4-chloro-N-(2-morpholinoethyl)benzamide [Moclobemide (Aurorix)]

Query Query O

Date

26 reactions in Reaxys

2016-07-25 14h:51m:40s (EST)

O N

1. Query

Results

N H Cl

Search as: As drawn, No mixtures, No charges, No radicals

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Cl NH 2

N

O I

11C

Cl

11C

NH

O N

O

Rx-ID: 9378326 View in Reaxys 1/26 Yield

Conditions & References Stage 1: With tetrakis(triphenylphosphine) palladium(0) in 1,4-dioxane Stage 2: in 1,4-dioxane, dimethyl sulfoxide Stage 3: in 1,4-dioxane, dimethyl sulfoxide, Time= 0.0833333h, p= 262526Torr , Heating, Further stages. Karimi, Farhad; Langstroem, Bengt; European Journal of Organic Chemistry; nb. 11; (2003); p. 2132 - 2137 View in Reaxys With (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine), bis(dibenzylideneacetone)-palladium(0) in DMFA, Time= 0.166667h, T= 120 °C , Glovebox, Inert atmosphere, Sealed tube Nordeman, Patrik; Friis, Stig D.; Andersen, Thomas L.; Audrain, Hlne; Larhed, Mats; Skrydstrup, Troels; Antoni, Gunnar; Chemistry - A European Journal; vol. 21; nb. 49; (2015); p. 17601 - 17604 View in Reaxys

Cl NH 2

O

O N

NH

Cl Cl N

O

Rx-ID: 4716294 View in Reaxys 2/26 Yield 95 %

Conditions & References With triethylamine, Time= 13h, T= 0 - 20 °C Kim, Dokyoung; Sambasivan, Sunderraman; Nam, Hyoseok; Ki, Hean Kim; Jin, Yong Kim; Joo, Taiha; Lee, Kyung-Ha; Kim, Kyong-Tai; Han Ahn, Kyo; Chemical Communications; vol. 48; nb. 54; (2012); p. 6833 - 6835 View in Reaxys

71 %

With pyridine Ghanbarpour, Alireza; Hadizadeh, Farzin; Piri, Faride; Rashidi-Ranjbar, Parviz; Pharmaceutica Acta Helvetiae; vol. 72; nb. 2; (1997); p. 119 - 122 View in Reaxys 1 : Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide EXAMPLE 1 Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide 35 G. of p-chlorobenzoyl chloride are added dropwise to a solution of 26 g. of N-(2-aminoethyl)-morpholine in 200 ml. of pyridine, while stirring and cooling with ice-water. Thereafter, the mixture is stirred overnight at room temperature and subsequently evaporated to dryness. Then, the residue is evaporated twice more with 200 ml. of toluene each time. The solid residue is taken up in 300 ml. of ice-water and 300 ml. of methylene chloride and rendered basic with 3-N sodium hydroxide solution. The phases are separated and the methylene chloride extract is washed with water, dried over sodium sulfate and evaporated to dryness. The residue is recrystallized from isopropanol and 41.5 g. of p-chloro-N-(2-morpholinoethyl)-benzamide, melting point 137° C., are obtained. in pyridine, ice-water, dichloromethane, toluene Patent; Hoffmann-La Roche Inc.; US4210754; (1980); (A1) English

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View in Reaxys 207 mg

Time= 3h Iqbal, Naeem; Cho, Eun Jin; Journal of Organic Chemistry; vol. 81; nb. 5; (2016); p. 1905 - 1911 View in Reaxys

Cl O NH

N O

Rx-ID: 5873285 View in Reaxys 3/26 Yield

Conditions & References Patent; Hoffmann-LaRoche; DE2706179; (1977); ; vol. 88; nb. 121196 View in Reaxys 3 : Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide EXAMPLE 3 Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide 10.5 G. of p-chlorobenzoic acid anhydride are added portionwise to a solution of 4.55 g. of N-(2-aminoethyl)-morpholine in 100 ml. of pyridine, with stirring and cooling with ice-water. After complete addition, the mixture is stirred overnight at room temperature and subsequently evaporated to dryness. The residue is then evaporated twice more with 100 ml. of toluene each time. The solid residue is taken up in 200 ml. of methylene chloride and 200 ml. of water and rendered basic with 3-N sodium hydroxide solution. The phases are separated and the methylene chloride extract is washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from isopropanol and 4.5 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1. Patent; Hoffmann-La Roche Inc.; US4210754; (1980); (A1) English View in Reaxys

Cl NH 2

O

O N

NH

Cl HO N

O

Rx-ID: 7264094 View in Reaxys 4/26 Yield 86 %

Conditions & References With zirconocene dichloride in toluene, Time= 24h, T= 110 °C , Inert atmosphere, sealed tube Allen, C. Liana; Chhatwal, A. Rosie; Williams, Jonathan M. J.; Chemical Communications; vol. 48; nb. 5; (2012); p. 666 - 668 View in Reaxys 2 : Example 2 4-Chloro-N-(2-morpholin-4-yl-ethyl)-benzamide (entry 2) was prepared from 4-chloro benzoic acid (0.10 mmol) and 2-morpholin-4-yl-ethylamine (0.10 mmol). Purification by solid phase extraction (ethyl acetate/heptane/triethylamine=5:1:0.1) furnished 12.2 mg (45percent) of the desired product as a colourless solid (LC-MS: 98percent UV-purity and 99percent ELSD-purity). 1H-NMR δ2.51 [m (broad), 4H), 2.61 (t, 2H, J=5.9), 3.55 (q, 2H, J=5.7), 3.73 (t, 4H, J=4.7), 6.75 [s (broad), 1H], 7.42 (d, 2H, J=8.5), 7.71 (d, 2H, J=8.5).

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Patent; H. Lundbeck A/S; US2003/138376; (2003); (A1) English View in Reaxys 9 : Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide EXAMPLE 9 Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide 2.8 G. of phosphorus trichloride in 20 ml. of pyridine are added to 5.2 g. of N-(2-aminoethyl)-morpholine in 80 ml. of pyridine at -5° C. over a period of 15 minutes, with stirring. The mixture is stirred for 30 minutes at -5° C. and 90 minutes at room temperature. Then, 3.1 g. of p-chlorobenzoic acid are added and the mixture is heated for 3 hours at 90° C. This mixture is evaporated to dryness and the residue is evaporated twice more with 100 ml. of toluene each time. The solid residue is taken up in 100 ml. of methylene chloride and 100 ml. of ice-water and the mixture is rendered basic with 3-N sodium hydroxide solution. The phases are separated and the methylene chloride extract is washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from isopropanol and 1.3 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1. With anhydrous phosphorus trichloride in pyridine, ice-water, dichloromethane, toluene Patent; Hoffmann-La Roche Inc.; US4210754; (1980); (A1) English View in Reaxys

Cl NH 2

N

O

Cl EN

Cl

NH

N

O

N

O

Rx-ID: 25393158 View in Reaxys 5/26 Yield

Conditions & References 12 : Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide EXAMPLE 12 Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide 26 G. of p-chlorobenzaldehyde and 24 g. of N-(2-aminoethyl)-morpholine are boiled in 150 ml. of benzene for 3 hours under reflux with water being separated. Then, the mixture is evaporated to dryness and the residue is distilled at 165° C./0.01 mmHg. 5 G. of the resulting 4{2-[(p-chlorobenzylidene)-amino]-ethyl}-morpholine, 2.3 g. of sodium acetate and 3 ml. of 30percent hydrogen peroxide are stirred in 60 ml. of methanol overnight at room temperature. in water, benzene Patent; Hoffmann-La Roche Inc.; US4210754; (1980); (A1) English View in Reaxys

Cl NH 2

O Cl

N

O

O NH

Cl O

HO N

O

Rx-ID: 25393707 View in Reaxys 6/26 Yield

Conditions & References 4 : Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide EXAMPLE 4 Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide 5.3 Ml. of chloroformic acid ethyl ester are added dropwise to a solution of 8.6 g. of p-chlorobenzoic acid and 7.6 ml. of triethylamine in 150 ml. of acetone, with stirring and cooling with ice-water.

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After one hour at 0° C., a solution of 6.5 g. of N-(2-aminoethyl)-morpholine in 50 ml. of acetone is added dropwise to the mixture and the mixture is then stirred overnight at room temperature. Thereafter it is concentrated, allowed to stand for 2 hours in the refrigerator and filtered. The filtrate is evaporated to dryness and the residue is taken up in 250 ml. of water and 250 ml. of methylene chloride. The phases are separated and the methylene chloride extract is dried over sodium sulfate and evaporated. The residue is recrystallized from isopropanol and 7.8 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1. With triethylamine in dichloromethane, water, acetone Patent; Hoffmann-La Roche Inc.; US4210754; (1980); (A1) English View in Reaxys

Cl O

H N

O

Cl

O

N H

NH Cl

N O

Rx-ID: 25393982 View in Reaxys 7/26 Yield 42 %

Conditions & References Moclobemide A mixture of compound 5a (109.0 mg, 0.5 mmol) and morpholine (348 μL, 4 mmol) was then stirred at 100 °C for 2 h. After cooling to room temperature, 5 mL of H2O and then a 10percent ammonia solution were added. The solution was extracted with CH2Cl2. The organic layers were combined, dried over MgSO4, filtered and evaporated under reduced pressure. Purification on silica gel using a mixture CH2Cl2/MeOH 95:5 afforded 56.6 mg of moclobemide as a white solid (42percent yield). 1H NMR (CDCl3, 200 MHz): δ (ppm)=7.72 (dd, J=8.9, 2.2 Hz, 2H), 7.41 (dd, J=8.9, 2.2 Hz, 2H), 6.78 (s, 1H), 3.78-3.69 (m, 4H), 3.54 (dd, J=11.4, 5.4 Hz, 2H), 2.67-2.56 (m, 2H), 2.56-2.46 (m, 4H). 13C NMR (CDCl3, 75 MHz): δ (ppm)=166.4, 137.6, 133.0, 128.8, 128.4, 66.9, 56.9, 53.4, 36.2. With ammonia in methanol, Time= 2h, T= 100 °C Bantreil, Xavier; Kanfar, Nasreddine; Gehin, Nicolas; Golliard, Ethan; Ohlmann, Pauline; Martinez, Jean; Lamaty, Frederic; Tetrahedron; vol. 70; nb. 34; (2014); p. 5093 - 5099 View in Reaxys 11 : Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide EXAMPLE 11 Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide 5.45 G. of p-chloro-N-(2-chloroethyl)-benzamide and 8.7 g. of morpholine are stirred together for 2 hours at 100° C. The mixture is cooled to room temperature and 50 ml. of water are added. Then, the mixture is rendered basic with 10percent ammonia solution and extracted three times with 50 ml. of methylene chloride each time. The methylene chloride extract is dried over sodium sulfate and evaporated. The residue is chromatographed over a silica gel column with a mixture of chloroform and ethanol. The product is recrystallized from isopropanol, and 2.2 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1. With ammonia in ethanol, chloroform, water Patent; Hoffmann-La Roche Inc.; US4210754; (1980); (A1) English View in Reaxys

56.6 mg

31 : 4.1.31. Moclobemide Alcohol 5b (350 mg, 1.97 mmol), triethylamine (826 μL, 5.93 mmol) DMAP (24.1 mg, 0.20 mmol), and sodium chloride (346.6 mg, 5.93 mmol) were stirred in CH2Cl2 (9.9 mL) and methanesulfonyl chloride (460 μL, 5.93 mmol) was added dropwise. The mixture was stirred overnight and completion of the reaction was assessed by HPLC. Reaction was quenched using a saturated solution of NH4Cl and extracted with CH2Cl2. The combined organic layers were washed with a saturated solution of NaHCO3, brine, dried over MgSO4 filtered and concentrated under reduced pres-

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sure. The crude chloride was filtered through a pad of silica using CH2Cl2 as eluant. Filtered compound (white solid, 450 mg) was found pure enough for further reaction. 1H NMR (CDCl3, 200 MHz): δ (ppm)=7.81-7.62 (m, 2H), 7.47-7.33 (m, 2H), 6.69 (s, 1H), 3.87-3.64 (m, 4H). 13C NMR (CDCl3, 75 MHz): δ (ppm)=166.7, 138.2, 132.6, 129.1, 128.6, 44.2, 41.9. A mixture of compound 5a (109.0 mg, 0.5 mmol) and morpholine (348 mL, 4 mmol) was then stirred at 100°C for 2 h. After cooling to room temperature, 5 mL of H2O and then a 10percent ammonia solution were added. The solution was extracted with CH2Cl2. The organic layers were combined, dried over MgSO4, filtered and evaporated under reduced pressure. Purification on silica gel using a mixture CH2Cl2/MeOH95:5 afforded 56.6 mg of moclobemide as a white solid (42percent yield). 1H NMR (CDCl3, 200 MHz): d (ppm)7.72 (dd, J8.9, 2.2 Hz, 2H), 7.41 (dd, J8.9, 2.2 Hz, 2H), 6.78 (s, 1H), 3.78e3.69 (m, 4H), 3.54 (dd,J11.4, 5.4 Hz, 2H), 2.67e2.56 (m, 2H), 2.56e2.46 (m, 4H). 13C NMR(CDCl3, 75 MHz): d (ppm)166.4, 137.6, 133.0, 128.8, 128.4, 66.9,56.9, 53.4, 36.2. Stage 1:, Time= 2h, T= 100 °C Stage 2: With ammonium hydroxide, T= 20 °C Bantreil, Xavier; Kanfar, Nasreddine; Gehin, Nicolas; Golliard, Ethan; Ohlmann, Pauline; Martinez, Jean; Lamaty, Frdric; Tetrahedron; vol. 70; nb. 34; (2014); p. 5093 - 5099 View in Reaxys

Cl

H N

O

O Cl

NH

N

O

N O

Rx-ID: 25393983 View in Reaxys 8/26 Yield

Conditions & References 10 : Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide EXAMPLE 10 Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide 55.4 G. of p-chlorobenzoylaziridine and 26.5 g. of morpholine are boiled in 250 ml. of toluene for 2 hours under reflux. The solution is then cooled to room temperature, whereupon crystals separate out. The solution which crystallizes is allowed to stand overnight in a refrigerator. Thereafter, the product is removed by filtration, washed with toluene and recrystallized from isopropanol, and 75.9 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1. in toluene Patent; Hoffmann-La Roche Inc.; US4210754; (1980); (A1) English View in Reaxys

Cl NH 2

O O

N

NH

Cl O

N

O

Rx-ID: 25403293 View in Reaxys 9/26 Yield

Conditions & References 5 : Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide EXAMPLE 5 Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide 8.2 G. of p-chlorobenzoic acid methyl ester and 6.25 g. of N-(2-aminoethyl)-morpholine are stirred together for 6 hours at 120° C. The mixture is then cooled to room temperature and 40 ml. of diethyl ether are added. Thereafter, the mixture is allowed to stand overnight in the refrigerator.

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The crystalline product is removed by filtration, washed with diethyl ether and recrystallized from isopropanol, and 2.6 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1. in diethyl ether Patent; Hoffmann-La Roche Inc.; US4210754; (1980); (A1) English View in Reaxys

Cl NH 2

Cl

O

NH

N

O

N

O

Rx-ID: 25403294 View in Reaxys 10/26 Yield

Conditions & References 7 : Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide EXAMPLE 7 Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide 2.4 G. of N-(p-chlorobenzoyl)-succinimide are added to a solution of 1.3 g. of N-(2-aminoethyl)-morpholine in 100 ml. of dioxane and the mixture is stirred overnight at room temperature. The mixture is then evaporated to dryness. 50 Ml. of ice-water are added to the oily residue and the mixture which crystallizes is allowed to stand overnight in a refrigerator. The product is removed by filtration, washed with cold water, dried and recrystallized from isopropanol, and 0.65 g. of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in Example 1. in 1,4-dioxane, ice-water Patent; Hoffmann-La Roche Inc.; US4210754; (1980); (A1) English View in Reaxys

Cl NH 2

O

O O

N

Cl N

NH

O

N O

Rx-ID: 25403295 View in Reaxys 11/26 Yield

Conditions & References 6 : Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide EXAMPLE 6 Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide 5.55 G. of p-chlorobenzoic acid p-nitrophenyl ester are added to a solution of 2.6 g. of N-(2-aminoethyl)-morpholine in 100 ml. of tetrahydrofuran and the mixture is allowed to stand overnight at room temperature. It is then evaporated to dryness and the residue is taken up in 200 ml. of methylene chloride. The methylene chloride solution is washed three times with 50 ml. of a 1percent sodium hydroxide solution each time and twice with 50 ml. of water each time until neutral, dried over sodium sulfate and evaporated to dryness. The residue is recrystallized from isopropanol, and 3.1 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1. With sodium hydroxide in tetrahydrofuran, dichloromethane, water Patent; Hoffmann-La Roche Inc.; US4210754; (1980); (A1) English View in Reaxys

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Cl

O

S

O

NH

Cl

NH

H

N

O

Rx-ID: 25405190 View in Reaxys 12/26 Yield

Conditions & References 14 : Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide EXAMPLE 14 Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide 1.0 G. of p-chloro-N-(2-morpholinoethyl)-thiobenzamide hydrochloride is boiled in 100 ml. of methanol with 35 ml. of 1,2-butylene oxide for 14 hours under reflux. The mixture is evaporated to dryness. The residue is recrystallized from isopropanol, and 0.6 g. of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in Example 1. in methanol Patent; Hoffmann-La Roche Inc.; US4210754; (1980); (A1) English View in Reaxys

Cl

O

S NH

Cl

NH

H

N

O

Rx-ID: 25409378 View in Reaxys 13/26 Yield

Conditions & References 13 : Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide EXAMPLE 13 Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide 900 Mg. of p-chloro-N-(2-morpholinoethyl)-thiobenzamide hydrochloride are boiled in 100 ml. of water with 2 g. of lead tetraacetate for 10 hours under reflux. The mixture is filtered and the filtrate is evaporated to dryness. The residue is chromatographed over a silica gel column with a mixture of chloroform and ethanol. The product is recrystallized from isopropanol, and 0.3 g. of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in Example 1. With lead(IV) tetraacetate in ethanol, chloroform, water Patent; Hoffmann-La Roche Inc.; US4210754; (1980); (A1) English View in Reaxys

Cl

O N

NH

O

N O

Rx-ID: 25409379 View in Reaxys 14/26 Yield

Conditions & References 15 : Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide

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EXAMPLE 15 Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide 4.0 G. of α-(p-chlorophenyl)-N-(2-morpholinoethyl)-nitrone are heated to 90° C. in 15 ml. of glacial acetic acid and 15 ml. of acetic anhydride for 24 hours. The mixture is then cooled to room temperature, poured into 200 ml. of ice-water and rendered basic with 20percent sodium hydroxide solution. Thereafter, the mixture is extracted twice with 100 ml. of methylene chloride each time. The methylene chloride extract is washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed over a silica gel column with a mixture of chloroform and ethanol. The product is recrystallized from isopropanol, and 0.13 g. of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in Example 1. With sodium hydroxide, acetic anhydride in ice-water, ethanol, chloroform, acetic acid Patent; Hoffmann-La Roche Inc.; US4210754; (1980); (A1) English View in Reaxys

Cl NH 2

N

O N

NH

Cl

N

O

Rx-ID: 28729513 View in Reaxys 15/26 Yield 54 %

Conditions & References With Iron (III) nitrate nonahydrate, Time= 24h, T= 125 °C , Neat (no solvent), Sealed tube Allen, C. Liana; Lapkin, Alexei A.; Williams, Jonathan M.J.; Tetrahedron Letters; vol. 50; nb. 29; (2009); p. 4262 4264 View in Reaxys

Cl NH 2

N

O NH

Cl O N

O

Rx-ID: 30029076 View in Reaxys 16/26 Yield 73 %

Conditions & References With NiII chloride hexahydrate, hydroxylamine hydrochloride, sodium hydroxide in para-xylene, Time= 18h, T= 155 °C , Inert atmosphere Allen, C. Liana; Davulcu, Simge; Williams, Jonathan M. J.; Organic Letters; vol. 12; nb. 22; (2010); p. 5096 5099 View in Reaxys

Cl NH 2

N

O

O I

Cl

C

NH

O

N O

Rx-ID: 32478848 View in Reaxys 17/26

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Yield 99 %

Conditions & References With triethylamine, triphenylphosphine, bis(dibenzylideneacetone)-palladium(0) in 1,4-dioxane, Time= 18h, T= 80 °C , Glovebox, Sealed tube, Inert atmosphere Lescot, Camille; Nielsen, Dennis U.; Makarov, Ilya S.; Lindhardt, Anders T.; Daasbjerg, Kim; Skrydstrup, Troels; Journal of the American Chemical Society; vol. 136; nb. 16; (2014); p. 6142 - 6147 View in Reaxys

94 %

With potassium carbonate in toluene, Time= 24h, T= 120 °C , p= 1034.32Torr Dang, Tuan T.; Zhu, Yinghuai; Ghosh, Subhash C.; Chen, Anqi; Chai, Christina L. L.; Seayad, Abdul M.; Chemical Communications; vol. 48; nb. 12; (2012); p. 1805 - 1807 View in Reaxys

76 %

With 1,4-diaza-bicyclo[2.2.2]octane in toluene, Time= 20h, T= 105 °C , p= 760.051Torr , chemoselective reaction Tinnis, Fredrik; Verho, Oscar; Gustafson, Karl P. J.; Tai, Cheuk-Wai; Baeckvall, Jan-E.; Adolfsson, Hans; Chemistry - A European Journal; vol. 20; nb. 20; (2014); p. 5885 - 5889 View in Reaxys

Cl NH 2

O Br

N

Cl

C

NH

O

N

O

Rx-ID: 35905099 View in Reaxys 18/26 Yield 96 %

Conditions & References With potassium carbonate, bis[2-(diphenylphosphino)phenyl] ether in toluene, Time= 12h, T= 105 °C , p= 3000.3Torr Dang, Tuan T.; Zhu, Yinghuai; Ngiam, Joyce S. Y.; Ghosh, Subhash C.; Chen, Anqi; Seayad, Abdul M.; ACS Catalysis; vol. 3; nb. 6; (2013); p. 1406 - 1410 View in Reaxys

Cl NH 2

O

H 2N

NH

Cl

N

O N

O

Rx-ID: 37772071 View in Reaxys 19/26 Yield 90 %

Conditions & References With niobium oxide in neat (no solvent), T= 160 °C , Sealed tube, Inert atmosphere Ghosh, Subhash Chandra; Li, Cheng Chao; Zeng, Hua Chun; Ngiam, Joyce S. Y.; Seayad, Abdul M.; Chen, Anqi; Advanced Synthesis and Catalysis; vol. 356; nb. 2-3; (2014); p. 475 - 484 View in Reaxys

Cl O NH

Cl HO N O

Rx-ID: 38085894 View in Reaxys 20/26

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Yield

Conditions & References Reaction Steps: 4 1.1: iron(II) chloride tetrahydrate; calcium carbonate; tert.-butylhydroperoxide / acetonitrile; water / 4 h / 80 °C / | Sealed tube 2.1: sodium tetrahydroborate / tetrahydrofuran / 0.25 h / 65 °C 2.2: 0.25 h / 65 °C 3.1: sodium chloride; methanesulfonyl chloride; triethylamine; dmap / dichloromethane 4.1: ammonia / methanol / 2 h / 100 °C With tert.-butylhydroperoxide, dmap, sodium tetrahydroborate, iron(II) chloride tetrahydrate, ammonia, methanesulfonyl chloride, triethylamine, calcium carbonate, sodium chloride in tetrahydrofuran, methanol, dichloromethane, water, acetonitrile Bantreil, Xavier; Kanfar, Nasreddine; Gehin, Nicolas; Golliard, Ethan; Ohlmann, Pauline; Martinez, Jean; Lamaty, Frederic; Tetrahedron; vol. 70; nb. 34; (2014); p. 5093 - 5099 View in Reaxys Reaction Steps: 2 1.1: iron(II) chloride tetrahydrate; calcium carbonate; tert.-butylhydroperoxide / acetonitrile / 4 h / 80 °C 2.1: 2 h / 100 °C 2.2: 20 °C With tert.-butylhydroperoxide, iron(II) chloride tetrahydrate, calcium carbonate in acetonitrile Bantreil, Xavier; Kanfar, Nasreddine; Gehin, Nicolas; Golliard, Ethan; Ohlmann, Pauline; Martinez, Jean; Lamaty, Frdric; Tetrahedron; vol. 70; nb. 34; (2014); p. 5093 - 5099 View in Reaxys Reaction Steps: 3 1.1: iron(II) chloride tetrahydrate; calcium carbonate; tert.-butylhydroperoxide / acetonitrile / 4 h / 80 °C 2.1: triethylamine; dmap; sodium chloride; methanesulfonyl chloride / dichloromethane 3.1: 2 h / 100 °C 3.2: 20 °C With tert.-butylhydroperoxide, dmap, iron(II) chloride tetrahydrate, methanesulfonyl chloride, triethylamine, calcium carbonate, sodium chloride in dichloromethane, acetonitrile Bantreil, Xavier; Kanfar, Nasreddine; Gehin, Nicolas; Golliard, Ethan; Ohlmann, Pauline; Martinez, Jean; Lamaty, Frdric; Tetrahedron; vol. 70; nb. 34; (2014); p. 5093 - 5099 View in Reaxys Reaction Steps: 4 1.1: iron(II) chloride tetrahydrate; calcium carbonate; tert.-butylhydroperoxide / acetonitrile; water / 4 h / 80 °C / | Sealed tube 2.1: sodium tetrahydroborate / tetrahydrofuran; methanol / 0.5 h / 65 °C 3.1: triethylamine; dmap; sodium chloride; methanesulfonyl chloride / dichloromethane 4.1: 2 h / 100 °C 4.2: 20 °C With tert.-butylhydroperoxide, dmap, sodium tetrahydroborate, iron(II) chloride tetrahydrate, methanesulfonyl chloride, triethylamine, calcium carbonate, sodium chloride in tetrahydrofuran, methanol, dichloromethane, water, acetonitrile Bantreil, Xavier; Kanfar, Nasreddine; Gehin, Nicolas; Golliard, Ethan; Ohlmann, Pauline; Martinez, Jean; Lamaty, Frdric; Tetrahedron; vol. 70; nb. 34; (2014); p. 5093 - 5099 View in Reaxys

Cl O O O

O

N H

NH Cl

N O

Rx-ID: 38085907 View in Reaxys 21/26

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Yield

Conditions & References Reaction Steps: 3 1.1: sodium tetrahydroborate / tetrahydrofuran / 0.25 h / 65 °C 1.2: 0.25 h / 65 °C 2.1: sodium chloride; methanesulfonyl chloride; triethylamine; dmap / dichloromethane 3.1: ammonia / methanol / 2 h / 100 °C With dmap, sodium tetrahydroborate, ammonia, methanesulfonyl chloride, triethylamine, sodium chloride in tetrahydrofuran, methanol, dichloromethane Bantreil, Xavier; Kanfar, Nasreddine; Gehin, Nicolas; Golliard, Ethan; Ohlmann, Pauline; Martinez, Jean; Lamaty, Frederic; Tetrahedron; vol. 70; nb. 34; (2014); p. 5093 - 5099 View in Reaxys Reaction Steps: 3 1.1: sodium tetrahydroborate / tetrahydrofuran; methanol / 0.5 h / 65 °C 2.1: triethylamine; dmap; sodium chloride; methanesulfonyl chloride / dichloromethane 3.1: 2 h / 100 °C 3.2: 20 °C With dmap, sodium tetrahydroborate, methanesulfonyl chloride, triethylamine, sodium chloride in tetrahydrofuran, methanol, dichloromethane Bantreil, Xavier; Kanfar, Nasreddine; Gehin, Nicolas; Golliard, Ethan; Ohlmann, Pauline; Martinez, Jean; Lamaty, Frdric; Tetrahedron; vol. 70; nb. 34; (2014); p. 5093 - 5099 View in Reaxys

Cl O HO

O

N H

NH Cl

N O

Rx-ID: 38850822 View in Reaxys 22/26 Yield

Conditions & References Reaction Steps: 2 1.1: triethylamine; 4-(N,N-dimethlyamino)pyridine; sodium chloride; methanesulfonyl chloride / dichloromethane 2.1: 2 h / 100 °C 2.2: 20 °C With 4-(N,N-dimethlyamino)pyridine, methanesulfonyl chloride, triethylamine, sodium chloride in dichloromethane Bantreil, Xavier; Kanfar, Nasreddine; Gehin, Nicolas; Golliard, Ethan; Ohlmann, Pauline; Martinez, Jean; Lamaty, Frdric; Tetrahedron; vol. 70; nb. 34; (2014); p. 5093 - 5099 View in Reaxys

Cl NH 2

O

Cl N

I

Cl

NH

Cl

Cl N

O

Rx-ID: 40443656 View in Reaxys 23/26 Yield 99 %

Conditions & References With cesium hydroxide monohydrate, palladium diacetate, bis[2-(diphenylphosphino)phenyl] ether in toluene, Time= 24h, T= 80 °C , Glovebox, Inert atmosphere, Sealed tube Gockel, Samuel N.; Hull, Kami L.; Organic Letters; vol. 17; nb. 13; (2015); p. 3236 - 3239 View in Reaxys

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Cl O NH

Cl O N O

Rx-ID: 42353641 View in Reaxys 24/26 Yield

Conditions & References Reaction Steps: 2 1: tris(2,2'-bipyridyl)ruthenium dichloride; tert.-butylhydroperoxide; N-chloro-succinimide / acetonitrile / 24 h / 20 °C / | Sealed tube; |Irradiation 2: 3 h With tert.-butylhydroperoxide, N-chloro-succinimide, tris(2,2'-bipyridyl)ruthenium dichloride in acetonitrile Iqbal, Naeem; Cho, Eun Jin; Journal of Organic Chemistry; vol. 81; nb. 5; (2016); p. 1905 - 1911 View in Reaxys

NH 2

O I

N

13C

Cl

O

13

C

O

N H

N

Cl

O

Rx-ID: 37942273 View in Reaxys 25/26 Yield

Conditions & References

98 %

With triethylamine, triphenylphosphine, bis(dibenzylideneacetone)-palladium(0) in 1,4-dioxane, Time= 18h, T= 80 °C , Glovebox, Sealed tube, Inert atmosphere Lescot, Camille; Nielsen, Dennis U.; Makarov, Ilya S.; Lindhardt, Anders T.; Daasbjerg, Kim; Skrydstrup, Troels; Journal of the American Chemical Society; vol. 136; nb. 16; (2014); p. 6142 - 6147 View in Reaxys

Cl O NH

Cl

H

N O

Rx-ID: 25387842 View in Reaxys 26/26 Yield

Conditions & References 2 : Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide hydrochloride EXAMPLE 2 Preparation of p-chloro-N-(2-morpholinoethyl)-benzamide hydrochloride 13 G. of N-(2-aminoethyl)-morpholine are added dropwise to a solution of 17.5 g. of p-chlorobenzoyl chloride in 100 ml. of diethyl ether, with stirring and cooling with ice-water. After complete addition, the mixture is stirred for 2 hours at room temperature. The crystalline product is removed by filtration and washed with diethyl ether. 9.1 G. of p-chloro-N-(2-morpholinoethyl)-benzamide hydrochloride, melting point 207° C. to 208° C., are obtained after recrystallization from isopropanol. 4-Chloro-N-(2-morpholinoethyl)-2-nitrobenzamide hydrochloride, melting point 208° C., was prepared in an analogous manner. Patent; Hoffmann-La Roche Inc.; US4210754; (1980); (A1) English View in Reaxys

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