* 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.
Polyphosphoric acid (20 g, excess) was place in a beaker and heated to 90oC. 4-(4-chlorophenyl)butanoic acid (Preparation example 31, 3 g, 17 mmol) was added in portions. The mixture was stirred for 5 min an additional portion of polyphosphoric acid (20 g, excess) was added and heated to 90oC for 5 min. The thick, homogenous viscous orange oil was cooled to 60oC before water was added. When the reaction was completed, the mixture was cooled to room temperature and extracted with EtOAc. The organic layer was washed with water, 1N NaOH and water, dried over MgSO4, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to give as a white solid (2.5 g, 81 percent).1H NMR (400 MHz, CDCl3) δ 2.12-2.18 (m, 2H), 2.67 (t,J= 6.8, 2H), 2.95 (t,J= 6.8, 2H), 7.22 (d,J= 8.0, 1H), 7.42 (dd,J= 10.2, 2.4, 1H), 7.85 (d,J= 2.4, 1H).
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 41, p. 12476 - 12480[2] Angew. Chem., 2017, vol. 129, p. 12650 - 12654,5
[3] Journal of Medicinal Chemistry, 2009, vol. 52, # 21, p. 6768 - 6781
[4] Patent: WO2017/150904, 2017, A1, . Location in patent: Paragraph 312-314
[5] Synthetic Communications, 1991, vol. 21, # 8-9, p. 981 - 987
[6] Advanced Synthesis and Catalysis, 2018, vol. 360, # 15, p. 2894 - 2899
[7] Journal of the Chemical Society, 1950, p. 1027,1032
[8] Phytochemistry (Elsevier), 1984, vol. 23, # 2, p. 313 - 318
[9] Australian Journal of Chemistry, 2010, vol. 63, # 2, p. 211 - 226
2
[ 4619-18-5 ]
[ 26673-32-5 ]
[ 529-34-0 ]
Reference：
[1] Patent: US5492905, 1996, A,
[2] Patent: US5502048, 1996, A,
3
[ 3984-34-7 ]
[ 4619-18-5 ]
Yield
Reaction Conditions
Operation in experiment
96%
With potassium hydroxide; hydrazine hydrate In dichloromethane; water; diethylene glycol
4-(p-chlorophenyl)butanoic acid (34a) A mixture of 3-(4-chlorobenzoyl) propionic acid (33) (2.50 g, 12.0 mmol), KOH (s) (1.75 g, 31.2 mmol), and hydrazine monohydrate (1.25 mL, 25.8 mmol) in 12.5 mL of diethylene glycol was refluxed azeotropically at 120-130° C. for 90 min to remove water. The reaction mixture was then refluxed at 170° C. for 3 h, cooled to RT, diluted with 12.5 mL of water, and poured into 15 mL 2.5 N HCl(aq). The precipate was filtered off, dissolved in CH2Cl2, and the solvent removed to give 34a (2.23 g, 96percent) as a white solid. UV λmax 223 (8980, 95percent ETHANOL); 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J=7 Hz, 2H), 7.12 (d, J=8 Hz, 2H), 2.66 (t, J=4 Hz, 2H), 2.38 (t, J=4 Hz, 2H), 1.96 (m, 2H); 13C NMR (CDCl3) δ 179.3, 140.0, 132.2, 130.2, 128.9, 34.7, 33.4, 26.4; IR (drift) 3063 (s), 3051 (s), 2955 (s), 2923 (s,b), 2905 (s), 2814, 2797, 2493 (b), 2466, 2413, 2367 (b), 2321, 1706 (s), 1492 (s), 1212 (s), cm-1; MS (El) m/z (rel. intensity) 198 (M+, 22), 200 (7), 198 (22), 140 (32), 139 (17), 138 (99), 127 (15), 125 (48), 103 (10), 89 (13), 60 (9); HRMS (EI) calcd for 198.0448, found 198.0441.
89%
With potassium hydroxide; hydrazine In ethylene glycol at 120 - 190℃; for 8 h; Heating / reflux
A mixture of 4-(4-chlorophenyl)4-oxobutanoic acid (1 eq.), KOH (3 eq.) and hydrazine hydrate (2.2 eq.) in ethylene glycol was refluxed azeotropically at 120-130° C. for 5 hours, the temperature was increased gradually to 180° C. Heating under reflux was then continued at 190° C. for 3 hours. The reaction mixture was cooled to 25° C., diluted with water and poured into a solution 2.5N HCl to give white crystals of 4-(4-chlorophenyl)butanoic acid (89percent).
89%
With hydrazine hydrate; potassium hydroxide In diethylene glycol at 120 - 200℃; for 5 h; Dean-Stark
4-(4-Chlorophenyl)butanoic acid: 4-(4-Chlorophenyl)-4-oxobutanoic acid (1.06 g, 5 mmol) and KOH (85percent by wt, 0.79 g, 12 mmol) were placed in a round-bottomed flask fitted with a Dean-Stark apparatus and a reflux condenser and suspended in diethylene glycol (10 mL) at RT. Then, hydrazine monohydrate (50percent by wt., 1.20 g, 12 mmol) was added slowly to the reaction at RT after which it was heated to 120- 130 °C for 2 h. The reaction became homogenous after heating for approximately 45 min. After 2 h, the temperature was increased to 180-200 °C and the reaction stirred for an additional 3 h to remove residual hydrazine and water via the Dean-Stark trap. The reaction was then cooled to RT, diluted with H20 (10 mL), and poured into a 2.5 N aqueous solution of HQ (20 mL). The suspension was cooled in an ice bath and the resulting precipitate was isolated by filtration. To remove residual diethylene glycol, the solid was dissolved in a saturated aqueous solution of K2CO3 (20 mL), diluted with H20 (20 niL), and poured into a 2.5 N aqueous solution of HC1 (20 mL). The suspension was again cooled in an ice bath and the precipitate isolated by filtration, washed with cold H20 (2x 15 mL), and dried under vacuum. The title compound was isolated as a white solid (0.89 g, 89percent). NMR (500 MHz, DMSO- d6): δ 12.06 (br, 1H), 7.32 (d, J= 8.5 Hz, 2H), 7.21 (d, J= 8.5 Hz, 2H), 2.57 (t, J= (0563) 7.4 Hz, 2H), 2.20 (t, J= 7.3 Hz, 2H), 1.77 (q, J= 7.5 Hz, 2H). 13C NMR (125 MHz, DMSO-i/6): δ 174.16, 140.57, 130.41, 130.17, 128.20, 33.63, 32.95, 26.1 1. ESI- LRMS: [M-H]- = m/z 284.3. ESI-HRMS: calcd. for C10H1 1C102: [M-H]- = m/z 197.0375, found: [M-H]- = m/z 197.0379.
79%
With hydrazine hydrate; potassium hydroxide In diethylene glycol at 120 - 180℃; for 4.5 h; Dean-Stark
A heterogeneous mixture of 3-(4-chlorobenzoyl)-propionic acid (20 g, 188.1 mmol), potassium hydroxide (11.7 g, 208.7 mmol), hydrazine monohydrate (10 mL, 205.1 mmol), and diethylene glycol (84 mL) were heated in a flask equipped with a Dean-Stark trap and condenser. The mixture became homogeneous on heating. The mixture maintained at 120-130oC for 1.5 h and raised to 180oC for 3 h. The reaction mixture was cooled to room temperature, diluted with water and added 2.5M HCl. The mixture was allowed to stand for 16 h and the white solid collected by filtration. To remove the residual diethylene glycol, the solid dissolved in sat. K2CO3and water. The clear solution was poured into stirred 2.5M HCl. White solid was collected by filtration, washed with water (30.0 g, 79 percent).1H NMR (400 MHz, CDCl3) δ 2.12 -2.14 (m, 2H), 2.37 (t,J= 9.0, 2H), 2.56 (t,J= 6.0, 2H), 7.12 (s, 2H), 7.26 (s, 2H).
Reference：
[1] Patent: US6410585, 2002, B1,
[2] Journal of Medicinal Chemistry, 1982, vol. 25, # 8, p. 947 - 952
[3] Patent: US2005/165004, 2005, A1, . Location in patent: Page/Page column 28
[4] Patent: WO2015/134973, 2015, A1, . Location in patent: Page/Page column 97; 98
[5] Angewandte Chemie - International Edition, 2017, vol. 56, # 41, p. 12476 - 12480[6] Angew. Chem., 2017, vol. 129, p. 12650 - 12654,5
[7] Journal of Medicinal Chemistry, 2013, vol. 56, # 23, p. 9427 - 9440
[8] Journal of Medicinal Chemistry, 2009, vol. 52, # 21, p. 6768 - 6781
[9] Patent: WO2017/150904, 2017, A1, . Location in patent: Paragraph 309-311
[10] Justus Liebigs Annalen der Chemie, 1928, vol. 462, p. 147
[11] Patent: US5492905, 1996, A,
[12] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 20, p. 5586 - 5590
[13] Australian Journal of Chemistry, 2010, vol. 63, # 2, p. 211 - 226
[14] Chemical Communications, 2016, vol. 52, # 56, p. 8757 - 8760
[15] Advanced Synthesis and Catalysis, 2018, vol. 360, # 15, p. 2894 - 2899
[16] Patent: US5502048, 1996, A,
Polyphosphoric acid (20 g, excess) was place in a beaker and heated to 90oC. 4-(4-chlorophenyl)butanoic acid (Preparation example 31, 3 g, 17 mmol) was added in portions. The mixture was stirred for 5 min an additional portion of polyphosphoric acid (20 g, excess) was added and heated to 90oC for 5 min. The thick, homogenous viscous orange oil was cooled to 60oC before water was added. When the reaction was completed, the mixture was cooled to room temperature and extracted with EtOAc. The organic layer was washed with water, 1N NaOH and water, dried over MgSO4, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to give as a white solid (2.5 g, 81 %).1H NMR (400 MHz, CDCl3) delta 2.12-2.18 (m, 2H), 2.67 (t,J= 6.8, 2H), 2.95 (t,J= 6.8, 2H), 7.22 (d,J= 8.0, 1H), 7.42 (dd,J= 10.2, 2.4, 1H), 7.85 (d,J= 2.4, 1H).
4-(4.chlorophenyl)butanoic acid (1.6 eq.) was dissolved in SOCl2 and refluxed under nitrogen for 4 hours. Then the remaining SOCl2 was evaporated and the residue dissolved in DMF (dry).
With potassium hydroxide; hydrazine hydrate; In dichloromethane; water; diethylene glycol;
4-(p-chlorophenyl)butanoic acid (34a) A mixture of 3-(4-chlorobenzoyl) propionic acid (33) (2.50 g, 12.0 mmol), KOH (s) (1.75 g, 31.2 mmol), and hydrazine monohydrate (1.25 mL, 25.8 mmol) in 12.5 mL of diethylene glycol was refluxed azeotropically at 120-130 C. for 90 min to remove water. The reaction mixture was then refluxed at 170 C. for 3 h, cooled to RT, diluted with 12.5 mL of water, and poured into 15 mL 2.5 N HCl(aq). The precipate was filtered off, dissolved in CH2Cl2, and the solvent removed to give 34a (2.23 g, 96%) as a white solid. UV lambdamax 223 (8980, 95% ETHANOL); 1H NMR (400 MHz, CDCl3) delta 7.26 (d, J=7 Hz, 2H), 7.12 (d, J=8 Hz, 2H), 2.66 (t, J=4 Hz, 2H), 2.38 (t, J=4 Hz, 2H), 1.96 (m, 2H); 13C NMR (CDCl3) delta 179.3, 140.0, 132.2, 130.2, 128.9, 34.7, 33.4, 26.4; IR (drift) 3063 (s), 3051 (s), 2955 (s), 2923 (s,b), 2905 (s), 2814, 2797, 2493 (b), 2466, 2413, 2367 (b), 2321, 1706 (s), 1492 (s), 1212 (s), cm-1; MS (El) m/z (rel. intensity) 198 (M+, 22), 200 (7), 198 (22), 140 (32), 139 (17), 138 (99), 127 (15), 125 (48), 103 (10), 89 (13), 60 (9); HRMS (EI) calcd for 198.0448, found 198.0441.
89%
With potassium hydroxide; hydrazine; In ethylene glycol; at 120 - 190℃; for 8h;Heating / reflux;
A mixture of 4-(4-chlorophenyl)4-oxobutanoic acid (1 eq.), KOH (3 eq.) and hydrazine hydrate (2.2 eq.) in ethylene glycol was refluxed azeotropically at 120-130 C. for 5 hours, the temperature was increased gradually to 180 C. Heating under reflux was then continued at 190 C. for 3 hours. The reaction mixture was cooled to 25 C., diluted with water and poured into a solution 2.5N HCl to give white crystals of 4-(4-chlorophenyl)butanoic acid (89%).
89%
With hydrazine hydrate; potassium hydroxide; In diethylene glycol; at 120 - 200℃; for 5h;Dean-Stark;
4-(4-Chlorophenyl)butanoic acid: 4-(4-Chlorophenyl)-4-oxobutanoic acid (1.06 g, 5 mmol) and KOH (85% by wt, 0.79 g, 12 mmol) were placed in a round-bottomed flask fitted with a Dean-Stark apparatus and a reflux condenser and suspended in diethylene glycol (10 mL) at RT. Then, hydrazine monohydrate (50% by wt., 1.20 g, 12 mmol) was added slowly to the reaction at RT after which it was heated to 120- 130 C for 2 h. The reaction became homogenous after heating for approximately 45 min. After 2 h, the temperature was increased to 180-200 C and the reaction stirred for an additional 3 h to remove residual hydrazine and water via the Dean-Stark trap. The reaction was then cooled to RT, diluted with H20 (10 mL), and poured into a 2.5 N aqueous solution of HQ (20 mL). The suspension was cooled in an ice bath and the resulting precipitate was isolated by filtration. To remove residual diethylene glycol, the solid was dissolved in a saturated aqueous solution of K2CO3 (20 mL), diluted with H20 (20 niL), and poured into a 2.5 N aqueous solution of HC1 (20 mL). The suspension was again cooled in an ice bath and the precipitate isolated by filtration, washed with cold H20 (2x 15 mL), and dried under vacuum. The title compound was isolated as a white solid (0.89 g, 89%). NMR (500 MHz, DMSO- d6): delta 12.06 (br, 1H), 7.32 (d, J= 8.5 Hz, 2H), 7.21 (d, J= 8.5 Hz, 2H), 2.57 (t, J= (0563) 7.4 Hz, 2H), 2.20 (t, J= 7.3 Hz, 2H), 1.77 (q, J= 7.5 Hz, 2H). 13C NMR (125 MHz, DMSO-i/6): delta 174.16, 140.57, 130.41, 130.17, 128.20, 33.63, 32.95, 26.1 1. ESI- LRMS: [M-H]- = m/z 284.3. ESI-HRMS: calcd. for C10H1 1C102: [M-H]- = m/z 197.0375, found: [M-H]- = m/z 197.0379.
83%
With potassium hydroxide; hydrazine; In diethylene glycol; at 170℃; for 5h;
A solution of 4-(4-chlorophenyl)-4-oxobutanoic acid (50 g, 235 mmol, 1.0 eq.), hydrazine (9.78 g, 305 mmol, 1.3 eq.) and potassium hydroxide (34 g, 606 mmol, 2.6 eq.) in diethylene glycol (250 ml_) was heated at 170 C for 5 h, then cooled to room temperature and quenched by the addition of aqueous HCI (200 ml_). The resulting solution was diluted with H20 (100 ml_) and the pH of the solution was adjusted to 12 by the action of sodium hydroxide (2 M). The resulting mixture was extracted with CH2CI2 (3 c 200 ml_), then the combined organic layers were dried (Na2S04) and concentrated to give 39 g (83%) of 4-(4- chlorophenyl)butanoic acid as a yellow solid.
79%
With hydrazine hydrate; potassium hydroxide; In diethylene glycol; at 120 - 180℃; for 4.5h;Dean-Stark;
A heterogeneous mixture of 3-(4-chlorobenzoyl)-propionic acid (20 g, 188.1 mmol), potassium hydroxide (11.7 g, 208.7 mmol), hydrazine monohydrate (10 mL, 205.1 mmol), and diethylene glycol (84 mL) were heated in a flask equipped with a Dean-Stark trap and condenser. The mixture became homogeneous on heating. The mixture maintained at 120-130oC for 1.5 h and raised to 180oC for 3 h. The reaction mixture was cooled to room temperature, diluted with water and added 2.5M HCl. The mixture was allowed to stand for 16 h and the white solid collected by filtration. To remove the residual diethylene glycol, the solid dissolved in sat. K2CO3and water. The clear solution was poured into stirred 2.5M HCl. White solid was collected by filtration, washed with water (30.0 g, 79 %).1H NMR (400 MHz, CDCl3) delta 2.12 -2.14 (m, 2H), 2.37 (t,J= 9.0, 2H), 2.56 (t,J= 6.0, 2H), 7.12 (s, 2H), 7.26 (s, 2H).
With potassium hydroxide; hydrazine hydrate; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; 2,2'-[1,2-ethanediylbis(oxy)]bisethanol;
a. 4-(4-Chlorophenyl)butyric acid. 3-(4-Chlorobenzoyl)propionic acid (49.94 g) was dissolved in triethylene glycol (320 mL). To the stirred solution was added potassium hydroxide (44.5 g) followed by 98% hydrazine hydrate (29.0 g). The mixture was heated to reflux (142 C.) for 2 hours. Water and hydrazine hydrate were distilled at atmospheric pressure; the pot temperature rose to 195-200 C. After 0.5 hour at 195-200 C., the mixture was cooled to ambient temperature and diluted with water (320 mL). The aqueous solution was poured into 6N hydrochloric acid (200 mL) and further diluted with 200 mL of ice water. Upon standing, a solid formed which was filtered, washed (water) and dried under vacuum (25 C., 15 Pa) to afford the acid as a white solid (43.61 g).
With potassium hydroxide; hydrazine hydrate; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; 2,2'-[1,2-ethanediylbis(oxy)]bisethanol;
a. 4-(4-Chlorophenyl)butyric acid. 3-(4-Chlorobenzoyl)-propionic acid (49.94 g) was dissolved in triethylene glycol (320 mL). To the stirred solution was added potassium hydroxide (44.5 g) followed by 98% hydrazine hydrate (29.0 g). The mixture was heated to reflux (142 C.) for 2 hours. Water and hydrazine hydrate were distilled at atmospheric pressure; the pot temperature rose to 195-200 C. After 0.5 hour at 195-200 C., the mixture was cooled to ambient temperature and diluted with water (320 mL). The aqueous solution was poured into 6N hydrochloric acid (200 mL) and further diluted with 200 mL of ice water. Upon standing, a solid formed which was filtered, washed (water) and dried under vacuum (25 C. 15 Pa) to afford the acid as a white solid (43.61 g).
To a stirred solution of<strong>[4619-18-5]4-(4-chlorophenyl)butanoic acid</strong> (3.97 g, 20.0 mmol) and 1-hydroxybenzotriazole hydrate (3.37 g, 22.0 mmol) in Lambda/,Lambda/-dimethylformamide (40 mL) at ambient temperature was added solid l-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.21 g, 22 mmol). The resulting mixture was stirred at ambient temperature for 25 minutes, and a solution of ammonia in methanol (7M, 14.3 mL, 100 mmol) was added. After stirring at ambient temperature for a further 15 minutes, the reaction mixture was diluted with water (400 mL) and extracted with chloroform (100 mL). The organic layer was dried over sodium sulfate and concentrated. The residual oil was triturated with hexane to afford a solid, which was collected by filtration, washed with hexane, and dried under vacuum to afford 4-(4- chlorophenyl)butanamide as an off- white powder (2.40 g, 61% yield).
4-(p-chlorophenyl)butanamide (35a) A mixture of 34a (1.880 g, 10.1 mmol) and thionyl chloride (3.0 mL, 40.9 mmol) in 15 mL CHCl3 was stirred at reflux (75 C.) for 4 h. Solvent and excess thionyl chloride were removed in vacuo, and residue was twice diluted with 7.5 mL toluene and evaporated to remove traces of thionyl chloride. To a solution of the residue in 3 mL toluene was slowly added 9 mL of cold concentrated NH4OH. The precipitate was filtered off and recrystallized in CHCl3/heptane to give 35a (1.02 g, 55%) as a white solid. UV lambdamax 224 (9300, 95% ETHANOL). 1H NMR (400 MHz, CDCl3) delta 7.25 (d, J=8 Hz, 2H), 7.12 (d, J=8 Hz, 2H), 5.31 (s, 2H), 2.66 (t, J=8 Hz, 2H), 2.23 (t, J=7 Hz, 2H), 1.98 (m, 2H); 13C NMR (CDCl3) delta 175.4, 140.2, 134.5, 130.2, 128.9, 35.1, 34.8, 27.0; IR (drift) 3434, 2948, 2282 (w), 1901 (w), 1655 (s), 1607, 1491, 1420, 1306, 1094, 1016, 836 (s), 825, 804, 666, cm-1. Calcd for C10H12ClNO: C, 60.76; H, 6.12; N, 7.09; Cl, 17.94. Found: C, 60.60; H, 6.11; N, 6.96.
55%
With thionyl chloride; In chloroform; toluene;
4-(p-chlorophenyl)butanamide (36a). A mixture of 35a (1.880 g, 10.1 mmol) and thionyl chloride (3.0 mL, 40.9 mmol) in 15 mL CHCl3 was stirred at reflux (75 C.) for 4 h. Solvent and excess thionyl chloride were removed in vacuo, and residue was twice diluted with 7.5 mL toluene and evaporated to remove traces of thionyl chloride. To a solution of the residue in 3 mL toluene was slowly added 9 mL of cold concentrated NH4OH. The precipitate was filtered off and recrystallized in CHCl3/heptane to give 36a (1.02 g, 55%) as a white solid. UV lambdamax 224 (9300, 95% ETHANOL). 1H NMR (400 MHz, CDCl3) delta 7.25 (d, J=8 Hz, 2H), 7.12 (d, J=8 Hz, 2H), 5.31 (s, 2H), 2.66 (t, J=8 Hz, 2H), 2.23 (t, J=7 Hz, 2H), 1.98 (m, 2H); 13C NMR (CDCl3) delta 175.4, 140.2, 134.5, 130.2, 128.9, 35.1, 34.8, 27.0; IR (drift) 3434, 2948, 2282 (w), 1901 (w), 1655 (s), 1607, 1491, 1420, 1306, 1094, 1016, 836 (s), 825, 804, 666, cm-1. Calcd for C10H12ClNO: C, 60.76; H, 6.12; N, 7.09; Cl, 17.94. Found: C, 60.60; H, 6.11; N, 6.96.
8.70 g (97%)
With thionyl chloride; In diethyl ether; water;
(iii) 4-(4-Chlorophenyl)butyric acid amide A mixture of 8.8 g (44.3 mmole) of the saturated acid from Part (ii) and 45 ml thionyl chloride was heated at reflux for three hours. The mixture was cooled and excess thionyl chloride removed by evaporation in vacuo. The crude acid chloride was dissolved in 20 ml ethyl ether and the solution added dropwise to 67 ml concentrated ammonium hydroxide at 0 C. over 20 minutes. A tan solid formed immediately. The mixture was stirred one hour at 0 C., 80 ml water added and the mixture extracted with 3*100 ml ethyl ether. The combined ether layers were washed with brine, dried (MgSO4) and concentrated in vacuo to give 8.70 g (97%) of amide. 1 H-NMR(CDCl3)ppm(delta): 1.60-2.40 (m, 4H), 2.45-2.85 (t, 2H), 5.25-6.10 (bs, 2H), 6.90-7.30 (q, 4H).
With thionyl chloride; In chloroform; toluene;
A mixture of 4-(p-chlorophenyl)-butyric acid (6.7 g., 0.0337 mole) in 50 ml. of dry chloroform and 10 ml. (0.134 mole) of thionyl chloride was refluxed for 8 hours. Excess thionyl chloride was removed in vacuo and the residual oil was treated with toluene to remove traces of chloride. The residue was taken up in 10 ml. of toluene and added to 30 ml. of concentrated ammonium hydroxide in an ice-water bath to give 4-(p-chlorophenyl)-butyramide, m.p. 110-113 C.
8.70 g (97%)
With thionyl chloride; In diethyl ether; water;
(iii) 4-(4-Chlorophenyl)butyric acid amide A mixture of 8.8 g (44.3 mmole) of the saturated acid from Part (ii) and 45 ml thionyl chloride was heated at reflux for three hours. The mixture was cooled and excess thionyl chloride removed by evaporation in vacuo. The crude acid chloride was dissolved in 20 ml ethyl ether and the solution added dropwise to 67 ml concentrated ammonium hydroxide at 0 C. over 20 minutes. A tan solid formed immediately. The mixture was stirred one hour at 0 C., 80 ml water added and the mixture extracted with 3*100 ml ethyl ether. The combined ether layers were washed with brine, dried (MgSO4) and concentrated in vacuo to give 8.70 g (97%) of amide. 1 H-NMR(CDCl3)ppm(delta): 1.60-2.40 (m, 4H), 2.45-2.85 (t, 2H), 5.25-6.10 (bs, 2H), 6.90-7.30 (q, 4H).
8.70 g (97%)
With thionyl chloride; In diethyl ether; water;
(iii) 4-(4-Chlorophenyl)butyric acid amide A mixture of 8.8 g (44.3 mmole) of the saturated acid from Part (ii) and 45 ml thionyl chloride was heated at reflux for three hours. The mixture was cooled and excess thionyl chloride removed by evaporation in vacuo . The crude acid chloride was dissolved in 20 ml ethyl ether and the solution added dropwise to 67 ml concentrated ammonium hydroxide at 0 C. over 20 minutes. A tan solid formed immediately. The mixture was stirred one hour at 0 C., 80 ml water added and the mixture extracted with 3 x 100 ml ethyl ether. The combined ether layers were washed with brine, dried (MgSO4) and concentrated in vacuo to give 8.70 g (97%) of amide. 1H-NMR(CDCl3)ppm(delta): 1.60-2.40 (m, 4H), 2.45-2.85 (t, 2H), 5.25-6.10 (bs, 2H), 6.90-7.30 (q, 4H).
8.70 g (97%)
With thionyl chloride; In diethyl ether; water;
(iii) 4-(4-Chlorophenyl)butyric acid amide A mixture of 8.8 g (44.3 mmole) of the saturated acid from Part (ii) and 45 ml thionyl chloride was heated at reflux for three hours. The mixture was cooled and excess thionyl chloride removed by evaporation in vacuo . The crude acid chloride was dissolved in 20 ml ethyl ether and the solution added dropwise to 67 ml concentrated ammonium hydroxide at 0 C. over 20 minutes. A tan solid formed immediately. The mixture was stirred one hour at 0 C., 80 ml water added and the mixture extracted with 3 x 100 ml ethyl ether. The combined ether layers were washed with brine, dried (MgSO4) and concentrated in vacuo to give 8.70 g (97%) of amide. 1H-NMR(CDCl3)ppm(delta): 1.60-2.40 (m, 4H), 2.45-2.85 (t, 2H), 5.25-6.10 (bs, 2H), 6.90-7.30 (q, 4H).
b. 7-Chloro-1-tetralone. 4-(4-Chlorophenyl)butyric acid (26.62 g) was added to 150 g of hot polyphosphoric acid (90 C.); the mixture was maintained at 90-95 C. for 0.33 hour. After cooling to room temperature, the reaction mixture was added to 400 mL of ice-cold stirred water. The solution was allowed to warm to room temperature; and the resulting precipitate was filtered, washed (water) and air dried to give a pale yellow solid (22.3 g). The solid was recrystallized from toluene (50 mL) at -10 C. The crystals were collected and washed with cold toluene and then hexanes to give the tetralone as pale yellow crystals (18.18 g); mp 100.3-101.1 C.
With PPA; In water;
b. 7-Chloro-1-tetralone. 4-(4-Chlorophenyl)butyric acid (26.62 g) was added to 150 g of hot polyphosphoric acid (90 C.); the mixture was maintained at 90-95 C. for 0.33 hour. After cooling to room temperature, the reaction mixture was added to 400 mL of ice-cold stirred water. The solution was allowed to warm to room temperature; and the resulting precipitate was filtered, washed (water) and air dried to give a pale yellow solid (22.3 g). The solid was recrystallized from toluene (50 mL) at -10 C. The crystals were collected and washed with cold toluene and then hexanes to give the tetralone as pale yellow crystals (18.18 g); mp 100.3-101.1 C.
(ii) 4-(4-Chlorophenyl)butanoic acid A mixture of 19.5 g (98.2 mmole) of the unsaturated acid from Part (i), above, 1.95 g palladium-on-carbon catalyst and 200 ml ethyl acetate was hydrogenated at 3.5 kg/cm2 and worked up in the usual manner to give the desired saturated acid in 91% yield. 1 H-NMR(CDCl3)ppm(delta): 1.75-2.80 (m, 6H), 6.95-7.40 (q, 4H), 9.15-10.25 (bs, 1H).
91%
palladium; In ethyl acetate;
(ii) 4-(4-Chlorophenyl)butanoic acid A mixture of 19.5 g (98.2 mmole) of the unsaturated acid from Part (i), above, 1.95 g palladium-on-carbon catalyst and 200 ml ethyl acetate was hydrogenated at 3.5 kg/cm2 and worked up in the usual manner to give the desired saturated acid in 91% yield. 1 H-NMR(CDCl3)ppm(delta): 1.75-2.80 (m, 6H), 6.95-7.40 (q, 4H), 9.15-10.25 (bs, 1H).
91%
palladium; In ethyl acetate;
(ii) 4-(4-Chlorophenyl)butanoic acid A mixture of 19.5 g (98.2 mmole) of the unsaturated acid from Part (i), above, 1.95 g palladium-on-carbon catalyst and 200 ml ethyl acetate was hydrogenated at 3.5 kg/cm2 and worked up in the usual manner to give the desired saturated acid in 91% yield. 1H-NMR(CDCl3)ppm(delta): 1.75-2.80 (m, 6H), 6.95-7.40 (q, 4H), 9.15-10.25 (bs, 1H).
91%
palladium; In ethyl acetate;
(ii) 4-(4-Chlorophenyl)butanoic acid A mixture of 19.5 g (98.2 mmole) of the unsaturated acid from Part (i), above, 1.95 g palladium-on-carbon catalyst and 200 ml ethyl acetate was hydrogenated at 3.5 kg/cm2 and worked up in the usual manner to give the desired saturated acid in 91% yield. 1H-NMR(CDCl3)ppm(delta): 1.75-2.80 (m, 6H), 6.95-7.40 (q, 4H), 9.15-10.25 (bs, 1H).
7,8-dihydroxy-2,3,4,5-tetrahydro-2-benzazepine hydrobromide[ No CAS ]
N-[2-(4-chlorophenyl)ethyl]-7,8-dihydroxy-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7,8-Dihydroxy-2,3,4,5-tetrahydro-1H-2-benzazepinium bromide salt was dissolved in DMSO (dry), DBU (1 eq.) was added and the solution stirred for 15 min. Then 2,2,2-trichloro-N-[2-(2-chlorophenyl)ethyl]acetamide and DBU (1 eq.) were added. The reaction mixture was stirred at 80 C. for 48 hours. CH2Cl2 was added to the solution and the organic phase was washed with HCl (3% in H2O) and NaHCO3 (sat.). The organic phase was dried (MgSO4) and concentrated. The residue was chromatographed on silicagel (2% MeOH in CH2Cl2).
Triethylamine (7.8 mmol) was slowly added to the acetone solution (60 ml) of 4- (4-chlorophenyl) butanoic acid (6.5 mmol) at room temperature for 5 minutes at room temperature. Then, the reaction mixture was cooled to -10 C, and a solution of methyl chloroformate (7.8 mmol) in acetone (10 ml) was added thereto for 20-30 minutes, followed by stirring for an additional 20 minutes. A solution of sodium azide (13.1 mmol) in water (6 ml) was then added for 20-30 minutes and then stirred for another 30-45 minutes. The reaction was quenched with ice + water (300 ml), stirred for 5-10 minutes, toluene (250 ml) was added, and the mixture was further stirred for 20-30 minutes. The toluene layer was collected, treated with sodium sulfate, concentrated to about 100 ml, and then refluxed at 100-110 C for 2-3 hours to remove nitrogen and form an isocyanate. The solvent was distilled off and the residue was used in the next step without further purification
Triethylamine (7.8 mmol) was slowly added to the acetone solution (60 ml) of 4- (4-chlorophenyl) butanoic acid (6.5 mmol) at room temperature for 5 minutes at room temperature. Then, the reaction mixture was cooled to -10 C, and a solution of methyl chloroformate (7.8 mmol) in acetone (10 ml) was added thereto for 20-30 minutes, followed by stirring for an additional 20 minutes. A solution of sodium azide (13.1 mmol) in water (6 ml) was then added for 20-30 minutes and then for another 30-45 minutes. The reaction was quenched with ice + water (300 ml), stirred for 5-10 minutes, then toluene (250 ml) was added, and the mixture was further stirred for 20-30 minutes. The toluene layer was collected, treated with sodium sulfate, concentrated to about 100 ml, and then refluxed at 100-110 C for 2-3 hours to remove nitrogen and form an isocyanate. The solvent was distilled off and the residue was used in the next step without further purification.
To a solution of 4-(4-substituted phenyl)butanoic acid 57 (15.5mmol) in acetone (60mL) at ambient temperature, triethylamine (18.6mmol) was added slowly. Then the reaction mixture was cooled to-10C, and methyl chloroformate (18.6mmol) in acetone (10mL) was added within 20-30min and the reaction was stirred for another 30min. Then a solution of sodium azide (31.1mmol) in water (6mL) was added slowly and stirred for another 1h. The reaction mixture was quenched with ice water (300mL) and stirred for 5-10min. To this aqueous solution toluene (250mL) was added and stirred for another 20-30min. The toluene layer was collected and aqueous layer was once again extracted with toluene (100mL). The combined toluene layer was dried over anhydrous Na2SO4 and concentrated to about 100mL and then refluxed for 3h. After the formation of the product, the solvent was evaporated and the crude product 58a was used as such for the next step. Yield 65%.
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