| 93.8% |
Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 0.5h;
Stage #2: 1.3-chlorobromopropane In N,N-dimethyl-formamide at 25℃; for 10h; |
1.A Example 1 N-[3-fluoro-4-[6-methoxy-7-[3-(tetrahydropyrrol-1-yl)propyloxy]quinolin-4-oxy]phenyl]-2-phenyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide Step A 1-[4-(3-chloropropyloxy)-3-methoxy]phenylethanone (II)
3-methoxy-4-hydroxyphenylethanone (600 g, 3.61 mol) and anhydrous potassium carbonate (698 g, 5.055 mol) were added to DMF (5v/w, 2500 mL). The mixture was stirred thoroughly at 25° C. for 30 min. Then 1,3-bromochloropane (795.9 g, 1.4 mol) was slowly added dropwise to the mixture. After the dropwise addition, the mixture was reacted under stirring at 25° C. for 10 h. After completion of the reaction, the mixture was filtered by suction. The filtered cake was washed with a small amount of DMF. The filtrate was collected, and slowly poured into ice-water. The mixture was violently stirred to separate out a white solid. The white solid was filtered by suction. The filtered cake was dried to produce a white solid (827.2 g) in a yield of 93.8%. |
| 93.8% |
With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 10h; |
1.A Step A: 1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone (intermediate II)
Step A 1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone (intermediate II) A stirred solution of 1-(4-hydroxy-3-methoxyphenyl)ethanone (600 g, 3.61 mol, Purchased from Shanghai Bangcheng Chemical Co., Ltd.) and anhydrous potassium carbonate (698 g, 5.055 mol) in 2500 mL of N,N-dimethylformamide was added drop-wise with an N,N-dimethylformamide solution of 1-bromo-3-chloropropane (795.9g, 1.4 mol) while maintaining the temperature below 25°C. Then the resulted mixture was kept at 25°C for 10h. After completion of the reaction, the precipitate was filtered and the filter cake was washed by a small amount of N,N-dimethylformamide.The filtrate was poured into ice water slowly with vigorous stirring. The precipitate was filtered, washed with water, and dried to give 827.2g solid. Yield: 93.8%. |
| 93.8% |
With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 10h; |
1.A 1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone (Intermediate II)
A stirred solution of 1-(4-hydroxy-3-methoxyphenyl)ethanone (600 g, 3.61 mol, Purchased from Shanghai Bangcheng Chemical Co., Ltd.) and anhydrous potassium carbonate (698 g, 5.055 mol) in 2500 mL of N,N-dimethylformamide was added drop-wise with an N,N-dimethylformamide solution of 1-bromo-3-chloropropane (795.9 g, 1.4 mol) while maintaining the temperature below 25° C. Then the resulted mixture was kept at 25° C. for 10 h. After completion of the reaction, the precipitate was filtered and the filter cake was washed by a small amount of N,N-dimethylformamide. The filtrate was poured into ice water slowly with vigorous stirring. The precipitate was filtered, washed with water, and dried to give 827.2 g solid. Yield: 93.8%. |
| 93.8% |
Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 30h;
Stage #2: 1.3-chlorobromopropane In N,N-dimethyl-formamide at 25℃; for 10h; |
1.A Step A: 1-(4-(3-Chloropropoxy)-3-methoxy)acetophenone (III)
1-(4-Hydroxy-3-methoxyphenyl)ethanone (600 g, 3.61 mol, Purchased from Zhejiang Dongdong Pharmaceutical Co., Ltd.) and anhydrous potassium carbonate (698 g, 5.055 mol) was added to 2500 mL of dry N,N-dimethylformamide. The mixture was stirred for 30 min at room temperature and then 1-bromo-3-chloropropane (795.9 g, 1.4 mol) was drop-wise added while maintaining the temperature below 25° C. Then the resulted mixture was kept at 25° C. for 10 h. After completion of the reaction, the precipitate was filtered and the filter cake was washed by a small amount of N,N-dimethylformamide. The filtrate was poured into ice-water slowly with vigorous stirring. Then the resulted mixture was stirred for 30 min. The precipitate was filtered, washed with water, and dried to give 827.2 g as white solid. Yield: 93.8%. |
| 93.8% |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 10h; |
6.2. 4-(3-Chloropropoxy)-3-methoxyacetophenone (10)
To a solution of 4-hydroxy-3-methoxy-acetophenone (6.00 g,36.1 mmol) in DMF (25 mL) was added K2CO3 and 1-bromo-3-chloropropane (6.98 g, 50.6 mmol). The reaction mixture was thenstirred at rt for 10 h. The mixture was then poured into cold water(100 mL) with vigorously agitating, and the resulting precipitate was filtered off, washed with water, and dried under vacuum toafford the title compound 10 (8.27 g) as a white solid, yield:93.8%. Mp: 61-63 C. MS (ESI) m/z: 242.2, 244.1 [M+H]+. |
| 92.5% |
With potassium carbonate In acetone at 20℃; |
1 Experimental
7.1 1-(4-(3-Chloropropoxy)-3-methoxyphenyl)ethanone (1) A stirred solution of 1-(4-hydroxy-3-methoxyphenyl) ethanone (24.9 g, 0.15 mol) and anhydrous potassium carbonate (57.9 g, 0.21 mol) in acetone was added dropwise with an acetone solution of 1-bromo-3-chloropropane (66.1 g, 4.2 mol, in 200 mL acetone) while maintaining the temperature below 25 °C. Upon completion of the addition, the reaction mixture was stirred at room temperature for a whole night. The solid was removed by filtration, and the filtrate was poured slowly into 1 L ice water, which is stirred vigorously. A lot of precipitated white solid was filtered and dried in vacuo at 40 °C for 24 h to afford the target compound (69.5 g, yield: 92.5%). Mp 115-117 °C; MS (ESI) m/z (%): 264.8 [M+Na]+. |
| 92.5% |
With potassium carbonate In acetone at 20 - 25℃; |
|
| 92.5% |
With potassium carbonate In acetone at 20℃; |
1.2. 1-(4-(3-Chloropropoxy)-3-methoxyphenyl)ethanone(14)
Astirred solution of 1-(4-hydroxy-3-methoxyphenyl) ethanone (24.9 g, 0.15 mol)and anhydrous potassium carbonate (57.9 g, 0.21 mol) in acetone was addeddropwise with an acetone solution of 1-bromo-3-chloropropane (66.1 g, 4.2 molin 200mL acetone) while maintaining the temperature below 25. Uponcompletion of the addition, the reaction mixture was stirred at roomtemperature for a whole night. The solid was removed by filtration, and thefiltrate was poured slowly into 1L ice water, which is stirred vigorously. Alot of precipitated white solid was filtered and dried in vacuo at 40for 24 hours to afford the target compound (69.5 g, Yield: 92.5%) . M.p. 71-73;MS m/z (ESI): 264.8 [M+Na]+. |
| 92.5% |
With potassium carbonate In acetone at 20℃; |
2 5.2 1-(4-(3-Chloropropoxy)-3-methoxyphenyl)ethanone (1)
A stirred solution of 1-(4-hydroxy-3-methoxyphenyl)ethanone (24.9 g, 0.15 mol) and anhydrous potassium carbonate (57.9 g, 0.21 mol) in acetone was added drop-wise with an acetone solution of 1-bromo-3-chloropropane (66.1 g, 4.2 mol, in 200 mL acetone) while maintaining the temperature below 25 °C. Upon completion of the addition, the reaction mixture was stirred at room temperature overnight. The solid was removed by filtration, and the filtrate was poured slowly into 1 L of ice water, which was stirred vigorously. A lot of precipitated white solid was filtered and dried in vacuo at 40 °C for 24 h to yield the target compound (69.5 g, yield: 92.5%). M.p. 71-73 °C; MS (ESI) m/z (%): 264.8 [M + Na]+. |
| 92.5% |
With potassium carbonate In acetone at 20℃; |
1.A Step A 1-(4-(3-chloropropoxy)-3-methoxy)acetophenone (II)
the 3- methoxy-4-hydroxyacetophenone (249g, 1. 5mol) and Anhydrous potassiumcarbonate (579 · 6g, 2.1mol) added into 125m ml of acetone, under temperature below 25 ° C gradually added 1-bromo-3-chloropropane(661.3g, 4.2mol)/ acetone (1200ml), completion of drop wise addition it wasstirred for overnight at room temperature. After the completion of the reaction, suction filtration, filtrate cake was washed using 100ml of acetone, combinedthe filter cake , filtrate was slowlypoured into 15ml of cold water meanwhile vigorously stirring of reaction, precipitatedlarge amount of white solid , suction filtration ,filter cake was dried invacuo at 40 ° C for 48h to obtain whitepowder 695 · 5g, yield 92. 5%, |
| 92.5% |
With potassium carbonate In acetone at 20 - 25℃; |
A 1-(4-(3-chloropropoxy)-3-methoxy)acetophenone (II)
3-methoxy-4-hydroxyacetophenone (249 g, 1.5 mol) and anhydrous potassium carbonate (579 g, 2.1 mol) were added to 1,250 mL of acetone at a temperature below 25 °C 1-bromo-3-chloropropane (661.3 g, 4.2 mol) in acetone (1200 mL) was added dropwise and stirred overnight at room temperature. After filtration, the filter cake was rinsed with 100mL acetone. The filter cake was slowly poured into 15L of ice water and stirred vigorously. A large amount of white solid was precipitated. The filter cake was vacuum dried at 40 ° C for 48h, A white powder of 695.5 g was obtained in a yield of 92.5% |
| 92.5% |
With potassium carbonate In acetone at 20 - 25℃; |
1.A Step A1- (4- (3- chloropropoxy) -3-methoxy) acetophenone (II)
A mixture of 3-methoxy-4-hydroxyacetophenone (249g, 1.5moL) and anhydrous potassium carbonate (579.6g, 2.1mol) was added to1250mL of acetone was slowly added dropwise temperature below 25 -3-bromo-1- - chloropropane (661.3g, 4.2mol) / acetone (1200mL), a droppingwas completed, the mixture was stirred overnight at room temperature.After completion of the reaction, suction filtration, the filter cake was rinsed with 100mL of acetone, the combined filter cake, and the filtrate was slowly poured into15L of ice water with vigorous stirring, to precipitate a lot of white solid was suction filtered, the filter cake was dried in vacuo at 40 48 hours, a whitepowder 695.5g, yield: 92.5%. |
| 92.5% |
With potassium carbonate In acetone at 25℃; |
1.A Step A Preparation of 1- (4- (3-chloropropoxy) -3-methoxy) acetophenone (II)
3-methoxy-4-hydroxyacetophenone(249 g, 1.5 mol) and anhydrous potassium carbonate(579.6 g, 2.1 mol) was added to 1,250 mL of acetone,A solution of 1-bromo-3-chloropropane (661.3 g, 4.2 mol) / acetone (1200 mL) was slowly added dropwise at a temperature below 25 ° C,The mixture was stirred overnight at room temperature.After completion of the reaction,The filter cake was rinsed with 100 mL of acetone,The filter cake was combined and the filtrate was slowly poured into 15 L ice water,While vigorous stirring, precipitation of a large number of white solid,The filter cake is vacuum dried at 40 DEG C for 48 hours,A white powder of 695.5 g was obtained in a yield of 92.5%. |
| 92.5% |
With potassium carbonate In acetone at 20 - 25℃; |
A Step A 1- (4- (3-Chloropropoxy) -3-methoxy) acetophenone (a)
3-methoxy-4-hydroxyacetophenone (249g, 1.5mol) and anhydrous potassium carbonate (579.6g, 2.1mol) was added to 1250mL of acetone at a controlled temperature below 25 °C was slowly added dropwise 1-Bromo-3-chloropropane (661.3 g, 4.2 mol) in acetone (1200 mL) was added dropwise and the mixture was stirred at room temperature overnight. After completion of the reaction, suction filtration, the filter cake rinsed with 100mL acetone, the filter cake was combined, the filtrate slowly poured into 15L of ice water, while stirring vigorously, precipitated a large amount of white solid, suction filtration, the filter cake was vacuum dried at 40 °C 48h, White powder 695.5g, 92.5% |
| 92.5% |
With potassium carbonate In acetone at 20℃; |
A 1-(4-(3-chloropropoxy)-3-methoxy)acetophenone (II)
3-Methoxy-4-hydroxyacetophenone (249 g, 1.5 mol)And anhydrous potassium carbonate (579.6 g, 2.1 mol) were added to 1250 mL of acetone and 1-bromo-3-chloropropane (661.3 g, 4.2 mol) Stir overnight at room temperature.After the reaction was completed, suction filtration, the filter cake rinsed with 100mL acetone, the combined filter cake,The filtrate was slowly poured into 15L ice water, while vigorous stirring, precipitated a large number of white solid, suction filtration,The filter cake was vacuum dried at 40 ° C for 48 hours to give 695.5 g of white powder, yield: 92.5%. |
| 92.5% |
With potassium carbonate In acetone at 20 - 25℃; |
1.1 Step 1 Preparation of 1-(4-(3-chloropropoxy)-3-methoxy)acetophenone (II)
3-methoxy-4-hydroxyacetophenone (249 g, 1.5 mol) and anhydrous potassium carbonate (579.6 g, 2.1 mol) were added In 1250mL acetone, the temperature control is below 25 °C.1-Bromo-3-chloropropane (661.3 g, 4.2 mol) / acetone (1200 mL) was slowly added dropwise, and the mixture was stirred at room temperature overnight. After the reaction was completed, suction filtration, the filter cake was rinsed with 100 mL of acetone, and the filtrate was combined.The filtrate was slowly poured into 15 L of ice water while stirring vigorously to precipitate a large amount of white solid, which was suction filtered.The filter cake was dried under vacuum at 40 ° C for 48 hours.Obtained white powder 695.5g, yield: 92.5%; |
| 92.5% |
With potassium carbonate In acetone at 20 - 25℃; |
A Step A1-(4-(3-Chloropropoxy)-3-methoxy)acetophenone (a)
3-methoxy-4-hydroxyacetophenone (249 g, 1.5 mol) and anhydrous potassium carbonate (579.6 g, 2.1 mol) were addedIn 1250 mL of acetone, 1-bromo-3-chloropropane (661.3 g, 4.2 mol)/acetone (1200 mL) was slowly added dropwise under controlled temperature of 25 ° C or lower.After completion, stir at room temperature overnight. After the reaction was completed, suction filtration, the filter cake was rinsed with 100 mL of acetone, the filter cake was combined, and the filtrate was slowly poured.15L ice water, while stirring vigorously, a large amount of white solid was precipitated, suction filtration, and the filter cake was vacuum dried at 40 ° C for 48 h to obtain white powder.695.5 g, yield 92.5%, |
| 92.5% |
With potassium carbonate In acetone at 25℃; |
A Step A l-(4-(3-Chloropropoxy)-3-methoxy)acetophenone (II)
3-methoxy-4-hydroxyacetophenone (249 g, 1.5 mol) and anhydrous potassium carbonate (579.6 g, 2.lmol)Add to 1250mL of acetone,1-bromo-3-chloropropane (661.3 g, 4.2 mol) / acetone (1200 mL) was slowly added dropwise under controlled temperature of 25 ° C.After the drop,Stir at room temperature overnight.After the reaction is completed,Filtering,The filter cake was rinsed with 100 mL of acetone.Combine the filtrate,Slowly pour the filtrate into 15 L of ice water.Stirring at the same time,A large amount of white solid is precipitated,Filtering,The filter cake was dried under vacuum at 40 ° C for 48 h.White powder 695.5g,The yield was 92.5%. |
| 92.3% |
Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In N,N-dimethyl-formamide for 0.5h;
Stage #2: 1.3-chlorobromopropane In water; N,N-dimethyl-formamide at 20℃; for 5h; |
4.1.1. 4-(3-Chloropropoxy)-3-methoxyacetophenone (1)
To a solution of 1-(4-hydroxy-3-methoxyphenyl)ethenone (49.8 g,0.30 mol) in DMF (300 mL), K2CO3 (82.8 g, 0.60 mol) was added andstirred for 30 min. Then 1-bromo-3-chloropropane (56.7 g, 0.36 mol)was added to the above suspension. The mixture was then poured into cold water (1 L) with vigorously agitating for 15 min after 5 h. Theresulting precipitate was filtered off, washed with water, and driedunder vacuum to obtained acetophenone 1 as white solid, yield: 92.3%(67.0 g). HRMS (ESI) m/z 243.0768 [M+H]+, Calcd. for 243.0788. |
| 92.5% |
With potassium carbonate In acetone at 20℃; |
1.1 Preparation of 1-(4-(3-chloropropoxy)-3-methoxy)acetophenone (Intermediate II)
Add 3-methoxy-4-hydroxyacetophenone (249g, 1.5mol) and anhydrous potassium carbonate (579.6g, 2.1mol) to 1250mL of acetone and stir below 25°C.A solution of 1-bromo-3-chloropropane (661.3 g, 4.2 mol)/acetone (1200 mL) was slowly added dropwise, and stirred at room temperature (25° C.) overnight. After the reaction is completed, filter with suction, wash the filter cake with acetone 3 times, combine the filtrate, slowly pour the filtrate into 15L ice water (0), stir, a large amount of white solid precipitates, filter with suction, and dry the filter cake at 35 for 20h , Get 695.5g of white powder, get intermediate II. Calculated yield: 92.5% |
| 91% |
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 2h; |
1-[4-(3-Chloropropoxy)-3-methoxyphenyl]ethan-1-one (19)
A mixture of acetovanillone (250.0 g, 1.50 mol), 1-bromo-3-chloropropane (315.0 g, 2.0 mol), and K2CO3 (345.5 g, 2.50 mol) in DMF (1.5 kg) was stirred at 60 °C for 2 h then cooled to r.t., and poured slowly into ice-water (6 kg) while stirring constantly. The solid formed was filtered off, washed with cold water (2 × 0.8 kg), and dried at 45 °C for 6 h. The white product was stirred and heated with hexane-EtOAc (3:1, v/v, 0.8 kg) at 50 °C for 2 h then cooled to r.t. overnight. The resulting solid was filtered off, washed with hexane-EtOAc (3:1, v/v, 2 × 200 g), and dried at 40 °C for 4 h to afford 19 (331.3 g, 91%) as a white solid; mp 56.7-57.9 °C.1H NMR (400 MHz, CDCl3): δ = 2.34 (m, J = 6.4 Hz, 2 H), 2.58 (s, 3 H),3.79 (t, J = 6.4 Hz, 2 H), 3.93 (s, 3 H), 4.26 (t, J = 6.0 Hz, 2 H), 6.93 (d,J = 8.0 Hz, 1 H), 7.54 (d, J = 2.0 Hz, 1 H), 7.58 (dd, J = 2.0, 8.0 Hz, 1 H).13C NMR (100 MHz, CDCl3): δ = 26.3, 32.0, 41.4, 56.0, 65.4, 110.5,111.4, 123.2, 130.7, 149.3, 152.5, 196.8.MS (ESI): m/z = 243.2.0 [M + H]+. |
| 91.3% |
Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In acetone at 20℃; for 0.5h;
Stage #2: 1.3-chlorobromopropane In acetone at 0 - 25℃; for 20h; |
1.A Preparation of 4- (3-chloropropoxy) -3-methoxyacetophenone (A1)
will3-methoxy-4-hydroxyacetophenone (16.6 g, 0.1 mol)Dissolved in 100mL acetone,Anhydrous potassium carbonate (19.3 g, 0.14 mol) was added,Stirred at room temperature for 0.5 h,A solution of 1-bromo-3-chloropropane was added dropwise at 0 ° C(21.9 g, 0.14 mol),During the dropwise addition, the control temperature is below 25 ° C.After completion of the reaction, the reaction was stirred at 25 ° C for about 20 hours. After completion of the reaction,The filtrate was slowly poured into 200 mL of ice water. After stirring for 15 min, the filtrate was filtered and the cake was dried to give 22.2 g of a white solid in 91.3% yield. |
| 91.9% |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 6h; |
4.1.1 4-(3-Chloropropoxy)-3-methoxyacetophenone (1)
Anhydrous K2CO3 (165.6g, 1.2mol) and 1-bromo-3-chloropropane (105.4g, 0.66mol) was added to a solution of 4-hydroxy-3-methoxy-acetophenone (100.0g, 0.60mol) in DMF (500mL). The reaction mixture was then stirred at rt for 6h. The mixture was then poured into cold water (1500mL) with vigorously agitating for 15min, and the resulting precipitate was filtered off, washed with water, and dried under vacuum to afford 1 as white solid, yield: 91.9% (133.8g). MS (ESI) m/z 242.9 [M+H]+. |
| 91.2% |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; |
4.1.3. Synthesis of 4-(3-Chloropropoxy)-3-methoxyaceto-phenone (1c)
To a solution of 4-hydroxy-3-methoxy-acetophenone (6.00 g,36.0 mmol) in DMF (25 mL) was added K2CO3 (7.45 g, 54.0 mmol) and 1-bromo-3-chloropropane (7.94 g, 50.6 mmol). The reaction mixture was then stirred at rt for overnight. The mixture was then poured into cold water (100 mL) with vigorously agitating, and the resulting precipitate was filtered off, washed with water, and dried under vacuum to afford the title compound 1c (7.94 g) as a white solid, yield: 91.2%. Mp:61-62 °C. 1H NMR (400 MHz, CDCl3) δ 7.55 (dd, J=2.0, 8.4 Hz, 1H),7.52 (d, J=2.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 4,23 (t, J=6.0 Hz,2H), 3.90 (s, 3H), 3.76 (t, J=6.4 Hz, 2H), 2.55 (s, 3H), 2.34-2.28 (m,2H). 13C NMR (100 MHz, CDCl3) δ 196.7, 152.4, 149.2, 130.6, 123.1,111.4, 110.4, 65.3, 55.9, 41.3, 31.9, 26.1. ESI-MS: m/z 243.0 [M+H]+. |
| 85.6% |
With potassium carbonate In N,N-dimethyl-formamide at 25 - 30℃; Industrial scale; Green chemistry; |
|
| 84% |
With potassium carbonate In acetone for 24h; Heating; |
|
|
In sodium hydroxide; di-isopropyl ether; water |
12 1-[4-(3-Chloropropoxy)-3-methoxyphenyl]ethanone
PREPARATION 12 1-[4-(3-Chloropropoxy)-3-methoxyphenyl]ethanone To a mixture of 15.15 kg (96.26 mole) of 1-bromo-3-chloropropane and 25 liter of water heated to 86° C. was added a solution of 8 kg (48.13 mole) of acetovanillone in 3.93 kg (48.6 mole) of 50% aqueous sodium hydroxide and 89 liter of water over a 2.5 hr period. The mixture was heated at 80°-85° C. for 2.5 hr after addition was complete. The mixture was cooled and extracted twice with 49 kg portions of toluene. The combined extracts were washed once with 1.9 kg of 50% sodium hydroxide diluted to 5 gal and once with 5 gal of water. The toluene layer was dried over 3 lb of anhydrous sodium sulfate and concentrated under reduced pressure. The residue was heated to reflux in 15 gal of isopropylether, filtered, and the filtrate cooled. The crystallized title compound obtained by filtration together with additional compound obtained by concentrating the filtrate to 25% of its original volume amounted to 4.2 kg (36%). Acetovanillone recovered was 3.4 kg. The product was recrystallized twice from cyclohexane and twice from ligroin, m.p. 57.8°-58.5° C. analysis: Calculated for C12 H15 ClO3: C,59.39;H,6.23. Found: C,59.07;H,6.22. |
|
With potassium carbonate In N,N-dimethyl-formamide at 20℃; |
2
Reference Example (2): Process for preparing l-(4-(3-chloropropoxy)-3- methoxyphenvDethanoneTo a mixture of l-(4-hydroxy-3-methoxyphenyl)ethanone in dimethyl formamide were added potassium carbonate and l-bromo-3-chloropropane . The mixture was stirred at ambient temperature until completion of reaction. To the reaction mass was added purified water. The crystallized product was filtered, washed with water and dried to afford pure title compound. M.pt 63-66 °C. |
|
With potassium carbonate In butanone at 78℃; for 1.5h; |
1
A mixture of Methyl ethyl ketone (300 ml), Benzyl triethylammonium chloride (5.0 g), Potassium Carbonate (83.2 g), 4-hydroxy-3-methoxy acetophenone (100 g) and 1-bromo-3-chloropropane (190 g) was heated at 78°C for 1.5 h. After completion of reaction, the reaction mixture was cooled to 30°C and DM Water (300 ml) was added to the reaction mixture and extracted. The organic phase was separated and washed with 5% sodium chloride solution. The organic phase was distilled out under vacuum at 50°C. Cyclohexane (500 ml) was added to the oily residue and stirred to give solid. The solid was filtered, washed with cyclohexane (100ml) and suck dried. The solid was dried in oven at 45°C to give the title product (133.0 g).[130] Dimer impurity content: 3.0%[131] Purity by HPLC: 97% |
|
With potassium carbonate In acetonitrile at 75 - 80℃; |
2 Example 2
Example 2 synthesis of iloperidone Acetovanillone (50 g, 0.30 mol) is added to a suspension of potassium carbonate (60 g, 0.43 mol), acetonitrile (800 ml), N,N-dimethylformamide (200 ml) and 1-bromo-3-chloropropane (55.2 g, 0.35 mol). The mixture is heated at the temperature of 75-80°C and monitored by UPLC. After completion of the reaction, potassium carbonate (80 g, 0.58 mol), 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (90 g, 0.35 mol) and 100 ml of N,N-dimethylformamide are added. The mixture is heated at the temperature of 90-95°C and monitored by UPLC. After completion of the reaction, the resulting mixture is cooled to 55°C and the inorganic salts are filtered off. The clear solution obtained is concentrated under vacuum to a weight of 370 g, and cooled to 5°C. The resulting suspension is filtered. The solid isolated is dried under low pressure at 55°C to obtain iloperidone (97 g, 0.23 mol) as a white solid with a purity exceeding 99%. |
|
In acetone at 0 - 20℃; for 12.5h; |
|
|
With potassium carbonate In N,N-dimethyl-formamide; acetonitrile at 75 - 80℃; |
2 Example 2 Synthesis of Iloperidone
Example 2 Synthesis of Iloperidone [0049] Acetovanillone (50 g, 0.30 mol) is added to a suspension of potassium carbonate (60 g, 0.43 mol), acetonitrile (800 ml), N,N-dimethylformamide (200 ml) and 1-bromo-3-chloropropane (55.2 g, 0.35 mol). The mixture is heated at the temperature of 75-80° C. and monitored by UPLC. After completion of the reaction, potassium carbonate (80 g, 0.58 mol), 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (90 g, 0.35 mol) and 100 ml of N,N-dimethylformamide are added. The mixture is heated at the temperature of 90-95° C. and monitored by UPLC. After completion of the reaction, the resulting mixture is cooled to 55° C. and the inorganic salts are filtered off. The clear solution obtained is concentrated under vacuum to a weight of 370 g, and cooled to 5° C. The resulting suspension is filtered. The solid isolated is dried under low pressure at 55° C. to obtain iloperidone (97 g, 0.23 mol) as a white solid with a purity exceeding 99%. Molar yield from acetovanillone to iloperidone: 76%. |
|
In acetone at 0 - 25℃; for 12.5h; |
|
|
In acetone at 0 - 20℃; for 12h; |
|
|
With potassium carbonate; acetone at 20℃; |
|
|
In acetone at 0 - 20℃; for 12.5h; |
|
| 692.2 g |
Stage #1: 1-(3-methoxy-4-hydroxyphenyl)ethanone With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: 1.3-chlorobromopropane In N,N-dimethyl-formamide at 20℃; for 6h; |
1.1 Step (1) 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (III)
At room temperature, 500.0 g (3.01 mol) of 3-methoxy-4-hydroxyacetophenone II and 581.7 g (4.22 mol) of anhydrous potassium carbonate were added to 2 L of N,N-dimethylformamide (DMF). After sufficiently stirring for 30 min, 311.7 mL (3.16 mol) of 1-bromo-3-chloropropane was added dropwise. Drop finished, stir for 6 h at room temperature. The reaction solution was poured into 5 L of ice water. Filter. The filter cake was dried to give 692.2 g of a white solid. |
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In acetone at 0 - 20℃; for 12.5h; |
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In acetone at 0℃; for 12.5h; |
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| 68.8 g |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 6.5h; |
27.1 Step 1.1-[4-(3-Chloropropoxy)-3-methoxy]acetophenone (III-1)
50.0 g of 3-methoxy-4-hydroxyacetophenone and 58.2 g of anhydrous potassium carbonate were added to 200 mL of N at room temperature.After stirring for 30 minutes in N-dimethylformamide, 31.2 mL of 1,3-bromochloropropane was added dropwise, and the mixture was stirred at room temperature for 6 hours.The reaction solution was poured into 600 mL of ice water, suction filtered, and the filter cake was dried to give a white solid 68.8 g. |
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In acetone at 0 - 25℃; for 12.5h; Alkaline conditions; |
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With potassium carbonate In N,N-dimethyl-formamide at 20℃; |
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| 695.5 g |
With potassium carbonate In acetone at 25℃; |
1.4 Step 4 Synthesis of 4-(3-chloropropoxy)-3-methoxyacetophenone
Add 3-methoxy-4-hydroxyacetophenone (249g, 1.5mol) and anhydrous potassium carbonate (579.6g, 2.1mol) to 1250mL of acetone, slowly add 1-bromo-3-chloropropane (661.3 g, 4.2 mol)/acetone (1200 mL) dropwise at a temperature below 25°C., and then stir overnight at room temperature. After the reaction is complete, filter with suction, rinse the filter cake with 100 mL of acetone, combine the filter cakes, slowly pour the filtrate into 15 L of ice water, while stirring vigorously, and precipitate a large amount of white solid, which is filtered with suction.The filter cake was vacuum dried at 40°C for 48 hours to obtain 695.5 g of white powder. |
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With potassium carbonate In acetone at 0 - 20℃; for 12.5h; |
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