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CAS No. : | 58113-30-7 | MDL No. : | MFCD05156572 |
Formula : | C12H15ClO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RBBVSSYQKVBALO-UHFFFAOYSA-N |
M.W : | 242.70 | Pubchem ID : | 7314264 |
Synonyms : |
|
Num. heavy atoms : | 16 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.42 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 64.03 |
TPSA : | 35.53 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.06 cm/s |
Log Po/w (iLOGP) : | 2.46 |
Log Po/w (XLOGP3) : | 2.43 |
Log Po/w (WLOGP) : | 2.91 |
Log Po/w (MLOGP) : | 1.97 |
Log Po/w (SILICOS-IT) : | 3.47 |
Consensus Log Po/w : | 2.65 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.76 |
Solubility : | 0.425 mg/ml ; 0.00175 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.82 |
Solubility : | 0.368 mg/ml ; 0.00152 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.44 |
Solubility : | 0.00885 mg/ml ; 0.0000365 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.99 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P302+P352-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium carbonate; potassium iodide In butan-1-ol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With sodium carbonate; potassium iodide In butan-1-ol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium carbonate; potassium iodide In butan-1-ol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With sodium carbonate; potassium iodide In N,N-dimethyl-formamide Heating; | |
With sodium hydrogencarbonate In <i>N</i>-methyl-acetamide; chloroform | 67 1-[4-[3-[4-[(4-Fluorophenyl)hydroxyphenylmethyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone EXAMPLE 67 1-[4-[3-[4-[(4-Fluorophenyl)hydroxyphenylmethyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone A mixture of 6.5 g (0.023 mole) of α-(p-fluorophenyl)-α-phenyl-4-piperidinemethanol, 5.5 g (0.023 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.92 g (0.023 mole) of sodium bicarbonate in 80 ml of dimethylformamide was heated at 100°-110° C. for 2 hrs. The reaction mixture was cooled and filtered and the dimethylformamide was removed at reduced pressure. The residual oil was dissolved in chloroform and filtered. The chloroform was removed at reduced pressure. The solid residue which remained weighed 8.6 g (77%) and was recrystallized from ethanol to give 3.1 g of material melting at 147°-148° C. A sample was dried over refluxing toluene and submitted for analysis. (See Ex. 14, U.S. Pat. No. 3,956,296). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium carbonate; potassium iodide In butan-1-ol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium carbonate; potassium iodide In butan-1-ol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium carbonate; potassium iodide In butan-1-ol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium carbonate; potassium iodide In butan-1-ol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium carbonate; potassium iodide In butan-1-ol for 20h; Heating; | |
With sodium hydrogencarbonate In <i>N</i>-methyl-acetamide; benzene | 66 1-[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone EXAMPLE 66 1-[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone A mixture of 5.0 g (0.0165 mole) of α,α-bis(p-fluorophenyl)-4-piperidinemethanol, 4.0 g (0.0165 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.4 g (0.0165 mole) of sodium bicarbonate in 60 ml of dimethylformamide was stirred and heated at 80° C. for two hours. The temperature was raised to 100° C. for one hour. After cooling, the reaction mixture was filtered and the dimethylformamide was removed at reduced pressure. The residual oil which crystallized on standing in ether was dissolved in benzene and placed on a Florisil column. Using a gradient elution of acetone-benzene, 1.8 g (21.4%) of product was obtained from the column, m.p. 141.5°-143° C. (See Ex. 12, U.S. Pat. No. 3,956,296). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium carbonate; potassium iodide In butan-1-ol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium carbonate; potassium iodide In butan-1-ol Heating; | |
4.0 g (78%) | With potassium iodide; sodium carbonate In butan-1-ol | 187 1-[4-[3-[3-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone EXAMPLE 187 1-[4-[3-[3-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [α,α-bis(4-fluorophenyl)]-3-piperidinemethanol, 2.4 g (0.01 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave 4.0 g (78%) of the title compound as an off-white solid, mp 100°-105° C. (2-propanol). Analysis: Calculated for C30 H33 F2 NO4: C, 70.71; H, 6.53; N, 2.75. Found: C, 70.62; H, 6.61; N, 2.77. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium carbonate; potassium iodide In butan-1-ol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium carbonate; potassium iodide In butan-1-ol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With sodium carbonate; potassium iodide In butan-1-ol Heating; | |
1.1 g (48%) | With potassium iodide; sodium carbonate In butan-1-ol | 185 1-[4-[3-[4-[Bis(3,4-difluorophenyl)hydroxymethyl]1-piperidinyl]-propoxy]-3-methoxyphenyl]ethanone EXAMPLE 185 1-[4-[3-[4-[Bis(3,4-difluorophenyl)hydroxymethyl]1-piperidinyl]-propoxy]-3-methoxyphenyl]ethanone This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 1.4 g (0.004 mole) of α,α-bis(3,4-difluorophenyl)-4-piperidinemethanol, 1.0 g (0.004 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 1.6 g (0.015 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave 1.1 g (48%) of the title compound as an off-white solid, mp 143°-146° C. (2-propanol). Analysis: Calculated for C30 H31 F4 NO4: C, 66.05; H, 5.73; N, 2.57. Found: C, 66.03; H, 5.89; N, 2.50. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium carbonate; potassium iodide In butan-1-ol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With sodium carbonate; potassium iodide In N,N-dimethyl-formamide Heating; | |
With sodium hydrogencarbonate In <i>N</i>-methyl-acetamide; water | 70 1-[4-[3-[4-(Cyclohexylhydroxyphenylmethyl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone hydrochloride [1:1] EXAMPLE 70 1-[4-[3-[4-(Cyclohexylhydroxyphenylmethyl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone hydrochloride [1:1] A mixture of 3.9 g (0.143 mole) of α-cyclohexyl-α-phenyl-4-piperidinemethanol, 3.5 g (0.143 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 2.35 g (0.28 mole) of sodium bicarbonate in 100 ml of dimethylformamide was heated at 100° C. for 4 hrs. After cooling, the reaction mixture was diluted with about 600 ml of water and extracted with benzene. The collected benzene extracts were washed with water and dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. A crude solid weighing 5.1 g (74.5%) was obtained. The solid was dissolved in ether, and the ether solution was treated with an excess of ethereal hydrogen chloride. The hydrochloride salt obtained was recrystallized from isobutyl methyl ketone to give 4.0 g of the salt, m.p. 152°-155° C. (See Ex. 17, U.S. Pat. No. 3,956,296). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate In acetonitrile at 20 - 80℃; for 3h; | |
93.8% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 10h; | 1 7.1.1 4-(3-Chloropropoxy)-3-methoxyacetophenone (10) To a solution of 4-hydroxy-3-methoxy-acetophenone (6.00g, 36.1mmol) in DMF (25mL) was added K2CO3 and 1-bromo-3-chloropropane (6.98g, 50.6mmol). The reaction mixture was then stirred at rt for 10h. The mixture was then poured into cold water (100mL) with vigorously agitating, and the resulting precipitate was filtered off, washed with water, and dried under vacuum to afford the title compound 10 (8.27g) as a white solid, yield: 93.8%. Mp: 61-63°C (Lit.33 Mp: 57.5-58.5°C). MS (ESI) m/z: 242.2, 244.1 (M+). |
93.8% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 10h; |
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. |
In acetone at 0 - 20℃; for 12.5h; | ||
In acetone at 0℃; for 12.5h; | ||
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. |
In acetone at 0 - 25℃; for 12.5h; Alkaline conditions; | ||
With potassium carbonate In N,N-dimethyl-formamide at 20℃; | ||
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. |
With potassium carbonate In acetone at 0 - 20℃; for 12.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.5% | With sodium hydrogencarbonate; In toluene; acetonitrile; at 76℃; for 6h; | 25.4 g of 1-[4-(3-chloropropoxy)-3-methoxyphenyl ketene was added to a mixture of 200 ml of acetonitrile and 100 ml of toluene, 10.1 g of sodium bicarbonate was added, and the temperature was increased to 76C by magnetic stirring. ,25.6 g of <strong>[84163-13-3]6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride</strong> was added in four portions at a time interval of 10 min. After the addition was complete, the reaction was continued for 6 h, and the heating was stopped. At 20 C, the reaction solution was washed with water to neutrality, the organic layer was separated, and it was spin-dried to obtain a pale yellow oil. The solution was dissolved with 60 ml of methanol, and hydrochloric acid was added dropwise until the pH was 4 while stirring. A white solid precipitated and was filtered. After rinsing with 25 ml of isopropanol, a white powdery solid was obtained after drying. The yield was 90.5% and the purity of detection was 99.7%. |
Example 4: Process for preparing Iloperidone: A mixture of 6-Fluoro-3-piperidin-4-yl-benzo[d]isoxazole hydrochloride, l-(4-(3-chloropropoxy)-3-methoxyphenyl) ethanone and potassium carbonate in dimethyl formamide was heated at 70-95 C until the reaction gets completed and the reaction mixture was cooled to 15-35 C. The resulting reaction mass was poured into water and heated to 60-70 C and cooled to 15-35 C. The precipitated product was filtered, washed with water and dried. Optionally the wet product was purified by recrystallization using methanol, ethanol, acetone, ethyl methyl ketone or mixtures thereof. M.pt. 121-124 C. The PXRD of Iloperidone obtained is as shown in Fig- 12. Purity by HPCL: 99.9 %; content of compound of formula (X): < 0.05 % and more than 0.3 % in product obtained by prior art processes. Example 5: Purification of Iloperidone:A mixture of activated carbon and Iloperidone in acetone was heated to 50-55 C and the reaction mixture was cooled to 15-35 C. The reaction mass was filtered through hyflo bed and washed with acetone. The filtrate was distilled under vacuum to remove the solvent. Methanol was optionally added to the residue and heated to 60-65 C. The reaction mass was cooled to 0-35 C. The crystallized product was filtered, washed with acetone or methanol and dried to afford the pure Iloperidone. M.pt. 121-124 C. | ||
With potassium carbonate; In water; at 80 - 90℃; for 1.5h;Product distribution / selectivity; | 10 g of reactant 6-fluoro-3-(4-piperidinyl)-1,2-benzoisoxazole hydrochloride and 10.4 g of reactant 1-[4-(3-chloropropoxyl)-3-methoxyphenyl]ethyl ketone were placed in a 250 ml reaction flask, and a solution prepared with 17.9 g potassium carbonate and 120 ml water was added thereto. The reaction mixture was heated to 80-90 C. and stirred for 1.5 hours, then naturally cooled to room temperature under stirring and filtered. The filter cake was washed twice with water, and then washed twice with methanol, and dried in vacuum at 50 C. to obtain 15.1 g crude iloperidone. The yield was 91.0%. The crude product was decolored by active carbon, then recrystallized with toluene to obtain iloperidone. The purity was 99.5% (determined by HPLC), and the melting point was 118-120 C. |
With potassium carbonate; In N,N-dimethyl-formamide; at 90 - 95℃; for 17h; | Example 1:6-Fluoro-3-(4-piperidinyl)-l,2-benzisoxazole hydrochloride (25 g), l-[4-(3- chloropropoxy)-3-methoxyphenyl]ethanone (23.65 g), potassium carbonate (26.88 g) and N, N-dimethylformamide (250 mL) were added to a reaction vessel at a temperature of about 20C to 25C. The temperature was slowly raised to about 90C to 95C in a period of about 1 hour. The reaction mixture was stirred for about 16 hours and then dispersed into de-ionized water (250 mL), extracted with ethyl acetate (2 x 125 mL) followed by washing with water (100 mL). Ethyl acetate was recovered under vacuum at atemperature of about 40C to 45C to obtain crude iloperidone.Yield: 70%11 PLC Purity: 85-86% | |
With potassium carbonate; In water; at 80 - 90℃; for 1.5h;Product distribution / selectivity; | 10g of reactant 6-fluoro-3-(4-piperidinyl)-1,2-benzoisoxazole hydrochloride and 10.4g of reactant 1-[4-(3-chloropropoxyl)-3-inethoxyphenyl]ethyl ketone were placed in a 250ml reaction flask, and a solution prepared with 17.9g potassium carbonate and 120ml water was added thereto. The reaction mixture was heated to 80-90 C and stirred for 1.5 hours, then naturally cooled to room temperature under stirring and filtered. The filter cake was washed twice with water, and then washed twice with methanol, and dried in vacuum at 50 C to obtain 15.1g crude iloperidone. The yield was 91.0%. The crude product was decolored by active carbon, then recrystallized with toluene to obtain iloperidone. The purity was 99.5% (determined by HPLC), and the melting point was 118~120C. | |
97 g | In N,N-dimethyl-formamide; acetonitrile; at 90 - 95℃; | 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 75-80C and monitored by UPLC. After completion of the reaction, potassium carbonate (80 g, 0.58 mol), <strong>[84163-13-3]6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride</strong> (90 g, 0.35 mol) and 100 ml of N,N-dimethylformamide are added. The mixture is heated at the temperature of 90-95C and monitored by UPLC. After completion of the reaction, the resulting mixture is cooled to 55C and the inorganic salts are filtered off. The clear solution obtained is concentrated under vacuum to a weight of 370 g, and cooled to 5C. The resulting suspension is filtered. The solid isolated is dried under low pressure at 55C to obtain iloperidone (97 g, 0.23 mol) as a white solid with a purity exceeding 99%. Molar yield from acetovanillone to iloperidone: 76%. |
28 g | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; for 7h;Heating; | A mixture of 6-fluoro-3- (4-piperidinyl) -1,2-benzisoxazole hydrochloride was added to 400 mL of DMF, and potassium carbonate35 g, 3.5 g of potassium iodide and 33.5 g of 3-methoxy-4- (3-chloropropoxy) acetophenone were added and heated for about 7 h. Cold to room temperature, pumpingFilter, the filtrate stirring into the 1000mL cold water, stirring about 2h, pumping, washing, drying, light yellow crude 53g. EthanolAfter recrystallization, 28 g of iloperidone was obtained and the content of ILPI-07 was 0.12%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In hydrogenchloride; acetonitrile | 7.d c. d. [4-[3-[3-[1H-Indazol-3-yl[-8-azabicyclo[3.2.1]octan-8-yl]propoxy]-3-methoxyphenyl]ethanone A mixture of 3-(1H-indazol-3-yl)-8-azabicyclo[3.2.1]octane (5.46 g), 4-(3-chloropropoxy)-3-methoxyphenyl ethanone (6.4 g), potassium carbonate (6.6 g) and a catalytic amount of potassium iodide was heated in 100 ml of refluxing acetonitrile for 17 hours. The resulting mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated, and the residue was dissolved in 6N HCl solution and extracted with ethyl acetate. The aqueous layer was basified with 10% NaOH solution, and the product was extracted into dichloromethane. The combined organic layers were washed with brine, dried over K2 CO3, filtered, and concentrated to provide 7.0 g of a foam. Purification by HPLC on silica gel (elution initially with ethyl acetate, and then 10% methanol-90% ethyl acetate) afforded 4.2 g of product as a foam. The foam crystallized upon the addition of ethyl acetate, and the solid was then recrystallized from ethyl acetate-hexanes, affording 2.8 g of [4-[3-[3-[1H-indazol-3-yl]-8-azabicyclo[3.2.1]octan-8-yl]propoxyl]-3-methoxyphenyl]ethanone, as a powder, m.p. 173°-175° C. Analysis: Calculated for C26 H31 N3 O3: 72.03% C; 7.21% H; 9.69% N; Found: 71.69% C; 7.14% H; 9.64% N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In methanol; water; acetonitrile | 12 [4-[3-[3-[6-Fluoro-1H-indazol-3-yl]-8-azabicyclo[3.2.1]octan-8-yl]propoxy]-3-methoxyphenyl]ethanone EXAMPLE 12 [4-[3-[3-[6-Fluoro-1H-indazol-3-yl]-8-azabicyclo[3.2.1]octan-8-yl]propoxy]-3-methoxyphenyl]ethanone A mixture of 3-(6-fluoro-1H-indazol-3-yl)-8-azabicyclo[3.2.1]octane (4.3 g), 4-(3-chloropropoxy)-3-methoxyphenyl ethanone (4.7 g) and potassium carbonate (2.8 g) was heated in 150 ml of refluxing acetonitrile for 18 hours. The resulting mixture was allowed to cool to room temperature and then filtered. The filtrate was concentrated, and the residue was dissolved in H2 O and extracted with 4:1 CHCl3 /IPA. The combined organic layers were dried over Mg2 SO4, filtered and concentrated. Purification by HPLC on silica gel (elution initially with ethyl acetate, and then with 10% methanol-89% ethyl acetate-1% TEA) afforded 3.1 g of product as a foam. The foam was dissolved in methanol (50 ml) and the product crystallized affording 2.8 g of [4-[3-[3-[6-fluoro-1H-indazol-3-yl]-8-azabicyclo[3.2.1]octan-8-yl]propoxy]-3-methoxyphenyl]ethanone, as a solid, m.p. 157°- 158° C. Analysis: Calculated for C26 H30 FN3 O3: 69.14% C; 6.71% H; 9.31% N; Found: 68.97% C; 6.99% H; 9.31% N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In methanol; acetonitrile | 17 [4-[3-[3-[6-Fluoro-1,2-benzisothiazol-3-yl]-8-azabicyclo[3.2.1]octan-8-yl]propoxy]-3-methoxyphenyl] ethanone EXAMPLE 17 [4-[3-[3-[6-Fluoro-1,2-benzisothiazol-3-yl]-8-azabicyclo[3.2.1]octan-8-yl]propoxy]-3-methoxyphenyl] ethanone A mixture of 3-(6-fluoro-1,2-benzisothiazol-3-yl)-8-azabicyclo[3.2.1]octane (3.0 g), 4-(3-chloropropoxy)-3-methoxyphenyl ethanone (3.5 g) and potassium carbonate (1.9 g) was heated in 100 ml of refluxing acetonitrile for 22 hours. The resulting mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated and purified by HPLC on silica gel (elution with triethylamine- methanol- ethyl acetate) to afford 3.3 g of product as an oil. The oil was dissolved in methanol (approximately 10 ml) and crystallized slowly from solution to yield 2.75 g of [4-[3[-3-[6-fluoro-1,2-benzisothiazol-3-yl]-8-azabicyclo[3.2.1]octan-8-yl]propoxy]-3-methoxyphenyl] ethanone, m.p. 118°-119° C. Analysis: Calculated for C26 H29 FN2 O3 S: 66.63% C; 6.25% H; 5.98% N; Found: 66.70% C; 6.24% H; 5.85% N. | |
With potassium carbonate In methanol; acetonitrile | 17 [4-[3-[3-[6-Fluoro-1,2-Benzisothiazol-3-Yl]-8-Azabicyclo[3.2.1]Octan-8-Yl]Propoxy]-3-Methoxyphenyl] Ethanone EXAMPLE 17 [4-[3-[3-[6-Fluoro-1,2-Benzisothiazol-3-Yl]-8-Azabicyclo[3.2.1]Octan-8-Yl]Propoxy]-3-Methoxyphenyl] Ethanone A mixture of 3-(6-fluoro- 1,2-benzisothiazol-3-yl)-8-azabicyclo[3.2.1 ]octane (3.0 g), 4-(3-chloropropoxy)-3-methoxyphenyl ethanone (3.5 g) and potassium carbonate (1.9 g) was heated in 100 ml of refluxing acetonitrile for 22 hours. The resulting mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated and purified by HPLC on silica gel (elution with triethylamine- methanol- ethyl acetate) to afford 3.3 g of product as an oil. The oil was dissolved in methanol (approximately 10 ml) and crystallized slowly from solution to yield 2.75 g of [4-[3-[3-[6-fluoro-1,2-benzisothiazol-3-yl]-8-azabicyclo[3.2.1 ]octan-8-yl]propoxy]-3-methoxyphenyl] ethanone, m.p. 118° 119° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.77 g (61%) | With Ki; sodium carbonate In methanol; butan-1-ol | 47 1-[4-[3-[4-[(4-Fluorophenyl)[(2-phenylethyl)amino]methyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone (E)-2-butenedioate (1:1) monohydrate EXAMPLE 47 1-[4-[3-[4-[(4-Fluorophenyl)[(2-phenylethyl)amino]methyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone (E)-2-butenedioate (1:1) monohydrate A mixture of 4.52 g (0.0145 mol of α-(4-fluorophenyl)-N-(2-phenylethyl)-4-piperidinemethanamine, 3.51 g (0.0145 mol) of 3-(4-acetyl-2-methoxyphenoxy)-1-chloropropane, 0.41 g (0.0025 mol) of KI and 8.2 g (0.098 mol) of sodium carbonate in 400 mL of 1-butanol was heated at reflux for 18 h. The solvent was removed in vacuo to give an oil. To a solution of this oil in 100 mL of CH3 OH was added 3.40 g (0.029 mol) of fumaric acid. A precipitate was collected. This was recrystallized from CH3 OH-ether to give 5.77 g (61%) of white solid, mp 70°-74° C. Analysis calculated for: C36 H45 N2 O8 F: C, 66.24; H, 6.95; N, 4.29. Found: C, 66.10; H, 6.73; N, 4.33. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium iodide; potassium carbonate In hydrogenchloride; ethyl acetate; acetonitrile | 7.d d. d. [4-[3-[3-[1H -Indazol-3-Yl]-8-Azabicyclo[3.2.1]Octan-8-Yl]Propoxy]-3-Methoxyphenyl] Ethanone A mixture of 3-(1H-indazol-3-yl)-8-azabicyclo[3.2.1]octane (5.46 g), 4-(3-chloropropoxy)-3-methoxyphenyl ethanone (6.4 g), potassium carbonate (6.6 g) and a catalytic mount of potassium iodide was heated in 100 ml of refluxing acetonitrile for 17 hours. The resulting mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated, and the residue was dissolved in 6N HCl solution and extracted with ethyl acetate. The aqueous layer was basified with 10% NaOH solution, and the product was extracted into dichloromethane. The combined organic layers were washed with brine, dried over K2 CO3, filtered, and concentrated to provide 7.0 g of a foam. Purification by HPLC on silica gel (elution initially with ethyl acetate, and then 10% methanol-90% ethyl acetate) afforded 4.2 g of product as a foam. The foam crystallized upon the addition of ethyl acetate, and the solid was then recrystallized from ethyl acetate-hexanes, affording 2.8 g of [4-[3-[3-[1H-indazol-3-yl]-8-azabicyclo[3.2.1]octan-8-yl]propoxyl]-3-methoxyphenyl] ethanone, as a powder, m.p. 173°-175° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In methanol; water; acetonitrile | 12 [4-[3-[3-[6-Fluoro-1H-Indazol-3-Yl]-8-Azabicyclo[3.2.1]-Octan-8-Yl]Propoxyl-3-Methoxyphenyl] Ethanone EXAMPLE 12 [4-[3-[3-[6-Fluoro-1H-Indazol-3-Yl]-8-Azabicyclo[3.2.1]-Octan-8-Yl]Propoxyl-3-Methoxyphenyl] Ethanone A mixture of 3-(6-fluoro- 1H-indazol-3-yl)-8-azabicyclo[3.2.1 ]octane (4.3 g), 4-(3-chloropropoxy)-3-methoxyphenyl ethanone (4.7 g) and potassium carbonate (2.8 g) was heated in 150 ml of refluxing acetonitrile for 18 hours. The resulting mixture was allowed to cool to room temperature and then filtered. The filtrate was concentrated, and the residue was dissolved in H2 O and extracted with 4:1 CHCl3 /IPA. The combined organic layers were dried over Mg2 SO4, filtered and concentrated. Purification by HPLC on silica gel (elution initially with ethyl acetate, and then with 10% methanol-89% ethyl acetate-1% TEA) afforded 3.1 g of product as a foam. The foam was dissolved in methanol (50 ml) and the product crystallized affording 2.8 g of [4-[3-[3-[6-fluoro-1H-indazol-3-yl]-8-azabicyclo[3.2.1 ]octan-8-yl]propoxy]-3-methoxyphenyl] ethanone, as a solid, m.p. 157°-158° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Ki In acetonitrile | 31 1-[4-[3-[4-(6-Chloro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone EXAMPLE 31 1-[4-[3-[4-(6-Chloro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone A mixture of 6-chloro-3-(1-piperazinyl)-1H-indazole (3.4 g, 0.014 mol), K2 CO3 (2.5 g, 0.018 mol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (3.8 g, 0.016 mol), KI (200 mg), and acetonitrile (125 ml) was stirred at reflux under N2 for 30 hours. After standing at room temperature for 40 hours, the reaction was filtered and the filter cake was washed well with acetonitrile. The filtrate was concentrated to an oily solid, which was partitioned between water and ethyl acetate. The ethyl acetate extract was washed with water, dried with MgSO4, and concentrated to yield 6.9 g of a dark oil, which solidified after 2 days under vacuum. The product was purified by preparative HPLC (Waters Associates Prep LC/system 500 utilizing 2 silica gel columns and 6% methanol/methylene chloride as eluent) to yield 4.2 g. The material was recrystallized from ethanol to yield 3.4 g of glistening, beige, 1-[4-[3-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone crystals, m.p.=132°-134° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.3 g (64%) | With Ki; In N-methyl-acetamide; | (J) Synthesis of 1-[4-[3-[4-(1H-Indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone A mixture of <strong>[131633-88-0]3-(1-piperazinyl)-1H-indazole</strong> (4.0 g, 0.02 mol), K2 CO3 (3 g, 0.022 mol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3g, 0.022 mol), a few crystals of KI, and dimethylformamide (60 ml) was stirred at 90 C. for 5 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The extract was washed (brine), dried (MgSO4), and the solvent was concentrated to afford a white solid, which was triturated with diethyl ether and collected to yield 7.0g of product. Two recrystallizations from absolute ethyl alcohol yielded 5.3 g (64%) of analytically pure 1-[4-[3-[4-(1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone, m.p.=155-157 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Ki In <i>N</i>-methyl-acetamide | 12 1-[4-[3-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone EXAMPLE 12 1-[4-[3-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone A stirred mixture of 6-fluoro-3-(1-piperazinyl)-1H-indazole (2.3 g, 0.01 mol), K2 CO3 (1.5 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (2.8 g, 0,011 mol), several crystals of KI and dimethylformamide (60 ml) was heated at 90° C. for 16 hours. The reaction was poured into H2 O, and the aqueous suspension was extracted with ethyl acetate. The ethyl acetate was washed (H2 O), dried (MgSO4) and concentrated to afford 5.0 g of a yellow oil. The oil was chromatographed on a Waters Prep 500 utilizing silica gel columns and eluding with methylene chloride/methanol (7%). Concentration of the desired fractions yielded 2.0 g (46%) of an off-white solid. This sample was combined with 1.0 g of a previous sample, and this was recrystallized from toluene to afford 2.6 g of 1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl] propoxy]-3-methoxyphenyl]ethanone as a white solid, m.p.=135°-137° C. | |
With Ki In <i>N</i>-methyl-acetamide | 12 1-[4-[3-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]-ethanone EXAMPLE 12 1-[4-[3-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]-ethanone A stirred mixture of 6-fluoro-3-(1-piperazinyl)-1H-indazole (2.3 g, 100 mmol), K2 CO3 (1.5 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (2.8 g, 11 mmol), several crystals of KI and dimethylformamide (60 ml) was heated at 90° C. for 16 hours. The reaction was poured into H2 O, and the aqueous suspension was extracted with ethyl acetate. The ethyl acetate was washed (H2 O), dried (MgSO4) and concentrated to afford 5.0 g of a yellow oil. The oil was chromatographed on a Waters Prep 500 utilizing silica gel columns and eluding with methylene chloride/methanol (7%). Concentration of the desired fractions yielded 2.0 g (46%) of an off-white solid. This sample was combined with 1.0 g of a previous sample, and this was recrystallized from toluene to afford 2.6 g of 1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]-propoxy]-3-methoxyphenyl]ethanone as a white solid, m.p.=135°-137° C. ANALYSIS: Calculated for C23 H27 FN4 O3: 64.77%C, 6.38%H, 13.14%N; Found: 64.66%C, 6.21%H, 13.02%N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.7 g (21%) | With Ki In ethanol; acetonitrile | 75 1-[4-[3-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone hydrochloride EXAMPLE 75 1-[4-[3-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone hydrochloride A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (4.0 g, 0.017 mol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.1 g, 0,017 mol), K2 CO3 (2.3 g), KI (0.2 g), and acetonitrile (100 ml) was refluxed for 9 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The extract was washed (water), dried (MgSO4), and the solvent was concentrated to afford 8.0 g of a brown oil. The oil was chromatographed on a Waters Prep 500 HPLC on silica gel columns. Concentration of the appropriate fractions afforded a gum-like residue, which upon trituration with isopropyl ether afforded 1.9 g of a white solid. The solid was dissolved in absolute ethanol, and ethereal HCl was added to precipitate 1.7 g of a hydrochloride salt. Concentration of the isopropyl ether filtrate, and similar treatment of the residue, afforded an additional 0.5 g of the salt. The samples were combined and recrystallized from absolute ethanol to yield 1.7 g (21%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone hydrochloride as a white solid, m.p.=221°-223° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Ki In acetonitrile | 15 1-[4-[3-[4-(6-Chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-methoxyphenyl]ethanone EXAMPLE 15 1-[4-[3-[4-(6-Chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-methoxyphenyl]ethanone A stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2-benzisoxazole (4.7 g, 0.02 mol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone (4.8 g, 0.02 mol), K2 CO3 (2.8), several crystals of KI and acetonitrile (120 ml) was refluxed for 16 hours. The reaction was filtered and the filtrate was concentrated to yield a solid-oil mixture. The residue was chromatographed on a Waters Prep 500 utilizing silica columns and eluding with methylene chloride/methanol (5%). Concentration of the desired fractions yielded 3.2 g of a beige solid, which upon recrystallization from ethanol afforded 2.7 (31%) of 1-[4-[3-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone as a beige solid, m.p.=116°-118° C. | |
With Ki In acetonitrile | 15 1-[4-[3-[4-(6-Chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone EXAMPLE 15 1-[4-[3-[4-(6-Chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone A stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2-benzisoxazole (4.7 g, 20 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.8 g, 20 mmol), K2 CO3 (2.8 g), several crystals of KI and acetonitrile (120 ml) was refluxed for 16 hours. The reaction was filtered and the filtrate was concentrated to yield a solid-oil mixture. The residue was chromatographed on a Waters Prep 500 utilizing silica columns and eluding with methylene chloride/methanol (5%). Concentration of the desired fractions yielded 3.2 g of a beige solid, which upon recrystallization from ethanol afforded 2.7 g (31%) of 1-[4-[3-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-ethanone as a beige solid, m.p.=116°-118° C. ANALYSIS: Calculated for C24 H27 ClN2 O4: 65.08%C, 6.14%H, 6.32%N; Found: 65.35%C, 6.22%H, 6.28%N. | |
With Ki In acetonitrile | 15 1-[4-[3-[4-(6-Chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone EXAMPLE 15 1-[4-[3-[4-(6-Chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone A stirred mnixture of 6-chloro-3-(4-piperidinyl)-1,2-benzisoxazole (4.7 g, 20 mmol), 1-[4-(3-chloropropoxy)-3methoxyphenyl]ethanone (4.8 g, 20 mmol), K2 CO3 (2.8 g), several crystals of KI and acetonitrile (120 mnl) was refluxed for 16 hours. The reaction was filtered and the filtrate was concentrated to yield a solid-oil mixture. The residue was chromatographed on a Waters Prep 500 utilizing silica columns and eluding with methylene chloride/methanol (5%). Concentration of the desired fractions yielded 3.2 g of a beige solid, which upon recrystallization from ethanol afforded 2.7 g (31%) of 1-[4-[3-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-ethanone as a beige solid, m.p.=116°-118° C. ANALYSIS: Calculated for C24 H27 C1N2 O4: 65.08%C 6.14%H 6.32%N; Found: 65.35%C 6.22%H 6.28%N |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.6 g (33%) | With Ki; In N-methyl-acetamide; | EXAMPLE 2 1-[4-[3-[4-(1,2-Benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone A mixture of <strong>[84163-22-4]3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride</strong> (4.8 g, 0.02 mol), K2 CO3 (5.2 g, 0.04 mol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 0.022 mol), a few crystals of KI and dimethylformamide (60 ml) was stirred at 90 C. for 16 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The extract was washed (water), dried (MgSO4) and concentrated to afford a brown oil. The oil was chromatographed on a Waters Prep 500 utilizing silica gel columns and ethyl acetatediethylamine (2%), as eluent. Concentration of the appropriate fractions afforded 3.9 g of product as an off-white solid. Recrystallization from absolute ethyl alcohol afforded 2.6 g (33%) of 1-[4-[3-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanone, m.p.=102-104 C., as colorless needles. |
2.6 g (33%) | With Ki; In N-methyl-acetamide; | EXAMPLE 2 1-[4-[3-[4-(1,2-Benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-ethanone A mixture of <strong>[84163-22-4]3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride</strong> (4.8 g, 20 mmol), K2 CO3 (5.2 g, 40 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), a few crystals of KI and dimethylformamide (60 ml) was stirred at 90 C. for 16 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The extract was washed (water), dried (MgSO4) and concentrated to afford a brown oil. The oil was chromatographed on a Waters Prep 500 utilizing silica gel columns and ethyl acetate-diethylamine (2%), as eluent. Concentration of the appropriate fractions afforded 3.9 g of product as an off-white solid. Recrystallization from absolute ethyl alcohol afforded 2.6 g (33%) of 1-[4-[3-[4-(1,2-benzisoxazol-3-yl)-1-piperdinyl]propoxy]-3-methoxyphenyl]ethanone, m.p.=102-104 C., as colorless needles. ANALYSIS: Calculated for C24 H28 N2 O4: 70.56%C, 6.91%H, 6.86%N; Found: 70.73%C, 6.93%H, 6.85%N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In <i>N</i>-methyl-acetamide | 3 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone EXAMPLE 3 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole hydrochloride (5.1 g, 0.02 mol), K2 CO3 (5.2 g, 0.04 mol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 0.022 mol), and dimethylformamide (60 ml) was heated at 90° C. for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4) and concentrated to afford a moist solid. Recrystallization (twice) from ethyl alcohol afforded 5.0 (58%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3methoxyphenyl]ethanone as a beige solid, m.p.=118°-120° C. | |
5.0 g (58%) | In <i>N</i>-methyl-acetamide | 3 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanone EXAMPLE 3 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanone A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole hydrochloride (5.1 g, 20 mmol), K2 CO3 (5.2 g, 40 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), and dimethylformamide (60 ml) was heated at 90° C. for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4) and concentrated to afford a moist solid. Recrystallization (twice) from ethyl alcohol afforded 5.0 g (58%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperdinyl]propoxy]-3-methoxyphenyl]-ethanone as a beige solid, m.p.=118°-120° C. ANALYSIS: Calculated for C24 H27 FN2 O4: 67.60%C, 6.38%H, 6.57%N; Found: 67.47%C, 6.40%H, 6.53%N. |
5.0 g (58%) | 3 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanone EXAMPLE 3 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanone A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole hydrochloride (5.1 g, 20 mmol), K2 CO3 (5.2 g, 40 mmol), 1-[4(3-chloropropoxy)-3-methoxyphenyl]-ethanone (5.3 g, 22 mmol), and dimethylfonnamide (60 ml) was heated at 90° C for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4) and concentrated to afford a moist solid. Recrystallization (twice) from ethyl alcohol afforded 5.0 g (58%) of 1-[4-[3-[4(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]-ethanone as a beige solid, m.p.=118°-120° C. ANALYSIS: Calculated for C24 H27 FN2 O4: 67.60%C 6.38%H 6.57%N; Found: 67.47%C 6.40%H 6.53%N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.0 g (47%) | With Ki In acetonitrile | 17 1-[4-[3-[4-(5-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone EXAMPLE 17 1-[4-[3-[4-(5-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone A mixture of 5-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 0.01 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (2.4 g, 0.01 mole), K2 CO3 (1.4 g), a few crystals of KI and acetonitrile (100 ml) was stirred and refluxed for 8 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed (brine), dried (MgSO4), and concentrated to afford 4.0 g of a white solid. The solid was chromatographed on a Waters Prep 500 HPLC utilizing silica gel columns and eluding with methylene chloride/methanol (5%). Concentration of the appropriate fractions afforded 2.0 g (47%) of 1-[4-[3-[4-(5-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone as a white crystalline solid, m.p.=103°-105° C. |
2.0 g (47%) | With Ki In acetonitrile | 17 1-[4-[3-[4-(5-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanone EXAMPLE 17 1-[4-[3-[4-(5-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanone A mixture of 5-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (2.4 g, 10 mmol), K2 CO3 (1.4 g), a few crystals of KI and acetonitrile (100 ml) was stirred and refluxed for 8 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed (brine), dried (MgSO4), and concentrated to afford 4.0 g of a white solid. The solid was chromatographed on a Waters Prep 500 HPLC utilizing silica gel columns and eluding with methylene chloride/methanol (5%). Concentration of the appropriate fractions afforded 2.0 g (47%) of 1-[4-[3-[4-(5-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-ethanone as a white crystalline solid, m.p.: 103°-105° C. ANALYSIS: Calculated for C24 H27 FN2 O4: 67.59%C, 6.38%H, 6.57%N; Found: 67.50%C, 6.47%H, 6.53%N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With boron tribromide; sodium hydrogencarbonate In dichloromethane | 11.A (A) (A) Synthesis of 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone To a stirred solution of 1-[4-(3-chloropropoxy)-3 methoxyphenyl]ethanone (10.0 g, 0.041 mol) in methylene chloride (120 ml) cooled to -50° C. (dry ice-methanol) was added, dropwise, 1M boron tribromide in methylene chloride (123 ml, 0.12 mol). The temperature was kept between -40° C. and -50° C. After complete addition, the reaction was permitted to reach -30° C., and the TLC checked (ca. 15 min. after final boron tribromide was added). Saturated NaHCO3 was added, dropwise, never allowing the temperature to go above 0° C. during most of the addition. When sufficient NaHCO3 had been added to make the solution basic, the organic layer was collected. The layer was washed with brine, dried (MgSO4), and concentrated to yield 8.1 g of dark brown oil, which solidified on standing. This was chromatographed on a Waters Prep 500 LC (2 silica columns, 2% methanol-methylene chloride as eluent). Upon concentration of the appropriate fractions, 5.8 g of a brown tacky solid were obtained. This was recrystallized from isopropyl ether (with decanting of the yellow isopropyl ether supernatant from the dark brown oily residue) to give initially 2.5 g of a yellow solid. Concentration of the mother liquor gave an additional 0.5 g, m.p.=110°-113° C. | |
With boron tribromide; sodium hydrogencarbonate In dichloromethane | 11.A (A) (A) 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone To a stirred solution of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (10.0 g, 41 mmol) in methylene chloride (120 ml) cooled to -50° C. (dry ice-methanol) was added, dropwise, 1M boron tribromide in methylene chloride (123 ml, 120 mmol). The temperature was kept between -40° C. and -50° C. After complete addition, the reaction was permitted to reach -30° C., and the TLC checked (ca. 15 min. after final boron tribromide was added). Saturated NaHCO3 was added, dropwise, never allowing the temperature to go above 0° C. during most of the addition. When sufficient NaHCO3 had been added to make the solution basic, the organic layer was collected. The layer was washed with brine, dried (MgSO4), and concentrated to yield 8.1 g of dark brown oil, which solidified on standing. This was chromatographed on a Waters Prep 500 LC (2 silica columns, 2% methanol-methylene chloride as eluent). Upon concentration of the appropriate fractions, 5.8 g of a brown tacky solid were obtained. This was recrystallized from isopropyl ether (with decanting of the yellow isopropyl ether supernatant from the dark brown oily residue) to give initially 2.5 g of a yellow solid. Concentration of the mother liquor gave an additional 0.5 g, m.p.=110°-113° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium iodide; potassium carbonate In acetonitrile | 10 1-[4-[3-[4-(1,2-Benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone EXAMPLE 10 1-[4-[3-[4-(1,2-Benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone A mixture of 3-(4-piperidinyl)-1,2-benzisothiazole (3.0 g, 0.0137 mol), potassium carbonate (2.3 g, 0.0165 mol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.0 g, 0.0165 mol), potassium iodide (200 mg) and acetonitrile (100 ml) was stirred at reflux under N2 for 24 hours. The cooled reaction was filtered and the cake was washed well with acetonitrile. The filtrate was concentrated to an oily residue, which was partitioned between water and ethyl acetate. The ethyl acetate extract was washed well with water, dried with MgSO4 and concentrated to yield 6.1 g of a beige oil which solidified upon standing. The product was triturated with diethyl ether and filtered to give 4.2 g of a beige solid. The compound was recrystallized from ethyl alcohol to afford 3.5 g, and another recrystallization from ethyl alcohol (utilizing decolorizing carbon) provided 2.4 g (41%) of 1-[4-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperidinyl] propoxy]-3-methoxyphenyl]ethanone, m.p. 93°-95° C. | |
With potassium iodide; potassium carbonate In acetonitrile | 10 1-[4-[3-[4-(1,2-Benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-ethanone EXAMPLE 10 1-[4-[3-[4-(1,2-Benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-ethanone A mixture of 3-(4-piperidinyl)-1,2-benzisothiazole (3.0 g, 13.7 mmol), potassium carbonate (2.3 g, 16.5 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.0 g, 16.5 mmol), potassium iodide (200 mg) and acetonitrile (100 ml) was stirred at reflux under N2 for 24 hours. The cooled reaction was filtered and the cake was washed well with acetonitrile. The filtrate was concentrated to an oily residue, which was partitioned between water and ethyl acetate. The ethyl acetate extract was washed well with water, dried with MgSO4 and concentrated to yield 6.1 g of a beige oil which solidified upon standing. The product was triturated with diethyl ether and filtered to give 4.2 g of a beige solid. The compound was recrystallized from ethyl alcohol to afford 3.5 g, and another recrystallization from ethyl alcohol (utilizing decoIonizing carbon) provided 2.4 g (41%) of 1-[4-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone, m.p. 93°-95° C. ANALYSIS: Calculated for C24 H28 N2 O3 S: 67.90%C, 6.65%H, 6.60%N; Found: 67.89%C, 6.61%H, 6.59%N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.3 g (64%) | With Ki; In N-methyl-acetamide; | (J) 1-[4-[3-[4-(1H-Indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone A mixture of <strong>[131633-88-0]3-(1-piperazinyl)-1H-indazole</strong> (4.0 g, 20 mmol), K2 CO3 (3.0 g, 22 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), a few crystals of KI, and dimethylformamide (60 ml) was stirred at 90 C. for 5 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The extract was washed (brine), dried (MgSO4), and the solvent was concentrated to afford a white solid, which was triturated with diethyl ether and collected to yield 7.0 g of product. Two recrystallizations from absolute ethyl alcohol yielded 5.3 g (64%) of analytically pure 1-[4-[3-[4-(1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone, m.p.=155-157 C. ANALYSIS: Calculated for C23 H28 N4 O3: 67.62%C, 6.91%H, 13.72%N; Found: 67.45%C, 6.74%H, 13.56%N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Ki In acetonitrile | 14 1-[4-[3-[4-(1H-Indazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone EXAMPLE 14 1-[4-[3-[4-(1H-Indazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone A mixture of 3-(4-piperidinyl)-1H-indazole (3.0 g, 15 mmol), K2 CO3 (1.6 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), a few crystals of KI and acetonitrile (100 ml) was stirred and refluxed for 16 hours. The reaction was poured into water and a white solid separated from solution. The solid was collected, dried and afforded 5.1 g of product. Recrystallization from ethanol yielded 3.6 g of the compound, which upon chromatography (preparative HPLC on silica gel, eluding with methylene chloride/methanol-9:1) gave 3.0 g (49%) of an off-white solid. Recrystallization from ethanol afforded the analytically pure 1-[4-[3-[4-(1H-indazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]ethanone as a white solid, m.p.=171°-173° C. ANALYSIS: Calculated for C24 H29 N3 O3: 70.74%C, 7.17%H, 10.31%N; Found: 70.52%C, 7.27%H, 10.42%N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.7 g (21%) | With Ki In ethanol; acetonitrile | 75 1-[4-[3-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanone hydrochloride EXAMPLE 75 1-[4-[3-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanone hydrochloride A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (4.0 g, 17 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.1 g, 17 mmol), K2 O3 (2.3 g), KI (0.2 g), and acetonitrile (100 ml) was refluxed for 9 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The extract was washed (water), dried (MgSO4), and the solvent was concentrated to afford 8.0 g of a brown oil. The oil was chromatographed on a Waters Prep 500 HPLC on silica gel columns. Concentration of the appropriate fractions afforded a gum-like residue, which upon trituration with isopropyl ether afforded 1.9 g of a white solid. The solid was dissolved in absolute ethanol, and ethereal HCl was added to precipitate 1.7 g of a hydrochloride salt. Concentration of the isopropyl ether filtrate, and similar treatment of the residue, afforded an additional 0.5 g of the salt. The samples were combined and recrystallized from absolute ethanol to yield 1.7 g (21%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone hydrochloride as a white solid, m.p.=221°-223° C. ANALYSIS: Calculated for C24 H27 FN2 O3 S.HCl: 60.18%C, 5.89%H, 5.85%N; Found: 60.01%C, 5.97%H, 5.79%N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.4 g (22%) | In hydrogenchloride | 65.A (A) (A) 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone A mixture of 1-[4-(3-chloropropoxy)-3-methoxy-phenyl]ethanone (10.0 g, 41.2 mmol) and concentrated H2 SO4 (50 ml) was stirred at 65° C. for 23 hours. The cooled reaction was poured into 250 g of ice and was stirred vigorously for 10 minutes. The aqueous mixture was extracted with dichloromethane (CH2 Cl2) and the resultant dichloromethane extract was washed well with 5% sodium hydroxide. The basic phases were combined and washed with dichloromethane. The aqueous mixture was cooled in an ice bath and concentrated hydrochloric acid was added until a precipitate formed. The product was isolated by filtration and dried to yield 3.1 g of a light brown solid. This was combined with an additional sample (5.0 g total) and two consecutive recrystallizations from toluene provided 3.4 g (22%) of 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone as a beige solid, m.p.=101°-103° C. ANALYSIS: Calculated for C11 H13 ClO3: 57.78%C, 5.73%H, Found: 58.17%C, 5.66%H. |
3.4 g (22%) | In hydrogenchloride | 65.A (A) (A) 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone A mixture of 1-[4-(3-chloropropoxy)-3-methoxy-phenyl]ethanone (10.0 g, 41.2 mmol) and concentrated H2 SO4 (50 ml) was stirred at 65° C. for 23 hours. The cooled reaction was poured into 250 g of ice and was stirred vigorously for 10 minutes. The aqueous mixture was extracted with dichloromethane (CH2 Cl2) and the resultant dichloromethane extract was washed well with 5% sodium hydroxide. The basic phases were combined and washed with dichloromethane. The aqueous mixture was cooled in an ice bath and concentrated hydrochloric acid was added until a precipitate formed. The product was isolated by filtration and dried to yield 3.1 g of a light brown solid. This was combined with an additional sample (5.0 g total) and two consecutive recrystallizations from toluene provided 3.4 g (22%) of 1-[4(3chloropropoxy)-3-hydroxyphenyl]ethanone as a beige solid, m.p.=101°-103° C. ANALYSIS: Calculated for C11 H13 ClO3 57.78%C. 5.73%H; Found: 58.17%C. 5.66%H |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With K2CO3; Ki In acetonitrile | 31 1-[4-[3-[4-(6-Chloro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]-ethanone EXAMPLE 31 1-[4-[3-[4-(6-Chloro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]-ethanone A mixture of 6-chloro-3-(1-piperazinyl)-1H-indazole (3.4 g, 14 mmol), K2CO3 (2.5 g, 18 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (3.8 g, 16 mmol), KI (200 mg), and acetonitrile (125 ml) was stirred at reflux under N2 for 30 hours. After standing at room temperature for 40 hours, the reaction was filtered and the filter cake was washed well with acetonitrile. The filtrate was concentrated to an oily solid, which was partitioned between water and ethyl acetate. The ethyl acetate extract was washed with water, dried with MgSO4 and concentrated to yield 6.9 g of a dark oil, which solidified after 2 days under vacuum. The product was purified by preparative HPLC (Waters Associates Prep LC/system 500 utilizing 2 silica gel columns and 6% methanol/methylene chloride as eluent) to yield 4.2 g. The material was recrystallized from ethanol to yield 3.4 g of glistening, beige, 1-[4-[3-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]-ethanone crystals, m.p.=132-134C. ANALYSIS: Calculated for C23 H27 CIN4 O3: 62.37%C 6.14%H 12.65%N; Found: 62.49%C 6.16%H 12.60%N |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.3 g (64%) | With Ki; In N-methyl-acetamide; | (J) 1-[4-[3-[4-(1H-Indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxy-phenyl]ethanone A mxture of 3-(1-Piperazinyl)-1H-indazole (4.0 g, 20 mmol), K2 CO3 (3.0 g, 22 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 4 22 mmol), a few crystals of KI, and dimethylformamide (60 ml) was stirred at 90 C. for 5 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The extract was washed (brine), dried (MgSO4), and the solvent was concentrated to afford a white solid, which was triturated with diethyl ether and collected to yield 7.0 g of product. Two recrystallizations from absolute ethyl alcohol yielded 5.3 g (64%) of analytically pure 1 -[4-[3-[4-(1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone, m.p.=155-157 C. ANALYSIS: Calculated for C23 H28 N4 O3: 67.62%C 6.91 %H 13.72%N; Found: 67.45%C 6.74%H 13.56%N |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Ki In <i>N</i>-methyl-acetamide | 12 1-[4-[3-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxvl]-3-methoxyphenyl]-ethanone EXAMPLE 12 1-[4-[3-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxvl]-3-methoxyphenyl]-ethanone A stirred mixture of 6-fluoro-3-(1-piperazinyl)-1H-indazole (2.3 g, 100 mmol), K2 CO3 (1.5 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (2.8 g, 11 mmol), several crystals of KI and dimethylformamide (60 ml) was heated at 90° C. for 16 hours. The reaction was poured into H2 O, and the aqueous suspension was extracted with ethyl acetate. The ethyl acetate was washed (H2 O), dried (MgSO4) and concentrated to afford 5.0 g of a yellow oil. The oil was chromatographed on a Waters Prep 500 utilizing silica gel columns and eluding with methylene chloride/methanol (7%). Concentration of the desired fractions yielded 2.0 g (46%) of an off-white solid. This sample was combined with 1.0 g of a previous sample, and this was recrystallized from toluene to afford 2.6 g of 1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]-propoxy]-3-methoxyphenyl]ethanone as a white solid, m.p.=135°-137° C. ANALYSIS: Calculated for C23 H27 FN4 O3: 64.77%C 6.38%H 13.14%N; Found: 64.66%C 6.21%H 13.02%N |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Ki In acetonitrile | 14 1-[4-[3-[4-(1H-Indazol-3-yl)-1-giperidinl]propoxy]-3-methoxhenyl]ethanone EXAMPLE 14 1-[4-[3-[4-(1H-Indazol-3-yl)-1-giperidinl]propoxy]-3-methoxhenyl]ethanone A mixture of 3-(4-piperidinyl)-1H-indazole (3.0 g, 15 mmol), K2 CO3 (1.6 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), a few crystals of KI and acetonitrile (100 ml) was stirred and refluxed for 16 hours. The reaction was poured into water and a white solid separated from solution. The solid was collected, dried and afforded 5.1 g of product. Recrystallization from ethanol yielded 3.6 g of the compound, which upon chromatography (preparative HPLC on silica gel, eluding with methylene chloride/methanol-9:1) gave 3.0 g (49%) of an off-white solid. Recrystallization from ethanol afforded the analytically pure 1-[4-[3-[4-(1H-indazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]ethanone as a white solid, m.p.=171°-173° C. ANALYSIS: Calculated for C24 H29 N3 O3: 70.74%C 7.17%H 10.31%N; Found: 70.52%C 7.27%H 10.42%N |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.7 g (21%) | With Ki In ethanol; acetonitrile | 75 1-›4-[3-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-[3-methoxepheenyl]ethanone hydrochloride EXAMPLE 75 1-›4-[3-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-[3-methoxepheenyl]ethanone hydrochloride A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (4.0 g, 17 mmol), 1-[4-(3-chloropropoxy)3-methoxyphenyl]ethanone (4.1 g, 17 mmol), K2 CO3 (2,3 g), KI (0.2 g), and acetonitrile (100 ml) was refluxed for 9 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The extract was washed (water), dried (MgSO4), and the solvent was concentrated to afford 8.0 g of a brown oil. The oil was chromatographed on a Waters Prep 500 HPLC. on silica gel columns. Concentration of the appropriate fractions afforded a gum-like residue, which upon trituration with isopropyl ether afforded 1.9 g of a white solid. The solid was dissolved in absolute ethanol, and ethereal HCl was added to precipitate 1.7 g of a hydrochloride salt. Concentration of the isopropyl ether filtrate, and similar treatment of the residue, afforded an additional 0.5 g of the salt. The samples were combined and recrystallized from absolute ethanol to yield 1.7 g (21%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone hydrochloride as a white solid, m.p.=221°-223°C. ANALYSIS: Calculated for C24 H27 FN2 O3 S.HCl: 60.18%C. 5.89%H 5.85%N; Found: 60.01%C. 5.97%H 5.79%N |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.7 g (27%) | With Ki In ethyl acetate; acetonitrile | 37 1-[4-[3-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]-ethanone hemifumarate EXAMPLE 37 1-[4-[3-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]-ethanone hemifumarate A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (4.0 g, 18.2 mmol), K2 CO3 (3.0 g, 21.8 mmol), KI (200 mg), 1-[4-(3chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 20.0 mmol), and acetonitrile (125 ml) was stirred at reflux under N2 for 26 hours. The cooled reaction was filtered and the filter cake was w ashed wen with acetonitrile. The filtrate was concentrate d to afford 10.7 g of an oily residue, which was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried with MgSO4 a nd concentrated to yield 8.0 g of a dark oil. The oil was purified by preparative HPLC (Waters Associates Prep LClSystem 5001 utilizing 2 silica gel colurns and 3% methanollmethylene c hloride as eluent). Concentration of appropriate fractions provided 4.6 g of a red oil, which solidified upon standing. A 3.4 g sample was taken up in ethyl acetate (100 ml) and fumaric add (0.95 g) was added. The mixture was stirred at a mnild reflux for 1 hour and then at ambient for 1.5 hours. The resultant beige solid was collected by filtration and dried to yield 4.0 g. The product was recrystallized twice from ethanol to provide 2.7 g (27%) of 1-[4-[3-[4-(1,2benzisothiazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone hemnifumarate as a beige powder, m.p.=186-188.C ANALYSIS: Calculated for C23 H27 N3 O3 S*0.5C4 H4 O4: 62.09%C 6.06%H 8.69%N; Found: 62.01%C 6.06%H 8.68%N |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With potassium iodide; sodium carbonate In methanol; dichloromethane; water; acetone; butan-1-ol; benzene | 159 1-[4-[3-[3-[Bis(4-fluorophenyl)hydroxymethyl]-1-pyrrolidinyl]propoxy]-3-methoxyphenyl]ethanone EXAMPLE 159 1-[4-[3-[3-[Bis(4-fluorophenyl)hydroxymethyl]-1-pyrrolidinyl]propoxy]-3-methoxyphenyl]ethanone A mixture of 2.9 g (0.01 mole) of α,α-bis(4-fluorophenyl)-3-pyrrolidinemethanol, 2.4 g (0.01 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, b 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in 100 ml of 1-butanol was heated at reflux for 24 hr. The mixture was concentrated under reduced pressure and the residue partitioned between 100 ml of benzene and 100 ml of water. The benzene layer was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give a brown gum. The gum was purified by columne chromatography on 80 g of Florisil using a gradient elution system of 0-10% acetone in benzene. The fractions containing the desired product were combined and concentrated under reduced pressure to give 3.2 g of a brown gum. This gum was further purified by high-pressure liquid chromatography (Waters Associates Prep LC/System 500A; PrepPak 500 silica; 1% methanol in methylene chloride; flow rate 150 ml/min). The fractions containing the desired product were combined and concentrated under reduced pressure to yield 1.7 g (34% yield) of the title compound as a light-yellow, glassy solid, m.p. 44°-46° C. Analysis: Calculated for C29 H31 F2 NO4: C, 70.29; H, 6.31; N, 2.83. Found: C, 69.60; H, 6.26; N, 2.86. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.3 g (58%) | With potassium iodide; sodium carbonate In butan-1-ol | 131 1-[4-[3-[4[Bis(4-methylphenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate hydrate [1:1:1] EXAMPLE 131 1-[4-[3-[4[Bis(4-methylphenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate hydrate [1:1:1] This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 4.6 g (0.015 mole) of α, α-bis(4-methylphenyl)-4-piperidinemethanol, 3.6 g (0.015 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave a brown gum as residue. The gum was converted to the oxalic acid salt and the solid was recrystallized from absolute ethanol to yield 5.3 g (58%) of title compound as an off-white solid, mp 92°-95° C. with decomposition. Analysis: Calculated for C34 H41 NO8.H2 O: C, 66.97; H, 7.11; N, 2.30. Found: C, 66.61; H, 6.79; N, 2.29. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.4 g (30%) | With potassium iodide; sodium carbonate In butan-1-ol | 149 1-[4-[3-[4-[Bis(4-chlorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate [1:1.5] EXAMPLE 149 1-[4-[3-[4-[Bis(4-chlorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate [1:1.5] This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 2.5 g (0.0075 mole) of α,α-bis(4-chlorophenyl)-4-piperidinemethanol, 1.8 g (0.0075 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave a gummy solid as residue. This solid was converted to the oxalic acid salt and the solid was recrystallized from absolute ethanol to yield 1.4 g (30%) of title compound as a pale-yellow solid, mp 89°-113° C. with decomposition. Analysis: Calculated for C33 H36 Cl2 NO10: C, 58.50; H, 5.36; N, 2.07. Found: C, 58.22; H, 5.32; N, 2.07. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.43 g (62.7%) | With sodium hydroxide; potassium iodide; potassium carbonate In sulfuric acid; butan-1-ol | 111 α-[1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-4-piperidinyl]-α-(4-fluorophenyl)-2-pyridineacetonitrile fumarate [1:1] EXAMPLE 111 α-[1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-4-piperidinyl]-α-(4-fluorophenyl)-2-pyridineacetonitrile fumarate [1:1] A mixture of α-(4-fluorophenyl)-α-(4-piperidinyl)-2-pyridineacetonitrile (7.18 g, 0.024 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.89 g, 0.024 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight in 350 ml of 1-butanol containing potassium iodide (0.15 g). The reaction mixture was concentrated to dryness and the residue obtained was partitioned between chloroform and water. The chloroform layer was extracted in 1N sulfuric acid, 5% sodium hydroxide and water. The chloroform layer was dried over sodium sulfate, filtered, and the solvent removed to give an oil. The oil was converted to the fumarate salt and recrystallized from methanol-ethyl ether. A white solid was obtained and dried in vacuo overnight at 80° C. to give 9.43 g (62.7%) of white crystals, m.p. 166°-167° C. NMR indicated 0.25 H2 O was present. Analysis: Calculated for C34 H36 FN3 O7.0.25H2 O: C, 65.64; H, 5.91; N, 6.75. Found: C, 65.57; H, 5.89; N, 6.70. |
9.43 g (62.7%) | With potassium iodide; potassium carbonate In butan-1-ol | 111 α-[1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-4-piperidinyl]-α-(4-fluorophenyl)-2-pyridineacetonitrile fumarate [1:1] EXAMPLE 111 α-[1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-4-piperidinyl]-α-(4-fluorophenyl)-2-pyridineacetonitrile fumarate [1:1] A mixture of α-(4-fluorophenyl)-α-(4-piperidinyl)-2-pyridineacetonitrile (7.18 g, 0.024339 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.89 g, 0.024339 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight in 530 ml of 1-butanol containing potassium iodide (0.15 g). The reaction mixture was stripped to dryness and the residue obtained was partitioned between chloroform and water. The chloroform layer was extracted with 1N sulfuric acid, 5% sodium hydroxide and water. The chloroform layer was dried over sodium sulfate, filtered, and the solvent removed to give an oil. The oil was converted to the fumarate salt and recrystallized from methanol-diethyl ether. A white solid was obtained and dried in vacuo overnight at 80° C. to give 9.43 g (62.7%) of white crystals, m.p. 166°-167° C. Analysis: Calculated for C34 H36 N3 O7 F: C, 66.11; H, 5.87; N, 6.80. Found: C, 65.57; H, 5.89; N, 6.70. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.94 g (64.9%) | With potassium iodide; sodium hydrogencarbonate In dichloromethane; butan-1-ol | 144 1-[4-[3-[4-[2,2-Bis(4-fluorophenyl)-2-hydroxyethyl]-1- piperidinyl]propoxy]-3-methoxyphenyl]ethanone fumarate hydrate [1:1:1] EXAMPLE 144 1-[4-[3-[4-[2,2-Bis(4-fluorophenyl)-2-hydroxyethyl]-1- piperidinyl]propoxy]-3-methoxyphenyl]ethanone fumarate hydrate [1:1:1] A mixture of 4.52 g (0.0143 mole) of α,α-bis(4-fluorophenyl)-4-piperidineethanol, 3.75 g (0.0155 mole) of 3-(4-acetyl-2-methoxyphenoxy)-1-chloropropane, 4.1 g (0.049 mole) of sodium bicarbonate, and 0.20 g (0.0012 mole) of potassium iodide in 300 ml of 1-butanol was heated at reflux for 8 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was treated with a small portion of activated charcoal and was dried over magnesium sulfate. The solvent was removed in vacuo to give the non-salt form of the title compound. This was converted to the fumarate salt and the salt was crystallized from methanol/ether to give 5.94 g (64.9%) of the title compound as a white, crystalline solid, mp 135°-136° C. Analysis: Calculated for C35 H41 F2 NO9: C, 63.92; H, 6.28; N, 2.13. Found: C, 64.03; H, 6.07; N, 2.16. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.36 g (73.8%) | With potassium iodide; potassium carbonate In chloroform; ethyl acetate; butan-1-ol | 156 1-[4-[3-[4-[Cyclohexyl(4-fluorophenyl)methyl]-1-piperdinyl]propoxy]-3-methoxyphenyl]ethanone EXAMPLE 156 1-[4-[3-[4-[Cyclohexyl(4-fluorophenyl)methyl]-1-piperdinyl]propoxy]-3-methoxyphenyl]ethanone A mixture of 4-[cyclohexyl(4-fluorophenyl)methyl]piperidine (5.71 g, 0.0207 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.03 g, 0.207 mole), and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). The reaction mixture was cooled to room temperature and filtered. The 1-butanol was removed by rotary evaporation to give a brown oil. This oil was dissolved in chloroform and the chloroform layer was extracted with 5% sodium hydroxide and water. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a brown oil. This oil was subjected to flash chromatography on silica gel. Elution was performed using ethyl acetate, 5% methanol-ethyl acetate, and 10% methanol-ethyl acetate. Separate fractions of similar purity were combined and solvent was removed to give a yellow oil. This oil was dried in vacuo overnight at 80° C. to give 7.36 g (73.8%) of title compound. 1 H NMR(CDCl3): δ 6.7-7.4 (m, 7, aromatics), 4.0 (m, 2, --O--CH2), 3.9 (s, 3, --O--CH3), 2.5 (s, 3, STR22 1.0-3.0 (m, 25, remaining aliphatics). Analysis: Calculated for C30 H40 FNO3: C, 74.81; H, 8.37; N, 2.91. Found: C, 74.39; H, 8.36; N, 2.81. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium iodide; potassium carbonate In butan-1-ol | 148 1-[4-[3-[4-[Bis(4-chlorophenyl)methyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate hydrate [1:1:0.5] EXAMPLE 148 1-[4-[3-[4-[Bis(4-chlorophenyl)methyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate hydrate [1:1:0.5] A mixture of 4-[bis(4-chlorophenyl)methyl]piperidine (11.39 g, 0.0357 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (8.64 g, 0.0357 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at reflux in 300 ml of 1-butanol containing potassium iodide (0.2 g). The reaction mixture was concentrated to dryness, and the residue obtained was partitioned several times between chloroform and water. The chloroform layer was dried over sodium sulfate ad filtered, and the solvent was removed to give a dark brown oil. This oil was converted to the oxalate salt and the salt was recrystallized from methanol-ethyl ether. A yellow solid was isolated and dried in vacuo overnight at 80° C. The yellow solid was next exposed to the atmosphere for 24 hours and submitted for analysis. This procedure produced 6.65 g (30% yield) of light yellow solid, mp 160°-171° C. Analysis: Calculated for C32 H35 Cl2 NO7.0.5H2 O: C, 61.44; H, 5.80; N, 2.24. Found: C, 61.40; H, 5.71; N, 2.24. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.75 g (15.1%) | With potassium iodide; sodium hydrogencarbonate In methanol; butan-1-ol | 151 1-[4-[3-[4-[Bis(3-fluorophenyl)methyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone fumarate [1:1] EXAMPLE 151 1-[4-[3-[4-[Bis(3-fluorophenyl)methyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone fumarate [1:1] A mixture of 5.32 g (0.019 mole) of 4-[bis(3-fluorophenyl)methyl]piperidine, 4.80 g (0.020 mole) of 3-(4-acetyl-2-methoxyphenoxy)-1-chloropropane, 2.4 g (0.029 mole) of sodium bicarbonate and 0.20 g (0.0012) mole of potassium iodide in 400 ml of 1-butanol was heated at reflux for 23 hr. The solvent was removed in vacuo and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate and the solvent was removed in vacuo to give an oil. This was dissolved in methanol and the solution was treated with an excess of fumaric acid. Ether was added and a gum formed. The gum was triturated with acetonitrile to give 1.75 g (15.1%) of the title compound as a white crystalline solid, mp 180°-181° C. Analysis: Calculated for C34 H37 F2 NO7: C, 66.98; H, 6.12; N, 2.30. Found: C, 66.70; H, b 6.11; N, 2.32. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.5% | With potassium iodide; potassium carbonate In chloroform; ethyl acetate; butan-1-ol | 160 1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-α,α-bis(4-fluorophenyl)-3-pyrrolidineacetonitrile EXAMPLE 160 1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-α,α-bis(4-fluorophenyl)-3-pyrrolidineacetonitrile A mixture of α,α-bis(4-fluorophenyl)-3-pyrrolidineacetonitrile (5.13 g, 0.0172 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.17 g, 0.0172 mole), and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). The butanol was removed by rotary evaporation. The residue obtained was dissolved in chloroform and extracted several times with water. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed in vacuo to give a dark brown oil. The oil was subjected to flash chromatography on silica gel using ethyl acetate and 25% methanol-75% ethyl acetate for elution. Fractions of similar purity were combined and solvents removed. A dark brown oil was obtained and dried in vacuo 2 days at 80° C. to give 5.85 g (57.5% yield) of the title compound as a dark brown gum. 1 H NMR (CDCl3): δ6.8-7.6 (m, 11, aromatics), 4.3 (t, 2, --OCH2 --), 3.9 (s, 3--OCH3), 2.6 (s, 3, --COCH3 --), 1.3-3.8 (m, 11, aliphatics). Analysis: Calculated for C30 H30 F2 N2 O3: C, 7.41; H, 5.99; N, 5.55. Found: C, 70.94; H, 5.99; N, 5.51. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate In butan-1-ol; benzene | 60 1-[3-Methoxy-4-[3-[4-[phenyl[3-(trifluoromethyl)phenyl]methylene]-1-piperidinyl]propoxy]phenyl]ethanone oxalate [1:1] EXAMPLE 60 1-[3-Methoxy-4-[3-[4-[phenyl[3-(trifluoromethyl)phenyl]methylene]-1-piperidinyl]propoxy]phenyl]ethanone oxalate [1:1] The title compound was prepared by the method described in U.S. Pat. No. 3,922,276 (see Example 10 of that patent) as follows; A mixture of 5.0 g (0.0157 mole) of 4-[α-phenyl-α-(m-trifluoromethylphenyl)methylene]piperidine, 3.82 g (0.0157 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 2.52 g (0.03 mole) of sodium bicarbonate in 75 ml of 1-butanol was stirred and heated at reflux for 17.5 hrs. The mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure. The glassy residue obtained weighed 4.25 g (52%) and was dissolved in benzene and placed on a Florisil column. Using an acetone-benzene gradient elution, product was obtained as a glassy residue. This residue was dissolved in ether and the oxalate salt was obtained. The salt has a glassy appearance, m.p. 120°-125° C. Analysis: Calculated for C33 H34 F3 NO7: C,74.59;H,5.58;N,2.28. Found: C,64.34;H,5.72;N,2.04. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate In <i>N</i>-methyl-acetamide | 61 1-[4-[3-[4(Cyclohexylphenylmethylene)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate [1:1] EXAMPLE 61 1-[4-[3-[4(Cyclohexylphenylmethylene)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate [1:1] The free base of the title compound was obtained as in Example 1 of U.S. Pat. No. 3,922,276 by reacting 4-[(α-cyclohexyl-α-phenyl)methylene]piperidine with 3-(p-acetyl-o-methoxyphenoxy)propyl chloride in a mixture with sodium bicarbonate in dimethylformamide and converted to the oxalate salt, m.p. 184°-185° C. Analysis: Calculated for C32 H41 NO7: C,69.67;H,7.49;N,2.54. Found: C,69.83;H,7.58;N,2.56. | |
With sodium hydrogencarbonate In <i>N</i>-methyl-acetamide | 61 1-[4-[3-[4(Cyclohexylphenylmethylene)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate [1:1] EXAMPLE 61 1-[4-[3-[4(Cyclohexylphenylmethylene)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate [1:1] The free base of the title compound was obtained as in Example 1 of U.S. Pat. No. 3,922,276 by reacting 4-[(α-cyclohexyl-α-phenyl)methylene]piperidine with 3-(p-acetyl-o-methoxyphenoxy)propyl chloride in a mixture with sodium bicarbonate in dimethylformamide and converted to the oxalate salt, m.p. 184°-185° C. Analysis: Calculated for C32 H41 NO7: C, 69.67; H, 7.49; N, 2.54. Found: C, 69.83; H, 7.58; N, 2.56. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.6 g (71%) | With potassium iodide; sodium carbonate In butan-1-ol | 161 1-[(3-(4-Acetyl-2-methoxyphenoxy)propyl]-α,α-bis(3-fluorophenyl)-4-piperidinemethanol EXAMPLE 161 1-[(3-(4-Acetyl-2-methoxyphenoxy)propyl]-α,α-bis(3-fluorophenyl)-4-piperidinemethanol This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 4-[α,α-bis(4-fluorophenyl)hydroxymethyl]piperdine, 2.4 g (0.01 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave 3.6 g (71%) of the title compound as an off-white solid, m.p. 149°-151° C. (absolute ethanol). Analysis: Calculated for C30 H35 F2 NO4: C, 70.71; H, 6.53; N, 2.75. Found: C, 70.66; H, 6.53; N, 2.79. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium iodide; potassium carbonate In butan-1-ol | 22 1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-α,α-bis(4-fluorophenyl)-4-piperidineacetamide fumarate hydrate [1:0.5:0.5] EXAMPLE 22 1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-α,α-bis(4-fluorophenyl)-4-piperidineacetamide fumarate hydrate [1:0.5:0.5] A mixture of α,α-bis(4-fluorophenyl)-4-piperidineacetamide (6.94 g, 0.021 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.09 g, 0.021 mole), and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). The mixture was concentrated to dryness. The residue obtained was partitioned between chloroform and water. The chloroform layer was dried (sodium sulfate) and filtered. The solvent was removed to give a yellowish-brown residue. This material was converted to the fumarate, and the salt was recrystallized from methanol-diethyl ether. A white solid was obtained and dried in vacuo overnight at 80° C. This method provided 8.47 g (66.8%) of white, crystalline product, mp 258°-260° C. (dec). Analysis: Calc. for C31 H34 F2 N2 O4.0.5C4 H4 O4.0.5H2 O: C, 65.66; H, 6.18; N, 4.64. Found: C, 65.88; H, 6.13; N, 4.65. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In 2-methylpropyl acetate | 2 1-[3-(p-Acetyl-o-methoxyphenoxy)-propyl]-4-(p-fluorobenzoyl)-4-hydroxy-piperidine hydrochloride EXAMPLE 2 1-[3-(p-Acetyl-o-methoxyphenoxy)-propyl]-4-(p-fluorobenzoyl)-4-hydroxy-piperidine hydrochloride A stirred mixture of 11.1 g (0.05 mole) of 4-(p-fluorobenzoyl)-4-hydroxy-piperidine, 14.6 g (0.06 mole) of 3-(p-acetyl-o-methoxyphenoxy)-propyl chloride and 25 g of anhydrous sodium carbonate in 350 ml iso-butylacetate was allowed to reflux for 48 h. The mixture was filtered and the filtrate was concentrated under vacuum. The residual oil was converted to the HCl salt. 1-[3-(p-Acetyl-o-methoxyphenoxy)propyl]-4-(p-fluorobenzoyl)-4-hydroxy-piperidine hydrochloride was recrystallized from ethanol. Melting point 160°-162° C. Yield 16.2 g. Said product contained a certain amount of ethanol which can only be removed by extreme means. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate In <i>N</i>-methyl-acetamide; benzene-isooctane | 68 1-[4-[3-[4-(Diphenylhydroxymethyl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate [1:1] EXAMPLE 68 1-[4-[3-[4-(Diphenylhydroxymethyl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate [1:1] A mixture of 5.2 g (0.0194 mole) of α,α-diphenyl-4-piperidinemethanol, 4.7 g (0.0194 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.6 g (0.0194 mole) of sodium bicarbonate in 60 ml of dimethylformamide was stirred at 100° C. for 3 hrs. After cooling, the reaction mixture was filtered and the dimethylformamide was removed under reduced pressure. The residual oil weighed 8.3 g (90%). Some of the product crystallized upon trituration in anhydrous ether and was collected by filtration. The filtrate was evaporated to dryness and the residue was dissolved in hot benzene-isooctane. Upon cooling, the crystalline product was obtained. A total yield of 6.3 g of solid product was obtained. The solid free base was converted to the oxalate salt. Recrystallization from isobutyl methyl ketone gave the off-white solid melting at 174°-176° C. (See Ex. 15, U.S. Pat. No. 3,956,296). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium iodide; oxalic acid In methanol | 76 1-[4-[3-[4-[(4-Fluorophenyl)phenylmethyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate [1:1] EXAMPLE 76 1-[4-[3-[4-[(4-Fluorophenyl)phenylmethyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate [1:1] A solution of 4.42 g (0.0164 mole) of 4-[(4-fluorophenyl)phenylmethyl]piperidine and 4.11 g (0.0170 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 0.01 g of potassium iodide and 1-butanol was refluxed for 18 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The solvent was removed in vacuo to give an oil. A solution of the oil in methanol was treated with an equivalent of oxalic acid, ethyl ether was added, and 6.39 g (68.9%) of white crystalline solid, m.p. 161°-163° C. was obtained. Analysis: Calculated for C32 H36 NO7 F: C, 67.95; H, 6.42; N, 2.48. Found: C, 67.92; H, 6.42; N, 2.44. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With oxalic acid; sodium hydrogencarbonate; In N-methyl-acetamide; benzene; | EXAMPLE 58 1-[4-[3-[4-[Bis(4-fluorophenyl)methylene]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate [1:1] The title compound was prepared by the method described in U.S. Pat. No. 3,922,276 (See Ex. 12 of that patent) as follows: A mixture of 4.7 g (0.0165 mole) of 4-[alpha,alpha-bis(p-fluorophenyl)methylene]piperidine, 4.0 g (0.0165 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.4 g of sodium bicarbonate in 60 ml of dimethylformamide was heated at 100 C. overnight. After cooling, the reaction mixture was filtered and the dimethylformamide was removed at reduced pressure. The residuel oil was dissolved in benzene and placed on a Florisil column. Elution with a gradient of acetone-benzene gave 5.7 g (70%) of a viscous brown oil. The free base was reacted with oxalic acid to give the oxalate salt, m.p. 169-170 C. after recrystallization from isopropyl alcohol and drying under nitrogen. Analysis: Calculated for C32 H33 F2 NO7: C, 66.08; H, 5.72; N, 2.41. Found: C, 66.01; H, 5.67; N, 2.40. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With oxalic acid; sodium hydrogencarbonate In <i>N</i>-methyl-acetamide; chloroform | 59 1-[4-[3-[4-[(4-Fluorophenyl)phenylmethylene]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate [1:1] EXAMPLE 59 1-[4-[3-[4-[(4-Fluorophenyl)phenylmethylene]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate [1:1] The title compound was prepared by the method described in U.S. Pat. No. 3,922,276 (See Ex. 12 of that patent) as follows: A mixture of 7.1 g (0.027 mole) of 4-[α-(p-fluorophenyl)-α-phenylmethylene]piperidine, 6.5 g (0.027 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 2.3 g. (0.027 mole) of sodium bicarbonate in 100 ml of dimethylformamide was stirred and heated at 100° C. for approximately 8 hours. The mixture was filtered and the dimethylformamide was removed under reduced pressure. The residual oil was dissolved in chloroform and the mixture was filtered. The filtrate was concentrated under vacuum to give 11.5 g. of crude free base (92%). The free base was reacted with oxalic acid to give the oxalate salt, m.p. 143°-145° C. after recrystallization from methylisobutyl ketone. Analysis: Calculated for C32 H34 FNO7: C, 68.19; H, 6.08; N, 2.49. Found: C, 68.14; H, 6.12; N, 2.54. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate In butan-1-ol; benzene | 60 1-[3-Methoxy-4-[3-[4-[phenyl[3-(trifluoromethyl)phenyl]methylene]-1-piperidinyl]propoxy]phenyl]ethanone oxalate [1:1] EXAMPLE 60 1-[3-Methoxy-4-[3-[4-[phenyl[3-(trifluoromethyl)phenyl]methylene]-1-piperidinyl]propoxy]phenyl]ethanone oxalate [1:1] The title compound was prepared by the method described in U.S. Pat. No. 3,922,276 (See Ex. 10 of that patent) as follows: A mixture of 5.0 g (0.0157 mole) of 4-[α-phenyl-α-(m-trifluoromethylphenyl)methylene]piperidine, 3.82 g (0.0157 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 2.52 g (0.03 mole) of sodium bicarbonate in 75 ml of 1-butanol was stirred and heated at reflux for 171/2 hrs. The mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure. The glassy residue obtained weighed 4.25 g (52%) and was dissolved in benzene and placed on a Florisil column. Using an acetone-benzene gradient elution, product was obtained as a glassy residue. This residue was dissolved in ether and the oxalate salt was obtained. The salt has a glassy appearance, m.p. 120°-125° C. Analysis: Calculated for C33 H34 F3 NO7: C, 64.59; H, 5.58; N, 2.28. Found: C, 64.34; H, 5.72; N, 2.04. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.16 g (27.4%) | With potassium iodide; oxalic acid; potassium carbonate In chloroform; butan-1-ol | 77 1-[4-[3-[4-[Bis(4-methoxyphenyl)methyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate [1:1] EXAMPLE 77 1-[4-[3-[4-[Bis(4-methoxyphenyl)methyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate [1:1] A mixture of 7.78 g (0.025 mole) of 4-[bis(4-methoxyphenyl)methyl]piperidine, 6.05 g (0.025 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, and potassium carbonate (5.53 g, 0.04 mole) in 300 ml of 1-butanol containing potassium iodide (0.3 g) was refluxed overnight. The reaction mixture was stripped to dryness and the residue was partitioned between chloroform and water; removal of chloroform in vacuo gave a dark brown oil. The oil was subjected to column chromatography on silica gel using a gradient elution composed of methanol and ethyl acetate. The corresponding fractions from the column were combined and reacted with oxalic acid. Recrystallization of the salt from methanol-diethyl ether gave 4.16 g (27.4%) of white solid, m.p. 163.5°-165° C. Analysis: Calculated for C34 H41 NO9: C, 67.20; H, 6.80; N, 2.31. Found: C, 66.76; H, 6.84; N, 2.26. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate In <i>N</i>-methyl-acetamide; benzene | 69 1-[4-[3-[4-[Hydroxyphenyl[-3-(trifluoromethyl)phenyl]methyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone hydrochloride hydrate [1:1:0.5] EXAMPLE 69 1-[4-[3-[4-[Hydroxyphenyl[-3-(trifluoromethyl)phenyl]methyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone hydrochloride hydrate [1:1:0.5] A mixture of 7.0 g (0.021 mole) of α-phenyl-α-(m-trifluoromethylphenyl)-4-piperidinemethanol, 5.1 g (0.021 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 3.0 g (0.036 mole) of sodium bicarbonate in 125 ml of dry dimethylformamide was stirred and heated at 90°-95° C. for 5 hours. The mixture was cooled and filtered. An excess of water was added to the reaction mixture. The mixture was extracted several times with benzene and the collected extracts were dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude solid which was obtained was dissolved in benzene and placed on a Florisil column. Elution using an acetone-benzene gradient gave a gummy solid. The gum was dissolved in ether and the hydrochloride salt was prepared. The hydrochloride salt weighed 3.1 g (25%) and became a clear melt at 95° C. (See Ex. 16, U.S. Pat. No. 3,956,296). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.16 g (61%) | With potassium iodide In butan-1-ol | 75 1-[4-[3-[4-[Bis(4-chlorophenyl)methylene]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone EXAMPLE 75 1-[4-[3-[4-[Bis(4-chlorophenyl)methylene]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone A mixture of 3.96 g (0.01305 mole) of 4-[bis(4-chlorophenyl)methylene]piperidine, 3.16 g (0.013 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone in 300 ml of 1-butanol containing 0.3 g of potassium iodide was heated overnight at gentle reflux. The reaction mixture was stripped to dryness and partitioned between chloroform-water and chloroform-5% sodium hydroxide. Removal of chloroform gave an oil which crystallized from isopropyl alcohol. The solid was again crystallized from isopropyl alcohol to give 4.16 g (61%) of light yellow solid, m.p. 143°-144° C. Analysis: Calculated for C30 H31 NO3 Cl2: C, 68.70; H, 5.96; N, 2.67. Found: C, 69.11; H, 6.02; N, 2.55. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium iodide; sodium hydrogencarbonate In methanol; butan-1-ol | 57 1-[4-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone fumarate [5:6] EXAMPLE 57 1-[4-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone fumarate [5:6] A mixture of 58.26 g (0.203 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine, 54.5 g (0.225 mole) of 1-chloro-3-(4-acetyl-2-methoxyphenoxy)propane, 18.7 g (0.223 mole) of sodium bicarbonate and 1.2 g (0.0072 mole) of potassium iodide in 800 ml of 1-butanol was refluxed for 16 hr. The hot reaction mixture was filtered, and the solvent was removed in vacuo from the filtrate. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil. The oil was dissolved in 600 ml of anhydrous ether, and 4.91 g of a solid was collected at room temperature. The ether solution was then treated with a solution of 30.2 g (0.26 mole) of fumaric acid in methanol. Anhydrous ether was added and 99.88 g (77.7%), m.p. 160°-163° C. of title compound was isolated. This was recrystallized from isopropanol-diethyl ether, (2.5 g, 0.0216 mole of additional fumaric acid was added) to give 2 crops of title compound. [Crop I-44.15 g, m.p. 163°-164.5° C.; Crop II-38.75 g, m.p. 161°-163° C.]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In N-methyl-acetamide; chloroform; | EXAMPLE 65 1-[4-[3-[4-(Diphenylmethyl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate [1:1] A mixture of 5.0 g (0.02 mole) of 4-(alpha-phenylbenzyl)piperidine, 4.85 g (0.02 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride, and 3.4 g (0.04 mole) of sodium bicarbonate in 100 ml of dimethylformamide was heated at 100 C. for about 3 hrs. The reaction mixture was cooled, filtered and the filtrate was concentrated under reduced pressure. The residual oil was dissolved in chloroform and the chloroform was filtered to remove insolubles. The filtrate was concentrated under reduced pressure to give 8.6 g of a red oil (94.5%). The oil was dissolved in a mixture of 4:1 ether-isopropanol and treated with 2.3 g of <strong>[6153-56-6]<strong>[6153-56-6]oxalic acid</strong> dihydrate</strong>. The oxalate salt crystallized upon standing and trituration in ether gave 8.4 g of salt melting at 149-155 C. Recrystallization from isobutyl methyl ketone gave 7.0 g of the salt, m.p. 153-155 C. (See Ex. 11, U.S. Pat. No. 3,956,296). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate In <i>N</i>-methyl-acetamide; chloroform; benzene | 56 1-[4-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate [1:1] EXAMPLE 56 1-[4-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate [1:1] The title compound was prepared by the method described in U.S. Pat. No. 3,956,296 (See Example 13 of that patent) as follows: A mixture of 4.75 g (0.0165 mole) of 4-[α,α-bis(p-fluorophenyl)methyl]piperidine, 4.0 g (0.0165 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.4 g (0.0165 mole) of sodium bicarbonate in 60 ml of dimethylformamide was heated at 80° C. for about 2 hours. TLC showed no product at this point. The temperature was raised to 100° C. for 1 hr, at which time TLC showed the reaction to be complete. After cooling, the reaction mixture was filtered and the dimethylformamide was removed under reduced pressure. The crude product was dissolved in chloroform and filtered and the filtrate was concentrated under reduced pressure to give 7.7 g (94%) of crude product. The solid was dissolved in benzene and placed on a Florisil column. Upon eluding with an acetone-benzene gradient, 5.5 g of product was obtained. The oxalate salt was prepared and upon recrystallization from isopropanol-methanol gave 3.8 g of salt, m.p. 164.5°-166° C. Analysis: Calculated for C32 H35 F2 NO7: C, 65.86; H, 6.05; N, 2.40. Found: C, 66.11; H, 6.13; N, 2.39. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate In <i>N</i>-methyl-acetamide | 3 3-(2-Dimethylaminoethoxy)-1-[3-(4-acetyl-2-methoxyphenoxy)propyl]pyrrolidine Dioxalate. EXAMPLE 3 3-(2-Dimethylaminoethoxy)-1-[3-(4-acetyl-2-methoxyphenoxy)propyl]pyrrolidine Dioxalate. A mixture of 6.9 g. (0.029 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride, 5 g. (0.032 mole) of 3-[2-(dimethylamino)-ethoxy]pyrrolidine and 3.4 g. (0.04 mole) of sodium bicarbonate in 100 ml. of dry dimethylformamide was heated at 95° C. overnight. The mixture was cooled, an excess of water was added and the aqueous mixture was extracted with chloroform. The chloroform extracts were dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 8.2 g. (79%) of crude product. The dioxalate salt was prepared using isopropyl alcohol and oxalic acid dihydrate. | |
With sodium hydrogencarbonate In <i>N</i>-methyl-acetamide | 6 3-(2-Dimethylaminoethoxy)-1-[3-(4-acetyl-2-methoxyphenoxy) propyl]pyrrolidine Dioxalate EXAMPLE 6 3-(2-Dimethylaminoethoxy)-1-[3-(4-acetyl-2-methoxyphenoxy) propyl]pyrrolidine Dioxalate A mixture of 6.9 g. (0.029 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride, 5 g. (0.032 mole) of 3-[2-(dimethylamino)-ethoxy]pyrrolidine and 3.4 g. (0.04 mole) of sodium bicarbonate in 100 ml. of dry dimethylformamide was heated at 95° C. overnight. The mixture was cooled, an excess of water was added and the aqueous mixture was extracted with chloroform. The chloroform extracts were dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 8.2 g. (79%) of crude product. The dioxalate salt was prepared using isopropyl alcohol and oxalic acid dihydrate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With nitric acid In dichloromethane at -20 - -10℃; for 2h; | 1.B 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 B 1-[4-(3-chloropropyloxy)-5-methoxy-2-nitro]phenylethanone (III) 1-[4-(3-chloropropyloxy)-5-methoxy-2-nitro]phenylethanone (III) Intermediate II (200 g, 0.82 Mol) was added to CH2Cl2 (5v/w, 1000 mL). The mixture was stirred thoroughly so as to dissolve Intermediate II completely. Then, after cooling the reaction solution to -20° C., fuming nitric acid (130 g, 2.06 mol) was slowly added dropwise thereto while keeping the temperature of the reaction solution below -10° C. After the dropwise addition, the reaction was conducted at -20° C. for 2 h. After completion of the reaction, the reaction solution was poured into ice-water. The organic layer was collected, and washed with a saturated saline solution until the aqueous layer became neutral. The organic layer was collected and dried over anhydrous sodium sulfate. Then the solvent was evaporated off to produce a reddish brown oil, which was thoroughly cooled to produce a yellow solid (210 g) in a yield of 89%. |
89% | With nitric acid In dichloromethane at -20 - -10℃; for 2h; | 1.B Step B: 1-(4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl)ethanone (intermediate III) Step B 1-(4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl)ethanone (intermediate III) To a solution of intermediate II (200 g, 0.82 mol) in dichloromethane (5v/w, 1000 mL), fuming nitric acid (130 g, 2.06 mol) was added drop-wise at a rate to maintain the reaction temperature below -10°C. Upon the completion of addition, the mixture was stirred for 2h at -10∼-20°C. After completion of the reaction, the reaction mixture was poured slowly into ice water, and the organic layer was separated and washed with brine until the aqueous layer became neutral, then dried with anhydrous sodium sulphate .The solution was evaporated to give 210g of yellow solid. Yield : 89%. |
89% | With nitric acid In dichloromethane at -20 - -10℃; for 2h; | 1.B 1-(4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl)ethanone (intermediate III) To a solution of intermediate II (200 g, 0.82 mol) in dichloromethane (5 v/w, 1000 mL), fuming nitric acid (130 g, 2.06 mol) was added drop-wise at a rate to maintain the reaction temperature below -10° C. Upon the completion of addition, the mixture was stirred for 2 h at -10˜-20° C. After completion of the reaction, the reaction mixture was poured slowly into ice water, and the organic layer was separated and washed with brine until the aqueous layer became neutral, then dried with anhydrous sodium sulphate. The solution was evaporated to give 210 g of yellow solid. Yield: 89%. |
89% | With nitric acid In dichloromethane at -20 - -10℃; for 2h; | 1.B Step B: 1-(4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl)ethanone (N) To a solution of intermediate III (200 g, 0.82 mol) in dichloromethane (1000 mL), fuming nitric acid (130 g, 2.06 mol) was added drop-wise at a rate to maintain the reaction temperature at -10-20° C. Upon the completion of addition, the mixture was stirred for 2 h at -10-20° C. After completion of the reaction, the reaction mixture was poured slowly into ice water, and the organic layer was separated and washed with saturated sodium bicarbonate solution until the aqueous layer became neutral, then dried with anhydrous sodium sulphate. The solution was evaporated to give 210.0 g yellow solid. Yield: 89.0%. |
89% | With nitric acid In dichloromethane at -10 - 20℃; for 2h; | 1.B Step B 1- (4- (3-chloropropoxy) -5-methoxy-2-Nitro) acetophenone (III) theintermediate II (200g0.82mol) added into CH2Cl2(5v/w1000mL), sufficiently stirred to dissolve allintermediate II, after the reaction solution was cooled to -20 ° C , slowlyadded drop wise Fuming nitric acid (130g2. 06mol), Control of drop wise addition speed to maintain reaction temperature below-10 ° c,after the completion of the reaction kept the reaction for 2h at -10 -20 ° c. afterthe completion of the reaction , the reaction liquid was poured into cold water, collect the organic layers , then organic layers washed using Saturated brine,until the aqueous layer as neutral and dried over anhydrous sodium sulfate. Thesolvent was evaporated to give a yellow solid 210g, yield 89%, |
89% | With nitric acid In dichloromethane at -20 - -10℃; for 2h; | B 1-(4-(3-chloropropoxy)-5-methoxy-2-nitro)acetophenone (III) Intermediate II (200 g, 0.82 mol) was added to CH2Cl2 (: 12 (5 v / w, 1000 mL) and the whole was dissolved with stirring. Fuming nitric acid (130g, 2.06mol), control the dropping rate to keep the reaction solution temperature below -l0 ° C, after the completion of the drop reaction at -10 ~ -20 ° C for 2h.After the reaction is complete, pour the reaction solution into ice water The organic layer was collected and the organic layer was washed with saturated brine until the aqueous layer was neutral and dried over anhydrous sodium sulfate.The solvent was evaporated to dryness to give 210 g of a yellow solid in a yield of 89% |
89% | With nitric acid In dichloromethane at -20 - -10℃; for 2h; | 1.B Step B 1- (4- (3- chloropropoxy) -5-methoxy-2-nitro) acetophenone (III) The Intermediate II (200g, 0.82MoL) was added to a CH2of Cl2(5V / W, 1000mL), and stirred to make intermediate IIafter completely dissolved, then the reaction solution was cooled to minus 20 , slowly 71/92 fuming nitric acid (130g, 2.06moL), was added dropwise to controlthe speed of the reaction was maintained the temperature below -10 , after the addition was complete the reaction at -10 ~ -20 2h.After completion of the reaction, the reaction solution waspoured into ice water, the organic layer was collected, the organic layer was washed with saturated brine, the aqueous layer until neutral, dried over anhydrous sodium sulfate.Steameddry solvent gave a yellow solid 210g, 89% yield. |
89% | With nitric acid In dichloromethane at -20 - -10℃; for 2h; | 1.B Step B Preparation of 1- (4- (3-chloropropoxy) -5-methoxy-2-nitro) acetophenone (III) A mixture of intermediate II (200 g, 0.82 mol)Was added to CH2Cl2 (5 v / w, 1000 mL)The intermediate II was completely dissolved by thorough stirring,After cooling the reaction solution to minus 20 ° C,Fuming nitric acid (130 g, 2.06 mol) was slowly added dropwise,The dropping acceleration was controlled to keep the temperature of the reaction liquid below -10 ° C,After the dropwise addition, the reaction was carried out at -10 to -20 ° C for 2 hours.After completion of the reaction, the reaction solution was poured into ice water,The organic layer was collected, and the organic layer was washed with saturated brine,Until the water layer is neutral, anhydrous sodium sulfate drying.The solvent was evaporated to dryness to give 210 g of a yellow solid in 89% yield. |
89% | With nitric acid In dichloromethane at -20 - -10℃; for 2h; | B Step B Preparation of 1- (4- (3-chloropropoxy) -5-methoxy-2- nitro) acetophenone (b) Intermediate II (200 g, 0.82 mol) was added to CH2Cl2 (5 v/w, 1000 mL), and all the intermediate II was dissolved with thorough stirring. After the reaction mixture was cooled to -20 °C., Add fuming nitric acid (130g, 2.06mol), control the dropping rate to maintain the reaction liquid temperature is below -10 °C, after completion of the addition at -10 ~ -20 °C reaction 2h. After completion of the reaction, the reaction solution was poured into ice water and the organic layer was collected. The organic layer was washed with saturated brine until the aqueous layer was neutral and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness to give 210 g of a yellow solid, yield 89% |
89% | With nitric acid In dichloromethane at -20 - -10℃; for 2h; | B 1-(4-(3-Chloropropoxy)-5-methoxy-2-nitro)acetophenone (III) Intermediate II (200 g, 0.82 mol) was added to CH2Cl2 (5 v / w, 1000 mL)Fully stirred to make all the intermediate II dissolved,After cooling the reaction solution to minus 20 ° C,Slowly add fuming nitric acid (130g, 2.06mol),Control the dropping rate to keep the temperature of the reaction solution below -10 ° C. After the addition is completed, the reaction solution is reacted at -10 to -20 ° C. for 2 h.After the reaction was completed, the reaction solution was poured into ice water, the organic layer was collected,The organic layer was washed with saturated brine until the aqueous layer was neutral and dried over anhydrous sodium sulfate.The solvent was evaporated to dryness to give 210 g of a yellow solid in 89% yield. |
89% | With nitric acid In dichloromethane at -20 - -10℃; for 2h; | 1.2 Step 2 Preparation of 1-(4-(3-chloropropoxy)-5-methoxy-2-nitro)acetophenone (III) Intermediate II (200 g, 0.82 mol) was added to CH2Cl2 (5 v/w, 1000 mL).After thoroughly stirring, the intermediate II was completely dissolved, and then the reaction liquid was cooled to minus 20 ° C.Slowly add fuming nitric acid (130 g, 2.06 mol),The dropping rate was controlled to keep the temperature of the reaction solution below -10 ° C. After the completion of the dropwise addition, the reaction was carried out at -10 to -20 ° C for 2 hours.After the reaction was completed, the reaction solution was poured into ice water, and the organic layer was collected, and the organic layer was washed with saturated brine.Until the water layer is neutral, anhydrous sodium sulfate is dried. Evaporate the solvent,Obtained 210g of yellow solid with a yield of 89%; |
89% | With nitric acid In dichloromethane at -20 - -10℃; for 2h; | B Step B 1-(4-(3-Chloropropoxy)-5-methoxy-2-nitro)acetophenone (b) Intermediate a (200 g, 0.82 mol) was added to CH 2Cl 2 (5 v/w, 1000 mL).All dissolved, and then the reaction solution was cooled to -20 ° C, slowly added fuming nitric acid (130 g, 2.06 mol), controlled drop accelerationThe temperature of the reaction solution was kept below -10 ° C, and after the completion of the dropwise addition, the reaction was carried out at -10 to -20 ° C for 2 hours. After the reaction is completed, the reaction solution is pouredThe organic layer was collected and the organic layer was washed with saturated brine until the aqueous layer was neutral and dried over anhydrous sodium sulfate. EvaporateThe solvent was obtained as a yellow solid 210 g (yield: 89%) |
89% | With nitric acid In dichloromethane at -20 - -10℃; for 2h; | B Step B 1-(4-(3Chloropropoxy)-5-methoxy 2-nitro)acetophenone (III) Intermediate II (200 g, 0.82 mol) was added to CH2C12 (5 v/w, 1000 mL).Stir well to dissolve all of the intermediate II.After cooling the reaction solution to minus 20 ° C,Slowly add fuming nitric acid (130g, 2.06mol),Control the drop rate, keep the temperature of the reaction solution below -10 °C,After the completion of the dropwise addition, after reacting at -10 to -20 ° C for 2 hours, the reaction is completed.Pour the reaction solution into ice water.Collect organic layers,The organic layer was washed with saturated brine.Until the water layer is neutral,The organic phase was dried over anhydrous sodium sulfate.Evaporate the solvent,Obtained 21g of yellow solid, yield 89% |
88.3% | With nitric acid In dichloromethane at -20 - -10℃; for 5h; | 4.1.2 4-(3-Chloropropoxy)-5-methoxy-2-nitroacetophenone (2) A stirred solution of 1 (113.8g, 0.46mol) in CH2Cl2 (675mL) was cooled to-20°C, and fuming nitric acid (56.5mL) was added at a rate such that the temperature maintained at-15 to-10°C. The reaction mixture was allowed to stir at about-10°C for 5h, then poured into cold water (250mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate solution (2×200mL) and water (200mL) orderly, then concentrated under reduced pressure to afford 2 as light yellow solid, yield: 88.3% (117.5g). 1H NMR (400MHz, CDCl3) δ 7.64 (s, 1H), 6.76 (s, 1H), 4.26 (t, J=8.0Hz, 2H), 3.96 (s, 3H), 3.77 (t, J=8.8Hz, 2H), 2.50 (s, 3H), 2.29-2.37 (m, 2H). MS (ESI) m/z 288.1 [M+H]+. |
87.5% | With nitric acid In dichloromethane at -15 - -10℃; for 6h; | 4.1.2. 4-(3-Chloropropoxy)-5-methoxy-2-nitroacetophenone (2) Fuming nitric acid (33.5 mL) was added to a stirred solution of 1(67.0 g, 0.28 mol) in CH2Cl2 (340 mL) at -15--10 °C. The resultantmixture was stirred at about -10 °C for 6 h. Cold water (100 mL) was added to the solution. The organic layer was separated and washed withsaturated NaHCO3 solution (3×100 mL), and then the CH2Cl2 wasconcentrated to yield 2 as light yellow solid, yield: 87.5% (69.5 g). 1HNMR (400 MHz, DMSO-d6) δ 7.63 (s, 1H), 6.75 (s, 1H), 4.23 (t, J=8.0 Hz, 2H), 3.97 (s, 3H), 3.76 (t, J=8.8 Hz, 2H), 2.51 (s, 3H),2.29-2.38 (m, 2H). HRMS (ESI) m/z 288.0619 [M+H]+, Calcd. for288.0638. |
86.7% | With nitric acid In dichloromethane at 0℃; for 4h; | 2 1-(4-(3-Chloropropoxy)-3-methoxyphenyl)ethanone (1) 7.2 1-(4-(3-Chloropropoxy)-5-methoxy-2-nitrophenyl)ethanone (2) To a solution of 1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone 1 (35 g, 0.14 mol) in dichloromethane (150 mL), fuming nitric acid (10 mL, 0.28 mol) was added dropwise at a rate to maintain the reaction temperature below 0 °C. Upon the completion of addition, the mixture was stirred at 0 °C for another 4 h. The reaction mixture was poured slowly into the mixed solution of cold water (200 mL) and dichloromethane (100 mL). The organic layer was separated and washed with brine (600 mL * 5), dried with anhydrous sodium sulfate and evaporated. The residue was cooled and dried at room temperature to give a light yellow solid (360 g, yield 86.7%). Mp 60-61 °C; MS (ESI) m/z (%): 288.0 [M+H]+, 310.0 [M+Na]+. |
86.7% | With nitric acid In dichloromethane at 0℃; for 4h; | |
86.7% | With nitric acid In dichloromethane at 0℃; for 4h; | 1.3. 1-(4-(3-Chloropropoxy)-5-methoxy-2-nitrophenyl)ethanone (15) To asolution of 1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone 14 (35 g, 0.14 mol) in dichloromethane(150 mL), fuming nitric acid (10 mL, 0.28 mol) was added dropwise at a rate tomaintain the reaction temperature below 0. Upon the completionof addition, the mixture was stirred at 0 foranother 4 hours. The reaction mixture was poured slowly into the mixed solutionof cold water (200 mL) and dichloromethane (100 mL). The organic layer wasseparated and washed with brine (600 mL × 5), dried with anhydrous sodiumsulfate and evaporated. The residue was cooled and dried at room temperature togive a light yellow solid (360 g,yield 86.7%). M.p. 60-61; MS m/z (ESI): 288.0 [M+H]+, 310.0 [M+Na]+. |
86.7% | With nitric acid In dichloromethane at 0℃; for 4h; | 3 5.3 1-(4-(3-Chloropropoxy)-5-methoxy-2-nitrophenyl)ethanone (2) To a solution of 1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone 1 (35 g, 0.14 mol) in dichloromethane (150 mL), fuming nitric acid (10 mL, 0.28 mol) was added drop-wise at a rate to maintain the reaction temperature below 0 °C. Upon the completion of addition, the mixture was stirred at 0 °C for another 4 h. The reaction mixture was poured slowly into the mixed solution of cold water (200 mL) and dichloromethane (100 mL). The organic layer was separated and washed with brine (600 mL * 5), dried with anhydrous sodium sulphate and evaporated. The residue was cooled and dried at room temperature to give a light yellow solid (360 g, yield: 86.7%). M.p. 60-61 °C; MS (ESI) m/z (%): 288.0 [M + H]+, 310.0 [M + Na]+. |
86.7% | With nitric acid In dichloromethane at -20 - -15℃; for 8h; | 1.B 2-Nitro-4- (3-chloropropoxy) -5-methoxyacetophenone(A2) Intermediate A1 (12.1 g, 0.05 mol) was dissolved in 50 mL of dichloromethane,After sufficient agitation to complete dissolution,Cooled to -20 ° C, slowly dropping fuming nitric acid (8.46 mL, 0.18 mol)Control the reaction solution temperature does not exceed -15 .Drop finished, -15 to continue the reaction 8h.After completion of the reaction, the reaction solution was slowly poured into 100 mL of ice-water mixture, While stirring vigorously, collecting the methylene chloride layer, the methylene chloride layer was washed four times with water, washed twice with saturated brine, the organic layer was collected, dried over anhydrous sodium sulfate,Evaporated to dryness as a red oil and petroleum ether to give 12.4 g of a pale yellow solid in a yield of 86.7%. |
81% | With nitric acid; acetic acid In water at 40 - 50℃; for 6h; | 1-[4-(3-Chloropropoxy)-5-methoxy-2-nitrophenyl]ethan-1-one (20) A suspension of 19 (300.0 g, 1.24 mol), 65% HNO3 (179 g, 1.85 mol), and AcOH (1.5 kg) was stirred at 40-50 °C for 6 h to form a white solution. The mixture was poured slowly into ice-water (5 kg) over 20 min and stirred at r.t. for 2 h. The resulting white solid was filtered, washed with H2O (3 × 300 g), and dried at 50 °C for 5 h. The crude product was stirred and heated with MeOH (0.7 kg) at 60 °C for 2 h then cooled to r.t. overnight. The resulting solid was filtered off, washed with MeOH (2 × 0.2 kg), dried at 40 °C for 4 h to afford 20 (288.1 g, 81%) as a white solid; mp 66.8-67.0 °C.1H NMR (400 MHz, CDCl3): δ = 2.36 (m, J = 6.0 Hz, 2 H), 2.52 (s, 3 H),3.80 (t, J = 6.0 Hz, 2 H), 3.98 (s, 3 H), 4.28 (t, J = 6.0 Hz, 2 H), 6.78 (s, 1H), 7.67 (s, 1 H).13C NMR (100 MHz, CDCl3): δ = 30.3, 31.6, 40.9, 56.5, 66.0, 108.2,108.7, 133.0, 138.4, 148.8, 154.3, 200.1.MS (ESI): m/z = 288.1 [M + H]+. |
80.1% | With nitric acid In dichloromethane at -10℃; for 2h; regioselective reaction; | 2 7.1.2 4-(3-Chloropropoxy)-5-methoxy-2-nitroacetophenone (11) A stirred solution of 10 (2.00g, 8.22mmol) in CH2Cl2 (10mL) was cooled to -10°C, and fuming nitric acid (95%, 1.30g, 20.6mmol) was added at a rate such that the temperature did not exceed -10°C. The reaction mixture was allowed to stir at -10°C for 2h, then transferred with stirring to cold water (20mL). After 15min, the organic layer was separated and the aqueous layer washed with additional CH2Cl2 (10mL). The organic portions were combined and washed with 10% w/w aqueous sodium bicarbonate solution (2×10mL), then water (10mL), then concentrated under reduced pressure to afford crude 11, which was recrystallized from 90% ethanol to afford 11 (1.91g) as a light yellow solid, yield: 80.1%. 1H NMR (300MHz, CDCl3) δ 7.64 (s, 1H), 6.76 (s, 1H), 4.26 (t, J=6.0Hz, 2H), 3.96 (s, 3H), 3.77 (t, J=6.6Hz, 2H), 2.50 (s, 3H), 2.29-2.37 (m, 2H). Mp: 60-61°C. MS (ESI) m/z: 287.0, 289.0 (M+). |
80.1% | With nitric acid In dichloromethane at -10℃; for 2h; | |
80.1% | With nitric acid In dichloromethane at 10℃; for 2h; | 6.2 6.3. 4-(3-Chloropropoxy)-5-methoxy-2-nitroacetophenone (11) A stirred solution of 10 (2.00 g, 8.22 mmol) in CH2Cl2 (10 mL)was cooled to 10 C, and fuming nitric acid (95%, 1.30 g,20.6 mmol) was added at a rate such that the temperature did not exceed 10 C. The reaction mixture was allowed to stir at10 C for 2 h, then transferred with stirring to cold water (20 mL).After 15 min, the organic layer was separated and the aqueouslayer washed with additional CH2Cl2 (10 mL). The organic portionswere combined and washed with 10% w/w aqueous sodium bicarbonatesolution (2 10 mL), then water (10 mL), then concentratedunder reduced pressure to afford crude 11, which wasrecrystallized from 90% ethanol to afford 11 (1.91 g) as a light yellowsolid, yield: 80.1%. 1H NMR (400 MHz, CDCl3) d 7.64 (s, 1H),6.76 (s, 1H), 4.26 (t, J = 6.0 Hz, 2H), 3.96 (s, 3H), 3.77 (t, J = 6.6 Hz,2H), 2.50 (s, 3H), 2.29-2.37 (m, 2H). Mp: 60-61 C. MS (ESI) m/z:287.0, 289.0 [M+H]+. |
50.5% | With nitric acid at 0 - 20℃; | 4.1.4. General procedure for preparation of 4,5-disubstituted-2-nitroacetophenone (2a-c) General procedure: 3,4-Disubstituted acetophenone 1a-c (28.0 mmol) were added inportions to 65% concentrated nitric acid (30 mL) under 0 °C. After stirring at room temperature overnight, the mixture was poured intoH2O (50 mL) and stirred for a while, and extracted with EtOAc(2×30 mL). The combined organic layer were washed with brine,dried over Na2SO4, and concentrated in vacuo to yield crude product.The crude product was purified by silica gel chromatography elutedwith PE/EA=20:1-5:1 to give compounds 2a-c, respectively. |
With sulfuric acid; nitric acid In water at 5 - 10℃; Industry scale; | A pre-mixed solution of water (80 L) and concentrated sulfuric acid, 96 % (88 L) cooled to approximately 5 0C was charged to a reactor containing to the solution of l-[4-(3- halo propoxy)- 3-methoxy phenyl] ethanone (both of which are commercially available) at a rate such that the batch temperature did not exceed approximately 18°C. The resulting solution was cooled to approximately 5°C, and 65 % nitric acid (68 L) was added at a rate such that batch temperature did not exceed approximately 1O0C. HPLC analysis was used to determine when the reaction was complete. Methylene chloride (175 L) was charged to a separate reactor containing cooled water (1800 L; by dissolving 450 Kg of ice in 1500 of water). The acidic reaction mixture was then added into this mixture. The methylene chloride layer was separated, and the aqueous layer was back extracted with methylene chloride (78 L). The combined methylene chloride layers were washed with two portions of a solution of aqueous sodium bicarbonate followed by water (50 L) and then concentrated by vacuum distillation. 1-Butanol (590 L) was added, and the mixture was again concentrated by vacuum distillation. The resulting solution was stirred at approximately 20°C during which time the product crystallized. The solids were recovered by filtration, washed with heptane (100 L) to afford the title compound (89.8 kg wet). Mother liquor was concentrated and the resulting solid was filtered and washed with n-heptane (45 L) to afford second crop of the title compound (25 kg wet). Both product crops were combined and dried in a tumble drier at 35 0C to yield product (99.7 kg; 25.6 % LOD) which was used directly in the next step without further drying. Three production batches were made. | |
With nitric acid In dichloromethane at 0℃; for 4h; | ||
With nitric acid In dichloromethane at -20℃; | ||
With nitric acid In dichloromethane; water at 0℃; for 4h; | ||
With nitric acid In dichloromethane at 0℃; for 4h; | ||
521.4 g | With nitric acid In dichloromethane at -20 - -10℃; for 2h; | 1.2 Step (2) 1-[4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl]ethanone (IV) 500.0 g (2.05 mol) of intermediate III was added to 2.5 L of dichloromethane. The temperature of the reaction solution is maintained between -20 ° C and -10 ° C. Slowly drop 320.0g fuming nitric acid. Drop finished, reaction at -10 ° C for 2 h. The reaction solution was poured into ice water. Collecting organic layer. The organic layer was washed with saturated aqueous sodium bicarbonate solution to neutral. Dried over anhydrous sodium sulfate. Evaporated solvent to give 521.4 g of a yellow solid. |
With nitric acid In dichloromethane at 0℃; for 4h; | ||
51.7 g | With nitric acid In dichloromethane at -20 - -10℃; for 2h; | 27.2 Step 2. 1-[4-(3-Chloropropoxy)-5-methoxy-2-nitro]acetophenone (III-2) 50.0 g of intermediate III-1 was added to 500 mL of dichloromethane. Keep the temperature of the reaction solution at -20 ° C to -10 ° CDuring the dropwise addition, 32.0 g of fuming nitric acid was slowly added dropwise, and the reaction was carried out at -10 ° C for 2 h. Pour the reaction solution into ice water, collect the organic layer, organicLayer was washed with saturated aqueous sodium bicarbonate until neutral, dried over anhydrous sodium sulfate, and the solvent evaporated to dryness to give a yellow solid 51.7g |
With nitric acid at 0℃; regioselective reaction; | ||
210 g | With nitric acid In dichloromethane at -20 - -10℃; for 2h; | 1.5 Step 5 Synthesis of 4-(3-chloropropoxy)-3-methoxy-2-nitroacetophenone Add 4-(3-chloropropoxy)-3-methoxyacetophenone (200g, 0.82mol) to CH2Cl2 (5v/w, 1000mL),Stir thoroughly to dissolve all 4-(3-chloropropoxy)-3-methoxyacetophenone,Then after cooling the reaction liquid to -20°C,Slowly add fuming nitric acid (130g, 2.06mol) dropwise, control the dropping rate to keep the temperature of the reaction liquid below -10°C,After the addition is completed, react at -10°C ~ -20°C for 2h.After the completion of the reaction, the reaction solution was poured into ice water, the organic layer was collected, and the organic layer was washed with saturated brine until the water layer was neutral and dried with anhydrous sodium sulfate.Evaporate the solvent to obtain 210g of yellow solid, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(3-chloropropoxy)-3-methoxyacetophenone; 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole hydrochloride With potassium carbonate In acetonitrile at 60 - 85℃; Stage #2: With hydrogenchloride In water; isopropyl alcohol at 0 - 30℃; | 1 Example 1; Process for preparing Iloperidone hydrochloride:A mixture of 6-Fluoro-3-piperidin-4-yl-benzo[d]isoxazole hydrochloride, l-(4-(3-chloropropoxy)-3-methoxyphenyl) ethanone and potassium carbonate in acetonitrile was heated at 60-85° C until the reaction gets completed. The reaction mixture was cooled to 15-35° C, the by-product formed was filtered and washed with acetonitrile. The mother liquor was concentrated under vacuum to remove solvent and cooled to 15-30° C. To the residue was added isopropanol and aqueous hydrochloric acid. The reaction mass cooled to 0-10° C. The crystallized product was filtered, washed with isopropanol and drying afforded the title compound. The PXR of the product is as shown in Fig-1. IB2010/002712 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With pyridine; chromium(VI) oxide In dichloromethane; toluene at 30℃; | 1 (24.5g, 0.245moles) Chromium trioxide was added to a solution of 38.8g (0.49moles) of dry pyridine in 200ml of dry dichloromethane and stirred for 15 minutes in a clean and dry 500 ml 4 neck R.B.Flask at about 30°C. A solution of the l-[4-(3'-chloropropoxy)-3-methoxy phenyl]ethanol (lOg, 41 mmoles) in 100ml of toluene was added in one portion. A tarry black deposit was separated immediately, after stirring for an additional 15 minutes at about 30°C, the solution was decanted from the residue, and washed with 100ml of dichloromethane. The organic layers were combined and distilled completely under vacuum to obtain the residue. To the residue ether (100ml) was added, filtered to remove insoluble chromium salts followed by washing with 5% cold aqueous sodium hydroxide solution and saturated brine solution. The solvent was evaporated under vacuum to afford the oily residue. To the oily residue 30ml of diisopropyl ether was added and cooled to about 0°C and stirred for 30minutes. The solid separated was filtered and washed with chilled diisopropylether (10ml) to give the title compound.Yield: 8.15 gms (% Yield: 82%). |
With potassium dichromate; sulfuric acid In diethyl ether; water at 10 - 20℃; for 2h; | 2 Example 2; To a stirred mixture of potassium dichromate (11.8 gm, 0.04 moles), water (37 ml) added slowly sulfuric acid (9 ml, 0.16 mol) at 20°C. l-[4-(3-chloro propoxy)-3-methoxy phenyl)ethanol (30 gm, 0.12 moles) dissolved in ether (120 ml) was added slowly to the above mixture at 10 to 15°C. The mixture was stirred for 2 hours at ambient temperature. Separated the organic layer from the reaction mass and aqueous layer was extracted with ether (45 ml). Combined extracts were washed with 2% sodium bicarbonate solution (15 ml) and water (30 ml), evaporated the solvent to afford residue, which was then triturated in diisopropyl ether (10 - ml) gave 16 gm of l-[4-(3-chloropropoxy)-3- methoxyphenyl]ethanone. The solid was recrsytallized from ethylalcohol (50 ml) to yield 11 gm of l-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (M. P: 57.5 to 58.5°C). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; sodium bromide In water; N,N-dimethyl-formamide at 70℃; for 20h; | 2 A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (105.76 g), 1-[4-(3-chloropropoxy)-3- methoxyphenyl]ethanone (100 gm) (obtained from example 1), Potassium carbonate (71.16 g), Sodium Bromide (42.4 g), DMF (200 ml) and DM Water (100 ml) was heated at 70°C for 20 hours. After completion of the reaction, DM Water (500 ml) was added slowly to the reaction mixture. The reaction mixture was cooled to 30°C and stirred for 1 hour. The resulting precipitates were filtered and suck dried. The solid was added to DM Water (300 ml) and heated at 50°C for 30mins. The reaction mixture was filtered and washed first with DM Water (100 ml) and then with Ethyl acetate (140 ml). The solid was suck dried and then dried in oven at 50°C to give the title product (150.0 g).[136] Purity by HPLC: 99.4% | |
97 g | In N,N-dimethyl-formamide at 90 - 95℃; | 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%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: methyl iodide With magnesium In diethyl ether for 0.5h; Reflux; Stage #2: 4-(3-chloropropoxy)-3-methoxybenzonitrile In toluene for 3h; Reflux; Stage #3: With hydrogenchloride; water at 0℃; for 6h; Reflux; | 16 (10.6gr., 0.44moles) Magnesium turnings and 100ml. diethyl ether were charged in a clean and dry 1 lilt. 4 neck R.B.Flask. 78.7gms (0.55moles) of methyl iodide in 100ml. of ether was added at about 20°C.(after addition of 4-5gr. Of methyl iodide initiation started). The resultant reaction mixture was refluxed for about 30min. To the resultant suspension 1 litre of toluene was added and the solvent was distilled to a volume of about 200ml. Then 50gms (0.22moles) of 4-(3'-chloropropoxy)-3-methoxybenzonitrile in 250 ml of toluene was added and the resultant reaction mixture was refluxed for about 3hrs. The reaction mixture was cooled to about 0°C and 800ml. of 10% HC1 solution was added drop-wise. The resultant reaction mixture was refluxed for about 6hrs. The reaction mixture was cooled and the organic layer was separated. The organic layer was washed with 200ml of 10%w/v sodium carbonate solution followed by 200ml of water. The organic layer was separated and the solvent was distilled-off completely under vacuum to afford the residue. The residue was re-crystallized from 200ml of di-isopropyl ether to afford the title compound as an off-white crystalline solid. Yield: 37.6 gms (% Yield: 75%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.5% | Stage #1: methyl magnesium iodide; 4-(3-chloropropoxy)-3-methoxybenzonitrile With copper(l) chloride In diethyl ether; toluene for 1h; Inert atmosphere; Reflux; Stage #2: With sulfuric acid; water In toluene at 25℃; for 2.25h; Reflux; | 18 To a 3 molar solution of methyl magnesium iodide in diethyl ether (86.3 gms (0.26mol) added 30 gms (0.13 mol) of 4-(3'-chloropropoxy)-3-rnethoxybenzonitrile in 300 ml of anhydrous toluene and 230 mg (2.32 mmol) of cuprous chloride and the resultant mixture was refluxed under nitrogen for about lhr.The reaction mixture was cooled to about 25-30°C and 50 ml of water was added slowly for about 15 minutes followed by addition of 332 ml of (15% v/v) sulphuric acid. The reaction mixture was stirred for about 2 hours under reflux, 100ml of toluene was added. Organic and aqueous layers were separated and the aqueous layer was extracted with 100 ml of toluene. The organic layers were combined and washed with 100 ml of 10%w/v sodium carbonate solution and then with 100 ml of water. The solvent was distilled completely under vacuum and the residue was re-crystallized from 200ml of di-isopropyl ether to afford the title compound as an light brown coloured solid. Yield: 25 gms (%Yield: 77.5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide at 90℃; for 16.1667h; | 12 Example-12: (Preparation of carbonated impurity of formula IV)To a well stirred solution of compound of formula II (10.0 g) and compound of formula-Ill (11.0 g) in DMF (80 mL) was added K2C03 (12.71 g) in one lot and stirred for 10 min. Temperature was then raised to 90°C and maintained it for 16 h. DMF was recovered under reduced pressure. Oily concentrated mass was diluted with water (250 mL) to yield semisolid suspension which was then extracted with ethyl acetate (5x 50 mL).The combined organic layer was dried over sodium sulfate and solvent was removed under vacuum. The obtained crude product contained carbonated impurity of formula IV (13% by HPLC). It was isolated by column chromatography, eluted by 10 to 20 % ethyl acetate in hexane to yield semisolid material, carbonated impurity of formula IV is identified and named as 3-(4-acetyl-2-methoxyphenoxy)propyl 4-(6- fluorobenzo[d]isoxazol-3-yl)piperidine- 1 -carboxylate.Characterization of the impurity is supported by the following analytical tools:.H NMR (Varian, 400MHz), (CDC13): δ 1.880(m,2H), 1.996(m,2H), 2.206(m,2H), 2.518(s, 3H), 2.999(t, 2H), 3.216(m,lH), 3.860(s,3H), 4.262(m,6H), 6.860(d,lH), 7.026(t,lH), 7.219(t,lH), 7.488(m,2H) and 7.589(m,lH) ppm.13C NMR (Varian, 400MHz) (CDC13): 26.116, 28.857, 30.042, 34.138, 43.640, 55.929, 55.968, 62.186, 65.369, 65.694, 97.486(d), 110.537, 111.355(d), 112.501(d), 122.131(d), 123.090(d), 130.589, 149.280, 152.579, 155.158, 160.308, 162.871, 163.846(d), 165.364 andl96.880 ppm.IR (Shimadzu, KBr): 470.6, 569.0, 642.3, 804.3, 956.7, 1031.9, 1099.5, 1122.6, 1220.9, 1263.4, 1350.2, 1415.8, 1512.2, 1591.3, 1612.5, 1680.1, 1695.5, 2852.8, 2924.2, 2960.8 and 3076.6 cm-1.LCMS (Thermo.) M/Z= 471.02 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide at 90℃; for 16.1667h; | 13 Example-13To a well stirred solution hydrochloride of compound of formula II (10.0 g) and compound of formula III (9.45 g) in DMF (80 mL) was added K2CO3 (10.8g) in one lot and stirred for 10 min. Reaction mixture was heated at 90°C for 16 h. and then cooled to 50°C. DMF was recovered under reduced pressure. Oily concentrated mass was diluted with water (250 mL) to yield semisolid suspension which was then extracted with ethyl acetate (5X 50 mL).The combined organic layer was dried and solvent was removed under vacuum to yield iloperidone of formula I (16.0 g) as crude product. The carbonated impurity is found to be 10.01%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrabutylammomium bromide; potassium carbonate In acetonitrile at 80℃; Industry scale; | 1 Example 1: Preparation of l-[4-(3-chloro/bromo propoxy)-3-methoxyphenyl] ethanone (III)Acetonitrile (1L) was charged to 4-hydroxy-3-methoxy acetophenone (IV) (0.5 kg, 3.009 moles). l-Bromo-3-chloropropane (V) (1.89 Kg, 12.036 moles) was added to the reaction mixture and was stirred followed by addition of TBAB (0.030 Kg, 0.0903 moles ). Potassium carbonate (0.78 Kg, 5.657 moles) was added to the reaction mixture and heated to 80°C The mixture was cooled and filtered. The solid obtained was charged to dichloromethane (2 liters) and stirred. The reaction mixture was heated to 40-45 °C and distilled. The reaction mixture was cooled and methanol (0.5 liters ) was added followed by the addition of water (5 liters). The entire reaction mixture was added to chilled water and stirred. The reaction mixture was filtered and washed with water and dried. Yield: 0.779 Kg.Purity: 99.35% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; nitric acid In dichloromethane; water at 4 - 18℃; Large scale; | Preparation of l-[5 methoxy-4 (3-halo propoxy)- 2 nitro-phenyl]- ethanone Preparation of l-[5 methoxy-4 (3-halo propoxy)- 2 nitro-phenyl]- ethanone[0075] Water (70 L) was charged to the solution of l-[4-(3-halo propoxy)- 3-methoxy phenyl] ethanone (both the bromo and the chloro compound are commercially available). The solution was cooled to approximately 4 °C. Concentrated sulfuric acid (129.5 kg) was added at a rate such that the batch temperature did not exceed approximately 18 °C. The resulting solution was cooled to approximately 5 °C and 70 percent nitric acid (75.8 kg) was added at a rate such that the batch temperature did not exceed approximately 10 °C. Methylene chloride, water, and ice were charged to a separate reactor. The acidic reaction mixture was then added into this mixture. The methylene chloride layer was separated, and the aqueous layer was back extracted with methylene chloride. The combined methylene chloride layers were washed with aqueous potassium bicarbonate solution and concentrated by vacuumdistillation. 1-Butanol was added and the mixture was again concentrated by vacuum distillation. The resulting solution was stirred at approximately 20 °C, during which time the product crystallized. The solids were collected by filtration, washed with 1-butanol to afford compound the title compound, which was isolated as a solvent wet cake, and used directly in the next step. 1H NMR (400MHz, DMSO-d6): ? 7.69 (s, 1H), 7.24 (s, 1H); 4.23 (m, 2H), 3.94 (s, 3H), 3.78 (t)-3.65 (t) (2H), 2.51 (s, 3H), 2.30-2.08 (m, 2H) LC/MS Calcd for[M(C1)+H]+ 288.1, found 288.0; Calcd for [M(Br)+H]+ 332.0, 334.0, found 331.9, 334.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: acetic acid / 2 h / 60 - 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: iron; acetic acid / 2 h / 60 - 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 2 h / -10 °C 2: toluene / 110 °C 3: iron / acetic acid / 2 h / 40 - 80 °C |
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 2 h / -10 °C 2: toluene / 110 °C 3: iron; acetic acid / 2 h / 40 - 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: dimethyl amine; toluene / 10 h / 110 °C 3: iron; acetic acid / 2.5 h / 20 - 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: iron; acetic acid / 2.5 h / 20 - 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: nitric acid / toluene / 10 h / 110 °C 3: iron / acetic acid / 2 h / 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: acetic acid; iron / 2 h / 60 - 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: iron; acetic acid / 2.5 h / 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: iron; acetic acid / 2.5 h / 20 - 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / -20 °C 2: toluene; dimethyl amine / 110 °C 3: acetic acid; iron / 85 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene; N,N-dimethyl-formamide / 10 h / 110 °C 3: iron; acetic acid / 2.5 h / 20 - 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 2 h / 10 °C 2: toluene / 110 °C 3: iron; acetic acid / toluene / 2 h / 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / water; dichloromethane / 4 h / 0 °C 2: N,N-dimethyl acetamide; toluene / 10 h / 110 °C 3: iron; acetic acid / 2.5 h / 20 - 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: acetic acid; iron / 2.5 h / 20 - 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: iron; acetic acid / 2.5 h / 20 - 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: iron; acetic acid / 2.5 h / 20 - 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 8 h / -20 - -15 °C 2: toluene; N,N-dimethyl-formamide / 10 h / 113 °C 3: acetic acid; iron / 2 h / 20 - 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: acetic acid; iron / 2.5 h / 20 - 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: iron; acetic acid / 0.5 h | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 2 h / -20 - -10 °C 2: toluene / 16 h / 110 °C 3: acetic acid; iron / 2 h / 40 - 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 6 h / -15 - -10 °C 2: 5,5-dimethyl-1,3-cyclohexadiene / 13 h / Reflux 3: acetic acid; iron / 2 h / 100 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / 0 - 20 °C 2: toluene / 110 °C 3: iron; acetic acid / 2 h / 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / -20 °C 2: toluene / 10 h / 110 °C 3: iron; acetic acid / 2.5 h / 25 - 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / 0 °C 2: toluene / 10 h / Reflux 3: iron; acetic acid / 2 h / 80 °C | ||
Multi-step reaction with 3 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: iron; acetic acid / 2 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: acetic acid / 2 h / 60 - 80 °C 4: acetonitrile / 10 h / 85 °C 5: trichlorophosphate / acetonitrile / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: iron; acetic acid / 2 h / 60 - 80 °C 4: acetonitrile / 10 h / 85 °C 5: trichlorophosphate / acetonitrile / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 2 h / -10 °C 2: toluene / 110 °C 3: iron / acetic acid / 2 h / 40 - 80 °C 4: acetonitrile / 8 h / 25 - 80 °C 5: trichlorophosphate / acetonitrile / Reflux |
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 2 h / -10 °C 2: toluene / 110 °C 3: iron; acetic acid / 2 h / 40 - 80 °C 4: acetonitrile / 8 h / 25 - 85 °C 5: trichlorophosphate / acetonitrile / 6 h / Reflux | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: dimethyl amine; toluene / 10 h / 110 °C 3: iron; acetic acid / 2.5 h / 20 - 80 °C 4: acetonitrile / 10 h / 85 °C 5: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: iron; acetic acid / 2.5 h / 20 - 80 °C 4: acetonitrile / 10 h / 85 °C 5: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: nitric acid / toluene / 10 h / 110 °C 3: iron / acetic acid / 2 h / 80 °C 4: acetonitrile / 10 h / 85 °C 5: trichlorophosphate / acetonitrile / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: acetic acid; iron / 2 h / 60 - 80 °C 4: acetonitrile / 10 h / 25 - 85 °C 5: trichlorophosphate / acetonitrile / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: iron; acetic acid / 2.5 h / 80 °C 4: acetonitrile / 10 h / 85 °C 5: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: iron; acetic acid / 2.5 h / 20 - 80 °C 4: acetonitrile / 10 h / 85 °C 5: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / -20 °C 2: toluene; dimethyl amine / 110 °C 3: acetic acid; iron / 85 °C 4: acetonitrile / Reflux 5: trichlorophosphate / acetonitrile / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: iron; acetic acid / 2.5 h / 20 - 80 °C 4: acetonitrile / 10 h / 85 °C 5: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene; N,N-dimethyl-formamide / 10 h / 110 °C 3: iron; acetic acid / 2.5 h / 20 - 80 °C 4: acetonitrile / 10 h / 85 °C 5: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 2 h / 10 °C 2: toluene / 110 °C 3: iron; acetic acid / toluene / 2 h / 80 °C 4: acetonitrile / 8 h / 80 °C 5: trichlorophosphate / acetonitrile / 6 h / Reflux | ||
Multi-step reaction with 5 steps 1: nitric acid / water; dichloromethane / 4 h / 0 °C 2: N,N-dimethyl acetamide; toluene / 10 h / 110 °C 3: iron; acetic acid / 2.5 h / 20 - 80 °C 4: acetonitrile / 10 h / 85 °C 5: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: acetic acid; iron / 2.5 h / 20 - 80 °C 4: acetonitrile / 10 h / 85 °C 5: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: iron; acetic acid / 2.5 h / 20 - 80 °C 4: acetonitrile / 10 h / 85 °C 5: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 2 h / -20 - -10 °C 2: toluene / 16 h / 110 °C / Reflux 3: acetic acid; iron / 2 h / 40 - 80 °C 4: acetonitrile / 8 h 5: trichlorophosphate / acetonitrile / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: iron; acetic acid / 2.5 h / 20 - 80 °C 4: acetonitrile / 10 h / 85 °C 5: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 2 h / -20 - -10 °C 2: toluene / 16 h / 110 °C 3: acetic acid; iron / 2 h / 40 - 80 °C 4: acetonitrile / 8 h / Reflux 5: trichlorophosphate / acetonitrile / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 2 h / -20 - -10 °C 2: toluene / 16 h / 110 °C 3: iron; acetic acid / 2 h / 80 °C 4: acetonitrile / 8 h / Reflux 5: trichlorophosphate / acetonitrile / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: acetic acid; iron / 2.5 h / 20 - 80 °C 4: acetonitrile / 10 h / 85 °C 5: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: iron; acetic acid / 0.5 h 4: acetonitrile / 10 h / 85 °C 5: trichlorophosphate / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 2 h / -20 - -10 °C 2: toluene / 16 h / 110 °C 3: acetic acid; iron / 2 h / 40 - 80 °C 4: acetonitrile / 8 h / Reflux 5: trichlorophosphate / acetonitrile / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / 0 - 20 °C 2: toluene / 110 °C 3: iron; acetic acid / 2 h / 80 °C 4: trichlorophosphate; N,N-dimethyl-formamide / 1 h / 110 °C 5: sodium iodide; potassium carbonate / N,N-dimethyl-formamide / 10 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / -20 °C 2: toluene / 10 h / 110 °C 3: iron; acetic acid / 2.5 h / 25 - 80 °C 4: acetonitrile / 10 h / 85 °C 5: trichlorophosphate / acetonitrile / 6 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / 0 °C 2: toluene / 10 h / Reflux 3: iron; acetic acid / 2 h / 80 °C 4: trichlorophosphate; N,N-dimethyl-formamide / 1 h / Reflux 5: sodium iodide / N,N-dimethyl-formamide / 10 h / 85 °C | ||
Multi-step reaction with 5 steps 1: nitric acid / dichloromethane / 4 h / 0 °C 2: toluene / 10 h / 110 °C 3: iron; acetic acid / 2 h / 80 °C 4: acetonitrile / 10 h / 80 °C 5: trichlorophosphate / 6 h / 85 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine In water at 60 - 65℃; for 14h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.65% | With potassium carbonate; potassium iodide; In ethyl acetate; N,N-dimethyl-formamide; at 80℃; for 50h;Inert atmosphere; | A mixture of 40.00 g of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethyl ketone, 42.31 g of 6-fluoro-3- (4-piperidinyl) -1,2-benzisoxazole hydrochloride, 56.94 g of potassium carbonate, 5. 47 g of potassium iodide, 252 g of ethyl acetate and 113. 69 g of dimethyl Was added to a four-necked flask and heated to 80 C for 50 hours under N2 protection. The reaction of the starting material was confirmed by TLC complete. After cooling, the ethyl acetate was removed by distillation under reduced pressure, and the precipitate was added with stirring. After filtration, the residue was recrystallized from 550 ml of isopropanol Times, and the use of activated carbon decolorization, a white crystal 59. 5g, yield 84. 65% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With nitric acid In dichloromethane at -20 - -10℃; for 3h; | 1.2 Preparation of 1-(4-(3-chloropropoxy)-5-methoxy-2-nitro)acetophenone (Intermediate III) Add Intermediate II (200g, 0.82mol) to CH2Cl2 (5v/w, 1000mL),Stir thoroughly to dissolve Intermediate II to obtain a reaction solution. After cooling the reaction solution to -20°C, add fuming nitric acid (130g, 2.06mol) slowly, so that the fuming nitric acid is added dropwise within 1 hour. After completion, react at -20-10 for 2h. After the completion of the reaction, the reaction solution was poured into ice water (0°C), the pH was adjusted to neutral, the organic layer was collected, the organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. The solvent was evaporated to dryness, and 210 g of a yellow solid was obtained, which was Intermediate III. Calculated yield: 89% |
Tags: 58113-30-7 synthesis path| 58113-30-7 SDS| 58113-30-7 COA| 58113-30-7 purity| 58113-30-7 application| 58113-30-7 NMR| 58113-30-7 COA| 58113-30-7 structure
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H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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