: 1.21 g (94.5%). [0128] This product is purified by forming its oxalate salt as follows: to the residue 6 ml of methylethyl ketone is added and the mixture heated to 70° C. To this solution 0.26 g of oxalic acid dissolved in 2.5 ml of methylethyl ketone is added at 70° C. After cooling to 20° C. in 6 hours the mixture is stirred at 10° C. for 1 hour and filtered. To the obtained oxalate salt 4 ml of water and 6 ml of dichloromethane and 0.70 g of potassium carbonate are added. After stirring for 30 minutes the separated potassium oxalate is filtered and washed with 3 ml of dichloromethane and the solvent is evaporated. [0129] Mass of purified product 1.08 g (89%). [0130] Purity of product: 99.7% (HPLC). [0131] 1H NMR (DMSO): 0.8-0.9 ppm (m, 9H); 1.2-1.5 ppm (m, 10H); 1.67 ppm (5′, 2H); 1.87 ppm (5′, 2H); 2.38 ppm (t, J=7.2 Hz, 4H); 2.57 ppm (m, 2H); 2.88 ppm (t, J=7.5 Hz, 2H); 2.91 ppm (s, 3H); 9.51 ppm (t, J=6.2 Hz, 2H); 7.09 ppm (d, J=8.8 Hz, 2H); 7.24 ppm (dd, J=8.9, 2.2 Hz, 1H); 7.38 ppm (d, J=2.1 Hz, 1H); 7.65 ppm (d, J=8.8 Hz, 1H); 7.81 ppm (d, J=8.8 Hz, 2H)
  • 70
  • [ 1026754-33-5 ]
  • [ 107-92-6 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
Stage #1: N-[2-butyl-3-{4-[(3-amino)propoxy]benzoyl}-1-benzofuran-5-yl]-methansulfonamide; butyric acid With sodium tetrahydroborate at 55℃; for 8h; Stage #2: With water; potassium hydroxide 3 1 g of N- [2-butyl-3 - {4- [(3 -amino)propoxy] benzoyl }- 1 -benzofuran-5 - yl]methanesulfonamide is dissolved in 12 ml of butanoic acid and 0.39 g of sodium borohydride are added. The mixture is stirred at 55°C for 8 hours. Cooled down to 0°C and 20 ml of water is added. The mixture is made strongly basic with solid potassium hydroxide and extracted with 2 x 20 ml of dichloromethane. The solution is washed with 25 ml of water, with 15 ml of 5% NaHC03 and with 10 ml of water, and evaporated.Yield: 0.88 g (69%)The product is purified through its oxalate salt according to Example 1 (81%).Purity of product: 99.4% (HPLC). The product is identical with the compound prepared in example 1.
  • 71
  • [ 1420180-98-8 ]
  • [ 111-92-2 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogen In methanol at 50℃; for 4h; 2 X-[2-butyl-3- {4-[(3-dibut)'lamino)propoxy]benzoyl } - l -benzofuran-5-yl]- methanesulfonamide (I) 1 g of N- {2-butyl-3-[4-(3 -oxopropoxy)benzoyl]- l -benzofuran-5-yl } - methanesulfonamide and 0.30 g of dibutylamine were dissolved in 15 ml methanol, 0.25 g of Raney Xi was added and the mixture was stirred under hydrogen pressure of 10 bar at 50°C for 4 hours. When no hydrogen consumption was observed the mixture was worked up as follows: the reaction mixture was cooled down to ambient temperature, the hydrogen pressure was led out and the reactor was flushed with nitrogen, After this the catalyst was filtered out and the solvent was evaporated. The residue was dissolved in isopropyl acetate and washed with 1 5 ml of water with 10 ml of 5% aHC03 solution and with 10 ml of water.- The solvent was evaporated. Yield: 1 .24 g ( 101 %) The product was purified by its oxalate salt as follows: to the residue 4 ml of methylethyl ketone is added and the mixture heated to70 °C . To this solution 0.24 g of oxalic acid dissolved in l .5 ml of methylethyl ketone is added at 70° C. After cooling to 20 °C in 6 hours the mixture is stirred at 10 °C for 1 hour and filtered. To the obtained oxalate salt 2,5 ml of water and 4 ml of dichloromethane and 0.63 g of potassium carbonate are added. After stirring for 30 minutes the separated potassium oxalate is filtered and washed with 2 ml of dichloromethane and the solvent is evaporated. Yield of purified product: 1.14 g (91%). Purity of product: 99.8% (HPLC) lH R(D SO): 0.8-0.9ppm (m, 9H); 1.2-1.5ppm (m, 10H); 1.67ppm (5 2H); 1 ,87ppm (5 2H); 2.38ppm (ΐ. J=7.2Hz; 4H); 2.57ppm (m, 2H); 2.88ppm (t, J=7.5Hz, 2H); 2.91ppm (s, 3H); 9.51ppm (t, J=6.2Hz, 2H); 7.09ppm (d, J=8.8Hz, 2H); 7.24ppm (dd, J=8.9, 2.2Hz.1H); 7.38ppm (d, J=2.1Hz, 1H); 7.65ppm (d, J=8.8Hz, 1H); 7.81ppm (d, J=8.8Hz, 2'H)
  • 72
  • [ 1421311-24-1 ]
  • [ 111-92-2 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
83% With sodium tetrahydroborate; boric acid In tetrahydrofuran at 50 - 55℃; for 9.25h; 2 1 g of 3-[4-(-{2-butyl-5-[(methanesulfonyl)-amino]-l-benzofuran-3- yl}carbonyl)phenoxy] -propanoic acid (II) was dissolved in 20 ml of THF and 0.30 g of dibutylamine was added. After stirring of 1 minute 0.64 g of methanesulfonic acid was added to the mixture and it was warmed to 50 °C. 0.34 g of sodium borohydride was added at 50- 55 °C in 15 minutes and the mixture was stirred at this temperature for 9 hours. The reaction mixture was cooled down, and it was made alkaline (pH= 10) with 2N sodium hydroxide. The solvent was evaporated, 15 ml of dichloromethane and 15 ml of water were added. The phases were separated. The dichloromethane phase was washed with 2 x 15 ml of water and the solvent was evaporated. Yield: 1.05 g. The product was purified by column chromatography on silica gel (ethyl acetate/heptanes = 1 :3) Yield: 82% Purity : 99.9% (HPLC). lH NMR(DMSO): 0.8-0.9 ppm (m, 9H); 1.2-1.5 ppm (m, 10H); 1.67 ppm (5 2H); 1.87 ppm (5', 2H); 2.38 ppm (t, J=7.2 Hz, 4H); 2.57 ppm (m, 2H); 2.88 ppm (t, J=7.5Hz, 2H); 2.91 ppm (s, 3H); 9.51 ppm (t, J=6.2Hz, 2H); 7.09 ppm (d, J=8.8Hz, 2H); 7.24 ppm (dd, J=8.9, 2.2Hz, 1H); 7.38 ppm (d, J=2.1Hz, 1H); 7.65 ppm (d, J=8.8Hz, 1H); 7.81 ppm (d, J=8.8Hz, 2H); The process was performed according to example 1 with the difference that instead of methanesulfonic acid 0,40 g of boric acid was added. Yield of purified product: 83%. Purity: 99.9% (HPLC).
  • 73
  • [ 1421316-69-9 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
92% With borane-THF In tetrahydrofuran at 0℃; for 1.25h; Reflux; 3 N- [2-butyl-3 - {4- [(3 -dibutylamino)propoxy] benzoyl } - 1 -benzofuran-5 - yl]methanesulfonamide (I) 1 g of N.N-dibutyl-3-[4-({2-butyl-5-[(methylsulfonyl])amino]-l-benzofuran-3- yl}carbonyl)-phenoxy]propanamide (II) was dissolved in 5 ml of THF and was added at 0 °C over 15 minutes to 3 ml of 1.67 M borane solution in THF. The mixture was warmed to boiling point and maintained there for 1 hour. The mixture was cooled down to room temperature and 3 ml of 1 M aq hydrochloric acid was added slowly. The THF was removed by evaporation at atmospheric pressure. NaOH pellets were added to make basic the mixture. The aqueous mixture was extracted with 3 x 5 ml of dichloromethane. The dichloromethane phase was washed with 1 x 5 ml of water and evaporated. Yield 0.96 g. The product was purified by chromatography (silica gel; ethyl acetate/hexane; 1 :3 v/v). Yield of purified product: 0.92 g (92%) Purity: 100% (HPLC)
  • 74
  • [ 1356536-08-7 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide In methanol at 65℃; for 2h; 2 N-[2-n-butyl-3-[4-[-3(-di-n-butylamino)propoxy]benzoyl]-1-benzofuran-5-yl]-methanesulfonamide (I) EXAMPLE 2 N-[2-n-butyl-3-[4-[-3(-di-n-butylamino)propoxy]benzoyl]-1-benzofuran-5-yl]-methanesulfonamide (I) [0046] 2 g of N-[2-n-butyl-3-[4-[3 (-di-n-butylamino)propoxy]benzoyl]-1-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 dissolution 0.89 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 2×25 ml of water. The solvent is removed by evaporation. [0047] Mass of the raw product: 1.68 g (94.8%). [0048] Purity (HPLC): 96.7%. [0049] The raw product is purified through its oxalate salt. [0050] Purity of the liberated dronedarone base: 100%. [0051] The product is identical with that obtained in Example 1.
  • 75
  • N-[2-n-butyl-3-[4-[3(-di-n-butylamino)propoxyl]benzoyl]-1-benzofuran-5-yl]-N′-benzoyl-methanesulfonamide [ No CAS ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride In methanol at 55 - 60℃; for 3h; 3 N-[2-n-butyl-3-[4-[-3(-di-n-butylamino)propoxy]benzoyl]-1-benzofuran-5-yl]-methanesulfonamide (I) N-[2-n-butyl-3-[4-[-3(-di-n-butylamino)propoxy]benzoyl]-1-benzofuran-5-yl]-methanesulfonamide (I) [0052] 2.5 g of N-[2-n-butyl-3-[4-[3 (-di-n-butylamino)propoxyl]benzoyl]-1 -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 2×20 ml of 5% sodium carbonate solution, then with 2×20 ml of water. The solvent is removed by evaporation. [0053] Mass of the raw product: 2.02 g (95.8%). [0054] The raw product is purified through its oxalate salt. [0055] Purity of the oxalate salt: 100%. [0056] The product is identical with that obtained in Example 1.
  • 76
  • [ 1448297-08-2 ]
  • [ 1448297-07-1 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
96.1% With copper(l) iodide In 2,4,6-trimethyl-pyridine at 100℃; for 10h; 2 N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-benzofuran-5-yl]-methanesulfonamide (I) 1.7 g of N-[2-butyl-3-(4-chlorobenzoyl)-1-benzofuran-5-yl])methanesulfonamide (2a), 0.8 g of powered Cul was added to a solution of 1.05 g of dibutylamino-propanol sodium salt dissolved in 8 ml of collidine. The mixture was stirred at 100°C for 10 hours. After cooling the solution was filtered and the reaction mixture was evaporated in reduced pressure. 10 ml of water was added and the mixture was extracted with 10 ml of dichloromethane. The dichloromethane phase was washed with 10 ml of sodium carbonate of 5% and with 2 x 10 ml of water. After drying the dichloromethane was evaporated. Mass of product: 2.25 g (96.1%). The product was identical with the compound prepared in Example 1.
  • 77
  • [ 1448297-09-3 ]
  • [ 1448297-10-6 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
89.7% With copper(l) iodide In dimethyl sulfoxide at 130℃; for 0.5h; 3 N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}benzofuran-5-yl]-methanesulfonamide (I) 2.1 g of N-[2-butyl-3-(4-iodobenzoyl)-l-benzofuran-5-yl])methanesulfonamide (2c) and 1.14 g of dibutylamino-propanol potassium salt was dissolved in 10 ml of dimethyl-sulfoxide. The mixture was stirred for 30 minutes at 130°C. After cooling to the mixture 15 ml of water was added and extracted with 2 x 10 ml of dichloromethane. After drying the dichloromethane was evapored and purified using column chromatography on silica gel (eluent: ethyl acetate/hexane 1:3). Mass of product: 2.1 g (89.7%). The product was identical with the compound prepared in Example 1.
  • 78
  • [ 1448297-11-7 ]
  • [ 1448297-10-6 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
97.4% In N,N,N,N,N,N-hexamethylphosphoric triamide at 90℃; for 20h; 4 N-[2-butyl-3-{4-[(3-dibuylamino)propoxy]benzoyl}-benzofuran-5-yl]-methanesulfonamide (I) 2.7 of N-[2-butyl-3-(4-bromobenzoyl)-l-benzofuran-5-yl])methanesulfonamide (2b) and 1.36 of dibutylamino-propanol potassium salt was dissolved in 25 ml of hexamethylphosphor-amide and the reaction mixture was stirred et 90°C for 20 hours. The mixture was cooled, 50 ml of water was added and the mixture was extracted with 2 x 20 ml of dichloromethane. The dichloromethane was evaporated after drying and purified using column chromatography on silica gel (eluent: ethyl acetate/ hexane 1:3). Mass of product: 3.25 g (97.4%) The product was identical with compound prepared in Example 1.
  • 79
  • [ 2050-51-3 ]
  • [ 1448297-12-8 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
93.6% With potassium hydroxide In N,N-dimethyl-formamide at 40℃; for 9h; 5 N-[2-butyl-3-{4-[(3-dibutylamino)propoxy] benzoyl}-benzofuran-5-yl]-methanesulfonamide (I) 2.4 g of 4-({2-butyl-5-[(methylsulfonyl)amino]-1-benzofuran-3-yl}carbonyl)phenyl-trifluoro-methanesulfonate (2g) was dissolved in the solution of 0.33 g of potassium hydroxide of 85% in abs. dimethylformamide. After complete dissolution 0.98 g of dibutylamino-propanol was added and the mixture was stirred at 40°C for 9 hours and cooled down. The solvent was evaporated and the residue was dissolved in 15 ml of dichloromethane. 10 ml of water was added and the mixture was stirred for 5 minutes. The phases were separated. The dichloromethane was washed with 2 x 10 ml of water and after drying evaporated and purified using column chromatography on silica gel (eluent: ethyl acetate/ hexane 1:3). Mass of product: 2.67 g (93.6%). The product was identical with compound prepared in Example 1.
  • 80
  • [ 2050-51-3 ]
  • [ 1448297-13-9 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
92.7% With sodium hydride In N,N-dimethyl-formamide at 25℃; for 10h; 6 N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-benzofuran-5-yl]-methanesulfonamide (I) 3 g of 4-({2-butyl-5-[(methylsulfonyl)amino]-1-benzofuran-3-yl}carbonyl)phenyl-4-methyl-benzenesulfonate (2h) was added to a dispersion prepared from 0.3 g of sodium hydride of 50% dispersed in 10 ml of dimethylformamide. 1.1 g of dibutylamino-propanol was added and the mixture was stirred at 25°C for 10 hours. The dimethylformamide was evaporated in reduced pressure. 12 ml of water was added and the mixture was extracted with 2 x 10 ml of dichloromethane. The dichloromethane was washed with 10 ml of sodium carbonate of 5% and with 2 x 10 ml of water. The solvent was evaporated and purified using column chromatography on silica gel (eluent: ethyl acetate/ hexane 1:3). Mass of product: 2.78 g (92.7%). The product was identical with compound prepared in example 1.
  • 81
  • [ 1448297-06-0 ]
  • [ 1448297-07-1 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
100% With copper(l) iodide In N,N-dimethyl-formamide at 90 - 100℃; for 25h; 1 N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-benzofuran-5-yl]-methanesulfonamide (I) 2 g of N-[2-butyl-3-(4-fluorobenzoyl)-1-benzofuran-5-yl])methanesulfonamide (2d), 1.0 g of powered Cul was added to a solution of 1.1 g of dibutylamino-propanol sodium salt dissolved in 5 ml of dimethylformamide. The mixture was stirred at 90-100 °C for 25 hours. After cooling the solution was filtered. The dimethylformamide was evaporated in reduced pressure. 10 ml of water was added and the mixture was extracted with 10 ml of dichloromethane. The dichloromethane phase was washed at first with 10 ml of sodium carbonate of 5% then with 2 x 10 ml of water and evaporated. The product was purified by column chromatography on silica gel (eluent: ethyl acetate/ hexane 1:3). Mass of product: 2.86 g (100 %). Purity (HPLC): 99.5 %. 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=7.2Hz, 4H); 2.57 (m, 2H); 2.81(t, J=7.5Hz, 2H); 29.91 (s, 3H); 4.15 (t, J=6.2Hz, 2H); 7.09 (d, J=8.8Hz, 2H); 7.24 (dd, J=8.9, 2.2Hz, 1H); 7.34 (d, H=2.1 Hz, 1H); 7.65 (d, J=8.8Hz, 1H); 7.81 (d, J=8.8Hz, 2H).
  • 82
  • [ 3144-09-0 ]
  • [ 1338547-30-0 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
92.1% With tripotassium phosphate tribasic; copper (I) iodide; N<SUP>1</SUP>,N<SUP>2</SUP>-bis(thiophen-2-ylmethyl)oxalamide In <i>tert</i>-butyl alcohol at 90℃; for 24h; Schlenk technique; Inert atmosphere; 1-3 1. Preparation of Dronedarone The Schlenk reaction flask was equipped with magnetic stirring, and (5-bromo-2-butylbenzofuran-3-yl)(4-(3-(dibutylamino)propoxy)phenyl)methanone was added successively under nitrogen protection. (5.45 g, 10.04 mmol), methanesulfonamide (1.15 g, 12.1 mmol), cuprous iodide (230 mg, 1.2 mmol), potassium phosphate (4.3 g, 20.3 mmol) and N1,N2-bis(thiophen-2-ylmethyl)oxalic diamide (285 mg, 1.02 mmol). The system was replaced with nitrogen twice, and then tert-butanol (12 mL) was added to the reaction system under nitrogen protection. After the addition was completed, the system was replaced with nitrogen three times again, the Schlenk reaction flask was closed, and the system was heated to 90±5°C for rapid stirring and reaction for 24 hours. After the reaction was completed, the system was naturally cooled to room temperature, ethanol (50 mL) was added, stirred for 5 minutes, filtered, the organic solvent was removed from the filtrate under reduced pressure, and the residue was purified by ethyl acetate/heptane column chromatography to obtain dronedarone (white solid). , 5.15g, 92.1%).
78% With Cs2CO3; Palladium(0) bis(dibenzylideneacetone); di-tert-butyl(2’,4’,6’-triisopropyl-[1,1‘-biphenyl]-2-yl)phosphine In 1,4-dioxane for 24h; Inert atmosphere; Sealed tube; Reflux; 1 2-n-Butyl-3-{4-[3-(di-n-butylamino)-propoxy]-benzoyl}-5-methanesulfonamido-benzofuran or dronedarone (compound I: R=CH3; R1=n-C4H9; R2=4-[3-(di-n-butylamino)-propoxy)-phenyl) Example 1 2-n-Butyl-3-{4-[3-(di-n-butylamino)-propoxy]-benzoyl}-5-methanesulfonamido-benzofuran or dronedarone (compound I: R=CH3; R1=n-C4H9; R2=4-[3-(di-n-butylamino)-propoxy)-phenyl) 360 mg of cesium carbonate (1.11 mmol) and 79 mg of methanesulfonamide (0.83 mmol), 9.5 mg of Pd(dba)2 (0.01 mmol) and 14.5 g of 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl (ligand L1) (0.03 mmol) are introduced into a 20 ml tube previously dried in an oven. The tube is sealed with a septum and inerted with argon and then 300 mg of 2-n-butyl-3-{4-[3-(di-n-butylamino)-propoxyl-benzoyl}-5-bromo-benzofuran (compound III) (0.55 mmol) in solution in 2 ml of dioxane are added with a syringe. The reaction medium is then stirred and heated under the reflux temperature of dioxane for 24 hours, while monitoring the progress of the reaction by HPLC. At the end of the reaction, the desired compound I is obtained. Yield: 78% 1H NMR (400 MHz, CDCl3): δ 0.81 (t, J=7.4 Hz, 3H, CH3-CH2-CH2-); 0.91 (t, J=7.4 Hz, 6H, 2*CH3-CH2-CH2-); 1.18-1.28 (m, 2H, CH3-CH2-CH2-); 1.28-1.38 (m, 4H, 2*CH3-CH2-CH2-); 1.62-1.70 (m, 6H, 2*CH3-CH2-CH2-CH2-+CH3-CH2-CH2-CH2-); 2.18-2.22 (m, 2H, -CH2-CH2-O-); 2.80 (t, J=7.4 Hz, 2H, -CH2-CH2-CH2-CH3); 2.88 (s, 3H, CH3-S-); 3.03-3.08 (m, 4H, 2*CH2-CH2-NH+); 3.19-3.24 (m, 2H, NH+-CH2-); 4.19 (t, J=6 Hz, 2H, -CH2-O); 7.09 (d, J=8.8 Hz, 2H, 2*ArH); 7.21 (dd, J=8.8 Hz and 2.4 Hz, 1H, 2*ArH); 7.28 (d, J=2.4 Hz, 1H, 2*ArH); 7.62 (d, J=8.8 Hz, 1H, 2*ArH); 7.79 (d, J=8.8 Hz, 2H, 2*ArH) 13C NMR (DMSO-d6): δ 189.1-164.4-162.6-150.2-134.2-131.3-130.7-127.2-118.7-116.3-114.3-113.1-111.5-65.9-53.2-49.5-38.5-29.3-28.8-27.1-26.4-21.5-19.9-13.3 ppm
  • 83
  • [ 3144-09-0 ]
  • [ 1342290-41-8 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
56% With caesium carbonate; bis(dibenzylideneacetone)-palladium(0); tert-butyl XPhos In 1,4-dioxane for 24h; Reflux; 2 2-n-Butyl-3-{4-[3-(di-n-butylamino)-propoxy]-benzoyl}-5-methanesulfonamido-benzofuran or dronedarone (compound I: R=CH3; R1=n-C4H9; R2=4-[3-(di-n-butylamino)-propoxy)-phenyl) Example 1 2-n-Butyl-3-{4-[3-(di-n-butylamino)-propoxy]-benzoyl}-5-methanesulfonamido-benzofuran or dronedarone (compound I: R=CH3; R1=n-C4H9; R2=4-[3-(di-n-butylamino)-propoxy)-phenyl) 360 mg of cesium carbonate (1.11 mmol) and 79 mg of methanesulfonamide (0.83 mmol), 9.5 mg of Pd(dba)2 (0.01 mmol) and 14.5 g of 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl (ligand L1) (0.03 mmol) are introduced into a 20 ml tube previously dried in an oven. The tube is sealed with a septum and inerted with argon and then 300 mg of 2-n-butyl-3-{4-[3-(di-n-butylamino)-propoxyl-benzoyl}-5-bromo-benzofuran (compound III) (0.55 mmol) in solution in 2 ml of dioxane are added with a syringe. The reaction medium is then stirred and heated under the reflux temperature of dioxane for 24 hours, while monitoring the progress of the reaction by HPLC. At the end of the reaction, the desired compound I is obtained. Yield: 78% 1H NMR (400 MHz, CDCl3): δ 0.81 (t, J=7.4 Hz, 3H, CH3-CH2-CH2-); 0.91 (t, J=7.4 Hz, 6H, 2*CH3-CH2-CH2-); 1.18-1.28 (m, 2H, CH3-CH2-CH2-); 1.28-1.38 (m, 4H, 2*CH3-CH2-CH2-); 1.62-1.70 (m, 6H, 2*CH3-CH2-CH2-CH2-+CH3-CH2-CH2-CH2-); 2.18-2.22 (m, 2H, -CH2-CH2-O-); 2.80 (t, J=7.4 Hz, 2H, -CH2-CH2-CH2-CH3); 2.88 (s, 3H, CH3-S-); 3.03-3.08 (m, 4H, 2*CH2-CH2-NH+); 3.19-3.24 (m, 2H, NH+-CH2-); 4.19 (t, J=6 Hz, 2H, -CH2-O); 7.09 (d, J=8.8 Hz, 2H, 2*ArH); 7.21 (dd, J=8.8 Hz and 2.4 Hz, 1H, 2*ArH); 7.28 (d, J=2.4 Hz, 1H, 2*ArH); 7.62 (d, J=8.8 Hz, 1H, 2*ArH); 7.79 (d, J=8.8 Hz, 2H, 2*ArH) 13C NMR (DMSO-d6): δ 189.1-164.4-162.6-150.2-134.2-131.3-130.7-127.2-118.7-116.3-114.3-113.1-111.5-65.9-53.2-49.5-38.5-29.3-28.8-27.1-26.4-21.5-19.9-13.3 ppm
  • 84
  • [ 1450631-34-1 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
83% With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 4h; 3 N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-yl]-methanesulfonamide (I) 5.27 g of MCPBA (0.022 mol, 1.1 eq) and 10.49 g of (2-butyl-5-methylsulfanylamino-benzofuran-3-yl)-[4-(3-dibutylamino-propoxy)-phenyl]-methanone (IV) (0.02 mol, 1 eq) were dissolved in 90 mL of dichloromethane. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed (followed by HPLC) 50 mL of 5 % NaOH solution was added and the mixture was stirred for 30 min. The phases were separated and the aqueous phase was extracted with 30 mL of dichloromethane. The combined organic phase was washed with 50 mL of water, dried and concentrated. The crude product was purified by column chromatography (column: spheric silica (60 A); eluent: toluene:ethyl acetate=70:30) to obtain 9.24 g of dronedarone (I) (83 %). Purity by HPLC: 99.7 %. 1H NMR (DMSO): 7.77 (d, J=8.5 Hz, 2H); 7.27 (m, 3H); 6.91 (d, J=8.5 Hz, 2H); 5.52 (bs, 1H); 4.05 (t, J=6.0 Hz, 2H); 2.87 (s, 3H); 2.78 (t, J=7.0 Hz, 2H); 2.55 (t, J=7.0 Hz, 2H); 2.39 (t, J=7.0. Hz, 4H); 1.90 (m, 2H); 1.70 (m, 2H); 1.3-1.4 (m, 10 H); 0.8-0.9, (m, 9H).
83% With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 4h; 3 N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-yl]-methanesulfonamide (I) Example 3 N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-yl]-methanesulfonamide (I) 5.27 g of MCPBA (0.022 mol, 1.1 eq) and 10.49 g of (2-butyl-5-methylsulfanylamino-benzofuran-3-yl)-[4-(3-dibutylamino-propoxy)-phenyl]-methanone (IV) (0.02 mol, 1 eq) were dissolved in 90 mL of dichloromethane. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed (followed by HPLC) 50 mL of 5% NaOH solution was added and the mixture was stirred for 30 min. The phases were separated and the aqueous phase was extracted with 30 mL of dichloromethane. The combined organic phase was washed with 50 mL of water, dried and concentrated. The crude product was purified by column chromatography (column: spheric silica (60 Å); eluent: toluene:ethyl acetate-70:30) to obtain 9.24 g of dronedarone (I) (83%). Purity by HPLC: 99.7%. 1H NMR (DMSO): 7.77 (d, J=8.5 Hz, 2H); 7.27 (m, 3H); 6.91 (d, J=8.5 Hz, 2H); 5.52 (bs, 1H); 4.05 (t, J=6.0 Hz, 2H); 2.87 (s, 3H); 2.78 (t, J=7.0 Hz, 2H); 2.55 (t, J=7.0 Hz, 2H); 2.39 (t, J=7.0 Hz, 4H); 1.90 (m, 2H); 1.70 (m, 2H); 1.3-1.4 (m, 10H); 0.8-0.9 (m, 9H).
  • 85
  • [ 1450639-61-8 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
92% With dimethylsilicon dichloride; sodium iodide In acetonitrile at 25℃; for 0.25h; 2 0.8 g of N-(2-butyl-3-{4-[3-(dibutylamino)-2-hydroxy-propoxy]benzoyl}-l- benzofuran-5-yl)methanesulfonamide (II) was dissolved in 2 ml of acetonitrile and 0.9 g of sodium iodide was added. Under stirring at 25°C 0.2 g of dichlorodimethylsilane wasadded." After stirring for 15 rriin the mixture was diluted with 5 ml of ethyl acetate and washed with 5 ml of water, with 5 ml of sodium hydrocarbonate solution of 5%, with sodium thiosulfate solution of 10% and with water. The solvent was evaporated. Mass of product 0.8 g. ' The product is purified by forming its oxalate salt as follows: to the residue 4 ml of methylethyl ketone is added and the mixture heated to70 °C . To this solution 0.17g of oxalic acid dissolved inl .5 ml of methylethyl ketone is added at 70° C. After cooling to 20 °C in 6 hours the mixture is stirred at 10 °C for 1 hour and filtered. To the obtained oxalate salt 2.5 ml of water and 4 ml of dichloromethane and 0.46g of potassium carbonate are added. After stirring for 30 minutes the separated potassium oxalate is filtered and washed with 2 ml of dichloromethane and the solvent is evaporated. Mass of purified product 0.75 g (92 %). Purify (HPLC): 98.9 %
90% With phosphonic Acid; hydrogen iodide; acetic acid In water at 60 - 80℃; for 5h; 1 N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-1-benzofuran-5-yl]-methanesulfonamide (I) N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-1-benzofuran-5-yl]-methanesulfonamide (I) 0.5 g of N-(2-butyl-3-{4-[3-(dibutylamino)-2-hydroxy-propoxy]benzoyl}-1-benzofuran-5-yl)methanesulfonamide (II) 0.1 g of phosphorous acid (H3PO3) of 99% and 0.05 g of aqueous hydrogen iodide solution of 57% was dissolved in 5 ml of acetic acid. The mixture was warmed at 60° C. for 1 hour and at 80° C. for 4 hours. The mixture was cooled to 25° C. and diluted with 10 ml of water. The pH was set to pH=7 using diluted sodium hydroxide. The mixture was extracted with 2*5 ml of dichloromethane. The dichloromethane was washed with 2*5 ml of water and evaporated. Mass of product 0.48 g (98%). The product was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:3 v/v). Mass of purified product: 0.44 g (90%). Purity (HPLC): 99.44%. 1H NMR (DMSO): 0.8-0.9 ppm (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).
  • 86
  • [ 2050-51-3 ]
  • [ 1448297-14-0 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
96.5% With potassium hydroxide In N,N-dimethyl-formamide at 40℃; for 9h; 7 N-[2-butyl-3-{4-[(3-dibutylamino)propoxy] benzoyl}-benzofuran-5-yl]-methanesulfonamide (I) The process according to example 5 was performed with the different that in the reaction 3.2 g of 4-({2-butyl-5-[(methylsulfonyl)amino]-1-benzofuran-3-yl}carbonyl)phenyl-4-[(methyl-sulfonyl)amino]benzenesulfonate (2e) was used as reactant. The product was purified by column chromatography on silica gel (eluent: ethyl acetate/ hexane 1:3). [0056] Mass of product: 3.67 g (96.5%). The product was identical with compound prepared in Example 1.
  • 87
  • [ 2050-51-3 ]
  • [ 1448297-15-1 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
89.6% With sodium hydride In N,N-dimethyl-formamide at 25℃; for 10h; 8 N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-benzofuran-5-yl]-methanesulfonamide (I) The process according to example 6 was performed with the difference that in the reaction 3.1 g of 4-({2-butyl-5-[(methylsulfonyl)amino]-1-benzofuran-3-yl}carbonyl)phenyl-4-chloro-benzenesulfonate (2f) was used as reactant. The product was purified by column chromatography on silica gel (eluent: ethyl acetate/ hexane 1:3). [0058] Mass of product: 2.67 g (89.6%). The purified product was identical with compound prepared in Example 1.
  • 88
  • [ 2050-51-3 ]
  • [ 1448297-16-2 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
89.1% With sodium hydride In N,N-dimethyl-formamide at 25℃; for 10h;
  • 89
  • [ 141644-94-2 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
88% With pyridinium chlorochromate In dichloromethane at 20℃; Inert atmosphere;
78% With dihydrogen peroxide; acetic acid at 20℃; for 36h; 4 Example 4. N-[2-butyl-3 - [4- [3 -(dibutylamino)propoxy] benzoyl] - 1 -benzofuran-5 -yl] - methanesulfonamide (I) 5.59 g of N-(2-butyl-3-[4-(3-dibutylamino-propoxy)-phenyl]-hydroxymethyl}- benzofuran-5-yl)-methanesulfonamide (VI) (0.01 mol, 1 eq) is dissolved in 40 mL of glacial acetic acid. 15 mL of 30 % hydrogen peroxide solution is added in 1 hour at room temperature and the reaction mixture is stirred for 36 hours. 80 mL of water is added to the reaction mixture and the product is extracted with 50 mL of dichloromethane. The organic phase is concentrated and the crude product is purified by column chromatography (spheric silica; eluent: toluene:ethyl acetate=70:30) to obtain 4.34 g of dronedarone (I) (78 %). Purity by HPLC: 99.7 %. The product is identical with the compound prepared in Example 3.
  • 90
  • C13H16BrMgNO3S [ No CAS ]
  • 4-(3-dibutylaminopropoxy)-N,N-diethyl-benzamide [ No CAS ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
76% With iron(III) chloride In tetrahydrofuran at 35℃; for 3h; Inert atmosphere; 12 Example 12. N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-l-benzofuran-5-yl]- methanesulfonamide (I) 9.26 g of N-(2-butyl-3-magnesium-chloro-l-benzofuran-5-yl)methanesulfonamide (IVb) (0.025 mol) in 40 mL of THF (prepared as in Example 4), 9.06 g of 4-(3-dibutylaminopropoxy)- Ν,Ν-diethyl-benzamide (VId) (0.025 mol), 0.12 g of FeCl3 (0.75 mmol, 0.03 eq) and 100 mL of THF are added into a flask under nitrogen. The reaction mixture is heated to 35 °C and stirred for 3 hours at this temperature. After the reaction is completed the mixture is cooled to 10 °C and poured into 1 M HCl solution, and the product is extracted with 60 mL of diethyl ether. The organic phase is washed with NaHC03 solution and evaporated. The product is purified by column chromatography (spheric silica; eluent: toluene:ethyl acetate=7:3) to give 10.58 g of dronedarone (I) (76 %). Purity by HPLC: 99.6 %. The product is identical with the compound prepared in Example 10.
  • 91
  • 4-(3-dibutylaminopropoxy)benzamide [ No CAS ]
  • C13H16ClMgNO3S [ No CAS ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
8.8 g With iron(III) chloride In tetrahydrofuran at 35℃; for 1h; Inert atmosphere; 10 Example 10. N- [2-butyl-3 -[4- [3 -(dibutylamino)propoxy]benzoyl] - 1 -benzofuran-5 -yl] - methanesulfonamide (I) 6.52 g of N-(2-butyl-3-magnesium-chloro-l-benzofuran-5-yl)methanesulfonamide (IV a) (0.02 mol) in 32 mL of THF (prepared as in Example 3), 6.12 g of 4-(3-dibutylamino- propoxy)benzamide (Via) (0.02 mol), 0.096 g of FeCl3 (0.6 mmol, 0.03 eq) and 80 mL of THF are added into a flask under nitrogen. The reaction mixture is heated to 35 °C and stirred for 1 hour at this temperature. After the reaction is completed the mixture is cooled to 10 °C and poured into 1 M HCl solution, and the product is extracted with 50 mL of diethyl ether. The organic phase is washed with NaHC03 solution and evaporated. The product is purified by column chromatography (spheric silica; eluent: toluene:ethyl acetate=7:3) to give 8.80 g of dronedarone (I) (79 %). Purity by HPLC: 99.8 %. 1H NMR (DMSO): 7.77 (d, J=8.5 Hz, 2H); 7.27 (m, 3H); 6.91 (d, J=8.5 Hz, 2H); 5.52 (bs, 1H); 4.05 (t, J=6.0 Hz, 2H); 2.87 (s, 3H); 2.78 (t, J=7.0 Hz, 2H); 2.55 (t, J=7.0 Hz, 2H); 2.39 (t, J=7.0 Hz, 4H); 1.90 (m, 2H); 1.70 (m, 2H); 1.3-1.4 (m, 30 H); 0.8-0.9 (m, 9H).
  • 92
  • 4-(3-dibutylaminopropoxy)-N,N-dimethyl-benzamide [ No CAS ]
  • C13H16ClMgNO3S [ No CAS ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
75% With iron(III) chloride In tetrahydrofuran at 35℃; for 3h; Inert atmosphere; 11 Example 11. N- [2-butyl-3 - [4- [3 -(dibutyl amino )propoxy]benzoyl] - 1 -benzofuran-5-yl] - methanesulfonamide (I) 8.15 g of N-(2-butyl-3-magnesium-chloro-l-benzofuran-5-yl)methanesulfonamide (IVa) (0.025 mol) in 38 mL of THF (prepared as in Example 3), 8.36 g of 4-(3-dibutylaminopropoxy)- Ν,Ν-dimethyl-benzamide (VIb) (0.025 mol), 0.12 g of FeCl3 (0.75 mmol, 0.03 eq) and 100 mL of THF are added into a flask under nitrogen. The reaction mixture is heated to 35 °C and stirred for 3 hours at this temperature. After the reaction is completed the mixture is cooled to 10 °C and poured into 1 M HCl solution, and the product is extracted with 60 mL of diethyl ether. The organic phase is washed with NaHC03 solution and evaporated. The product is purified by column chromatography (spheric silica; eluent: toluene:ethyl acetate=7:3) to give 10.44 g of dronedarone (I) (75 %). Purity by HPLC: 99.6 %. The product is identical with the compound prepared in Example 10.
  • 93
  • [ 1329684-25-4 ]
  • [ 1397749-84-6 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
With aluminum (III) chloride In 1,2-dichloro-ethane at 0 - 25℃; for 4h; 13 Synthesis of dronedarone coupling by Friedel-Crafts reaction of 2-butyl-5-methanesulfonamidobenzofuran-3-carboxylic acid chloride with N,N- dibutyl-N-(3-phenoxypropyl)amine hydrochloride Example 13 Synthesis of dronedarone coupling by Friedel-Crafts reaction of 2-butyl-5-methanesulfonamidobenzofuran-3-carboxylic acid chloride with N,N- dibutyl-N-(3-phenoxypropyl)amine hydrochloride 7.34 g (22.5 mmol) of N,N-dibutyl-N-(3-phenoxypropyl)amine hydrochloride and 40 g of DCE are introduced into the total amount (55 g) of the preceding reaction medium of Example 10. The mixture is cooled to between 0 and 5° C. and 12 g (4 eq.) of AlCl3 are added. The reaction medium is stirred at 20-25° C. for 4 hours and then hydrolyzed by pouring it into 75 ml of water at between 0 and 5° C. The organic phase is washed twice with 75 ml of water, filtered and then washed again with 75 ml of water and concentrated under reduced pressure. 6.8 g of crude product are obtained. The crude product is purified by dissolution in 50 ml of DCE and washed with 40 ml of 10% sodium hydroxide and 50 ml of water, and finally the crude product thus obtained is purified by chromatography on silica, eluting with ethyl acetate (90v)/methanol (10v). 2.2 g of dronedarone are obtained in a purity of 94.6%. Mass yield: 16.6% by weight 1H NMR (DMSO) δ 0.83 (t, 3 H, CH3), 0.85 (t, 6 H, 2-CH3), 1.20 to 1.50 (unresolved complex, 6H, 3-CH2), 1.69 (m, 2H, CH2), 1.90 (m, 2H, CH2), 2.40 (m, 4H, 2-CH2-N), 2.57 (m, 2H, CH2-N), 2.80 (t, 2H, CH2), 2.87 (s, 3H, CH3-S), 4.06 (broad t, 2H, CH2-O), 6.92 (d, 2H, CHarom), 7.25, 7.34, 7.39 (m, 3H, CHarom), 7.78 (d, 2H, CHarom), 12.19 (s, 1H, NH); 13C NMR (DMSO) δ 13.7 (1-CH3), 14.1 (2-CH3), 20.7 (2-CH2), 26.9, 28.0 (2-CH2), 30.0 (1-CH2), 29.2 (2-CH2), 38.9 (1-CH3-S), 53.9 (2-CH2-N), 50.3 (1-CH2-N), 66.6 (1-CH2-O), 114.3, 131.7 (4-CHarom), 111.7, 115.6, 120.2 (3-CHarom), 116.8, 128.1, 132.8 (3-Carom), 131.3 (1-Carom-N), 151.8, 163.3, 165.7 (3-Carom-O), 190.4 (1-CO).
  • 94
  • [ 144-62-7 ]
  • [ 141626-36-0 ]
  • N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-1-benzofuran-5-yl]methanesulfonamide oxalate salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.1 g In butanone at 10 - 70℃; for 7h; 1 Example 1 N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-1-benzofuran-5-yl]methanesulfonamide (I) 1 g of N-[2-butyl-3-{4-[(3-amino)propoxy]benzoyl}-1-benzofuran-5-yl]-methansulfonamide (II) is dissolved in 5 ml of methyl ethyl ketone. 0.18 g of pyridine and 0.34 g of sodium iodide are added and the mixture is heated to boiling point. 0.62 g of 1-bromobutane (III) dissolved in 1 ml of methyl ethyl ketone is added at this temperature during 15 minutes and the mixture is boiled for 16 hours. The reaction mixture is evaporated, 20 ml of water and 20 ml of dichloromethane are added. The organic phase is washed with 5 ml of 5% NaHCO3, solution, separated and evaporated. The product is purified by forming its oxalate salt as follows: to the residue 4 ml of methylethyl ketone is added and the mixture heated to 70. To this solution 0.24 g of oxalic acid dissolved in 1.5 ml of methylethyl ketone is added at 70° C. After cooling to 20° C. in 6 hours the mixture is stirred at 10° C. for 1 hour and filtered. To the obtained oxalate salt 2.5 ml of water and 4 ml of dichloromethane and 0.63 g of potassium carbonate are added. After stirring for 30 minutes the separated potassium oxalate is filtered and washed with 2 ml of dichloromethane and the solvent is evaporated. [0095] Yield: 1.1 g (88%). Purity of the oxalate salt: 99.8% (HPLC). [0096] 1H NMR (DMSO): 0.8-0.9 ppm (m, 9H); 1.2-1.5 ppm (m, 10H); 1.67 ppm (5′, 2H); 1.87 ppm (5′, 2H); 2.38 ppm (t, J=7.2 Hz, 4H); 2.57 ppm (m, 2H); 2.88 ppm (t, J=7.5 Hz, 2H); 2.91 ppm (s, 3H); 9.51 ppm (t, J=6.2 Hz, 2H); 7.09 ppm (d, J=8.8 Hz, 2H); 7.24 ppm (dd, J=8.9, 2.2 Hz, 1H); 7.38 ppm (d, J=2.1 Hz, 1H); 7.65 ppm (d, J=8.8 Hz, 1H); 7.81 ppm (d, J=8.8 Hz, 2H)
In butanone at 10 - 70℃; for 7h; 2 N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-1-benzofuran-5-yl]-methanesulfonamide (I) The product is purified by forming its oxalate salt as follows: to the residue 4 ml of methylethyl ketone is added and the mixture heated to 70. To this solution 0.17 g of oxalic acid dissolved in 1.5 ml of methylethyl ketone is added at 70° C. After cooling to 20° C. in 6 hours the mixture is stirred at 10°C. for 1 hour and filtered. To the obtained oxalate salt 2.5 ml of water and 4 ml of dichloromethane and 0.46 g of potassium carbonate are added. Afier stirring for 30 minutes the separated potassium oxalate is filtered and washed with 2 ml of dichloromethane and the solvent is evaporated. Mass of purified product 0.75 g (92%).1 Purify (HPLC): 98.9%. The product was identical with compound prepared in example 1.
  • 95
  • [ 133238-87-6 ]
  • [ 141626-57-5 ]
  • [ 141626-36-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: aluminum (III) chloride / dichloromethane 2: aluminum (III) chloride / chlorobenzene 3: sodium carbonate / toluene; isopropyl alcohol 4: palladium on activated charcoal; ammonium formate / 55 °C 5: organic base / dichloromethane
  • 96
  • [ 141627-42-1 ]
  • [ 141626-57-5 ]
  • [ 141626-36-0 ]
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[ 141626-36-0 ]

Chemical Structure| 141625-93-6

A127630[ 141625-93-6 ]

N-(2-Butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl)methanesulfonamide hydrochloride

Reason: Free-salt