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2-Chloro-1-(4-fluorobenzyl)benzimidazole is an intermediate.
Synonyms: 2-Chloro-1-(4-fluorobenzyl)benzimidazole
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Batch number can be found on the product's label following the word 'Batch'.
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CAS No. : | 84946-20-3 |
Formula : | C14H10ClFN2 |
M.W : | 260.69 |
SMILES Code : | FC1=CC=C(C=C1)CN2C(Cl)=NC3=CC=CC=C23 |
Synonyms : |
2-Chloro-1-(4-fluorobenzyl)benzimidazole
|
MDL No. : | MFCD00800240 |
InChI Key : | PGXALMVNIRPELS-UHFFFAOYSA-N |
Pubchem ID : | 3020241 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
With sodium hydroxide; In water; | Step B: 2-chloro 1-(4 fluorobenzyl) benzimidazole 11 g 2-chlorobenzimidazole are dissolved in 74 ml water and 17.35 ml 30% sodium hydroxide. The mixture is heated to 82 C. and to this they are slowly added 23.76 g 4-fluorobenzyl chloride within 5 hours. When the reaction is achieved, the solution is cooled to 20 C. and extracted with methylene chloride. The compound is recrystallized from ethyl acetate. | |
With potassium iodide; sodium carbonate; In chloroform; N,N-dimethyl-formamide; | EXAMPLE 8 A mixture of 60 parts of 2-chloro-1H-benzimidazole, 58 parts of 1-(chloromethyl)-4-fluorobenzene, 42.5 parts of sodium carbonate, 0.1 parts of potassium iodide and 135 parts of N,N-dimethylformamide was stirred and heated overnight at 70 C. The reaction mixture was poured into water. The precipitated product was filtered off and dissolved in trichloromethane. The solution was dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 62.5 parts of 2-chloro-1-(4-fluorophenylmethyl)-1H-benzimidazole (61). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | In N,N-dimethyl acetamide; at 155℃; for 68h;Inert atmosphere; | Compound 3 (0.38 mmol, 100 mg) was dissolved in dimethylacetamide (3 mL), followed by addition of ethyl 4-aminopiperidinecarboxylate (3.8 mmol, 0.65 mL). The reaction mixture was stirred at 155 C in a silicone oil bath for 68 hours and then cooled to room temperature. The reaction mixture was then diluted with ethyl acetate and poured into a 50% saturated brine solution and then extracted with dichioromethane. The crude product was purified by column chromatography on silica gel (hexnne/ethyl acetate; 10:90) to afford Compound 4 (69.5 mg, 45%) as a yellow solid. [00124] 1H NMR (500 MHz, Methanol-d4 σ 7.35 - 7.26 (m, 1 H), 7.15 - 7.09 (m, 2H), 7.06 - 6.98 (m, 4H), 6.93 (ddd, J = 8.1 , 7.3, 1 .1 Hz, 1 H), 5.22 (s, 2H), 4.10 (qd, J = 7.0, 4.0 Hz, 4H), 3.95 (it, J = 11.0, 4.0 Hz, 2H), 2.98 (s, 1 H), 2.10 - 1.98 (m, 2H), 1.45 (dd, J = 11.9, 4.2 Hz, 2H), 1.24 (td, J = 7.1 , 3.3 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) σ 163.56 (d, J = 244.6 Hz), 157.19, 155.18, 142.92, 135.30, 133.75, 129.56, 122.50, 120.86, 116.52, 116.35, 116.08, 109.13, 62.70, 51.43, 45.24, 44.10, 33.11 , 14.96. IR (neat): 3275, 1694, 1220 cm'1, m/z: [(M+H)+ ] calcd for (C22H26FNO2) 397.2040; Found 397.2070. mp 120-123 C. |
45% | In N,N-dimethyl acetamide; at 155℃; for 68h;Inert atmosphere; | Compound 3 (0.38 mmol, 100 mg) was dissolved in dimethylacetamide (3 mL), followed by addition of ethyl 4-aminopiperidinecarboxylate (3.8 mmol, 0.65 mL). The reaction mixture was stirred at 155 C in a silicone oil bath for 68 hours and then cooled to room temperature. The reaction mixture was then diluted with ethyl acetate and poured into a 50% saturated brine solution and then extracted with dichioromethane. The crude product was purified by column chromatography on silica gel (hexnne/ethyl acetate; 10:90) to afford Compound 4 (69.5 mg, 45%) as a yellow solid. [00124] 1H NMR (500 MHz, Methanol-d4 σ 7.35 - 7.26 (m, 1 H), 7.15 - 7.09 (m, 2H), 7.06 - 6.98 (m, 4H), 6.93 (ddd, J = 8.1 , 7.3, 1 .1 Hz, 1 H), 5.22 (s, 2H), 4.10 (qd, J = 7.0, 4.0 Hz, 4H), 3.95 (it, J = 11.0, 4.0 Hz, 2H), 2.98 (s, 1 H), 2.10 - 1.98 (m, 2H), 1.45 (dd, J = 11.9, 4.2 Hz, 2H), 1.24 (td, J = 7.1 , 3.3 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) σ 163.56 (d, J = 244.6 Hz), 157.19, 155.18, 142.92, 135.30, 133.75, 129.56, 122.50, 120.86, 116.52, 116.35, 116.08, 109.13, 62.70, 51.43, 45.24, 44.10, 33.11 , 14.96. IR (neat): 3275, 1694, 1220 cm'1, m/z: [(M+H)+ ] calcd for (C22H26FNO2) 397.2040; Found 397.2070. mp 120-123 C. |
34% | at 180℃; for 0.0166667h;Microwave irradiation; | A mixture of intermediate 1(. 5 g, 1.9 mmol) and 4-amino-1-ethoxycarbonylpiperidine as a colorless oil (0.495 g, 2.8 mmol) was added to the microwave tube, stirred uniformly, microwave 180 C reaction 1min, cooled to room temperature, reddish brown solid, with methanol 15mL and dichloromethane 5mL dissolved after mixing, the column was purified to obtain a white solid, The yield was 34.0% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In isoamylic alcohol; for 48h;Heating / reflux; | EXAMPLE 4 8-[1-(4-Fluorobenzyl)-1H-benzimidazol-2-yl]-1,4-dioxa-8-azaspiro[4.5]decane (2) A mixture formed by 50 g of 2-chloro-1-(4-fluorobenzyl)benzimidazol, 41 g of 1,4-dioxa-8-azaspiro[4.5]decane and 84 mL of diisopropylethylamine in 350 mL of isoamylic alcohol is heated under reflux for 48 hours. Once the reaction has finished, 175 mL of solvent are distilled and slowly cooled to a temperature of 0-5C so that a white solid precipitates. The precipitate produced is filtered and washed with 75 mL of cold isoamylic alcohol, and is dissolved again in 250 mL of water and 250 mL of ethyl acetate. It is stirred, and the organic phase is isolated by decanting. The product is isolated by removing the solvent under reduced pressure, obtaining 60 g of 8-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-1,4-dioxa-8-azaspiro[4.5]decane (2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isoamylic alcohol; for 12h;Heating / reflux; | EXAMPLE 2 1-[1-(4-Fluorobenzyl)-1H-benzimidazol-2-yl]-4-hydroxypiperidine (3) A mixture of 3.9 g of 4-hydroxypiperidine, 5 g of 2-chloro-1-(4-fluorobenzyl)-benzimidazol in 30 mL of isoamylic alcohol is taken to reflux for 12 hours. Once the reaction has finished, the product is isolated by removal of the solvent under reduced pressure and redissolving the residue in 15 mL of ethyl acetate and 15 mL of water. The organic phase is decanted, and the aqueous phase is extracted again with 7 mL of ethyl acetate. The organic phases are brought together and the solvent is removed. The obtained residue is crystallized in toluene, obtaining 3.7 g of 1-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-hydroxypiperidine (3). 13C-NMR (CDCl3, δ in ppm): 34.17 (CH2), 47.05 (CH2), 48.64 (CH2), 67.04 (CH), 109.27 (CH), 143.40 (C), 163.37 (C). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 150℃; for 2h;Microwave; | Example 4; A/-[3-(1-{3-[1-(4-Fluoro-benzyl)-1H-benzoimidazol-2-ylamino]-propyl}-piperidin-4-yl)-phenyl]-acetamide; 2-Chloro-1-(4-fluoro-benzyl)-1H-benzoimidazole (58 mg, 0.22 mmol) and A/-{3-[1-(3-Amino-propyl)-piperidin-4-yl]-phenyl}-acetamide (Example 1 Step 2, 90 mg, 0.33mmol) were mixed in ethanol (1 ml) and heated in the micro wave at 150 C for 2h.The reaction was extracted with dichloromethane and Na2CO3(aq) and the combinedorganic phases was dried over Na2SO4, filtered, and evaporated giving the crudeproduct which was purified by chromatography (silica,dichloromethane/methanol/ammoniac, 9:1:1%) giving the title compound Example 4.1H-NMR (300 MHz, CDCI3); 8 7.5.1 (d, 1H), 7.38 (s, 1H), 7.10-7.31 (m, 6H), 6.92-7.02(m, 4H), 6.79 (d, 1H), 6.61 (br s, 1H), 5.17 (s, 2H), 3.71 (t, 2H), 3.14 (d, 2H), 2.62 (t,2H), 2.48-2.61 (m, 1H), 2.21 (s, 3H) 2.06-2.15 (m, 2H), 1.91-2.00 (m, 2H), 1.65-1.86(m, 4H).LCMS: Rt 3.48 min, m/z 499.6 [M+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.85 g (65%) | In water; N,N-dimethyl-formamide; | EXAMPLE B8 (+-)-cis-1-(3,5-dimethylbenzoyl)-2-(phenylmethyl)-4-piperidinol (2.6 g) dissolved in N,N-dimethylformamide (100 ml) was stirred under N2. Sodium hydride (60%) (0.36 g) was added and the mixture was stirred at 40 C. for 1 hour. <strong>[84946-20-3]2-Chloro-1-[(4-fluorophenyl)-methyl]-1H-benzimidazole</strong> (2.6 g) was added and the mixture was stirred at 60 C. for 20 hours. The solvent was evaporated and the residue was taken up in water and CH2 Cl2. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2 Cl2 /CH3 OH 97/3). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE, yielding 2.85 g (65%) of (+-)-cis-1-(3,5-dimethylbenzoyl)-4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]oxy]-2-(phenylmethyl)piperidine (comp. 70; mp. 154.1 C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-methyl-pyrrolidin-2-one; sodium hydroxide; In tetrahydrofuran; | EXAMPLE 42 To a 25 mL 3-neck flask equipped with a thermometer, reflux consenser and stir bar were added, under a nitrogen atmosphere, 885.6 mg (4.8 mmol) of Compound XXII, obtained according to the procedure of Example 41, and 0.93 mL (8.0 mmol) of lutidine. The mixture was heated to 120 C., whereupon a solution of 1.04 g (4 mmol., 1 eq.) of Compound X (Aldrich Chemical Co., Milwaukee, Wis.), 8 mmol of tetrabutylammonium fluoride (obtained from its 1.0M THF solution by distillation under vacuum with anhydrous toluene) and 4 mL of N-methylpyrrolidinone was added slowly over 2 h. The reaction mixture was allowed to stir at 120 C. for 1 h. High-performance liquid chromatography revealed >95% coversion to Compound XXIII. The reaction mixture was allowed to cool to ambient temperature, and slowly poured into a solution of 5% aqueous NaOH while stirring. The resulting suspension was allowed to stir at 0-10 C. for 30 minutes, and the resulting solid product was collected by vacuum filtration, washed with water (3*5 mL), and air dried for 30 minutes under vacuum to afford crude Compound XXIII: 1 H NMR (300 MHz, CDCl3) δ7.52 (1H, d, J=7.8 Hz), 7.20-7.00 (7H, m, two groups), 5.13 (2H, s), 4.40 (1H, NH br. d), 4.32 (2H, pseudo d), 4.20 (1H, m), 3.00 (2H, pseudo t), 2.15 (2H, pseudo d), 1.30 (2H, m overlapped), 1.26 (9H, s); 13 C NMR (75 MHz, CDCl3) δ176.3, 164.2 and 161.0 (13 C-19 F coupling), 153.3, 142.4, 134.6, 131.4, 128.4, 121.7, 120.0, 116.6, 116.4, 116.1, 107.5, 50.5, 45.1, 44.2, 38.9, 33.1, 28.6. It is to be noted that under the same reaction conditions as above, but without the use of tetrabutylammonium fluoride, only 3.5% conversion (high-performance liquid chromatography) to Compound XXIII was achieved after 3 h at 120 C. The Compound XXIII obtained above was placed in a 50 mL, 3-neck flask equipped with a thermometer, reflux condenser and stir bar. 5 mL of 48% hydrobromic acid was added, and the resulting mixture was heated to 110 C. and allowed to stir at that temperature for 2 h. After the reaction was complete (>98% conversion to norastemizole as shown by high-performance liquid chromatography), the reaction mixture was allowed to cool to room temperature, and 10 mL of toluene and 10 mL of water were added, with stirring. | |
With 1-methyl-pyrrolidin-2-one; sodium hydroxide; In tetrahydrofuran; | EXAMPLE 43 Norastemizole. To a 25 mL 3-neck flask equipped with a thermometer, ref lux consenser and stir bar were added, under a nitrogen atmosphere, 822 mg (4.8 mmol) of Compound XVI, obtained according to the procedure of Example 6, and 0.93 mL (8.0 mmol) of lutidine. The mixture was heated to 120 C., whereupon a solution of 1.04 g (4 mmol., 1 eq.) of Compound X (Aldrich Chemical Co., Milwaukee, Wis.), 8 mmol of tetrabutylammonium fluoride (obtained from its 1.0M THF solution by distillation under vacuum with anhydrous toluene) and 4 mL of N-methylpyrrolidinone was added slowly over 2 h. The reaction mixture was allowed to stir at 120 C. for 2 h. High-performance liquid chromatography revealed >95% coversion to Compound XVIII. The reaction mixture was allowed to cool to ambient temperature, and slowly poured into a solution of 5% aqueous NaOH while stirring. The resulting suspension was allowed to stir at 0-10 C. for 30 minutes, and the resulting solid product was collected by vacuum filtration, washed with water (3*5 mL), and air dried for 30 minutes under vacuum to afford a crude mixture of Compound XVIII and 6% (HPLC) of migration product Compound XIX. NMR data for Compound XVIII: 1 H NMR (300 MHz, DMSO-d6) δ7.30-7.02 (6H, m two groups), 6.95 (1H, pseudo t, J=7.8, 2.3 Hz), 6.85 (1H, pseudo t, J=7.8, 2.3 Hz), 5.35 (2H, s), 4.33 (1H, pseudo d), 4.02 (1H, m), 3.83 (1H, pseudo d), 3.17 (1H, pseudo t), 2.75 (1H, pseudo t), 2.02 (3H, s), 2.0 (2H, m overlapped), 1.45 (2H, m); 13 C NMR (75 MHz, DMSO-d6) δ168.0, 163.0 and 159.7 (13 C-19 F coupling), 153.9, 142.8, 134.3, 133.5, 129.1, 129.0, 128.2, 120.5, 118.4, 115.5, 115.2, 107.9, 44.8, 43.7, 32.3, 31.5, 21.4. It is to be noted that under the same reaction conditions as above, but without the use of tetrabutylammonium fluoride, only 4.9% conversion (high-performance liquid chromatography) to Compound XVIII was achieved after 3 h at 120 C. In addition, without the use of tetrabutylammonium fluoride, the ratio of Compound XVIII:Compound XIX was 4:1. The mixture of Compound XVIII obtained above was placed in a 50 mL, 3-neck flask equipped with a thermometer, reflux condenser and stir bar. 5 mL of 6N hydrochloric were added, and the resulting mixture was heated to 110 C. and allowed to stir at that temperature for 5 h. After the reaction was complete (>98% conversion to norastemizole as shown by high-performance liquid chromatography), the reaction mixture was allowed to cool to room temperature, and 10 mL of toluene and 10 mL of water were added, with stirring. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,3-Lutidine; 1-methyl-pyrrolidin-2-one; sodium hydroxide; In tetrahydrofuran; | EXAMPLE 8a To a 25 mL 3-neck flask equipped with a thermometer, reflux consenser and stir bar were added, under a nitrogen atmosphere, 822 mg (4.8 mmol) of Compound XII (Lancaster Synthesis, Inc., Windham, N.H.), and 0.93 mL of lutidine. The mixture was heated to 120 C., whereupon a solution of 1.04 g (4 mmol., 1 eq.) of Compound X (Aldrich Chemical Co., Milwaukee, Wis.), 8 mmol of tetrabutylammonium fluoride (obtained from its 1.0M THF solution by distillation under vacuum with anhydrous toluene) and 4 mL of N-methylpyrrolidinone was added slowly over 2 h. The reaction mixture was allowed to stir at 120 C. for 1 h. High-performance liquid chromatography revealed >95% coversion to Compound XIVa (in free base form). The reaction mixture was allowed to cool to ambient temperature, and slowly poured into a solution of 5% aqueous NaOH while stirring. The resulting suspension was allowed to stir at 0-10 C. for 30 minutes, and the resulting solid product was collected by vacuum filtration, washed with water (3*5 mL), and air dried for 30 minutes under vacuum to afford crude Compound XIVa (in free base form): 1 H NMR (300 MHz, CDCl3) δ7.53 (1H, d, J=7.8 Hz), 7.22-6.92 (7H, m, two groups), 5.12 (2H, s), 4.37 (1H, NH br. d), 4.12 (2H+1H, m overlapped), 4.07 (2H, q, J=7.0 Hz), 2.98 (2H, pseudo t), 2.09 (2H, pseudo d), 1.30 (2H, m overlapped), 1.24 (3H, t, J=7.0 Hz); 13 C NMR (75 MHz, CDCl3) δ164.2 and 161.0 (13 C-19 F coupling), 155.6, 153.3, 142.2, 134.5, 131.4, 128.3, 121.8, 120.0, 116.6, 116.3, 116.1, 107.5, 61.5, 50.1, 45.0, 42.8, 32.6, 14.8. It is to be noted that under the same reaction conditions as above, but without the use of tetrabutylammonium fluoride, only 5% conversion (high-performance liquid chromatography) to Compound XIVa (in free base form) was achieved after 3 h at 120 C. The crude Compound XIVa (in free base form) obtained above was placed in a 50 mL, 3-neck flask equipped with a thermometer, reflux condenser and stir bar. 5 mL of 48% hydrobromic acid was added, and the resulting mixture was heated to 110 C. and allowed to stir at that temperature for 2 h. After the reaction was complete (>98% conversion to norastemizole as shown by high-performance liquid chromatography), the reaction mixture was allowed to cool to room temperature, and 10 mL of toluene and 10 mL of water were added, with stirring. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thiourea; In ethanol; di-isopropyl ether; | EXAMPLE 9 A mixture of 8.35 parts of thiourea, 26 parts of 2-chloro-1-[(4-fluorophenyl)methyl]-1H-benzimidazole and 400 parts of ethanol was stirred and refluxed for 5 hours. The reaction mixture was evaporated. The residue was suspended in 2,2'-oxybispropane. The precipitated product was filtered off and crystallized from ethanol, yielding 6.1 parts of 1-[(4-fluorophenyl)methyl]-1H-benzimidazole-2-thiol; mp. 194.7 C. (62). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium iodide; In methanol; water; | EXAMPLE 38 A mixture of 4 parts of 2-chloro-1-[(4-fluorophenyl)methyl]-1H-benzimidazole, 6.1 parts of N-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]-[1,4'-bipiperidine]-4-amine and 1 part of potassium iodide was stirred and heated for 3 hours at 130 C. The reaction mixture was cooled and taken up in water and trichloromethane. The whole was alkalized with potassium carbonate. The organic phase was separated, dried, filtered and evaporated. The residue was purified by HPLC using a mixture of trichloromethane and methanol (98:2 by volume), saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1.6 parts of 1-[(4-fluorophenyl)methyl]-N-[1'-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]-[1,4'-bipiperidin]-4-yl]-1H-benzimidazol-2-amine monohydrate; mp. 130.2 C. (compound 65). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.5 parts (31.5%) | In N,N-dimethyl-formamide; | EXAMPLE 20 To a stirred mixture of 3.5 parts of ethyl 4-hydroxy-1-piperidinecarboxylate and 135 parts of N,N-dimethylformamide was added 1 part of a sodium hydride dispersion 50% and stirring was continued for 2 hours at room temperature. After the addition of 5.2 parts of 2-chloro-1-[(4-fluorophenyl)methyl]-1H-benzimidazole, the whole was further stirred overnight at room temperature. The reaction mixture was poured into ice water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 2.5 parts (31.5%) of ethyl 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]oxy]-1-piperidinecarboxylate; mp. 94.0 C. (26). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In i-Amyl alcohol; water; Petroleum ether; | 1.2. 1-{1-[(4-Fluorophenyl)methyl]-1H-benzimidazol-2-yl}-N-methyl-4-piperidinamine (method B) 8.7 g (0.05 mole) of 4-methylaminopiperidine (in the form of acetate), 13 g (0.05 mole) of 1-(4-fluorobenzyl)-2-chlorobenzimidazole and 13.8 g (0.1 mole) of potassium carbonate in 250 ml of isoamyl alcohol are brought to reflux temperature for 192 h. The mixture is cooled and evaporated to dryness. The residue is taken up with a mixture of water and ether and agitated until crystallization occurs. The compound (V) obtained in hydrate form is filtered off. The precipitate is taken up with toluene and agitated until dissolution has occurred, and the solution is dried with magnesium sulphate, filtered and evaporated. The residual oil is ground in petroleum ether. The solid product is filtered off and dried. The compound thereby obtained melts at 77-80 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.1 parts (40.5%) | With sodium hydroxide; In water; | Example 4 A mixture of 9.8 parts of ethyl 4-amino-1-piperidinecarboxylate and 15 parts of 2-chloro-1-(4-fluorophenylmethyl)-1H-benzimidazole was heated to 120 C. The mixture was stirred at 120 C. during 43 hours. After cooling, 100 parts of trichloromethane were added and the whole was thouroughly stirred. The mixture was washed with water. The aqueous layer was separated and the organic mixture was filtered and evaporated. The collected solid material was dissolved in 100 parts of water and subsequently 100 parts of 20% sodium hydroxide solution were added. The precipitate was filtered and dried in vacuo at 50 C., yielding 12.1 parts (40.5%) of ethyl 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate; mp. 181 C. (compound 21). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; sodium methylate; In methanol; | 1.1.1. 19 g (0.09 mole) of ethyl 4-piperidylcarbamate hydrochloride is solubilized in 120 ml of methanol and neutralized with 17.2 ml of 5.3N sodium methylate. The mixture is filtered and the filtrate evaporated to dryness. The evaporation residue is then mixed with 21.6 g (0.083 mole) of 2-chloro-1-[(4-fluorophenyl)methyl]-1H-benzimidazole and heated to 140 C. for 5 hours. The reaction mass is taken up with methylene chloride and alkalinized with 2N sodium hydroxide. The organic phase is washed with water, dried, filtered and evaporated. The oil obtained is chromatographed on silica (eluent: methylene chloride/methanol, 97.5:2.5). Ethyl[1-{1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl}-4-piperidyl]carbamate is obtained. M.p. 136 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium tetrahydroborate; N,N,N,N,-tetramethylethylenediamine; In tetrahydrofuran; at 25℃; for 22h;Inert atmosphere; | General procedure: PdCl2(dppf), PdCl2(tbpf) and (A.caPhos)PdCl2. A mixture of the halogenated heterocycle (0.66 mmol) in anhydrous THF (13.2 mL) was degassed by bubbling argon for few minutes. Then, PdCl2(dppf) (27.0 mg, 0.033 mmol, 5.0 mol%), TMEDA (0.130 g, 1.12 mmol, 1.7 equiv) and finally NaBH4 (42.4 mg, 1.12 mmol, 1.7 equiv) were introduced in sequence. The mixture was stirred at room temperature under argon for the proper time and then worked up as described above. |
Yield | Reaction Conditions | Operation in experiment |
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at 150℃; for 0.5h;Microwave irradiation; | General procedure: A mixture of 1d (1.0 eq.) and ethanolamine (10 eq.) was heated to 150 C for 30 min by use of microwave irradiation. After the reaction was completed, the reaction mixture was cooled down to room temperature. The precipitated solid was filtered and washed with diethyl ether. The crude product was purified by flash column chromatography (MeOH/methylene chloride) to give desired product 1e. | |
at 150℃; for 0.5h;Microwave irradiation; | General procedure: A mixture of 1d (1.0 eq.) and ethanolamine (10 eq.) was heated to 150 C for 30 min by use of microwave irradiation. After the reaction was completed, the reaction mixture was cooled down to room temperature. The precipitated solid was filtered and washed with diethyl ether. The crude product was purified by flash column chromatography (MeOH/methylene chloride) to give desired product 1e. |